Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study.

PubMed

Wallach, Joshua D; Ciani, Oriana; Pease, Alison M; Gonsalves, Gregg S; Krumholz, Harlan M; Taylor, Rod S; Ross, Joseph S

2018-03-21

The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product's actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication. We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials. Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01-2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15-0.16). Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers.

Blood pressure reduction and antihypertensive medication use in the losartan intervention for endpoint reduction in hypertension (LIFE) study in patients with hypertension and left ventricular hypertrophy.

PubMed

Devereux, Richard B; de Faire, Ulf; Fyhrquist, Frej; Harris, Katherine E; Ibsen, Hans; Kjeldsen, Sverre E; Lederballe-Pedersen, Ole; Lindholm, Lars H; Nieminen, Markku S; Omvik, Per; Oparil, Suzanne; Wedel, Hans; Hille, Darcy A; Dahlöf, Björn

2007-02-01

To compare blood pressure response and antihypertensive medication use visit-by-visit from baseline in patients receiving losartan-based or atenolol-based therapy in the LIFE study. LIFE was a randomized, double-blind trial comparing losartan-based and atenolol-based treatment regimens on the primary composite endpoint of death, myocardial infarction (MI), or stroke in 9193 patients aged 55-80 years with hypertension and left ventricular hypertrophy. Systolic and diastolic, pulse, and mean arterial pressures, blood pressure responder rates, distribution of open-label antihypertensive agents utilized, and the proportion of patients on randomized treatment were determined for each group at each clinic visit over a follow-up period of at least 4 years. Overall blood pressure reductions were comparable in the losartan-based and atenolol-based treatment groups. The mean reductions in sitting trough systolic and diastolic blood pressures from baseline to the end of follow-up (or last visit before a primary endpoint event) were 30.2/16.6 mmHg in the losartan group and 29.1/16.8 mmHg in the atenolol group. The time-averaged difference in overall mean arterial pressure was similar between groups. The proportion of patients on individual dose combinations varied visit by visit but was generally comparable between groups. During the entire study, 56% (2579/4605) of losartan-treated patients received at least one dose of the combination of losartan 100 mg plus hydrochlorothiazide 12.5 mg and 51% of atenolol-treated patients received 100 mg of atenolol plus hydrochlorothiazide 12.5 mg at some time during the study. Differences in blood pressure or distribution of add-on medications between treatment groups were not evident in the LIFE trial and, thus, cannot account for the observed outcome difference in the primary endpoint of risk reduction of the composite of cardiovascular death, stroke and MI favoring losartan.

A rank test for bivariate time-to-event outcomes when one event is a surrogate

PubMed Central

Shaw, Pamela A.; Fay, Michael P.

2016-01-01

In many clinical settings, improving patient survival is of interest but a practical surrogate, such as time to disease progression, is instead used as a clinical trial’s primary endpoint. A time-to-first endpoint (e.g. death or disease progression) is commonly analyzed but may not be adequate to summarize patient outcomes if a subsequent event contains important additional information. We consider a surrogate outcome very generally, as one correlated with the true endpoint of interest. Settings of interest include those where the surrogate indicates a beneficial outcome so that the usual time-to-first endpoint of death or surrogate event is nonsensical. We present a new two-sample test for bivariate, interval-censored time-to-event data, where one endpoint is a surrogate for the second, less frequently observed endpoint of true interest. This test examines whether patient groups have equal clinical severity. If the true endpoint rarely occurs, the proposed test acts like a weighted logrank test on the surrogate; if it occurs for most individuals, then our test acts like a weighted logrank test on the true endpoint. If the surrogate is a useful statistical surrogate, our test can have better power than tests based on the surrogate that naively handle the true endpoint. In settings where the surrogate is not valid (treatment affects the surrogate but not the true endpoint), our test incorporates the information regarding the lack of treatment effect from the observed true endpoints and hence is expected to have a dampened treatment effect compared to tests based on the surrogate alone. PMID:27059817

Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.

PubMed

Zhang, Wenqian; Yu, Ying; Hertwig, Falk; Thierry-Mieg, Jean; Zhang, Wenwei; Thierry-Mieg, Danielle; Wang, Jian; Furlanello, Cesare; Devanarayan, Viswanath; Cheng, Jie; Deng, Youping; Hero, Barbara; Hong, Huixiao; Jia, Meiwen; Li, Li; Lin, Simon M; Nikolsky, Yuri; Oberthuer, André; Qing, Tao; Su, Zhenqiang; Volland, Ruth; Wang, Charles; Wang, May D; Ai, Junmei; Albanese, Davide; Asgharzadeh, Shahab; Avigad, Smadar; Bao, Wenjun; Bessarabova, Marina; Brilliant, Murray H; Brors, Benedikt; Chierici, Marco; Chu, Tzu-Ming; Zhang, Jibin; Grundy, Richard G; He, Min Max; Hebbring, Scott; Kaufman, Howard L; Lababidi, Samir; Lancashire, Lee J; Li, Yan; Lu, Xin X; Luo, Heng; Ma, Xiwen; Ning, Baitang; Noguera, Rosa; Peifer, Martin; Phan, John H; Roels, Frederik; Rosswog, Carolina; Shao, Susan; Shen, Jie; Theissen, Jessica; Tonini, Gian Paolo; Vandesompele, Jo; Wu, Po-Yen; Xiao, Wenzhong; Xu, Joshua; Xu, Weihong; Xuan, Jiekun; Yang, Yong; Ye, Zhan; Dong, Zirui; Zhang, Ke K; Yin, Ye; Zhao, Chen; Zheng, Yuanting; Wolfinger, Russell D; Shi, Tieliu; Malkas, Linda H; Berthold, Frank; Wang, Jun; Tong, Weida; Shi, Leming; Peng, Zhiyu; Fischer, Matthias

2015-06-25

Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.

KAST Study: The Kiva System As a Vertebral Augmentation Treatment-A Safety and Effectiveness Trial: A Randomized, Noninferiority Trial Comparing the Kiva System With Balloon Kyphoplasty in Treatment of Osteoporotic Vertebral Compression Fractures.

PubMed

Tutton, Sean M; Pflugmacher, Robert; Davidian, Mark; Beall, Douglas P; Facchini, Francis R; Garfin, Steven R

2015-06-15

The KAST (Kiva Safety and Effectiveness Trial) study was a pivotal, multicenter, randomized control trial for evaluation of safety and effectiveness in the treatment of patients with painful, osteoporotic vertebral compression fractures (VCFs). The objective was to demonstrate noninferiority of the Kiva system to balloon kyphoplasty (BK) with respect to the composite primary endpoint. Annual incidence of osteoporotic VCFs is prevalent. Optimal treatment of VCFs should address pain, function, and deformity. Kiva is a novel implant for vertebral augmentation in the treatment of VCFs. A total of 300 subjects with 1 or 2 painful osteoporotic VCFs were randomized to blindly receive Kiva (n = 153) or BK (n = 147). Subjects were followed through 12 months. The primary endpoint was a composite at 12 months defined as a reduction in fracture pain by at least 15 mm on the visual analogue scale, maintenance or improvement in function on the Oswestry Disability Index, and absence of device-related serious adverse events. Secondary endpoints included cement usage, extravasation, and adjacent level fracture. A mean improvement of 70.8 and 71.8 points in the visual analogue scale score and 38.1 and 42.2 points in the Oswestry Disability Index was noted in Kiva and BK, respectively. No device-related serious adverse events occurred. Despite significant differences in risk factors favoring the control group at baseline, the primary endpoint demonstrated noninferiority of Kiva to BK. Analysis of secondary endpoints revealed superiority with respect to cement use and site-reported extravasation and a positive trend in adjacent level fracture warranting further study. The KAST study successfully established that the Kiva system is noninferior to BK based on a composite primary endpoint assessment incorporating pain-, function-, and device-related serious adverse events for the treatment of VCFs due to osteoporosis. Kiva was shown to be noninferior to BK and revealed a positive trend in several secondary endpoints. 1.

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.

PubMed

Loudon, Peter; Siebenga, Pieter; Gorman, Donal; Gore, Katrina; Dua, Pinky; van Amerongen, Guido; Hay, Justin L; Groeneveld, Geert Jan; Butt, Richard P

2018-02-01

Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans. A randomized, double-blind, single-dose, placebo- and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50 mg, PF-06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo. Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the ultraviolet (UV) B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64-1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and electrical stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints. The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor. © 2017 The British Pharmacological Society.

Improved safety and reduction in stent thrombosis associated with biodegradable polymer-based biolimus-eluting stents versus durable polymer-based sirolimus-eluting stents in patients with coronary artery disease: final 5-year report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) randomized, noninferiority trial.

PubMed

Serruys, Patrick W; Farooq, Vasim; Kalesan, Bindu; de Vries, Ton; Buszman, Pawel; Linke, Axel; Ischinger, Thomas; Klauss, Volker; Eberli, Franz; Wijns, William; Morice, Marie Claude; Di Mario, Carlo; Corti, Roberto; Antoni, Diethmar; Sohn, Hae Y; Eerdmans, Pedro; Rademaker-Havinga, Tessa; van Es, Gerrit-Anne; Meier, Bernhard; Jüni, Peter; Windecker, Stephan

2013-08-01

This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N = 1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n = 857) or durable polymer sirolimus-eluting stents (SES) (n = 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, p for superiority = 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n = 5 [0.7%] vs. n = 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n = 3 of 749 vs. n = 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p = 0.005). The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220). Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Mechanistic modelling of infrared mediated energy transfer during the primary drying step of a continuous freeze-drying process.

PubMed

Van Bockstal, Pieter-Jan; Mortier, Séverine Thérèse F C; De Meyer, Laurens; Corver, Jos; Vervaet, Chris; Nopens, Ingmar; De Beer, Thomas

2017-05-01

Conventional pharmaceutical freeze-drying is an inefficient and expensive batch-wise process, associated with several disadvantages leading to an uncontrolled end product variability. The proposed continuous alternative, based on spinning the vials during freezing and on optimal energy supply during drying, strongly increases process efficiency and improves product quality (uniformity). The heat transfer during continuous drying of the spin frozen vials is provided via non-contact infrared (IR) radiation. The energy transfer to the spin frozen vials should be optimised to maximise the drying efficiency while avoiding cake collapse. Therefore, a mechanistic model was developed which allows computing the optimal, dynamic IR heater temperature in function of the primary drying progress and which, hence, also allows predicting the primary drying endpoint based on the applied dynamic IR heater temperature. The model was validated by drying spin frozen vials containing the model formulation (3.9mL in 10R vials) according to the computed IR heater temperature profile. In total, 6 validation experiments were conducted. The primary drying endpoint was experimentally determined via in-line near-infrared (NIR) spectroscopy and compared with the endpoint predicted by the model (50min). The mean ratio of the experimental drying time to the predicted value was 0.91, indicating a good agreement between the model predictions and the experimental data. The end product had an elegant product appearance (visual inspection) and an acceptable residual moisture content (Karl Fischer). Copyright © 2017 Elsevier B.V. All rights reserved.

Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

PubMed

Gilbert, P B; Ribaudo, H J; Greenberg, L; Yu, G; Bosch, R J; Tierney, C; Kuritzkes, D R

2000-09-08

At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

Vdrive Evaluation of Remote Steering and Testing in Lasso Electrophysiology Procedures Study: The VERSATILE Study in Atrial Fibrillation Ablation.

PubMed

Nölker, Georg; Schwagten, Bruno; Deville, J Brian; Burkhardt, J David; Horton, Rodney P; Sha, Qun; Tomassoni, Gery

2016-03-01

Circular mapping catheters (CMC) are an essential tool in most atrial fibrillation ablation procedures. The Vdrive™ with V-Loop™ system enables a physician to remotely manipulate a CMC during electrophysiology studies. Our aim was to compare the clinical performance of the system to conventional CMC navigation according to efficiency and safety endpoints. A total of 120 patients scheduled to undergo a CMC study followed by pulmonary vein isolation (PVI) were included. Treatment allocation was randomized 2:1, remote navigation:manual navigation. The primary effectiveness endpoint was assessed based on both successful navigation to the targeted pulmonary vein (PV) and successful recording of PV electrograms. All PVs were treated independently within and between patients. The primary safety endpoint was assessed based on the occurrence of major adverse events (MAEs) through seven days after the study procedure. Primary effectiveness endpoints were achieved in 295/302 PVs in the Vdrive arm (97.7%) and 167/167 PVs in the manual arm (100%). Effectiveness analysis indicates Vdrive non-inferiority (pnon-inferiority = 0.0405; δ = -0.05) per the Cochran-Mantel-Haenszel test adjusted for PV correlation. Five MAEs related to the ablation procedure occurred (three in the Vdrive arm-3.9%; two in the manual arm-2.33%). No device-related MAEs were observed; safety analysis indicates Vdrive non-inferiority (pnon-inferiority = 0.0441; δ = 0.07) per the normal Z test. Remote navigation of a CMC is equivalent to manual in PVI in terms of safety and effectiveness. This allows for single-operator procedures in conjunction with a magnetically guided ablation catheter. © 2016 Wiley Periodicals, Inc.

Application of process analytical technology for monitoring freeze-drying of an amorphous protein formulation: use of complementary tools for real-time product temperature measurements and endpoint detection.

PubMed

Schneid, Stefan C; Johnson, Robert E; Lewis, Lavinia M; Stärtzel, Peter; Gieseler, Henning

2015-05-01

Process analytical technology (PAT) and quality by design have gained importance in all areas of pharmaceutical development and manufacturing. One important method for monitoring of critical product attributes and process optimization in laboratory scale freeze-drying is manometric temperature measurement (MTM). A drawback of this innovative technology is that problems are encountered when processing high-concentrated amorphous materials, particularly protein formulations. In this study, a model solution of bovine serum albumin and sucrose was lyophilized at both conservative and aggressive primary drying conditions. Different temperature sensors were employed to monitor product temperatures. The residual moisture content at primary drying endpoints as indicated by temperature sensors and batch PAT methods was quantified from extracted sample vials. The data from temperature probes were then used to recalculate critical product parameters, and the results were compared with MTM data. The drying endpoints indicated by the temperature sensors were not suitable for endpoint indication, in contrast to the batch methods endpoints. The accuracy of MTM Pice data was found to be influenced by water reabsorption. Recalculation of Rp and Pice values based on data from temperature sensors and weighed vials was possible. Overall, extensive information about critical product parameters could be obtained using data from complementary PAT tools. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

PubMed Central

McDonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart W

2013-01-01

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013 PMID:23674289

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

PubMed

Bikdeli, Behnood; Punnanithinont, Natdanai; Akram, Yasir; Lee, Ike; Desai, Nihar R; Ross, Joseph S; Krumholz, Harlan M

2017-03-21

Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine , Lancet , and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals. Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: Recommendations on incorporating patient-reported outcomes in clinical trials in epithelial ovarian cancer.

PubMed

Joly, Florence; Hilpert, Felix; Okamoto, Aikou; Stuart, Gavin; Ochiai, Kasunori; Friedlander, Michael

2017-06-01

Despite the support for including patient-reported outcomes (PROs) and health-related quality of life in clinical trials, there have been deficiencies in how these have been assessed and reported in epithelial ovarian cancer (EOC) clinical trials. To redress this, the 5th Ovarian Cancer Consensus Conference, included a plenary session entitled 'How to include PROs in clinical trials'. The perspective is a summary of the recommendations made by the Gynecologic Cancer InterGroup unanimously agreed on the importance of PROs and PRO end-points in EOC clinical trials. They recognised that effort must be made to ensure the integrity of collection of PRO data and to avoid missing data. PRO end-points should be based on the PRO hypotheses, be context specific and reflect the patient population and the objectives of treatment (e.g. first line, maintenance therapy, early or late relapse). The PRO end-points inform the choice of PRO measures used in the trial and how the results are analysed and reported. There was agreement that progression-free survival should be supported by PROs among patients with late relapse (platinum sensitive) and that progression-free survival alone was not sufficient as the primary end-point of clinical trials in patients with platinum resistant/refractory EOC and PROs should be included as either the primary/co-primary end-point in this subset of patients. Novel approaches to measure the benefit of palliative chemotherapy such as time until definitive deterioration of Health-Related Quality of Life were recommended. There was consensus to endorse the ISOQOL and CONSORT-PRO guidelines on the inclusion and reporting of PRO endpoints in protocols and that all future EOC Gynecologic Cancer InterGroup trials should adhere to these. Copyright © 2017 Elsevier Ltd. All rights reserved.

Methodology of phase II clinical trials in metastatic elderly breast cancer: a literature review.

PubMed

Cabarrou, B; Mourey, L; Dalenc, F; Balardy, L; Kanoun, D; Roché, H; Boher, J M; Rougé-Bugat, M E; Filleron, Thomas

2017-08-01

As the incidence of invasive breast cancer will increase with age, the number of elderly patients with a diagnosis metastatic breast cancer will also rise. But the use of cytotoxic drugs in elderly metastatic breast cancer patients is not systematic and is dreaded by medical oncologists. The need for prospective oncologic data from this population seems increasingly obvious. The main objective of this review is to investigate design and characteristics of phase II trials that assess activity and feasibility of chemotherapies in elderly advanced/metastatic breast cancer patients. An electronic search in PUBMED allowed us to retrieve articles published in English language on phase II trials in elderly metastatic breast cancer between January 2002 and May 2016. Sixteen publications were finally included in this review. The primary endpoint was a simple, a composite, and a co-primary endpoints in 11, three, and two studies, respectively. Efficacy was the primary objective in 15 studies: simple (n = 10), composite (n = 3), co-primary endpoints (n = 2). Composite or co-primary endpoints combined efficacy and toxicity. Thirteen studies used multistage designs. Only five studies evaluated the feasibility, i.e., to jointly assess efficacy and tolerance to treatment (toxicity, quality of life, etc) as primary endpoint. Development of elderly specific phase III clinical trials might be challenging, it therefore seems essential to conduct phase II clinical trials evaluating jointly efficacy and toxicity in a well-defined geriatric population. Use of multistage designs that take into account heterogeneity would allow to identify a subpopulation at interim analysis and to reduce the number of patients exposed to an inefficient or a toxic treatment regimen. It is crucial to evaluate new therapies (targeted therapies, immunotherapies) using adequate methodologies (Study design, endpoint).

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

PubMed

Harris, P N A; McNamara, J F; Lye, D C; Davis, J S; Bernard, L; Cheng, A C; Doi, Y; Fowler, V G; Kaye, K S; Leibovici, L; Lipman, J; Llewelyn, M J; Munoz-Price, S; Paul, M; Peleg, A Y; Rodríguez-Baño, J; Rogers, B A; Seifert, H; Thamlikitkul, V; Thwaites, G; Tong, S Y C; Turnidge, J; Utili, R; Webb, S A R; Paterson, D L

2017-08-01

To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. All rights reserved.

The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations.

PubMed

Gettings, S D; Lordo, R A; Hintze, K L; Bagley, D M; Casterton, P L; Chudkowski, M; Curren, R D; Demetrulias, J L; Dipasquale, L C; Earl, L K; Feder, P I; Galli, C L; Glaza, S M; Gordon, V C; Janus, J; Kurtz, P J; Marenus, K D; Moral, J; Pape, W J; Renskers, K J; Rheins, L A; Roddy, M T; Rozen, M G; Tedeschi, J P; Zyracki, J

1996-01-01

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.

Note on simultaneous inferences about non-inferiority and superiority for a primary and a secondary endpoint.

PubMed

Guilbaud, Olivier

2011-11-01

In their review of challenges to multiple testing in clinical trials, Hung and Wang (2010) considered the situation where a treatment is to be compared with an active comparator and the aim is to show non-inferiority and (if possible) superiority with respect to a primary and a secondary endpoint. This note extends their discussion of this particular situation, taking the sequentially rejective procedure they used for illustration as a starting point. Some alternative multiple testing procedures (MTPs) are considered, and corresponding simultaneous confidence regions are discussed that provide additional information "for free". The choice may then be based on the properties of these MTPs and corresponding confidence regions. 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis.

PubMed

Kataoka, K; Nakamura, K; Mizusawa, J; Kato, K; Eba, J; Katayama, H; Shibata, T; Fukuda, H

2017-10-01

There have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. A systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R 2 ) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. Of 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R 2 0.283, 95% CI [0.00-0.90]). The sensitivity analysis did not show an association between PFS and OS (R 2 0.084, 95% CI [0.00-0.70]). Although the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

EDTA Chelation Therapy Alone and in Combination with Oral High-Dose Multivitamins and Minerals for Coronary Disease: The Factorial Group Results of the Trial to Assess Chelation Therapy

PubMed Central

Lamas, Gervasio A.; Boineau, Robin; Goertz, Christine; Mark, Daniel B.; Rosenberg, Yves; Stylianou, Mario; Rozema, Theodore; Nahin, Richard L.; Chappell, L. Terry; Lindblad, Lauren; Lewis, Eldrin F.; Drisko, Jeanne; Lee, Kerry L.

2014-01-01

Background Disodium ethylene diamine tetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. Objective This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. Methods Double-blind placebo-controlled 2 × 2 factorial multicenter randomized trial of 1708 post-MI patients ≥ 50 years and creatinine ≤2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitaminmultimineral mixture or placebo. Primary endpoint was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. Results Median age was 65 years, 18% female, 94% Caucasian, 37% diabetic, 83% prior coronary revascularization, and 73% on statins. Five-year Kaplan-Meier estimates for the primary endpoint in the chelation + high-dose vitamin group was 31.9%, in the chelation + placebo vitamin group 33.7%, in the placebo infusion + active vitamin group 36.6%, and in the placebo infusions + placebo vitamin group 40.2 %. The reduction in primary endpoint by double active treatment compared with double placebo was significant (HR 0.74, 95% CI (0.57,0.95); p=0.016). In patients with diabetes, the primary endpoint reduction of double active compared with double placebo was more pronounced (HR 0.49, 95% CI (0.33,0.75), p<0.001). Conclusions In stable post- MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance. PMID:24952858

Impact of age, sex, therapeutic intent, race and severity of advanced heart failure on short-term principal outcomes in the MOMENTUM 3 trial.

PubMed

Goldstein, Daniel J; Mehra, Mandeep R; Naka, Yoshifumi; Salerno, Christopher; Uriel, Nir; Dean, David; Itoh, Akinobu; Pagani, Francis D; Skipper, Eric R; Bhat, Geetha; Raval, Nirav; Bruckner, Brian A; Estep, Jerry D; Cogswell, Rebecca; Milano, Carmelo; Fendelander, Lahn; O'Connell, John B; Cleveland, Joseph

2018-01-01

Primary outcomes analysis of the Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3 (MOMENTUM 3) trial short-term cohort demonstrated a higher survival rate free of debilitating stroke and reoperation to replace/remove the device (primary end-point) in patients receiving the HeartMate 3 (HM3) compared with the HeartMate (HMII). In this study we sought to evaluate the individual and interactive effects of pre-specified patient subgroups (age, sex, race, therapeutic intent [bridge to transplant/bridge to candidacy/destination therapy] and severity of illness) on primary end-point outcomes in MOMENTUM 3 patients implanted with HM3 and HMII devices. Cox proportional hazard models were used to analyze patients enrolled in the "as-treated cohort" (n = 289) of the MOMENTUM 3 trial to: (1) determine interaction of various subgroups on primary end-point outcomes; and (2) identify independent variables associated with primary end-point success. Baseline characteristics were well balanced among HM3 (n = 151) and HMII (n = 138) cohorts. No significant interaction between the sub-groups on primary end-point outcomes was observed. Cox multivariable modeling identified age (≤65 years vs >65 years, hazard ratio 0.42 [95% confidence interval 0.22 to 0.78], p = 0.006]) and pump type (HM3 vs HMII, hazard ratio 0.53 [95% confidence interval 0.30 to 0.96], p = 0.034) to be independent predictors of primary outcomes success. After adjusting for age, no significant impact of sex, race, therapeutic intent and INTERMACS profiles on primary outcomes were observed. This analysis of MOMENTUM 3 suggests that younger age (≤65 years) at implant and pump choice are associated with a greater likelihood of primary end-point success. These findings further suggest that characterization of therapeutic intent into discrete bridge-to-transplant and destination therapy categories offers no clear clinical advantage, and should ideally be abandoned. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Weighted analysis of composite endpoints with simultaneous inference for flexible weight constraints.

PubMed

Duc, Anh Nguyen; Wolbers, Marcel

2017-02-10

Composite endpoints are widely used as primary endpoints of randomized controlled trials across clinical disciplines. A common critique of the conventional analysis of composite endpoints is that all disease events are weighted equally, whereas their clinical relevance may differ substantially. We address this by introducing a framework for the weighted analysis of composite endpoints and interpretable test statistics, which are applicable to both binary and time-to-event data. To cope with the difficulty of selecting an exact set of weights, we propose a method for constructing simultaneous confidence intervals and tests that asymptotically preserve the family-wise type I error in the strong sense across families of weights satisfying flexible inequality or order constraints based on the theory of χ¯2-distributions. We show that the method achieves the nominal simultaneous coverage rate with substantial efficiency gains over Scheffé's procedure in a simulation study and apply it to trials in cardiovascular disease and enteric fever. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Bias in reporting of randomised clinical trials in oncology.

PubMed

Vera-Badillo, Francisco E; Napoleone, Marc; Krzyzanowska, Monika K; Alibhai, Shabbir M H; Chan, An-Wen; Ocana, Alberto; Seruga, Bostjan; Templeton, Arnoud J; Amir, Eitan; Tannock, Ian F

2016-07-01

Bias in reporting efficacy and toxicity in clinical trials may impact treatment decisions. Here, we report quality of reporting of efficacy and of toxicity in articles describing randomised controlled trials (RCTs) of cancer therapy and the association between biased reporting and study results, funding and financial relationships of the authors with the sponsor. We reviewed articles published from July 2010 to December 2012 in six high-impact journals reporting RCTs of systemic treatment for cancer. Bias in reporting of the primary end-point and toxicity were assessed. Associations between biased reporting and study results, funding source and financial ties of the author with the funding source were evaluated using logistic regression. Two hundred articles were identified. Among 107 RCTs where there was no statistically significant difference in the primary end-point between the two arms, 50 (47%) reports used biased reporting in the abstract of the paper to imply benefit of the experimental treatment. Toxicity was not reported in the abstract in 18.5% of the studies and this was associated with a positive primary end-point. Source of funding and financial ties were not associated with biased reporting. Bias in reporting of efficacy outcomes is common for studies with a negative primary end-point and can lead to off-label misuse of experimental therapies, if they are approved for other indications. Toxicity is under-reported, especially for studies with a positive primary end-point, leading to a biased view of the safety of new treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial

PubMed Central

Murphy, Sabina A.; Antman, Elliott M.; Wiviott, Stephen D.; Weerakkody, Govinda; Morocutti, Giorgio; Huber, Kurt; Lopez-Sendon, Jose; McCabe, Carolyn H.; Braunwald, Eugene

2008-01-01

Aims In the TRITON-TIMI 38 trial, greater platelet inhibition with prasugrel reduced the first occurrence of the primary endpoint (cardiovascular death, MI, or stroke) compared with clopidogrel in patients with an acute coronary syndrome (ACS) undergoing planned percutaneous coronary intervention. We hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and therefore total events compared with clopidogrel. Methods and results Poisson regression analysis was performed to compare the number of occurrences of the primary endpoint between prasugrel and clopidogrel in TRITON-TIMI 38. Landmark analytic methods were used to evaluate the risk of a recurrent primary endpoint event following an initial non-fatal endpoint event. Among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65, 95% CI 0.46–0.92; P = 0.016), as was CV death following the non-fatal event (3.7 vs. 7.1%, HR 0.46, 95% CI 0.25–0.82; P = 0.008). Overall there was a reduction of 195 total primary efficacy events with prasugrel vs. clopidogrel (rate ratio 0.79, 95% CI 0.71–0.87; P < 0.001). Recurrent bleeding events occurred infrequently (TIMI major non-CABG bleeds: four with prasugrel and two with clopidogrel). Study drug discontinuation was frequent following the initial major bleeding event (42% of patients discontinued study drug). Conclusion While standard statistical analytic techniques for clinical trials censor patients who experience a component of the primary composite endpoint, total cardiovascular events remain important to both patients and clinicians. Prasugrel, a more potent anti-platelet agent, reduced both first and subsequent cardiovascular events compared with clopidogrel in patients with ACS. PMID:18682445

Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.

PubMed

Ponsioen, Cyriel Y; Chapman, Roger W; Chazouillères, Olivier; Hirschfield, Gideon M; Karlsen, Tom H; Lohse, Ansgar W; Pinzani, Massimo; Schrumpf, Erik; Trauner, Michael; Gores, Gregory J

2016-04-01

Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. © 2015 by the American Association for the Study of Liver Diseases.

Clinical endpoint adjudication in a contemporary all-comers coronary stent investigation: methodology and external validation.

PubMed

Vranckx, Pascal; McFadden, Eugene; Cutlip, Donald E; Mehran, Roxana; Swart, Michael; Kint, P P; Zijlstra, Felix; Silber, Sigmund; Windecker, Stephan; Serruys, Patrick W C J

2013-01-01

Globalisation in coronary stent research calls for harmonization of clinical endpoint definitions and event adjudication. Little has been published about the various processes used for event adjudication or their impact on outcome reporting. We performed a validation of the clinical event committee (CEC) adjudication process on 100 suspected events in the RESOLUTE All-comers trial (Resolute-AC). Two experienced Clinical Research Organisations (CRO) that had already extensive internal validation processes in place, participated in the study. After initial adjudication by the primary-CEC, events were cross-adjudicated by an external-CEC using the same definitions. Major discrepancies affecting the primary end point of target-lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), or clinically-indicated target-lesion revascularization (CI-TLR), were analysed by an independent oversight committee who provided recommendations for harmonization. Discordant adjudications were reconsidered by the primary CEC. Subsequently, the RAC database was interrogated for cases that based on these recommendations merited re-adjudication and these cases were also re-adjudicated by the primary CEC. Final discrepancies in adjudication of individual components of TLF occurred in 7 out of 100 events in 5 patients. Discrepancies for the (hierarchical) primary endpoint occurred in 5 events (2 cardiac deaths and 3 TV-MI). After application of harmonization recommendations to the overall RAC population (n=2292), the primary CEC adjudicated 3 additional clinical-TLRs and considered 1 TV-MI as no event. A harmonization process provided a high level of concordance for event adjudication and improved accuracy for final event reporting. These findings suggest it is feasible to pool clinical event outcome data across clinical trials even when different CECs are responsible for event adjudication. Copyright © 2012 Elsevier Inc. All rights reserved.

Conditional power and predictive power based on right censored data with supplementary auxiliary information.

PubMed

Sun, Libo; Wan, Ying

2018-04-22

Conditional power and predictive power provide estimates of the probability of success at the end of the trial based on the information from the interim analysis. The observed value of the time to event endpoint at the interim analysis could be biased for the true treatment effect due to early censoring, leading to a biased estimate of conditional power and predictive power. In such cases, the estimates and inference for this right censored primary endpoint are enhanced by incorporating a fully observed auxiliary variable. We assume a bivariate normal distribution of the transformed primary variable and a correlated auxiliary variable. Simulation studies are conducted that not only shows enhanced conditional power and predictive power but also can provide the framework for a more efficient futility interim analysis in terms of an improved accuracy in estimator, a smaller inflation in type II error and an optimal timing for such analysis. We also illustrated the new approach by a real clinical trial example. Copyright © 2018 John Wiley & Sons, Ltd.

Dose escalation methods in phase I cancer clinical trials.

PubMed

Le Tourneau, Christophe; Lee, J Jack; Siu, Lillian L

2009-05-20

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

A complex behavioural change intervention to reduce the risk of diabetes and prediabetes in the pre-conception period in Malaysia: study protocol for a randomised controlled trial.

PubMed

Skau, Jutta K H; Nordin, Awatef Binti Amer; Cheah, Julius C H; Ali, Roslinah; Zainal, Ramli; Aris, Tahir; Ali, Zainudin Mohd; Matzen, Priya; Biesma, Regien; Aagaard-Hansen, Jens; Hanson, Mark A; Norris, Shane A

2016-04-27

Over the past two decades, the population of Malaysia has grown rapidly and the prevalence of diabetes mellitus in Malaysia has dramatically increased, along with the frequency of obesity, hyperlipidaemia and hypertension. Early-life influences play an important role in the development of non-communicable diseases. Indeed, maternal lifestyle and conditions such as gestational diabetes mellitus or obesity can affect the risk of diabetes in the next generation. Lifestyle changes can help to prevent the development of type 2 diabetes mellitus. This is a protocol for an unblinded, community-based, randomised controlled trial in two arms to evaluate the efficacy of a complex behavioural change intervention, combining motivational interviewing provided by a community health promoter and access to a habit formation mobile application, among young Malaysian women and their spouses prior to pregnancy. Eligible subjects will be Malaysian women in the age group 20 to 39 years, who are nulliparous, not diagnosed with diabetes and own a smartphone. With an alpha-value of 0.05, a statistical power of 90 %, 264 subjects will need to complete the study. Subjects with their spouses will be randomised to either the intervention or the control arm for an 8-month period. The primary endpoint is change in waist circumference from baseline to end of intervention period and secondary endpoints are changes in anthropometric parameters, biochemical parameters, change in health literacy level, dietary habits, physical activity and stress level. Primary endpoint and the continuous secondary endpoints will be analysed in a linear regression model, whereas secondary endpoints on an ordinal scale will be analysed by using the chi-squared test. A multivariate linear model for the primary endpoint will be undertaken to account for potential confounders. This study has been approved by the Medical Research and Ethics Committee of the Ministry of Health Malaysia (protocol number: NMRR-14-904-21963) on 21 September 2015. This study protocol describes the first community-based randomised controlled trial, to examine the efficacy of a complex intervention in improving the pre-pregnancy health of young Malaysian women and their spouses. Results from this trial will contribute to improve policy and practices regarding complex behavioural change interventions to prevent diabetes in the pre-conception period in Malaysia and other low- and middle-income country settings. This trial is registered with ClinicalTrials.gov (www.clinicaltrials.gov) on 30 November 2015, Identifier: NCT02617693 .

Long-Term Follow-up to a Randomized Controlled Trial Comparing Peroneal Nerve Functional Electrical Stimulation to an Ankle Foot Orthosis for Patients With Chronic Stroke.

PubMed

Bethoux, Francois; Rogers, Helen L; Nolan, Karen J; Abrams, Gary M; Annaswamy, Thiru; Brandstater, Murray; Browne, Barbara; Burnfield, Judith M; Feng, Wuwei; Freed, Mitchell J; Geis, Carolyn; Greenberg, Jason; Gudesblatt, Mark; Ikramuddin, Farha; Jayaraman, Arun; Kautz, Steven A; Lutsep, Helmi L; Madhavan, Sangeetha; Meilahn, Jill; Pease, William S; Rao, Noel; Seetharama, Subramani; Sethi, Pramod; Turk, Margaret A; Wallis, Roi Ann; Kufta, Conrad

2015-01-01

Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle foot orthoses (AFO) for treatment of foot drop poststroke, but few long-term, randomized controlled comparisons exist. Compare changes in gait quality and function between FES and AFOs in individuals with foot drop poststroke over a 12-month period. Follow-up analysis of an unblinded randomized controlled trial (ClinicalTrials.gov #NCT01087957) conducted at 30 rehabilitation centers comparing FES to AFOs over 6 months. Subjects continued to wear their randomized device for another 6 months to final 12-month assessments. Subjects used study devices for all home and community ambulation. Multiply imputed intention-to-treat analyses were utilized; primary endpoints were tested for noninferiority and secondary endpoints for superiority. Primary endpoints: 10 Meter Walk Test (10MWT) and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test (6MWT), GaitRite Functional Ambulation Profile, and Modified Emory Functional Ambulation Profile (mEFAP). A total of 495 subjects were randomized, and 384 completed the 12-month follow-up. FES proved noninferior to AFOs for all primary endpoints. Both FES and AFO groups showed statistically and clinically significant improvement for 10MWT compared with initial measurement. No statistically significant between-group differences were found for primary or secondary endpoints. The FES group demonstrated statistically significant improvements for 6MWT and mEFAP Stair-time subscore. At 12 months, both FES and AFOs continue to demonstrate equivalent gains in gait speed. Results suggest that long-term FES use may lead to additional improvements in walking endurance and functional ambulation; further research is needed to confirm these findings. © The Author(s) 2015.

Thrombogenicity and central pulse pressure to enhance prediction of ischemic event occurrence in patients with established coronary artery disease: The MAGMA-ischemia score.

PubMed

Bliden, Kevin P; Chaudhary, Rahul; Navarese, Eliano P; Sharma, Tushar; Kaza, Himabindu; Tantry, Udaya S; Gurbel, Paul A

2018-01-01

Conventional cardiovascular risk estimators based on clinical demographics have limited prediction of coronary events. Markers for thrombogenicity and vascular function have not been explored in risk estimation of high-risk patients with coronary artery disease. We aimed to develop a clinical and biomarker score to predict 3-year adverse cardiovascular events. Four hundred eleven patients, with ejection fraction ≥40% undergoing coronary angiography, and found to have a luminal diameter stenosis ≥50%, were included in the analysis. Thrombelastography indices and central pulse pressure (CPP) were determined at the time of catheterization. We identified predictors of death, myocardial infarction (MI) or stroke and developed a numerical ischemia risk score. The primary endpoint of cardiovascular death, MI or stroke occurred in 22 patients (5.4%). The factors associated with events were age, prior PCI or CABG, diabetes, CPP, and thrombin-induced platelet-fibrin clot strength, and were included in the MAGMA-ischemia score. The MAGMA-ischemia score showed a c-statistic of 0.85 (95% Confidence Interval [CI] 0.80-0.87; p<0.001) for the primary endpoint. In the subset of patients who underwent revascularization, the c-statistic was 0.90 (p<0.001). Patients with MAGMA-ischemia score greater than 5 had highest risk to develop clinical events, hazard ratio for the primary endpoint: 13.9 (95% CI 5.8-33.1, p<0.001) and for the secondary endpoint: 4.8 (95% CI 2.3-9.6, p<0.001). When compared to previous models, the MAGMA-ischemia score yielded a higher discrimination. Inclusion of CPP and assessment of thrombogenicity in a novel score for patients with documented CAD enhanced the prediction of events. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical trial designs to obtain marketing authorization of drugs for haematological malignancy in Japan, the EU and the US.

PubMed

Nagai, Sumimasa; Ozawa, Keiya

2016-07-01

Differences in regulatory actions between Japan, the European Union (EU) and the United States (US) regarding the approval date and primary endpoints of pivotal trials have never been analysed comprehensively. This study aimed to examine such differences in haematological malignancy indications not only in applications for new molecular entity agents but also in supplemental applications for additional indications. A total of 101 haematological malignancy indications were examined for 58 drugs. Only 30 indications were approved by the regulatory agencies of all three regions with 25, 9 and 67 indications being first approved in Japan, the EU and the US, respectively. Regarding the 18 indications approved only in the US, 13 were approved based on results of single-arm trials. The approval of all nine indications approved first in the EU was based on results of comparative trials. The primary endpoints were different between the EU and the US in 4 of 49 indications approved by both regulatory agencies, all of which were approved earlier in the US than in the EU. This analysis shows that the US Food and Drug Administration has taken the most active attitude to acceptance of surrogate endpoints in single-arm trials. Therefore, not only shorter review time but also this attitude may lead to earlier approval in US. © 2016 John Wiley & Sons Ltd.

An exclusive human milk-based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: A reanalysis of the data

USDA-ARS?s Scientific Manuscript database

We have previously shown that an exclusively human-milk-based diet is beneficial for extremely premature infants who are at risk for necrotizing enterocolitis (NEC). However, no significant difference in the other primary study endpoint, the length of time on total parenteral nutrition (TPN), was fo...

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions.

PubMed

Karam, A; Ledermann, J A; Kim, J-W; Sehouli, J; Lu, K; Gourley, C; Katsumata, N; Burger, R A; Nam, B-H; Bacon, M; Ng, C; Pfisterer, J; Bekkers, R L M; Casado Herráez, A; Redondo, A; Fujiwara, H; Gleeson, N; Rosengarten, O; Scambia, G; Zhu, J; Okamoto, A; Stuart, G; Ochiai, K

2017-04-01

The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effectiveness and tolerability of second-line treatment with vildagliptin versus other oral drugs for type 2 diabetes in a real-world setting in the Middle East: results from the EDGE study

PubMed Central

Saab, Charles; Al-Saber, Feryal A; Haddad, Jihad; Jallo, Mahir Khalil; Steitieh, Habib; Bader, Giovanni; Ibrahim, Mohamed

2015-01-01

Background Type 2 diabetes mellitus (T2DM) is a chronic progressive disease that requires treatment intensification with antihyperglycemic agents due to progressive deterioration of β-cell function. A large observational study of 45,868 patients with T2DM across 27 countries (EDGE) assessed the effectiveness and safety of vildagliptin as add-on to other oral antidiabetic drugs (OADs) versus other comparator OAD combinations. Here, we present results from the Middle East countries (Bahrain, Jordan, Kuwait, Lebanon, Oman, Palestine, and the United Arab Emirates). Methods Patients inadequately controlled with OAD monotherapy were eligible after the add-on treatment was chosen by the physician based on clinical judgment and patient need. Patients were assigned to either vildagliptin or comparator OADs (sulfonylureas, thiazolidinediones, glinides, α-glucosidase inhibitors, or metformin, except incretin-based therapies) based on the add-on therapy. The primary endpoint was the proportion of patients achieving a glycated hemoglobin (HbA1c) reduction of >0.3% without peripheral edema, hypoglycemia, discontinuation due to a gastrointestinal event, or weight gain ≥5%. One of the secondary endpoints was the proportion of patients achieving HbA1c <7% without hypoglycemia or weight gain. Change in HbA1c from baseline to study endpoint and safety were also assessed. Results Of the 4,780 patients enrolled in the Middle East, 2,513 received vildagliptin and 2,267 received other OADs. Overall, the mean (± standard deviation) age at baseline was 52.1±10.2 years, mean HbA1c was 8.5%±1.3%, and mean T2DM duration was 4.2±4.0 years. The proportion of patients achieving the primary (76.1% versus 61.6%, P<0.0001) and secondary (54.8% versus 29.9%, P<0.0001) endpoints was higher with vildagliptin than with the comparator OADs. The unadjusted odds ratios for the primary and secondary endpoints were 1.98 (95% confidence interval 1.75–2.25) and 2.8 (95% confidence interval 2.5–3.2), respectively, in favor of vildagliptin. Vildagliptin achieved a numerically greater reduction in HbA1c (1.7%) from baseline versus comparator OADs (1.4%). The overall incidence of adverse events was comparable between studied cohorts. Conclusion In real life, treatment with vildagliptin was associated with a higher proportion of patients with T2DM achieving better glycemic control without tolerability issues in the Middle East. PMID:25750538

Effectiveness and tolerability of second-line treatment with vildagliptin versus other oral drugs for type 2 diabetes in a real-world setting in the Middle East: results from the EDGE study.

PubMed

Saab, Charles; Al-Saber, Feryal A; Haddad, Jihad; Jallo, Mahir Khalil; Steitieh, Habib; Bader, Giovanni; Ibrahim, Mohamed

2015-01-01

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease that requires treatment intensification with antihyperglycemic agents due to progressive deterioration of β-cell function. A large observational study of 45,868 patients with T2DM across 27 countries (EDGE) assessed the effectiveness and safety of vildagliptin as add-on to other oral antidiabetic drugs (OADs) versus other comparator OAD combinations. Here, we present results from the Middle East countries (Bahrain, Jordan, Kuwait, Lebanon, Oman, Palestine, and the United Arab Emirates). Patients inadequately controlled with OAD monotherapy were eligible after the add-on treatment was chosen by the physician based on clinical judgment and patient need. Patients were assigned to either vildagliptin or comparator OADs (sulfonylureas, thiazolidinediones, glinides, α-glucosidase inhibitors, or metformin, except incretin-based therapies) based on the add-on therapy. The primary endpoint was the proportion of patients achieving a glycated hemoglobin (HbA1c) reduction of >0.3% without peripheral edema, hypoglycemia, discontinuation due to a gastrointestinal event, or weight gain≥5%. One of the secondary endpoints was the proportion of patients achieving HbA1c<7% without hypoglycemia or weight gain. Change in HbA1c from baseline to study endpoint and safety were also assessed. Of the 4,780 patients enrolled in the Middle East, 2,513 received vildagliptin and 2,267 received other OADs. Overall, the mean (±standard deviation) age at baseline was 52.1±10.2 years, mean HbA1c was 8.5%±1.3%, and mean T2DM duration was 4.2±4.0 years. The proportion of patients achieving the primary (76.1% versus 61.6%, P<0.0001) and secondary (54.8% versus 29.9%, P<0.0001) endpoints was higher with vildagliptin than with the comparator OADs. The unadjusted odds ratios for the primary and secondary endpoints were 1.98 (95% confidence interval 1.75-2.25) and 2.8 (95% confidence interval 2.5-3.2), respectively, in favor of vildagliptin. Vildagliptin achieved a numerically greater reduction in HbA1c (1.7%) from baseline versus comparator OADs (1.4%). The overall incidence of adverse events was comparable between studied cohorts. In real life, treatment with vildagliptin was associated with a higher proportion of patients with T2DM achieving better glycemic control without tolerability issues in the Middle East.

Quality of patient-reported outcome reporting across cancer randomized controlled trials according to the CONSORT patient-reported outcome extension: A pooled analysis of 557 trials.

PubMed

Efficace, Fabio; Fayers, Peter; Pusic, Andrea; Cemal, Yeliz; Yanagawa, Jane; Jacobs, Marc; la Sala, Andrea; Cafaro, Valentina; Whale, Katie; Rees, Jonathan; Blazeby, Jane

2015-09-15

The main objectives of this study were to identify the number of randomized controlled trials (RCTs) including a patient-reported outcome (PRO) endpoint across a wide range of cancer specialties and to evaluate the completeness of PRO reporting according to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. RCTs with a PRO endpoint that had been performed across several cancer specialties and published between 2004 and 2013 were considered. Studies were evaluated on the basis of previously defined criteria, including the CONSORT PRO extension and the Cochrane Collaboration's tool for assessing the risk of bias of RCTs. Analyses were also conducted by the type of PRO endpoint (primary vs secondary) and by the cancer disease site. A total of 56,696 potentially eligible records were scrutinized, and 557 RCTs with a PRO evaluation, enrolling 254,677 patients overall, were identified. PROs were most frequently used in RCTs of breast (n = 123), lung (n = 85), and colorectal cancer (n = 66). Overall, PROs were secondary endpoints in 421 RCTs (76%). Four of 6 evaluated CONSORT PRO items were documented in less than 50% of the RCTs. The level of reporting was higher in RCTs with a PRO as a primary endpoint. The presence of a supplementary report was the only statistically significant factor associated with greater completeness of reporting for both RCTs with PROs as primary endpoints (β = .19, P = .001) and RCTs with PROs as secondary endpoints (β = .30, P < .001). Implementation of the CONSORT PRO extension is equally important across all cancer specialties. Its use can also contribute to revealing the robust PRO design of some studies, which might be obscured by poor outcome reporting. © 2015 American Cancer Society.

The multiple stressor ecological risk assessment for the mercury-contaminated South River and upper Shenandoah River using the Bayesian network-relative risk model.

PubMed

Landis, Wayne G; Ayre, Kimberley K; Johns, Annie F; Summers, Heather M; Stinson, Jonah; Harris, Meagan J; Herring, Carlie E; Markiewicz, April J

2017-01-01

We have conducted a regional scale risk assessment using the Bayesian Network Relative Risk Model (BN-RRM) to calculate the ecological risks to the South River and upper Shenandoah River study area. Four biological endpoints (smallmouth bass, white sucker, Belted Kingfisher, and Carolina Wren) and 4 abiotic endpoints (Fishing River Use, Swimming River Use, Boating River Use, and Water Quality Standards) were included in this risk assessment, based on stakeholder input. Although mercury (Hg) contamination was the original impetus for the site being remediated, other chemical and physical stressors were evaluated. There were 3 primary conclusions from the BN-RRM results. First, risk varies according to location, type and quality of habitat, and exposure to stressors within the landscape. The patterns of risk can be evaluated with reasonable certitude. Second, overall risk to abiotic endpoints was greater than overall risk to biotic endpoints. By including both biotic and abiotic endpoints, we are able to compare risk to endpoints that represent a wide range of stakeholder values. Third, whereas Hg reduction is the regulatory priority for the South River, Hg is not the only stressor driving risk to the endpoints. Ecological and habitat stressors contribute risk to the endpoints and should be considered when managing this site. This research provides the foundation for evaluating the risks of multiple stressors of the South River to a variety of endpoints. From this foundation, tools for the evaluation of management options and an adaptive management tools have been forged. Integr Environ Assess Manag 2017;13:85-99. © 2016 SETAC. © 2016 SETAC.

Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study.

PubMed

Brancati, Frederick L; Evans, Mary; Furberg, Curt D; Geller, Nancy; Haffner, Steven; Kahn, Steven E; Kaufmann, Peter G; Lewis, Cora E; Nathan, David M; Pitt, Bertram; Safford, Monika M

2012-02-01

The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up. The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues. The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power. Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.

An investigation into the two-stage meta-analytic copula modelling approach for evaluating time-to-event surrogate endpoints which comprise of one or more events of interest.

PubMed

Dimier, Natalie; Todd, Susan

2017-09-01

Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter-term surrogate endpoints as substitutes for costly long-term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long-term endpoint. A number of statistical methods to evaluate this prediction have been proposed; this paper uses a simulation study to explore one such method in the context of time-to-event surrogates for a time-to-event true endpoint. This two-stage meta-analytic copula method has been extensively studied for time-to-event surrogate endpoints with one event of interest, but thus far has not been explored for the assessment of surrogates which have multiple events of interest, such as those incorporating information directly from the true clinical endpoint. We assess the sensitivity of the method to various factors including strength of association between endpoints, the quantity of data available, and the effect of censoring. In particular, we consider scenarios where there exist very little data on which to assess surrogacy. Results show that the two-stage meta-analytic copula method performs well under certain circumstances and could be considered useful in practice, but demonstrates limitations that may prevent universal use. Copyright © 2017 John Wiley & Sons, Ltd.

Drug‐coated balloons for de novo lesions in small coronary arteries: rationale and design of BASKET‐SMALL 2

PubMed Central

Gilgen, Nicole; Farah, Ahmed; Scheller, Bruno; Ohlow, Marc‐Alexander; Mangner, Norman; Weilenmann, Daniel; Wöhrle, Jochen; Jamshidi, Peiman; Leibundgut, Gregor; Möbius‐Winkler, Sven; Zweiker, Robert; Krackhardt, Florian; Butter, Christian; Bruch, Leonhard; Kaiser, Christoph; Hoffmann, Andreas; Rickenbacher, Peter; Mueller, Christian; Stephan, Frank‐Peter; Coslovsky, Michael

2018-01-01

The treatment of coronary small vessel disease (SVD) remains an unresolved issue. Drug‐eluting stents (DES) have limited efficacy due to increased rates of instent‐restenosis, mainly caused by late lumen loss. Drug‐coated balloons (DCB) are a promising technique because native vessels remain structurally unchanged. Basel Stent Kosten‐Effektivitäts Trial: Drug‐Coated Balloons vs. Drug‐Eluting Stents in Small Vessel Interventions (BASKET‐SMALL 2) is a multicenter, randomized, controlled, noninferiority trial of DCB vs DES in native SVD for clinical endpoints. Seven hundred fifty‐eight patients with de novo lesions in vessels <3 mm in diameter and an indication for percutaneous coronary intervention such as stable angina pectoris, silent ischemia, or acute coronary syndromes are randomized 1:1 to angioplasty with DCB vs implantation of a DES after successful initial balloon angioplasty. The primary endpoint is the combination of cardiac death, nonfatal myocardial infarction, and target‐vessel revascularization up to 1 year. Secondary endpoints include stent thrombosis, Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding, and long‐term outcome up to 3 years. Based on clinical endpoints after 1 year, we plan to assess the noninferiority of DCB compared to DES in patients undergoing primary percutaneous coronary intervention for SVD. Results will be available in the second half of 2018. This study will compare DCB and DES regarding long‐term safety and efficacy for the treatment of SVD in a large all‐comer population. PMID:29527709

Randomized Trial of Complete Versus Lesion-Only Revascularization in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI and Multivessel Disease

PubMed Central

Gershlick, Anthony H.; Khan, Jamal Nasir; Kelly, Damian J.; Greenwood, John P.; Sasikaran, Thiagarajah; Curzen, Nick; Blackman, Daniel J.; Dalby, Miles; Fairbrother, Kathryn L.; Banya, Winston; Wang, Duolao; Flather, Marcus; Hetherington, Simon L.; Kelion, Andrew D.; Talwar, Suneel; Gunning, Mark; Hall, Roger; Swanton, Howard; McCann, Gerry P.

2015-01-01

Background The optimal management of patients found to have multivessel disease while undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction is uncertain. Objectives CvLPRIT (Complete versus Lesion-only Primary PCI trial) is a U.K. open-label randomized study comparing complete revascularization at index admission with treatment of the infarct-related artery (IRA) only. Methods After they provided verbal assent and underwent coronary angiography, 296 patients in 7 U.K. centers were randomized through an interactive voice-response program to either in-hospital complete revascularization (n = 150) or IRA-only revascularization (n = 146). Complete revascularization was performed either at the time of P-PCI or before hospital discharge. Randomization was stratified by infarct location (anterior/nonanterior) and symptom onset (≤3 h or >3 h). The primary endpoint was a composite of all-cause death, recurrent myocardial infarction (MI), heart failure, and ischemia-driven revascularization within 12 months. Results Patient groups were well matched for baseline clinical characteristics. The primary endpoint occurred in 10.0% of the complete revascularization group versus 21.2% in the IRA-only revascularization group (hazard ratio: 0.45; 95% confidence interval: 0.24 to 0.84; p = 0.009). A trend toward benefit was seen early after complete revascularization (p = 0.055 at 30 days). Although there was no significant reduction in death or MI, a nonsignificant reduction in all primary endpoint components was seen. There was no reduction in ischemic burden on myocardial perfusion scintigraphy or in the safety endpoints of major bleeding, contrast-induced nephropathy, or stroke between the groups. Conclusions In patients presenting for P-PCI with multivessel disease, index admission complete revascularization significantly lowered the rate of the composite primary endpoint at 12 months compared with treating only the IRA. In such patients, inpatient total revascularization may be considered, but larger clinical trials are required to confirm this result and specifically address whether this strategy is associated with improved survival. (Complete Versus Lesion-only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605) PMID:25766941

Confirmatory versus explorative endpoint analysis: Decision-making on the basis of evidence available from market authorization and early benefit assessment for oncology drugs.

PubMed

Niehaus, Ines; Dintsios, Charalabos-Markos

2018-06-01

The early benefit assessment of pharmaceuticals in Germany and their preceding market authorization pursue different objectives. This is reflected by the inclusion of varying confirmatory endpoints within the evaluation of oncology drugs in early benefit assessment versus market authorization, with both relying on the same evidence. Data from assessments up to July 2015 are used to estimate the impact of explorative in comparison to confirmatory endpoints on market authorization and early benefit assessment by contrasting the benefit-risk ratio of EMA and the benefit-harm balance of the HTA jurisdiction. Agreement between market authorization and early benefit assessment is examined by Cohen's kappa (k). 21 of 41 assessments were considered in the analysis. Market authorization is more confirmatory than early benefit assessment because it includes a higher proportion of primary endpoints. The latter implies a primary endpoint to be relevant for the benefit-harm balance in only 67% of cases (0.078). Explorative mortality endpoints reached the highest agreement regarding the mutual consideration for the risk-benefit ratio and the benefit-harm balance (0.000). For explorative morbidity endpoints (-0.600), quality of life (-0.600) and side effects (-0.949) no agreement is ascertainable. To warrant a broader confirmatory basis for decisions supported by HTA, closer inter-institutional cooperation of approval authorities and HTA jurisdictions by means of reliable joint advice for manufacturers regarding endpoint definition would be favorable. Copyright © 2018 Elsevier B.V. All rights reserved.

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis

PubMed Central

Márta, Katalin; Farkas, Nelli; Szabó, Imre; Illés, Anita; Vincze, Áron; Pár, Gabriella; Sarlós, Patrícia; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Mosztbacher, Dóra; Párniczky, Andrea; Szemes, Kata; Pécsi, Dániel; Hegyi, Péter

2016-01-01

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann–Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP. PMID:27775609

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis.

PubMed

Márta, Katalin; Farkas, Nelli; Szabó, Imre; Illés, Anita; Vincze, Áron; Pár, Gabriella; Sarlós, Patrícia; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Mosztbacher, Dóra; Párniczky, Andrea; Szemes, Kata; Pécsi, Dániel; Hegyi, Péter

2016-10-20

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann-Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP.

Idiopathic Pulmonary Fibrosis: Clinically Meaningful Primary Endpoints in Phase 3 Clinical Trials

PubMed Central

Collard, Harold R.; Anstrom, Kevin J.; Flaherty, Kevin R.; Fleming, Thomas R.; King, Talmadge E.; Martinez, Fernando J.; Brown, Kevin K.

2012-01-01

Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint—that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or funtional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. PMID:22505745

Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): Study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice. Methods/Design The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7-14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs. Discussion The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients. Trial Registration Netherlands Trial Register (NTR): NTR2666 PMID:22236534

Root length of aquatic plant, Lemna minor L., as an optimal toxicity endpoint for biomonitoring of mining effluents.

PubMed

Gopalapillai, Yamini; Vigneault, Bernard; Hale, Beverley A

2014-10-01

Lemna minor, a free-floating macrophyte, is used for biomonitoring of mine effluent quality under the Metal Mining Effluent Regulations (MMER) of the Environmental Effects Monitoring (EEM) program in Canada and is known to be sensitive to trace metals commonly discharged in mine effluents such as Ni. Environment Canada's standard toxicity testing protocol recommends frond count (FC) and dry weight (DW) as the 2 required toxicity endpoints-this is similar to other major protocols such as those by the US Environmental Protection Agency (USEPA) and the Organisation for Economic Co-operation and Development (OECD)-that both require frond growth or biomass endpoints. However, we suggest that similar to terrestrial plants, average root length (RL) of aquatic plants will be an optimal and relevant endpoint. As expected, results demonstrate that RL is the ideal endpoint based on the 3 criteria: accuracy (i.e., toxicological sensitivity to contaminant), precision (i.e., lowest variance), and ecological relevance (metal mining effluents). Roots are known to play a major role in nutrient uptake in conditions of low nutrient conditions-thus having ecological relevance to freshwater from mining regions. Root length was the most sensitive and precise endpoint in this study where water chemistry varied greatly (pH and varying concentrations of Ca, Mg, Na, K, dissolved organic carbon, and an anthropogenic organic contaminant, sodium isopropyl xanthates) to match mining effluent ranges. Although frond count was a close second, dry weight proved to be an unreliable endpoint. We conclude that toxicity testing for the floating macrophyte should require average RL measurement as a primary endpoint. © 2014 SETAC.

SOLITAIRE™ with the intention for thrombectomy (SWIFT) trial: design of a randomized, controlled, multicenter study comparing the SOLITAIRE™ Flow Restoration device and the MERCI Retriever in acute ischaemic stroke.

PubMed

Saver, J L; Jahan, R; Levy, E I; Jovin, T G; Baxter, B; Nogueira, R; Clark, W; Budzik, R; Zaidat, O O

2014-07-01

Self-expanding stent retrievers are a promising new device class designed for rapid flow restoration in acute cerebral ischaemia. The SOLITAIRE™ Flow Restoration device (SOLITAIRE) has shown high rates of recanalization in preclinical models and in uncontrolled clinical series. (1) To demonstrate non-inferiority of SOLITAIRE compared with a legally marketed device, the MERCI Retrieval System®; (2) To demonstrate safety, feasibility, and efficacy of SOLITAIRE in subjects requiring mechanical thrombectomy diagnosed with acute ischaemic stroke. DESIGN : Multicenter, randomized, prospective, controlled trial with blinded primary end-point ascertainment. Key entry criteria include: age 22-85; National Institute of Health Stroke Scale (NIHSS) ≥8 and <30; clinical and imaging findings consistent with acute ischaemic stroke; patient ineligible or failed intravenous tissue plasminogen activator; accessible occlusion in M1 or M2 middle cerebral artery, internal carotid artery, basilar artery, or vertebral artery; and patient able to be treated within 8 h of onset. Sites first participate in a roll-in phase, treating two patients with the SOLITAIRE device, before proceeding to the randomized phase. In patients unresponsive to the initially assigned therapy, after the angiographic component of the primary end-point is ascertained (reperfusion with the initial assigned device), rescue therapy with other reperfusion techniques is permitted. The primary efficacy end-point is successful recanalization with the assigned study device (no use of rescue therapy) and with no symptomatic intracranial haemorrhage. Successful recanalization is defined as achieving Thrombolysis In Myocardial Ischemia 2 or 3 flow in all treatable vessels. The primary safety end-point is the incidence of device-related and procedure-related serious adverse events. A major secondary efficacy end-point is time to achieve initial recanalization. Additional secondary end-points include clinical outcomes at 90 days and radiologic haemorrhagic transformation. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Multisite Comparison of Anti-Human Immunodeficiency Virus Microbicide Activity in Explant Assays Using a Novel Endpoint Analysis ▿ †

PubMed Central

Richardson-Harman, Nicola; Lackman-Smith, Carol; Fletcher, Patricia S.; Anton, Peter A.; Bremer, James W.; Dezzutti, Charlene S.; Elliott, Julie; Grivel, Jean-Charles; Guenthner, Patricia; Gupta, Phalguni; Jones, Maureen; Lurain, Nell S.; Margolis, Leonid B.; Mohan, Swarna; Ratner, Deena; Reichelderfer, Patricia; Roberts, Paula; Shattock, Robin J.; Cummins, James E.

2009-01-01

Microbicide candidates with promising in vitro activity are often advanced for evaluations using human primary tissue explants relevant to the in vivo mucosal transmission of human immunodeficiency virus type 1 (HIV-1), such as tonsil, cervical, or rectal tissue. To compare virus growth or the anti-HIV-1 efficacies of candidate microbicides in tissue explants, a novel soft-endpoint method was evaluated to provide a single, objective measurement of virus growth. The applicability of the soft endpoint is shown across several different ex vivo tissue types, with the method performed in different laboratories, and for a candidate microbicide (PRO 2000). The soft-endpoint method was compared to several other endpoint methods, including (i) the growth of virus on specific days after infection, (ii) the area under the virus growth curve, and (iii) the slope of the virus growth curve. Virus growth at the assay soft endpoint was compared between laboratories, methods, and experimental conditions, using nonparametric statistical analyses. Intra-assay variability determinations using the coefficient of variation demonstrated higher variability for virus growth in rectal explants. Significant virus inhibition by PRO 2000 and significant differences in the growth of certain primary HIV-1 isolates were observed by the majority of laboratories. These studies indicate that different laboratories can provide consistent measurements of anti-HIV-1 microbicide efficacy when (i) the soft endpoint or another standardized endpoint is used, (ii) drugs and/or virus reagents are centrally sourced, and (iii) the same explant tissue type and method are used. Application of the soft-endpoint method reduces the inherent variability in comparisons of preclinical assays used for microbicide development. PMID:19726602

Usefulness of morning home blood pressure measurements in patients with type 2 diabetes mellitus: results of a 10-year, prospective, longitudinal study.

PubMed

Kamoi, Kyuzi

2015-01-01

Previous cross-sectional studies and 6-year longitudinal study have demonstrated that home blood pressure (HBP) measurements upon awakening have a stronger predictive power for death, micro- and macrovascular complications than clinic blood pressure (CBP) measurements in patients with type 2 diabetes (T2DM). This study investigated which of these measurements offers stronger predictive power for outcomes over 10 years. At baseline, 400 Japanese patients with T2DM were classified as having hypertension (HT) or normotension (NT) based on HBP and CBP. The mean survey duration was 95 months. Primary and secondary end-points were death and new or worsened micro- and macrovascular complications, respectively. Differences in outcomes for each end-point between HT and NT patients were analyzed using Kaplan-Meier survival curves and log-rank testing. Associated risk factors were assessed using Cox proportional hazards analysis. Based on HBP, death and micro- and macrovascular complications were significantly higher in patients with HT than with NT at baseline and end-point. Based on CBP, there were no significant differences in incidence of death, micro- or macrovascular complications between patients with HT and NT at baseline and end-point, although a significant difference in incidence of death was observed between the HT and NT groups at end-point. However, the significance was significantly lower in CBP than in HBP. One risk factor associated with micro- and macrovascular complications in patients with HBP was therapy for HT. This 10-year longitudinal study of patients with T2DM demonstrated that elevated HBP upon awakening is predictive of death, and micro- and macrovascular complications.

Baseline Blood Pressure, the 2017 ACC/AHA High Blood Pressure Guidelines, and Long-Term Cardiovascular Risk in SPRINT.

PubMed

Vaduganathan, Muthiah; Pareek, Manan; Qamar, Arman; Pandey, Ambarish; Olsen, Michael H; Bhatt, Deepak L

2018-02-05

The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines include lower thresholds to define hypertension than previous guidelines. Little is known about the impact of these guideline changes in patients with or at high risk for cardiovascular disease. In this exploratory analysis using baseline blood pressure assessments in Systolic Blood Pressure Intervention Trial (SPRINT), we evaluated the prevalence and associated cardiovascular prognosis of patients newly reclassified with hypertension based on the 2017 ACC/AHA (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg) compared with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). The primary endpoint was the composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or cardiovascular death. In 4683 patients assigned to the standard treatment arm of SPRINT, 2328 (49.7%) met hypertension thresholds by JNC 7 guidelines, and another 1424 (30.4%) were newly reclassified as having hypertension based on the 2017 ACC/AHA guidelines. Over 3.3-year median follow-up, 319 patients experienced the primary endpoint (87 of whom were newly reclassified with hypertension based on the revised guidelines). Patients with hypertension based on prior guidelines compared with those newly identified with hypertension based on the new guidelines had similar risk of the primary endpoint (2.3 [95% confidence interval {CI}, 2.0-2.7] vs 2.0 [95% CI, 1.6-2.4] events per 100 patient-years; adjusted HR, 1.10 [95% CI, 0.84-1.44]; P = .48). The 2017 ACC/AHA high blood pressure guidelines are expected to significantly increase the prevalence of patients with hypertension (perhaps to a greater extent in higher-risk patient cohorts compared with the general population) and identify greater numbers of patients who will ultimately experience adverse cardiovascular events. Copyright © 2018 Elsevier Inc. All rights reserved.

The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

PubMed

Tafuri, Giovanni; Lucas, Inês; Estevão, Steve; Moseley, Jane; d'Andon, Anne; Bruehl, Hannah; Gajraj, Elangovan; Garcia, Sonia; Hedberg, Niklas; Massari, Marco; Molina, Andrea; Obach, Mercè; Osipenko, Leeza; Petavy, Frank; Petschulies, Marco; Pontes, Caridad; Russo, Pierluigi; Schiel, Anja; Van de Casteele, Marc; Zebedin-Brandl, Eva-Maria; Rasi, Guido; Vamvakas, Spiros

2018-05-01

The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective. © 2018 The British Pharmacological Society.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

PubMed

Dykens, Elisabeth M; Miller, Jennifer; Angulo, Moris; Roof, Elizabeth; Reidy, Michael; Hatoum, Hind T; Willey, Richard; Bolton, Guy; Korner, Paul

2018-06-21

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

PubMed

Waliszewski, Matthias; Rittger, Harald

2016-10-01

Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300-700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited. © The Author(s), 2016.

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

PubMed Central

Waliszewski, Matthias; Rittger, Harald

2016-01-01

Background: Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. Methods: The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Results: Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300–700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. Conclusions: From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited. PMID:27378486

Drug-coated balloons for de novo lesions in small coronary arteries: rationale and design of BASKET-SMALL 2.

PubMed

Gilgen, Nicole; Farah, Ahmed; Scheller, Bruno; Ohlow, Marc-Alexander; Mangner, Norman; Weilenmann, Daniel; Wöhrle, Jochen; Jamshidi, Peiman; Leibundgut, Gregor; Möbius-Winkler, Sven; Zweiker, Robert; Krackhardt, Florian; Butter, Christian; Bruch, Leonhard; Kaiser, Christoph; Hoffmann, Andreas; Rickenbacher, Peter; Mueller, Christian; Stephan, Frank-Peter; Coslovsky, Michael; Jeger, Raban

2018-05-01

The treatment of coronary small vessel disease (SVD) remains an unresolved issue. Drug-eluting stents (DES) have limited efficacy due to increased rates of instent-restenosis, mainly caused by late lumen loss. Drug-coated balloons (DCB) are a promising technique because native vessels remain structurally unchanged. Basel Stent Kosten-Effektivitäts Trial: Drug-Coated Balloons vs. Drug-Eluting Stents in Small Vessel Interventions (BASKET-SMALL 2) is a multicenter, randomized, controlled, noninferiority trial of DCB vs DES in native SVD for clinical endpoints. Seven hundred fifty-eight patients with de novo lesions in vessels <3 mm in diameter and an indication for percutaneous coronary intervention such as stable angina pectoris, silent ischemia, or acute coronary syndromes are randomized 1:1 to angioplasty with DCB vs implantation of a DES after successful initial balloon angioplasty. The primary endpoint is the combination of cardiac death, nonfatal myocardial infarction, and target-vessel revascularization up to 1 year. Secondary endpoints include stent thrombosis, Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding, and long-term outcome up to 3 years. Based on clinical endpoints after 1 year, we plan to assess the noninferiority of DCB compared to DES in patients undergoing primary percutaneous coronary intervention for SVD. Results will be available in the second half of 2018. This study will compare DCB and DES regarding long-term safety and efficacy for the treatment of SVD in a large all-comer population. © 2018 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

Endpoint design for future renal denervation trials - Novel implications for a new definition of treatment response to renal denervation.

PubMed

Lambert, Thomas; Nahler, Alexander; Rohla, Miklos; Reiter, Christian; Grund, Michael; Kammler, Jürgen; Blessberger, Hermann; Kypta, Alexander; Kellermair, Jörg; Schwarz, Stefan; Starnawski, Jennifer A; Lichtenauer, Michael; Weiss, Thomas W; Huber, Kurt; Steinwender, Clemens

2016-10-01

Defining an adequate endpoint for renal denervation trials represents a major challenge. A high inter-individual and intra-individual variability of blood pressure levels as well as a partial or total non-adherence on antihypertensive drugs hamper treatment evaluations after renal denervation. Blood pressure measurements at a single point in time as used as primary endpoint in most clinical trials on renal denervation, might not be sufficient to discriminate between patients who do or do not respond to renal denervation. We compared the traditional responder classification (defined as systolic 24-hour blood pressure reduction of -5mmHg six months after renal denervation) with a novel definition of an ideal respondership (based on a 24h blood pressure reduction at no point in time, one, or all follow-up timepoints). We were able to re-classify almost a quarter of patients. Blood pressure variability was substantial in patients traditionally defined as responders. On the other hand, our novel classification of an ideal respondership seems to be clinically superior in discriminating sustained from pseudo-response to renal denervation. Based on our observations, we recommend that the traditional response classification should be reconsidered and possibly strengthened by using a composite endpoint of 24h-BP reductions at different follow-up-visits. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Use of a Sea Salt-based Spray for Diabetic Foot Ulcers: A Novel Concept.

PubMed

Pougatsch, David A; Rader, Andrew; Rogers, Lee C

2017-02-01

Several patients present to wound healing specialists seeking a natural or alternative medical approach to their wounds. The purpose of this prospective, case-cohort study of 10 patients was to evaluate the use of Oceanzyme Wound Care Spray (Ocean Aid, Inc, Boynton Beach, FL) in improving healing in diabetic foot ulcers during a 12-week period. This product contains water purified by reverse osmosis, coral reef sea salt, lysozyme, and sodium benzoate. The primary endpoint was wound closure, and secondary endpoints were infection rate and wound area reduction. Overall, 2 patients healed, 2 withdrew, and the remaining 6 had an average of 73% reduction in wound area. While more study is needed, the use of this sea salt-based spray may provide a viable alternative for patients seeking a natural therapy for their wound care.

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

Eplerenone improves prognosis in postmyocardial infarction diabetic patients with heart failure: results from EPHESUS.

PubMed

O'Keefe, J H; Abuissa, H; Pitt, B

2008-06-01

The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated that selective aldosterone blockade with eplerenone significantly reduced total mortality by 15%, combined cardiovascular (CV) mortality/CV hospitalization by 13%, CV mortality by 17% and sudden cardiac death by 21%, vs. placebo when added to standard care in patients with left ventricular systolic dysfunction (LVSD) and signs of congestive heart failure (CHF) following acute myocardial infarction (AMI). We retrospectively evaluated the effect of eplerenone vs. placebo in a subset of 1483 diabetic patients with LVSD and signs of CHF following AMI. Diabetic status was determined from medical histories at screening. Analyses were based on time to first occurrence of an event. Results were based on a Cox's proportional hazards regression model stratified by region with treatment, subgroup and treatment-by-subgroup interaction as factors. The 95% confidence intervals for the risk ratios were based on the Wald's test. Treatment with eplerenone in diabetic patients with CHF following AMI reduced the risk of the primary endpoint, a composite of CV mortality or CV hospitalization, by 17% (p = 0.031). The absolute risk reduction of the primary endpoint was greater in the diabetic cohort (5.1%) than in the non-diabetic cohort (3%). Hyperkalaemia occurred more often with eplerenone than with placebo (5.6 vs. 3%, p = 0.015). Among the diabetic cohorts, the prespecified endpoint of 'any CV disorder' occurred in 28% of the eplerenone group and 35% of the placebo group (p = 0.007). Eplerenone treatment may reduce adverse CV events in diabetic patients with LVSD and signs of CHF following AMI.

Perioperative antibiotic prophylaxis in the treatment of acute cholecystitis (PEANUTS II trial): study protocol for a randomized controlled trial.

PubMed

Loozen, Charlotte S; van Santvoort, Hjalmar C; van Geloven, Antoinette A W; Nieuwenhuijzen, Grard A P; de Reuver, Philip R; Besselink, Mark H G; Vlaminckx, Bart; Kelder, Johannes C; Knibbe, Catherijne A J; Boerma, Djamila

2017-08-23

The additional value of perioperative antibiotic prophylaxis in preventing infectious complications after emergency cholecystectomy for acute cholecystitis is a much-debated subject in the surgical community. Evidence-based guidelines are lacking, and consequently the use of antibiotic prophylaxis varies greatly among surgeons and hospitals. Recently, high-level evidence became available demonstrating that postoperative antibiotic prophylaxis in patients with acute cholecystitis does not reduce the risk of infectious complications. Preoperative antibiotic prophylaxis in relation to the risk of infectious complications, however, has never been studied. The PEANUTS II trial is a randomized, controlled, multicenter, open-label noninferiority trial whose aim is to determine the utility of preoperative antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. Patients with mild or moderate acute cholecystitis, as defined according the Tokyo Guidelines, will be randomly assigned to a single preoperative dose of antibiotic prophylaxis (2000 mg of first-generation cephalosporin delivered intravenously) or no antibiotic prophylaxis before emergency cholecystectomy. The primary endpoint is a composite endpoint consisting of all postoperative infectious complications occurring during the first 30 days after surgery. Secondary endpoints include all the individual components of the primary endpoint, all other complications, duration of hospital stay, and total costs. The hypothesis is that the absence of antibiotic prophylaxis is noninferior to the presence of antibiotic prophylaxis. A noninferiority margin of 10% is assumed. With a 1-sided risk of 2.5% and a power of 80%, a total of 454 subjects will have to be included. Analysis will be performed according to the intention-to-treat principle. The PEANUTS II trial will provide evidence-based advice concerning the utility of antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. Netherlands Trial Register, NTR5802 . Registered on 4 June 2016.

Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis

PubMed Central

Tabibian, James H.; Gossard, Andrea; El-Youssef, Mounif; Eaton, John E.; Petz, Jan; Jorgensen, Roberta; Enders, Felicity B.; Lindor, Keith D.

2014-01-01

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week open-label pilot study to investigate the efficacy and safety of oral rifaximin 550 mg twice daily. The primary endpoint was serum alkaline phosphatase (ALK) at 12 weeks. Secondary endpoints included: i) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; ii) Fisk Fatigue Impact Scale (FFIS), Chronic Liver Disease Questionnaire (CLDQ), and Short Form Health Survey (SF-36) scores; and iii) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years, 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range 275-520). Following 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL, p=0.47) or any of the secondary biochemical endpoints (all p>0.05). Similarly, there were no significant changes in FFIS, CLDQ, or SF-36 scores (all p>0.05). Three patients withdrew from the study due to AEs; four others reported mild AEs but completed the study. In conclusion, while some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, appears inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC. (clinicaltrials.gov NCT01695174) PMID:24914504

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

Impact of Antithrombotic Therapy in Atrial Fibrillation on the Presentation of Coronary Artery Disease

PubMed Central

Chan, Pak Hei; Li, Wen Hua; Hai, Jo Jo; Tse, Hung Fat; Siu, Chung Wah

2015-01-01

Background Little is known about whether atrial fibrillation is a presentation of coronary disease. There is a paucity of knowledge about their causal relationship and also the impact of different antithrombotic strategies on the subsequent presentation of symptomatic coronary disease. Methods and Results We studied 7,526 Chinese patients diagnosed with non-valvular atrial fibrillation and no documented history of coronary artery disease. The primary endpoint was the new occurrence of coronary artery disease—either stable coronary artery disease or acute coronary syndrome. After a mean follow-up of 3.2±3.5 years (24,071 patient-years), a primary endpoint occurred in 987 patients (13.1%). The overall annual incidence of coronary artery disease was 4.10%/year. No significant differences in age, sex, and mean CHA2DS2-VASc score were observed between patients with and without the primary endpoint. When stratified according to the antithrombotic strategies applied for stroke prevention, the annual incidence of coronary artery disease was 5.49%/year, 4.45%/year and 2.16%/year respectively in those prescribed no antithrombotic therapy, aspirin, and warfarin. Similar trends were observed in patients with acute coronary syndromes. Diabetes mellitus, smoking history and renal failure requiring dialysis were predictors for primary endpoint in all antithrombotic therapies. Conclusion In patients with non-valvular atrial fibrillation, there is a modest association with coronary artery disease. Patients prescribed warfarin had the lowest risk of new onset coronary artery disease. PMID:26098876

ECOLOGICAL ENDPOINT MODELING FOR TMDLS: EFFECTS OF SEDIMENT ON FISH POPULATIONS

EPA Science Inventory

Sediment is one of the primary stressors of concern for Total Maximum Daily Loads (TMDLs) for streams, and often it is a concern because of its impact on ecological endpoints. A modeling approach relating sediment to stream fish population dynamics is presented. Equations are d...

Efficacy and safety of loxoprofen hydrogel patch versus loxoprofen tablet in patients with knee osteoarthritis: a randomized controlled non-inferiority trial.

PubMed

Mu, Rong; Bao, Chun-de; Chen, Zhi-wei; Zheng, Yi; Wang, Guo-chun; Zhao, Dong-bao; Hu, Shao-xian; Li, Yu-jun; Shao, Zeng-wu; Zhang, Zhi-yi; Xiao, Wei-guo; Zhang, Weiya; Li, Zhan-guo

2016-01-01

This study is aimed at comparing the efficacy and safety of loxoprofen sodium hydrogel patch (LX-P) with loxoprofen sodium tablet (LX-T) in patients with knee osteoarthritis (OA). One hundred sixty-nine patients were enrolled in a randomized, controlled, double-blind, double-dummy, multicenter, non-inferiority trial of LX-P. Patients were randomly assigned to either LX-P or LX-T groups for a 4-week treatment. The primary efficacy endpoint was the proportion of patients with an overall improvement of ≥50%, and the secondary efficacy endpoint was the proportion of patients with an improvement of ≥25% from baseline in each of the seven main symptoms. The non-inferiority trial was based on a power of 80% and significance level of 2.5% with a non-inferiority margin of -10%. In both intention-to-treat (ITT) and per-protocol (PP) analyses, LX-P was as effective as LX-T in regard to the primary endpoint. In the ITT analysis, the difference between the two groups was 12.6% [95% confidence interval, -1.7 to 26.9%]. No significant differences were found between the two groups in any of the secondary efficacy outcomes. A lower incidence of adverse events was observed in LX-P group; however, the difference was not statistically significant. No serious adverse events were reported in the LX-P group, whereas one case was reported in LX-T group. Based on the present study, topical loxoprofen patch was non-inferior to oral loxoprofen in patients with knee osteoarthritis.

ERic Acute StrokE Recanalization: A study using predictive analytics to assess a new device for mechanical thrombectomy.

PubMed

Siemonsen, Susanne; Forkert, Nils D; Bernhardt, Martina; Thomalla, Götz; Bendszus, Martin; Fiehler, Jens

2017-08-01

Aim and hypothesis Using a new study design, we investigate whether next-generation mechanical thrombectomy devices improve clinical outcomes in ischemic stroke patients. We hypothesize that this new methodology is superior to intravenous tissue plasminogen activator therapy alone. Methods and design ERic Acute StrokE Recanalization is an investigator-initiated prospective single-arm, multicenter, controlled, open label study to compare the safety and effectiveness of a new recanalization device and distal access catheter in acute ischemic stroke patients with symptoms attributable to acute ischemic stroke and vessel occlusion of the internal cerebral artery or middle cerebral artery. Study outcome The primary effectiveness endpoint is the volume of saved tissue. Volume of saved tissue is defined as difference of the actual infarct volume and the brain volume that is predicted to develop infarction by using an optimized high-level machine learning model that is trained on data from a historical cohort treated with IV tissue plasminogen activator. Sample size estimates Based on own preliminary data, 45 patients fulfilling all inclusion criteria need to complete the study to show an efficacy >38% with a power of 80% and a one-sided alpha error risk of 0.05 (based on a one sample t-test). Discussion ERic Acute StrokE Recanalization is the first prospective study in interventional stroke therapy to use predictive analytics as primary and secondary endpoint. Such trial design cannot replace randomized controlled trials with clinical endpoints. However, ERic Acute StrokE Recanalization could serve as an exemplary trial design for evaluating nonpivotal neurovascular interventions.

PHARMacy-based interdisciplinary program for patients with Chronic Heart Failure (PHARM-CHF): rationale and design of a randomized controlled trial, and results of the pilot study.

PubMed

Laufs, Ulrich; Griese-Mammen, Nina; Krueger, Katrin; Wachter, Angelika; Anker, Stefan D; Koehler, Friedrich; Rettig-Ewen, Volker; Botermann, Lea; Strauch, Dorothea; Trenk, Dietmar; Böhm, Michael; Schulz, Martin

2018-05-30

We report the rationale and design of a community PHARMacy-based prospective randomized controlled interdisciplinary study for ambulatory patients with Chronic Heart Failure (PHARM-CHF) and results of its pilot study. The pilot study randomized 50 patients to a pharmacy-based intervention or usual care for 12 months. It demonstrated the feasibility of the design and showed reduced systolic blood pressure in the intervention group as indicator for improved medication adherence. The main study will randomize patients ≥60 years on stable pharmacotherapy including at least one diuretic and a history of heart failure hospitalization within 12 months. The intervention group will receive a medication review at baseline followed by regular dose dispensing of the medication, counselling regarding medication use and symptoms of heart failure. The control patients are unknown to the pharmacy and receive usual care. The primary efficacy endpoint is medication adherence, pre-specified as a significant difference of the proportion of days covered between the intervention and control group within 365 days following randomization using pharmacy claims data for three CHF medications (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists). The primary composite safety endpoint is days lost due to blindly adjudicated unplanned cardiovascular hospitalizations or death. Overall, 248 patients shall be randomized. The minimum follow-up is 12 months with an expected mean of 24 months. Based on the feasibility demonstrated in the pilot study, the randomized PHARM-CHF trial will test whether an interdisciplinary pharmacy-based intervention can safely improve medication adherence and will estimate the potential impact on clinical endpoints. ClinicalTrials.gov Identifier: NCT01692119. © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.

Efficient estimation of the distribution of time to composite endpoint when some endpoints are only partially observed

PubMed Central

Daniel, Rhian M.; Tsiatis, Anastasios A.

2014-01-01

Two common features of clinical trials, and other longitudinal studies, are (1) a primary interest in composite endpoints, and (2) the problem of subjects withdrawing prematurely from the study. In some settings, withdrawal may only affect observation of some components of the composite endpoint, for example when another component is death, information on which may be available from a national registry. In this paper, we use the theory of augmented inverse probability weighted estimating equations to show how such partial information on the composite endpoint for subjects who withdraw from the study can be incorporated in a principled way into the estimation of the distribution of time to composite endpoint, typically leading to increased efficiency without relying on additional assumptions above those that would be made by standard approaches. We describe our proposed approach theoretically, and demonstrate its properties in a simulation study. PMID:23722304

A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial.

PubMed

Rao, Sunil V; Hess, Connie N; Barham, Britt; Aberle, Laura H; Anstrom, Kevin J; Patel, Tejan B; Jorgensen, Jesse P; Mazzaferri, Ernest L; Jolly, Sanjit S; Jacobs, Alice; Newby, L Kristin; Gibson, C Michael; Kong, David F; Mehran, Roxana; Waksman, Ron; Gilchrist, Ian C; McCourt, Brian J; Messenger, John C; Peterson, Eric D; Harrington, Robert A; Krucoff, Mitchell W

2014-08-01

This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access. In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (SAFE-PCI for Women; NCT01406236). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The effect of bronchodilators on forced vital capacity measurement in patients with idiopathic pulmonary fibrosis

PubMed Central

Assayag, Deborah; Vittinghoff, Eric; Ryerson, Christopher J.; Cocconcelli, Elisabetta; Tonelli, Roberto; Hu, Xiaowen; Elicker, Brett M.; Golden, Jeffrey A.; Jones, Kirk D.; King, Talmadge E.; Koth, Laura L.; Lee, Joyce S.; Ley, Brett; Shum, Anthony K.; Wolters, Paul J.; Ryu, Jay H.; Collard, Harold R.

2015-01-01

Background Forced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC. Methods IPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint. Results There were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04 liters (2.71 vs. 2.75 liters, p <0.001). Reversible airflow limitation (increase in FEV1 or FVC of ≥12% and ≥200 milliliters) occurred in 9.1% of patients. The inter-test difference in change in FVC over time were equivalent for pre and post-bronchodilator (p = 0.65), leading to similar sample size estimates in a hypothetical clinical trial using change in FVC as the primary endpoint. Conclusion Approximately one in ten patients with IPF has physiological evidence of reversible airflow limitation, and bronchodilator use in these patients may improve the assessment of disease progression based on FVC change over time. Bronchodilator use does not appear to meaningfully impact the precision of FVC as an endpoint in clinical trials. PMID:26140806

Methodological issues with adaptation of clinical trial design.

PubMed

Hung, H M James; Wang, Sue-Jane; O'Neill, Robert T

2006-01-01

Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re-estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re-estimation, we make a contrast between an adaptive test weighting the two-stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre-specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers.

Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers.

PubMed

Wilhelmsen, Michael; Christensen, Ib J; Rasmussen, Louise; Jørgensen, Lars N; Madsen, Mogens R; Vilandt, Jesper; Hillig, Thore; Klaerke, Michael; Nielsen, Knud T; Laurberg, Søren; Brünner, Nils; Gawel, Susan; Yang, Xiaoqing; Davis, Gerard; Heijboer, Annemieke; Martens, Frans; Nielsen, Hans J

2017-03-15

Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of (i) CRC and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had 'clean' colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC. © 2016 UICC.

A tale of three labels: translating the JUPITER trial data into regulatory claims.

PubMed

Ridker, Paul M

2011-08-01

Whether a pivotal randomized trial will be interpreted in a similar and consistent manner by different regulatory agencies is uncertain as policy perspectives may play a role in data interpretation and the translation of trial results into clinical practice. Using a contemporary example, to compare and contrast regulatory claims in the United States, Europe, and Canada that derive from a pivotal clinical trial. The recently completed JUPITER trial of rosuvastatin as compared to placebo conducted among 17,802 men and women with LDL-C <130 mg/dL and hsCRP ≥ 2 mg/L, provides the only available data on rosuvastatin for primary prevention of cardiovascular disease. Thus, the JUPITER trial provides an opportunity to compare and contrast how regulatory agencies in the United States, Canada, and Europe chose to interpret an identical database. Labeling indications based on earlier statin trials of primary and secondary prevention were also reviewed. JUPITER demonstrated a 44% reduction (p < 0.000001) in the trial pre-specified primary endpoint (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, coronary revascularization, or cardiovascular death) with no evidence of heterogeneity across geographic regions. In response to these data, the US Food and Drug Administration label for rosuvastatin in primary prevention came closest to the actual JUPITER trial population by stipulating that those eligible for treatment should be older men and women with hsCRP >2 mg/L, plus one additional risk factor for heart disease. The Canadian label is silent on age and hsCRP (the major trial inclusion criterion), stipulating instead that treatment can be considered for those with 'at least two conventional risk factors for cardiovascular disease,' a group more inclusive than that studied. In contrast, the European Medicines Agency label limits treatment only to 'high risk individuals' ignoring hsCRP and using instead a post hoc definition of 'high risk' that comprised a subgroup of less than 10% of the study population who contributed but 67 events to the study total and did not show statistical significance when compared to placebo. None of the regulatory labels included the trial primary endpoint; instead, each focused on separate and different components of the primary endpoint. Similar discrepancies were found between European and North American regulatory agencies with regard to earlier pivotal trials of statins for primary prevention, but not for secondary prevention. The JUPITER experience represents a case study and is not a systematic review of the regulatory decision process. Labeling indications can vary widely in different regulatory environments even when based on the same trial data.

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. 314.510 Section 314.510 Food... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on...

Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial.

PubMed

2013-11-01

Cost-effective strategies to maintain healthy active lifestyle in aging populations are required to address the global burden of age-related diseases. ASPREE will examine whether the potential primary prevention benefits of low dose aspirin outweigh the risks in older healthy individuals. Our primary hypothesis is that daily oral 100 mg enteric-coated aspirin will extend a composite primary endpoint termed 'disability-free life' including onset of dementia, total mortality, or persistent disability in at least one of the Katz Activities of Daily Living in 19,000 healthy participants aged 65 years and above ('US minorities') and 70 years and above (non-'US minorities'). ASPREE is a double-blind, randomized, placebo-controlled trial of oral 100mg enteric-coated acetyl salicylic acid (ASA) or matching placebo being conducted in Australian and US community settings on individuals free of dementia, disability and cardiovascular disease (CVD) events. Secondary endpoints are all-cause and cause specific mortality, fatal and non-fatal cardiovascular events, fatal and non-fatal cancer (excluding non-melanoma skin cancer), dementia, mild cognitive impairment, depression, physical disability, and clinically significant bleeding. To 20 September 2013 14,383 participants have been recruited. Recruitment and study completion are anticipated in July 2014 and December 2018 respectively. In contrast to other aspirin trials that have largely focused on cardiovascular endpoints, ASPREE has a unique composite primary endpoint to better capture the overall risk and benefit of aspirin to extend healthy independent lifespan in older adults in the US and Australia. © 2013. Published by Elsevier Inc. All rights reserved.

High dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis

PubMed Central

Imam, Mohamad H.; Sinakos, Emmanouil; Gossard, Andrea A.; Kowdley, Kris V.; Luketic, Velimir A. C.; Harrison, M. Edwyn; McCashland, Timothy; Befeler, Alex S.; Harnois, Denise; Jorgensen, Roberta; Petz, Jan; Keach, Jill; DeCook, Alisha C.; Enders, Felicity; Lindor, Keith D.

2013-01-01

Background Ursodeoxycholic acid (UDCA) in a dose of 28–30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. Aim Our aim was to compare the risk of adverse clinical endpoints in patients with varying disease status. Methods We reviewed records from patients previously enrolled in a study evaluating the effects of high-dose (28–30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histologic stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, esophageal varices and cholangiocarcinoma was sought. Results One hundred fifty patients were included of which 49 patients developed endpoints. There was an increased development of endpoints amongst patients using UDCA vs. placebo (14 vs. 4, p = 0.0151) with early histologic disease (stage 1–2, n = 88) but not with late stage (stage 3–4, n = 62) disease (17 vs. 14, p = 0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, p = 0.0008) with normal bilirubin levels (total bilirubin ≤ 1.0 mg/dl) but not in patients with elevated bilirubin levels (15 vs. 16, p = 0.6018). Among patients not reaching endpoints 31.68% had normalization of their alkaline phosphatase levels as compared to 14.29% in patients who reached endpoints (p = 0.073). Conclusion The increased risk of adverse events with UDCA treatment as compared to placebo is only apparent in patients with early histologic stage disease or normal total bilirubin. PMID:21957881

Investigation of standardized administration of anti-platelet drugs and its effect on the prognosis of patients with coronary heart disease.

PubMed

Ding, Chao; Zhang, Jianhua; Li, Rongcheng; Wang, Jiacai; Hu, Yongcang; Chen, Yanyan; Li, Xiannan; Xu, Yan

2017-10-01

The aim of the present study was to explore the effect of adherence to standardized administration of anti-platelet drugs on the prognosis of patients with coronary heart disease. A total of 144 patients newly diagnosed with coronary heart disease at Lu'an Shili Hospital of Anhui Province (Lu'an, China) between June 2010 and June 2012 were followed up. Kaplan-Meier curves and the Cox regression model were used to evaluate the effects of standardized administration of anti-platelet drugs on primary and secondary end-point events. Of the patients with coronary heart disease, 109 (76%) patients took standard anti-platelet drugs following discharge. Kaplan-Meier curve and Cox regression analysis showed that standardized administration of anti-platelet drugs reduced the risk of primary end-point events (including all-cause mortality, non-lethal myocardial infarction and stroke) of patients with coronary heart disease [hazard ratio (HR)=0.307; 95% confidence interval (CI): 0.099-0.953; P=0.041) and all-cause mortality (HR=0.162; 95% CI: 0.029-0.890; P=0.036); however, standardized administration had no predictive value with regard to secondary end-point events. Standardized administration of anti-platelet drugs obviously reduced the risk of primary end-point events in patients with coronary heart disease, and further analysis showed that only all-cause mortality exhibited a statistically significant reduction.

Primary endpoint results of the OMEGA Study: One-year clinical outcomes after implantation of a novel platinum chromium bare metal stent.

PubMed

Wang, John C; Carrié, Didier; Masotti, Monica; Erglis, Andrejs; Mego, David; Watkins, Matthew W; Underwood, Paul; Allocco, Dominic J; Hamm, Christian W

2015-03-01

Bare metal stents (BMS) have similar rates of death and myocardial infarction (MI) compared to drug-eluting stents (DES). DES lower repeat revascularization rates compared to BMS, but may have higher rates of late stent thrombosis (ST) potentially due to impaired endothelialization requiring longer dual anti-platelet therapy (DAPT). OMEGA evaluated a novel BMS designed to have improved deliverability and radiopacity, in comparison to currently available platforms. OMEGA was a prospective, multicenter, single-arm study enrolling 328 patients at 37 sites (US and Europe). Patients received the OMEGA stent (bare platinum chromium element stent) for the treatment of de novo native coronary artery lesions (≤28 mm long; diameter ≥2.25 mm to ≤4.50mm). The primary endpoint was 9-month target lesion failure (TLF: cardiac death, target vessel-related MI, target lesion revascularization [TLR]) compared to a prespecified performance goal (PG) based on prior generation BMS. All major cardiac events were independently adjudicated. DAPT was required for a minimum of 1 month post procedure. In the OMEGA study, the mean age was 65; 17% had diabetes mellitus. The primary endpoint was met; 9 month TLF rate was 11.5%, and the upper 1-sided 95% confidence bound of 14.79% was less than the prespecified PG of 21.2% (p<0.0001). One-year event rates were low including a TLF rate of 12.8% and an ST rate of 0.6% at 12 months. One-year outcomes of OMEGA show low rates of TLF, revascularization and ST. This supports safety and efficacy of the OMEGA BMS for the treatment of coronary artery disease. Copyright © 2015 Elsevier Inc. All rights reserved.

A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia

PubMed Central

Wang, Winfred C; Ware, Russell E; Miller, Scott T; Iyer, Rathi V; Casella, James F; Minniti, Caterina P; Rana, Sohail; Thornburg, Courtney D; Rogers, Zora R; Kalpatthi, Ram V; Barredo, Julio C; Brown, R Clark; Sarnaik, Sharada A; Howard, Thomas H; Wynn, Lynn W; Kutlar, Abdullah; Armstrong, F Daniel; Files, Beatrice A; Goldsmith, Jonathan C; Waclawiw, Myron A; Huang, Xiangke; Thompson, Bruce W

2011-01-01

Background Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined. Methods Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks. Findings Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia. Interpretation Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA. PMID:21571150

Cardiac magnetic resonance imaging parameters as surrogate endpoints in clinical trials of acute myocardial infarction

PubMed Central

2011-01-01

Cardiac magnetic resonance (CMR) offers a variety of parameters potentially suited as surrogate endpoints in clinical trials of acute myocardial infarction such as infarct size, myocardial salvage, microvascular obstruction or left ventricular volumes and ejection fraction. The present article reviews each of these parameters with regard to the pathophysiological basis, practical aspects, validity, reliability and its relative value (strengths and limitations) as compared to competitive modalities. Randomized controlled trials of acute myocardial infarction which have used CMR parameters as a primary endpoint are presented. PMID:21917147

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints

PubMed Central

Thompson, John R; Spata, Enti; Abrams, Keith R

2015-01-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing–remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions. PMID:26271918

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints.

PubMed

Bujkiewicz, Sylwia; Thompson, John R; Spata, Enti; Abrams, Keith R

2017-10-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing-remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions.

Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia

PubMed Central

Macciò, Antonio; Madeddu, Clelia; Serpe, Roberto; Massa, Elena; Dessì, Mariele; Panzone, Filomena; Contu, Paolo

2010-01-01

Purpose. A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia—lean body mass (LBM), resting energy expenditure (REE), and fatigue—and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. Patients and Methods. Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. Results. Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. Conclusion. The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. PMID:20156909

Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial.

PubMed

Brown, David; Nakagome, Kazuyuki; Cordes, Joachim; Brenner, Ronald; Gründer, Gerhard; Keefe, Richard S E; Riesenberg, Robert; Walling, David P; Daniels, Kristen; Wang, Lara; McGinniss, Jennifer; Sand, Michael

2018-05-01

Patients with cognitive impairment associated with schizophrenia may benefit from treatments targeting dysfunctional glutamatergic neurotransmission. BI 409306, a potent and selective phosphodiesterase 9 inhibitor, was assessed in patients with schizophrenia using a learn-and-confirm adaptive trial design. This double-blind, parallel-group trial randomized patients 2:1:1:1:1 to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks. Stage 1 (learn) assessed change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) scores (week 12) to identify ≥1 meaningful endpoints for stage 2 (confirm). If no domains showed efficacy, change from baseline in Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite scores (week 12) was the primary endpoint. The key secondary endpoint was change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) total score. Safety was monitored. Five hundred eighteen patients were randomized. In stage 1, CANTAB did not differentiate between BI 409306 and placebo (n = 120), so the primary endpoint of change from baseline in MCCB composite score was analyzed in 450 patients in stage 2. There was no significant difference between BI 409306 (1.2-2.8) and placebo (2.5) in MCCB composite score change. BI 409306 did not significantly improve change from baseline in SCoRS total score (-3.1 to -2.0) vs placebo (-2.5). Adverse events were dose-dependent, increasing from 33.3% (10 mg) to 53.5% (100 mg), vs 36.4% for placebo. The primary endpoint of cognitive function improvement was not met. BI 409306 was well-tolerated, with an acceptable safety profile.

Remote management of heart failure using implantable electronic devices

PubMed Central

Morgan, John M.; Kitt, Sue; Gill, Jas; McComb, Janet M.; Ng, Ghulam Andre; Raftery, James; Roderick, Paul; Seed, Alison; Williams, Simon G.; Witte, Klaus K.; Wright, David Jay; Harris, Scott; Cowie, Martin R.

2017-01-01

Abstract Aims Remote management of heart failure using implantable electronic devices (REM-HF) aimed to assess the clinical and cost-effectiveness of remote monitoring (RM) of heart failure in patients with cardiac implanted electronic devices (CIEDs). Methods and results Between 29 September 2011 and 31 March 2014, we randomly assigned 1650 patients with heart failure and a CIED to active RM or usual care (UC). The active RM pathway included formalized remote follow-up protocols, and UC was standard practice in nine recruiting centres in England. The primary endpoint in the time to event analysis was the 1st event of death from any cause or unplanned hospitalization for cardiovascular reasons. Secondary endpoints included death from any cause, death from cardiovascular reasons, death from cardiovascular reasons and unplanned cardiovascular hospitalization, unplanned cardiovascular hospitalization, and unplanned hospitalization. REM-HF is registered with ISRCTN (96536028). The mean age of the population was 70 years (range 23–98); 86% were male. Patients were followed for a median of 2.8 years (range 0–4.3 years) completing on 31 January 2016. Patient adherence was high with a drop out of 4.3% over the course of the study. The incidence of the primary endpoint did not differ significantly between active RM and UC groups, which occurred in 42.4 and 40.8% of patients, respectively [hazard ratio 1.01; 95% confidence interval (CI) 0.87–1.18; P = 0.87]. There were no significant differences between the two groups with respect to any of the secondary endpoints or the time to the primary endpoint components. Conclusion Among patients with heart failure and a CIED, RM using weekly downloads and a formalized follow up approach does not improve outcomes. PMID:28575235

Methylphenidate Transdermal System in Adults with Past Stimulant Misuse: An Open-Label Trial

ERIC Educational Resources Information Center

McRae-Clark, Aimee L.; Brady, Kathleen T.; Hartwell, Karen J.; White, Kathleen; Carter, Rickey E.

2011-01-01

Objective: This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. Method: The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the…

Is serial determination of inspiratory muscle strength a useful prognostic marker in chronic heart failure?

PubMed

Frankenstein, Lutz; Meyer, Franz Joachim; Sigg, Caroline; Nelles, Manfred; Schellberg, Dieter; Remppis, Andrew; Katus, Hugo A; Zugck, Christian

2008-04-01

Little data exists on the prognostic role of inspiratory muscle strength (PImax) in chronic heart failure (CHF). Training studies, however, frequently use it as a therapeutic target and surrogate marker for prognosis. The prognostic value of changes of PImax that allow this extrapolation is unknown. Patients with stable CHF were prospectively included and 1-year and all-time event rates recorded for endpoint analysis. In 158 patients (85% men; New York Heart Association functional class: 2.4+/-0.6), PImax was measured along with clinical evaluations at two visits, the initial visit and the second visit, 6.4+/-1.4 months apart. The mean follow-up was 59+/-34 months. Overall, 59 patients (37%) reached the primary endpoint of death or hospitalization (endpoint positive), and overall mortality rate (secondary endpoint) was 26% (42 patients). PImax did not differ between endpoint-negative and endpoint-positive patients, both at the initial and at the second visit (8.3+/-5.6 vs. 7.3+/-3.4 kPa and 8.8+/-6.0 vs. 7.9+/-3.6 kPa, respectively; P=NS), and both groups showed increased PImax (0.6+/-2.6 vs. 0.6+/-2.8 kPa; P=NS). Cox analyses found neither the absolute nor the relative change of PImax to be significant predictors for the primary and secondary endpoints (P=NS for both), both for the 1-year and for the all-time event rates. Endpoint rates did not differ between patients showing increasing or decreasing PImax (P=NS; relative risk (RR): 0.77; 95% confidence interval: 0.47-1.27). Trials focusing on inspiratory muscle function should use the actual levels of PImax as a surrogate marker to represent prognostic information, rather than relative or absolute changes. This is the first study to investigate the prognostic information of the changes of PImax over time, regarding both short-term and long-term morbidity and mortality in patients with stable CHF.

Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial.

PubMed

Torre-Amione, Guillermo; Anker, Stefan D; Bourge, Robert C; Colucci, Wilson S; Greenberg, Barry H; Hildebrandt, Per; Keren, Andre; Motro, Michael; Moyé, Lemuel A; Otterstad, Jan Erik; Pratt, Craig M; Ponikowski, Piotr; Rouleau, Jean Lucien; Sestier, Francois; Winkelmann, Bernhard R; Young, James B

2008-01-19

Evidence suggests that inflammatory mediators contribute to development and progression of chronic heart failure. We therefore tested the hypothesis that immunomodulation might counteract this pathophysiological mechanism in patients. We did a double-blind, placebo-controlled study of a device-based non-specific immunomodulation therapy (IMT) in patients with New York Heart Association (NYHA) functional class II-IV chronic heart failure, left ventricular (LV) systolic dysfunction, and hospitalisation for heart failure or intravenous drug therapy in an outpatient setting within the past 12 months. Patients were randomly assigned to receive IMT (n=1213) or placebo (n=1213) by intragluteal injection on days 1, 2, 14, and every 28 days thereafter. Primary endpoint was the composite of time to death from any cause or first hospitalisation for cardiovascular reasons. The study continued until 828 primary endpoint events had accrued and all study patients had been treated for at least 22 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00111969. During a mean follow-up of 10.2 months, there were 399 primary events in the IMT group and 429 in the placebo group (hazard ratio 0.92; 95% CI 0.80-1.05; p=0.22). In two prespecified subgroups of patients--those with no history of previous myocardial infarction (n=919) and those with NYHA II heart failure (n=689)--IMT was associated with a 26% (0.74; 0.57-0.95; p=0.02) and a 39% (0.61; 95% CI 0.46-0.80; p=0.0003) reduction in the risk of primary endpoint events, respectively. Non-specific immunomodulation may have a role as a potential treatment for a large segment of the heart failure population, which includes patients without a history of myocardial infarction (irrespective of their functional NYHA class) and patients within NYHA class II.

If the results of an article are noteworthy, read the entire article; do not rely on the abstract alone.

PubMed

Dal-Ré, R; Castell, M V; García-Puig, J

2015-11-01

Clinicians typically update their knowledge by reading articles on the Internet. Easy access to the articles' abstracts and a lack of time to access other information sources creates a risk that therapeutic or diagnostic decisions will be made after reading just the abstracts. Occasionally, however, the abstracts of articles from clinical trials that have not obtained statistically significant differences in the primary study endpoint have reported other positive results, for example, of a secondary endpoint or a subgroup analysis. The article, however, correctly reports all results, including those of the primary endpoint. In the abstract, the safety information of the experimental treatment is usually deficient. The whole article should be read if a clinical decision is to be made. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Changing the endpoints for determining effective obesity management.

PubMed

Ross, Robert; Blair, Steve; de Lannoy, Louise; Després, Jean-Pierre; Lavie, Carl J

2015-01-01

Health authorities worldwide recommend weight loss as a primary endpoint for effective obesity management. Despite a growing public awareness of the importance of weight loss and the spending of billions of dollars by Americans in attempts to lose weight, obesity prevalence continues to rise. In this report we argue that effective obesity management in today's environment will require a shift in focus from weight loss as the primary endpoint, to improvements in the causal behaviors; diet and exercise/physical activity (PA). We reason that increases in PA combined with a balanced diet are associated with improvement in many of the intermediate risk factors including cardiorespiratory fitness (CRF) associated with obesity despite minimal or no weight loss. Consistent with this notion, we suggest that a focus on healthy behaviors for the prevention of additional weight gain may be an effective way of managing obesity in the short term. Copyright © 2014 Elsevier Inc. All rights reserved.

Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.

PubMed

Stone, A M; Bushnell, W; Denne, J; Sargent, D J; Amit, O; Chen, C; Bailey-Iacona, R; Helterbrand, J; Williams, G

2011-08-01

Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval. These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions. (1) In the assessment of PFS, there is a critical distinction between measurement error that results from random variation, which by itself tends to attenuate treatment effect, versus bias which increases the probability of a false negative or false positive finding. Investigator bias can be detected by auditing a random sample of patients by blinded, independent, central review (BICR). (2) ITT analyses generally resulted in smaller treatment effects (HRs closer to 1) than analyses that censor patients for potentially informative events (such as starting other anti-cancer therapy). (3) Interval censored analyses (ICA) are more robust to time-evaluation bias than the log-rank test. A sample based BICR audit may be employed in open or partially blinded trials and should not be required in true double-blind trials. Patients should be followed until progression even if they have discontinued treatment to be consistent with the ITT principle. ICAs should be a standard sensitivity analysis to assess time-evaluation bias. Implementation of these recommendations would standardize and in many cases simplify phase III oncology clinical trials that use a PFS primary end-point. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Effect of an EDTA-based Chelation Regimen on Patients with Diabetes and Prior Myocardial Infarction in TACT

PubMed Central

Escolar, Esteban; Lamas, Gervasio A.; Mark, Daniel B.; Boineau, Robin; Goertz, Christine; Rosenberg, Yves; Nahin, Richard L.; Ouyang, Pamela; Rozema, Theodore; Magaziner, Allan; Nahas, Richard; Lewis, Eldrin F.; Lindblad, Lauren; Lee, Kerry L.

2014-01-01

Background The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an ethylene diamine tetraacetic acid (EDTA-based) infusion regimen in patients 50 years or older with prior myocardial infarction (MI). Diabetes prior to enrollment was a pre-specified subgroup. Methods and Results Patients received 40 infusions of EDTA chelation or placebo. 633 (37%) had diabetes (322 EDTA, 311 placebo). EDTA reduced the primary endpoint (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina) [25% vs 38%, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.44, 0.79), p<0.001] over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI (0.39, 0.88), adjusted p=0.002). All-cause mortality was reduced by EDTA chelation [10% vs 16%, HR 0.57, 95% CI (0.36, 0.88) p=0.011], as was the secondary endpoint (cardiovascular death, reinfarction, or stroke) [11% vs 17% HR 0.60, 95% CI (0.39, 0.91), p=0.017]. After adjusting for multiple subgroups, however, those results were no longer significant. The number needed to treat to reduce one primary endpoint was 6.5 over 5 years (95% CI (4.4, 12.7). There was no reduction in events in non-diabetics (n=1075, p=0.877), resulting in a treatment by diabetes interaction (p=0.004). Conclusions Post-MI diabetic patients age 50 or older demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients. PMID:24254885

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

PubMed Central

Murphy, William; Abbas, Richat; Chiles, Deborah; England, Richard D.; Ramaker, Sara; Wajsbrot, Dalia B.

2018-01-01

Abstract Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25–50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7–11 years) and adolescents (12–17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale–Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions–Severity, Clinical Global Impressions–Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, −22.6 [1.17]) or fluoxetine (−24.8 [1.17]; placebo, −23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25–50 mg/d was generally safe and well tolerated in children and adolescents in this study. PMID:29189044

Studies on potassium chlorate as a primary oxidimetric reagent.

PubMed

Murty, C R; Rao, G G

1972-01-01

Conditions have been established for the use of potassium chlorate as a primary oxidizing agent in the direct titration of vanadium(III), tin(II) and titanium(III) with visual or potentiometric end-points.

The intermediate endpoint effect in logistic and probit regression

PubMed Central

MacKinnon, DP; Lockwood, CM; Brown, CH; Wang, W; Hoffman, JM

2010-01-01

Background An intermediate endpoint is hypothesized to be in the middle of the causal sequence relating an independent variable to a dependent variable. The intermediate variable is also called a surrogate or mediating variable and the corresponding effect is called the mediated, surrogate endpoint, or intermediate endpoint effect. Clinical studies are often designed to change an intermediate or surrogate endpoint and through this intermediate change influence the ultimate endpoint. In many intermediate endpoint clinical studies the dependent variable is binary, and logistic or probit regression is used. Purpose The purpose of this study is to describe a limitation of a widely used approach to assessing intermediate endpoint effects and to propose an alternative method, based on products of coefficients, that yields more accurate results. Methods The intermediate endpoint model for a binary outcome is described for a true binary outcome and for a dichotomization of a latent continuous outcome. Plots of true values and a simulation study are used to evaluate the different methods. Results Distorted estimates of the intermediate endpoint effect and incorrect conclusions can result from the application of widely used methods to assess the intermediate endpoint effect. The same problem occurs for the proportion of an effect explained by an intermediate endpoint, which has been suggested as a useful measure for identifying intermediate endpoints. A solution to this problem is given based on the relationship between latent variable modeling and logistic or probit regression. Limitations More complicated intermediate variable models are not addressed in the study, although the methods described in the article can be extended to these more complicated models. Conclusions Researchers are encouraged to use an intermediate endpoint method based on the product of regression coefficients. A common method based on difference in coefficient methods can lead to distorted conclusions regarding the intermediate effect. PMID:17942466

Comparison of design strategies for a three-arm clinical trial with time-to-event endpoint: Power, time-to-analysis, and operational aspects.

PubMed

Asikanius, Elina; Rufibach, Kaspar; Bahlo, Jasmin; Bieska, Gabriele; Burger, Hans Ulrich

2016-11-01

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three-arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time-to-event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three-arm clinical trial with a time-to-event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking.

PubMed

Huffman, Cynthia; Stacey, Brett R; Tuchman, Michael; Burbridge, Claire; Li, Chunming; Parsons, Bruce; Pauer, Lynne; Scavone, Joseph M; Behar, Regina; Yurkewicz, Lorraine

2015-11-01

This randomized, double-blind, placebo-controlled, multicenter, 2-period crossover study (two 6-week treatment periods separated by a 2-week washout period) evaluated the efficacy and safety of pregabalin (150 to 300 mg/d) for treatment of pain and pain on walking in patients with painful diabetic peripheral neuropathy (DPN) who experienced pain while walking. Co-primary efficacy endpoints were: (1) mean pain score (last 7 daily pain diary scores, 0 to 10 numeric rating scale at end of each treatment period) and (2) DPN pain on walking (0 to 10 numeric rating scale immediately after walking 50 feet [15.2 m] on flat surface). Secondary endpoints included other pain parameters, patient-reported sleep, health-related quality of life, and safety measures. Two hundred three patients were treated (pregabalin, n=198; placebo, n=186), with no statistically significant treatment difference for pregabalin versus placebo in the co-primary efficacy endpoints, mean DPN pain (P=0.0656) and mean DPN pain on walking (P=0.412). A carryover effect was observed. Analysis of co-primary endpoints for period 1 showed significant treatment difference for DPN pain (P=0.034) and DPN pain on walking (P=0.001). Treatment with pregabalin resulted in significant improvements versus placebo on prespecified patient global impression of change (end of period 1; P=0.002), and sleep interference rating scale (end of period 2; P=0.011). Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 13 (6.6%) pregabalin patients versus 5 (2.7%) placebo patients. Failure to meet the co-primary objectives may be related to carryover effect from period 1 to period 2, lower pregabalin dose (150 to 300 mg/d), and/or placebo response in painful DPN.

Incidence and predictors of permanent pacemaker implantation following treatment with the repositionable Lotus™ transcatheter aortic valve.

PubMed

Zaman, Sarah; McCormick, Liam; Gooley, Robert; Rashid, Hashrul; Ramkumar, Satish; Jackson, Damon; Hui, Samuel; Meredith, Ian T

2017-07-01

To determine the incidence and predictors of permanent pacemaker (PPM) requirement following transcatheter aortic valve replacement (TAVR) with the mechanically expanded Lotus TM Valve System (Boston Scientific). Pacemaker implantation is the most common complication following TAVR. Predictors of pacing following TAVR with the Lotus valve have not been systematically assessed. Consecutive patients with severe aortic stenosis who underwent Lotus valve implantation were prospectively recruited at a single-centre. Patients with a pre-existing PPM were excluded. Baseline ECG, echocardiographic and multiple detector computed tomography as well as procedural telemetry and depth of implantation were independently analyzed in a blinded manner. The primary endpoint was 30-day incidence of pacemaker requirement (PPM implantation or death while pacing-dependent). Multivariate analysis was performed to identify independent predictors of the primary endpoint. A total of 104 consecutive patients underwent TAVR with the Lotus valve with 9/104 (9%) with a pre-existing PPM excluded. New or worsened procedural LBBB occurred in 78%. Thirty-day incidence of the primary pacing endpoint was 28%. The most common indication for PPM implantation was complete heart block (CHB) (69%). Independent predictors of the primary endpoint included pre-existing RBBB (hazard ratio [HR] 2.8, 95% CI 1.1-7.0; P = 0.032) and depth of implantation below the noncoronary cusp (NCC) (HR 2.4, 95% CI 1.0-5.7; P = 0.045). Almost a third of Lotus valve recipients require pacemaker implantation within 30 days. The presence of pre-existing RBBB and the depth of prosthesis implantation below the NCC were significant pacing predictors. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

PubMed

Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

2015-02-10

For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into FDA approvals for rare disease therapies. The focus of this paper is on the situation in the Unites States, but the recommendations are reasonably applicable to any jurisdiction.

Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial.

PubMed

Dekkers, Tanja; Prejbisz, Aleksander; Kool, Leo J Schultze; Groenewoud, Hans J M M; Velema, Marieke; Spiering, Wilko; Kołodziejczyk-Kruk, Sylwia; Arntz, Mark; Kądziela, Jacek; Langenhuijsen, Johannes F; Kerstens, Michiel N; van den Meiracker, Anton H; van den Born, Bert-Jan; Sweep, Fred C G J; Hermus, Ad R M M; Januszewicz, Andrzej; Ligthart-Naber, Alike F; Makai, Peter; van der Wilt, Gert-Jan; Lenders, Jacques W M; Deinum, Jaap

2016-09-01

The distinction between unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia as causes of primary aldosteronism is usually made by adrenal CT or by adrenal vein sampling (AVS). Whether CT or AVS represents the best test for diagnosis remains unknown. We aimed to compare the outcome of CT-based management with AVS-based management for patients with primary aldosteronism. In a randomised controlled trial, we randomly assigned patients with aldosteronism to undergo either adrenal CT or AVS to determine the presence of aldosterone-producing adenoma (with subsequent treatment consisting of adrenalectomy) or bilateral adrenal hyperplasia (subsequent treatment with mineralocorticoid receptor antagonists). The primary endpoint was the intensity of drug treatment for obtaining target blood pressure after 1 year of follow-up, in the intention-to-diagnose population. Intensity of drug treatment was expressed as daily defined doses. Key secondary endpoints included biochemical outcome in patients who received adrenalectomy, health-related quality of life, cost-effectiveness, and adverse events. This trial is registered with ClinicalTrials.gov, number NCT01096654. We recruited 200 patients between July 6, 2010, and May 30, 2013. Of the 184 patients that completed follow-up, 92 received CT-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist) and 92 received AVS-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist). We found no differences in the intensity of antihypertensive medication required to control blood pressure between patients with CT-based treatment and those with AVS-based treatment (median daily defined doses 3·0 [IQR 1·0-5·0] vs 3·0 [1·1-5·9], p=0·52; median number of drugs 2 [IQR 1-3] vs 2 [1-3], p=0·87). Target blood pressure was reached in 39 (42%) patients and 41 (45%) patients, respectively (p=0·82). On secondary endpoints we found no differences in health-related quality of life (median RAND-36 physical scores 52·7 [IQR 43·9-56·8] vs 53·2 [44·0-56·8], p=0·83; RAND-36 mental scores 49·8 [43·1-54·6] vs 52·7 [44·9-55·5], p=0·17) for CT-based and AVS-based treatment. Biochemically, 37 (80%) of patients with CT-based adrenalectomy and 41 (89%) of those with AVS-based adrenalectomy had resolved hyperaldosteronism (p=0·25). A non-significant mean difference of 0·05 (95% CI -0·04 to 0·13) in quality-adjusted life-years (QALYs) was found to the advantage of the AVS group, associated with a significant increase in mean health-care costs of €2285 per patient (95% CI 1323-3248). At a willingness-to-pay value of €30 000 per QALY, the probability that AVS compared with CT constitutes an efficient use of health-care resources in the diagnostic work-up of patients with primary aldosteronism is less than 0·2. There was no difference in adverse events between groups (159 events of which nine were serious vs 187 events of which 12 were serious) for CT-based and AVS-based treatment. Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. This finding challenges the current recommendation to perform AVS in all patients with primary aldosteronism. Netherlands Organisation for Health Research and Development-Medical Sciences, Institute of Cardiology, Warsaw. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of Primary Tumor Location on First-line Bevacizumab or Cetuximab in Metastatic Colorectal Cancer.

PubMed

Snyder, Matthew; Bottiglieri, Sal; Almhanna, Khaldoun

2018-01-01

Colorectal cancer is one of the most common malignancies in the United States, with a large proportion of patients presenting with metastatic disease or developing a recurrence. Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and irinotecan-based regimens which can be considered for first-line therapy. However, many significant questions remain as to which agent reflects best practice. Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease- and patient-related factors, addressing the paucity of evidence that currently exists in this area and contributing to current literature and clinical practices. The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment- Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient- and disease-related factors affecting PFS and OS. While there were trends towards improved OS in patients with left-sided primary tumors (n=57) compared to those with right-sided disease (n=23), there were no significant differences between the two groups in either primary endpoint. While no differences were found for patients with left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort (n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21-53 months) and right-sided (median first PFS = 13 months, 95% CI 9-17 months; median OS = 37 months, 95% CI 22-52 months) disease. These results raised questions regarding the true significance of primary tumor location when selecting bevacizumab or cetuximab for first-line therapy, particularly the current thought of using cetuximab for left-sided tumors. While the superiority of bevacizumab over cetuximab in rightsided disease remained evident upon comparison of our analysis with historical controls, survival outcomes with the agent in our analysis appeared to be similar to that of cetuximab in CRYSTAL, FIRE- 3, and CALGB/SWOG 80405 in left-sided disease. Further study is required to determine if bevacizumab truly does produce similar outcomes to cetuximab in left-sided primary tumors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[The PreFord Study. A prospective cohort study to evaluate the risk of a cardiovascular event (overall-collective) as well as a prospective, randomized, controlled, multicentre clinical intervention study (high-risk-collective) on primary prevention of cardiovascular diseases in the Ford Motor Company employees in Germany].

PubMed

Gysan, D B; Latsch, J; Bjarnason-Wehrens, B; Albus, C; Falkowski, G; Herold, G; Mey, E; Heinzler, R; Montiel, G; Schneider, C A; Stützer, H; Türk, S; Weisbrod, M; Predel, H G

2004-02-01

The PreFord Study is a multicenter prospective cohort study to evaluate guideline based risk management on primary prevention of cardiovascular diseases. Furthermore a randomised controlled trial (RCT) will be designed to analyse the effect of a special intervention program. 40,000 employees of the Ford Motor Company, Visteon Company and Deutz Company in Germany will be included, monitored for ten years and the following primary endpoints will be investigated: 1. evaluation and comparison of established and newly developed risk-scores, 2. the relative impact of single and combined cardiovascular risk factors on cardiovascular diseases, 3. the influence of a novel occupationally integrated ambulant rehabilitation program in combination with a guideline oriented optimal drug therapy within a high risk group on the primary endpoint: risk reduction by, 4. the influence of this intervention on secondary endpoints: death, myocardial infarction and stroke, combined appearance of angina pectoris and hospitalisation, occurrence of cerebral circulatory disorder and hospitalisation, occurrence of peripheral occlusive arterial disease and hospitalisation and single cardiovascular risk factors and cost-benefit-analysis. Beginning with an cross sectional study there will be a systemic screening of cardiovascular risk profiles, of anthropometric data and different lifestyle-factors. Based on these data participants will be differentiated into three risk-groups according to the risk score of the European Society of Cardiology (risk of a lethal primary acute cardiovascular event: I < or = 1%; II > 1-< 5% and III > or = 5%). In the following longitudinal study different strategies will be applied: Group I: low risk (< 0.5% per year): repetition of the investigation after five and ten years. Group II: middle risk, (0.6% to 1.4% per year), repetition of the investigation every two years, instruction of the patients general practitioner (GP) with respect to a risk factor oriented and evidence based treatment. Group III: high risk, (> 1.5% per year or >15% within the next 10 years) will be randomised into two interventional groups. The first one, the intervention-group "PreFord" will perform an occupational integrated rehabilitation program (2,5-3 hours twice a week, for 15 weeks according to the BAR guidelines) with a following engagement in heart-groups and an annual repetition of the check-ups. The second group, the "classic" intervention-group will be treated evidence based in cooperation with their GP. As a result of this long term interventional study efficient, area wide implementable and economically feasible prevention concepts with special regards to operational healthcare will be developed and evaluated. Core elements will be exercise- and lifestyle-oriented concepts as well as guideline-based pharmacotherapy.

[Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology].

PubMed

Vonend, Oliver; Böhm, Michael; Eckert, Siegfried; Hausberg, Martin; Rittger, Harald; Rump, Lars-Christian; Schmieder, Roland; Schulte, Karl-Ludwig; Schunkert, Heribert; Uder, Michael; Veelken, Roland; Vorwerk, Dierk; Weil, Joachim; Wenzel, Ulrich; Mahfoud, Felix

2015-03-01

Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN-3 trial did meet its primary safety endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation. © Georg Thieme Verlag KG Stuttgart · New York.

The preventive phase I trial with the HIV-1 Tat-based vaccine.

PubMed

Ensoli, Barbara; Fiorelli, Valeria; Ensoli, Fabrizio; Lazzarin, Adriano; Visintini, Raffaele; Narciso, Pasquale; Di Carlo, Aldo; Tripiciano, Antonella; Longo, Olimpia; Bellino, Stefania; Francavilla, Vittorio; Paniccia, Giovanni; Arancio, Angela; Scoglio, Arianna; Collacchi, Barbara; Ruiz Alvarez, Maria Josè; Tambussi, Giuseppe; Tassan Din, Chiara; Palamara, Guido; Latini, Alessandra; Antinori, Andrea; D'Offizi, Gianpiero; Giuliani, Massimo; Giulianelli, Marina; Carta, Maria; Monini, Paolo; Magnani, Mauro; Garaci, Enrico

2009-12-11

The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials based on its role in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune response with the asymptomatic stage as well as on its sequence conservation among HIV clades. A randomized, double blind, placebo-controlled phase I study (ISS P-001) was conducted in healthy adult volunteers without identifiable risk of HIV infection. Tat was administered 5 times monthly, subcute in alum or intradermic alone at 7.5 microg, 15 microg or 30 microg, respectively (ClinicalTrials.gov identifier: NCT00529698). Vaccination with Tat resulted to be safe and well tolerated (primary endpoint) both locally and systemically. In addition, Tat induced both Th1 and Th2 type specific immune responses in all subjects (secondary endpoint) with a wide spectrum of functional antibodies that are rarely seen in natural infection, providing key information for further clinical development of the Tat vaccine candidate.

Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J; Blocksome, Michael E; Ratterman, Joseph D; Smith, Brian E

2014-02-11

Endpoint-based parallel data processing in a parallel active messaging interface ('PAMI') of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective opeartion through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

2014-08-12

Endpoint-based parallel data processing in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective operation through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

Clinical endpoints in the controlled human challenge model for Shigella: A call for standardization and the development of a disease severity score

PubMed Central

Lynen, Amanda; Riddle, Mark S.; Talaat, Kawsar; Sack, David; Gutiérrez, Ramiro L.; McKenzie, Robin; DeNearing, Barbara; Feijoo, Brittany; Kaminski, Robert W.; Taylor, David N.; Kirkpatrick, Beth D.; Bourgeois, A. Louis

2018-01-01

Background Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary. Methods Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events. Results Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum. Conclusion Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints. PMID:29590182

Head-Elevated Patient Positioning Decreases Complications of Emergent Tracheal Intubation in the Ward and Intensive Care Unit.

PubMed

Khandelwal, Nita; Khorsand, Sarah; Mitchell, Steven H; Joffe, Aaron M

2016-04-01

Based on the data from elective surgical patients, positioning patients in a back-up head-elevated position for preoxygenation and tracheal intubation can improve patient safety. However, data specific to the emergent setting are lacking. We hypothesized that back-up head-elevated positioning would be associated with a decrease in complications related to tracheal intubation in the emergency room environment. This retrospective study was approved by the University of Washington Human Subjects Division (Seattle, WA). Eligible patients included all adults undergoing emergent tracheal intubation outside of the operating room by the anesthesiology-based airway service at 2 university-affiliated teaching hospitals. All intubations were through direct laryngoscopy for an indication other than full cardiopulmonary arrest. Patient characteristics and details of the intubation procedure were derived from the medical record. The primary study endpoint was the occurrence of a composite of any intubation-related complication: difficult intubation, hypoxemia, esophageal intubation, or pulmonary aspiration. Multivariable logistic regression was used to estimate the odds of the primary endpoint in the supine versus back-up head-elevated positions with adjustment for a priori-defined potential confounders (body mass index and a difficult intubation prediction score [Mallampati, obstructive sleep Apnea, Cervical mobility, mouth Opening, Coma, severe Hypoxemia, and intubation by a non-Anesthesiologist score]). Five hundred twenty-eight patients were analyzed. Overall, at least 1 intubation-related complication occurred in 76 of 336 (22.6%) patients managed in the supine position compared with 18 of 192 (9.3%) patients managed in the back-up head-elevated position. After adjusting for body mass index and the Mallampati, obstructive sleep Apnea, Cervical mobility, mouth Opening, Coma, severe Hypoxemia, and intubation by a non-Anesthesiologist score, the odds of encountering the primary endpoint during an emergency tracheal intubation in a back-up head-elevated position was 0.47 (95% confidence interval, 0.26-0.83; P = 0.01). Placing patients in a back-up head-elevated position, compared with supine position, during emergency tracheal intubation was associated with a reduced odds of airway-related complications.

The Comparison of the Outcomes between Primary PCI, Fibrinolysis, and No Reperfusion in Patients ≥ 75 Years Old with ST-Segment Elevation Myocardial Infarction: Results from the Chinese Acute Myocardial Infarction (CAMI) Registry.

PubMed

Peiyuan, He; Jingang, Yang; Haiyan, Xu; Xiaojin, Gao; Ying, Xian; Yuan, Wu; Wei, Li; Yang, Wang; Xinran, Tang; Ruohua, Yan; Chen, Jin; Lei, Song; Xuan, Zhang; Rui, Fu; Yunqing, Ye; Qiuting, Dong; Hui, Sun; Xinxin, Yan; Runlin, Gao; Yuejin, Yang

2016-01-01

Only a few randomized trials have analyzed the clinical outcomes of elderly ST-segment elevation myocardial infarction (STEMI) patients (≥ 75 years old). Therefore, the best reperfusion strategy has not been well established. An observational study focused on clinical outcomes was performed in this population. Based on the national registry on STEMI patients, the in-hospital outcomes of elderly patients with different reperfusion strategies were compared. The primary endpoint was defined as death. Secondary endpoints included recurrent myocardial infarction, ischemia driven revascularization, myocardial infarction related complications, and major bleeding. Multivariable regression analysis was performed to adjust for the baseline disparities between the groups. Patients who had primary percutaneous coronary intervention (PCI) or fibrinolysis were relatively younger. They came to hospital earlier, and had lower risk of death compared with patients who had no reperfusion. The guideline recommended medications were more frequently used in patients with primary PCI during the hospitalization and at discharge. The rates of death were 7.7%, 15.0%, and 19.9% respectively, with primary PCI, fibrinolysis, and no reperfusion (P < 0.001). Patients having primary PCI also had lower rates of heart failure, mechanical complications, and cardiac arrest compared with fibrinolysis and no reperfusion (P < 0.05). The rates of hemorrhage stroke (0.3%, 0.6%, and 0.1%) and other major bleeding (3.0%, 5.0%, and 3.1%) were similar in the primary PCI, fibrinolysis, and no reperfusion group (P > 0.05). In the multivariable regression analysis, primary PCI outweighs no reperfusion in predicting the in-hospital death in patients ≥ 75 years old. However, fibrinolysis does not. Early reperfusion, especially primary PCI was safe and effective with absolute reduction of mortality compared with no reperfusion. However, certain randomized trials were encouraged to support the conclusion.

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial.

PubMed

Soininen, Hilkka; Solomon, Alina; Visser, Pieter Jelle; Hendrix, Suzanne B; Blennow, Kaj; Kivipelto, Miia; Hartmann, Tobias

2017-12-01

Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial. LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was -0·028 (SD 0·453) in the active group and -0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI -0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of -0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. European Commission 7th Framework Programme. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Ataluren treatment of patients with nonsense mutation dystrophinopathy.

PubMed

Bushby, Katharine; Finkel, Richard; Wong, Brenda; Barohn, Richard; Campbell, Craig; Comi, Giacomo P; Connolly, Anne M; Day, John W; Flanigan, Kevin M; Goemans, Nathalie; Jones, Kristi J; Mercuri, Eugenio; Quinlivan, Ros; Renfroe, James B; Russman, Barry; Ryan, Monique M; Tulinius, Mar; Voit, Thomas; Moore, Steven A; Lee Sweeney, H; Abresch, Richard T; Coleman, Kim L; Eagle, Michelle; Florence, Julaine; Gappmaier, Eduard; Glanzman, Allan M; Henricson, Erik; Barth, Jay; Elfring, Gary L; Reha, Allen; Spiegel, Robert J; O'donnell, Michael W; Peltz, Stuart W; Mcdonald, Craig M

2014-10-01

Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. Copyright © 2014 Wiley Periodicals, Inc.

Comparative effectiveness of vildagliptin in combination with other oral anti-diabetes agents in usual-care conditions: the EDGE-Latin America study.

PubMed

Mendivil, Carlos O; Márquez-Rodríguez, Eduardo; Angel, Iván D; Paz, Gustavo; Rodríguez, Cruz; Almada, Jorge; Szyskowsky, Ofelia

2014-09-01

To assess the proportion of patients on vildagliptin add-on dual therapy who respond to treatment over a 12 month follow-up, relative to comparator oral anti-diabetes dual therapy, in a usual care setting. Participants were patients with type 2 diabetes (T2DM) aged 18 years and older from 311 centers in Argentina, Colombia, Ecuador, Mexico and Venezuela. Patients were taking monotherapy with an oral anti-diabetes drug (OAD), and were prescribed a new add-on OAD based on the judgment of their personal physician. According to this choice, patients were assigned to one of the two cohorts: vildagliptin or comparator OADs. The primary endpoint was the proportion of patients achieving an A1c drop >0.3% without edema, hypoglycemia, weight gain or discontinuation due to gastrointestinal (GI) events. The secondary endpoint was the proportion of patients with baseline A1c ≥7% who reached the goal of an A1c <7% without hypoglycemia or weight gain. The per-protocol population (a subset of the intention-to-treat population that excluded patients with pre-specified protocol deviations) comprised 3773 patients, 3002 in the vildagliptin cohort and 771 in the comparator cohort. The proportion of patients reaching the primary endpoint was higher in the vildagliptin cohort (60.3%) than the comparator cohort (50.7%), OR 1.48 (95% CI: 1.25-1.73). The same was observed for the secondary endpoint (44.8 versus 33.1%) OR 1.64 (95% CI: 1.37-1.98). The incidence of adverse events was low and similar between treatment cohorts. In a usual care setting, patients treated with a vildagliptin combination succeeded in lowering A1c to <7%, without weight gain, hypoglycemia or peripheral edema more often than patients treated with comparator combinations, without increased risk of adverse events. Key limitations are the observational nature of the study and its relatively limited 12 month timeframe.

A perfect correlate does not a surrogate make

PubMed Central

Baker, Stuart G; Kramer, Barnett S

2003-01-01

Background There is common belief among some medical researchers that if a potential surrogate endpoint is highly correlated with a true endpoint, then a positive (or negative) difference in potential surrogate endpoints between randomization groups would imply a positive (or negative) difference in unobserved true endpoints between randomization groups. We investigate this belief when the potential surrogate and unobserved true endpoints are perfectly correlated within each randomization group. Methods We use a graphical approach. The vertical axis is the unobserved true endpoint and the horizontal axis is the potential surrogate endpoint. Perfect correlation within each randomization group implies that, for each randomization group, potential surrogate and true endpoints are related by a straight line. In this scenario the investigator does not know the slopes or intercepts. We consider a plausible example where the slope of the line is higher for the experimental group than for the control group. Results In our example with unknown lines, a decrease in mean potential surrogate endpoints from control to experimental groups corresponds to an increase in mean true endpoint from control to experimental groups. Thus the potential surrogate endpoints give the wrong inference. Similar results hold for binary potential surrogate and true outcomes (although the notion of correlation does not apply). The potential surrogate endpointwould give the correct inference if either (i) the unknown lines for the two group coincided, which means that the distribution of true endpoint conditional on potential surrogate endpoint does not depend on treatment group, which is called the Prentice Criterion or (ii) if one could accurately predict the lines based on data from prior studies. Conclusion Perfect correlation between potential surrogate and unobserved true outcomes within randomized groups does not guarantee correct inference based on a potential surrogate endpoint. Even in early phase trials, investigators should not base conclusions on potential surrogate endpoints in which the only validation is high correlation with the true endpoint within a group. PMID:12962545

Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices.

PubMed

Martin, David T; Bersohn, Malcolm M; Waldo, Albert L; Wathen, Mark S; Choucair, Wassim K; Lip, Gregory Y H; Ip, John; Holcomb, Richard; Akar, Joseph G; Halperin, Jonathan L

2015-07-07

Atrial tachyarrhythmias (ATs) detected by implanted devices are often atrial fibrillation or flutter (AF) associated with stroke. We hypothesized that introduction and termination of anticoagulation based upon AT monitoring would reduce both stroke and bleeding. We randomized 2718 patients with dual-chamber and biventricular defibrillators to start and stop anticoagulation based on remote rhythm monitoring vs. usual office-based follow-up with anticoagulation determined by standard clinical criteria. The primary analysis compared the composite endpoint of stroke, systemic embolism, and major bleeding with the two strategies. The trial was stopped after 2 years median follow-up based on futility of finding a difference in primary endpoints between groups. A total of 945 patients (34.8%) developed AT, 264 meeting study anticoagulation criteria. Adjudicated atrial electrograms confirmed AF in 91%; median time to initiate anticoagulation was 3 vs. 54 days in the intervention and control groups, respectively (P < 0.001). Primary events (2.4 vs. 2.3 per 100 patient-years) did not differ between groups (HR 1.06; 95% CI 0.75-1.51; P = 0.732). Major bleeding occurred at 1.6 vs. 1.2 per 100 patient-years (HR 1.39; 95% CI 0.89-2.17; P = 0.145). In patients with AT, thromboembolism rates were 1.0 vs. 1.6 per 100 patient-years (relative risk -35.3%; 95% CI -70.8 to 35.3%; P = 0.251). Although AT burden was associated with thromboembolism, there was no temporal relationship between AT and stroke. In patients with implanted defibrillators, the strategy of early initiation and interruption of anticoagulation based on remotely detected AT did not prevent thromboembolism and bleeding. IMPACT ClinicalTrials.gov identifier: NCT00559988 ( http://clinicaltrials.gov/ct2/show/NCT00559988?term=NCT00559988&rank=1 ). Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Randomised controlled trial of mesalazine in IBS

PubMed Central

Barbara, Giovanni; Cremon, Cesare; Annese, Vito; Basilisco, Guido; Bazzoli, Franco; Bellini, Massimo; Benedetti, Antonio; Benini, Luigi; Bossa, Fabrizio; Buldrini, Paola; Cicala, Michele; Cuomo, Rosario; Germanà, Bastianello; Molteni, Paola; Neri, Matteo; Rodi, Marcello; Saggioro, Alfredo; Scribano, Maria Lia; Vecchi, Maurizio; Zoli, Giorgio; Corinaldesi, Roberto; Stanghellini, Vincenzo

2016-01-01

Objective Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. Design We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. Results A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI −12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI −2.7% to 26.0%) and 5.9% (p=0.404; 95% CI −7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. Conclusions Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. Trial registration number ClincialTrials.gov number, NCT00626288. PMID:25533646

NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

PubMed

Palmieri, C; Cleator, S; Kilburn, L S; Kim, S B; Ahn, S-H; Beresford, M; Gong, G; Mansi, J; Mallon, E; Reed, S; Mousa, K; Fallowfield, L; Cheang, M; Morden, J; Page, K; Guttery, D S; Rghebi, B; Primrose, L; Shaw, J A; Thompson, A M; Bliss, J M; Coombes, R C

2014-12-01

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE₁₀₀C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

In situ microbiota distinguished primary anthropogenic stressor in freshwater sediments.

PubMed

Xie, Yuwei; Floehr, Tilman; Zhang, Xiaowei; Xiao, Hongxia; Yang, Jianghua; Xia, Pu; Burton, G Allen; Hollert, Henner

2018-08-01

Conventional assessment and evaluation of sediment quality are based on laboratory-based ecotoxicological and chemical measurements with lack of concern for ecological relevance. Microbiotas in sediment are responsive to pollutants and can be used as alternative ecological indicators of sediment pollutants; however, the linkage between the microbial ecology and ecotoxicological endpoints in response to sediment contamination has been poorly evaluated. Here, in situ microbiotas from the Three Gorges Reservoir (TGR) area of the Yangtze River were characterized by DNA metabarcoding approaches, and then, changes of in situ microbiotas were compared with the ecotoxicological endpoint, aryl hydrocarbon receptor (AhR) mediated activity, and level of polycyclic aromatic hydrocarbons (PAHs) in sediments. PAHs and organic pollutant mixtures mediating AhR activity had different effects on the structures of microbiotas. Specifically, Shannon indices of protistan communities were negatively correlated with the levels of AhR mediated activity and PAHs. The sediment AhR activity was positively correlated with the relative abundance of prokaryotic Acetobacteraceae, but had a negative correlation with protistan Oxytrichidae. Furthermore, a quantitative classification model was built to predict the level of AhR activity based on the relative abundances of Acetobacteraceae and Oxytrichidae. These results suggested that in situ Protista communities could provide a useful tool for monitoring and assessing ecological stressors. The observed responses of microbial community provided supplementary evidence to support that the AhR-active pollutants, such as PAHs, were the primary stressors of the aquatic community in TGR area. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)

PubMed Central

Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P

2012-01-01

Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome. PMID:23078651

Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years.

PubMed

Zhang, Jianrong; Zhang, Yiyin; Tang, Shiyan; Liang, Hengrui; Chen, Difei; Jiang, Long; He, Qihua; Huang, Yu; Wang, Xinyu; Deng, Kexin; Jiang, Shuhan; Zhou, Jiaqing; Xu, Jiaxuan; Chen, Xuanzuo; Liang, Wenhua; He, Jianxing

2017-12-01

In previous studies, complete-case implementation of blind independent central review has been considered unnecessary based on no sign of systematic bias between central and local assessments. In order to further evaluate its value, this study investigated evaluation status between both assessments in phase III trials of anti-cancer drugs for non-hematologic solid tumors. Eligible trials were searched in PubMed with the date of Jan 1, 2010 to Jun 30, 2017. We compared objective response rate (ORR) and disease control rate (DCR) between central and local assessments by study-level pooled analysis and correlation analysis. In pooled analysis, direct comparison was measured by the odds ratio (OR) of central-assessed response status to local-assessed response status; to investigate evaluation bias between central and local assessments, the above calculated OR between experimental (exp-) and control (con-) arms were compared, measured by the ratio of OR. A total of 28 included trials involving 17,466 patients were included (28 with ORR, 16 with DCR). Pooled analysis showed central assessment reported lower ORR and DCR than local assessment, especially in trials with open-label design, central-assessed primary endpoint, and positive primary endpoint outcome, respectively. However, this finding could be found in both experimental [exp-ORR: OR=0.81 (95% CI: 0.76-0.87), P<0.01, I 2 =11%; exp-DCR: OR=0.90 (0.81-1.01), P=0.07, I 2 =42%] and control arms [con-ORR: OR=0.79 (0.72-0.85), P<0.01, I 2 =17%; con-DCR: OR=0.94 (0.86-1.02), P=0.14, I 2 =12%]. No sign of evaluation bias between two assessments was indicated through further analysis [ORR: ratio of OR=1.02 (0.97-1.07), P=0.42, I 2 =0%; DCR: ratio of OR=0.98 (0.93-1.03), P=0.37, I 2 =0%], regardless of mask (open/blind), sample size, tumor type, primary endpoint (central-assessed/local-assessed), and primary endpoint outcome (positive/negative). Correlation analysis demonstrated a high-degree concordance between central and local assessments (exp-ORR, con-ORR, exp-DCR, con-DCR: r>0.90, P<0.01). Blind independent central review remained irreplaceable to monitor local assessment, but its complete-case implementation may be unnecessary.

Evaluation of early efficacy endpoints for proof-of-concept trials.

PubMed

Chen, Cong; Sun, Linda; Li, Chih-Lin

2013-03-11

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

Gender-Based Differences in Outcomes After Orbital Atherectomy for the Treatment of De Novo Severely Calcified Coronary Lesions.

PubMed

Lee, Michael S; Shlofmitz, Evan; Mansourian, Pejman; Sethi, Sanjum; Shlofmitz, Richard A

2016-11-01

We evaluated the relationship between gender and angiographic and clinical outcomes in patients with severely calcified lesions who underwent orbital atherectomy. Female gender is associated with increased risk of adverse clinical events after percutaneous coronary intervention (PCI). Severe coronary artery calcification increases the complexity of PCI and increases the risk of adverse cardiac events. Orbital atherectomy is effective in plaque modification, which facilitates stent delivery and expansion. Whether gender differences exist after orbital atherectomy is unclear. Our analysis retrospectively analyzed 458 consecutive real-world patients (314 males and 144 females) from three centers who underwent orbital atherectomy. The primary endpoint was the major adverse cardiac and cerebrovascular event (MACCE) rate, defined as the composite of death, myocardial infarction (MI), target-vessel revascularization (TVR), and stroke, at 30 days. The primary endpoint of MACCE was low and similar in females and males (0.7% vs 2.9%; P=.14). The individual endpoints of death (0.7% vs 1.6%; P=.43), MI (0.7% vs 1.3%; P=.58), TVR (0% vs 0%; P>.99), and stroke (0% vs 0.3%; P=.50) were low in both groups and did not differ. Angiographic complications were low: perforation (0.8% vs 0.7%; P>.90), dissection (0.8% vs 1.1%; P=.80), and no-reflow (0.8% vs 0.7%; P>.90). Plaque modification with orbital atherectomy was safe and provided similar angiographic and clinical outcomes between females and males. Randomized trials with longer-term follow-up are needed to support our results.

Lifetime competing risks between coronary heart disease mortality and other causes of death during 50years of follow-up.

PubMed

Puddu, Paolo Emilio; Piras, Paolo; Menotti, Alessandro

2017-02-01

To study coronary heart disease (CHD) death versus 11 other causes of death using the cumulative incidence function (CIF) and the competing risks procedures to disentangle the differential role of risk factors for different end-points. Standard Cox and Fine-Gray models among 1712 middle-aged men were compared during 50years of follow-up. CHD death was the primary event, while deaths from 11 selected causes, mutually exclusive from the primary end-point, were considered as secondary events. Reverse solutions were also performed. We considered 10 selected risk factors. CHD death risk was the second highest among 12 mostly specific causes of death. Some risk factors were specific: serum cholesterol for CHD death whereas, systolic blood pressure, cigarette smoking and age may have a differential role in other causes of death. Application of the Fine-Gray model based on CIF enabled to dissect, at least in part, the respective role that baseline covariates may have to segregate the probabilities of two types of death in contrast from each other. They also point to the absence of contributing significance for some of the selected risk factors and this calls for a parsimonious approach in predictions. The relative rarity of competing risk challenges when defining the risk factors role at long-term needs now be corrected since we have clearly shown, with Fine-Gray model, at direct or reverse use, that comparing different end-points heavily influences the risk factor predictive capacity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A phase III, randomized, non-inferiority study comparing the efficacy and safety of biosimilar filgrastim versus originator filgrastim for chemotherapy-induced neutropenia in breast cancer patients

PubMed Central

Hegg, Roberto; Mattar, André; de Matos, João Nunes; Pedrini, José Luiz; Aleixo, Sabina Bandeira; Rocha, Roberto Odebrecht; Cramer, Renato Peixoto; van-Eyll-Rocha, Sylvie

2016-01-01

OBJECTIVES: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa's approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima®). PMID:27759847

South Platte River Basin Data Browser Report

EPA Science Inventory

The purpose of this data browser is to provide a spatial toolkit that delivers primary data that can be used for primary input information for assessments related to environmental endpoints, e.g. surface water hydrology and habitat mapping, related to ecosystem services. A neces...

Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Lin, Chieh-Hsin; Chen, Ping-Kun; Chang, Yue-Cune; Chuo, Liang-Jen; Chen, Yan-Syun; Tsai, Guochuan E; Lane, Hsien-Yuan

2014-05-01

N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists.

PubMed

Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

2010-06-10

Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

PubMed Central

2010-01-01

Background Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). Methods In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Results Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations. Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. Conclusion The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient. PMID:20537166

CAN A MODEL TRANSFERABILITY FRAMEWORK IMPROVE ECOSYSTEM SERVICE ESTIMATES? A CASE STUDY OF SOIL FOREST CARBON SEQUESTRATION IN TILLAMOOK BAY, OR, USA

EPA Science Inventory

Budget constraints and policies that limit primary data collection have fueled a practice of transferring estimates (or models to generate estimates) of ecological endpoints from sites where primary data exists to sites where little to no primary data were collected. Whereas bene...

SEMICONDUCTOR TECHNOLOGY A signal processing method for the friction-based endpoint detection system of a CMP process

NASA Astrophysics Data System (ADS)

Chi, Xu; Dongming, Guo; Zhuji, Jin; Renke, Kang

2010-12-01

A signal processing method for the friction-based endpoint detection system of a chemical mechanical polishing (CMP) process is presented. The signal process method uses the wavelet threshold denoising method to reduce the noise contained in the measured original signal, extracts the Kalman filter innovation from the denoised signal as the feature signal, and judges the CMP endpoint based on the feature of the Kalman filter innovation sequence during the CMP process. Applying the signal processing method, the endpoint detection experiments of the Cu CMP process were carried out. The results show that the signal processing method can judge the endpoint of the Cu CMP process.

Equipment management risk rating system based on engineering endpoints.

PubMed

James, P J

1999-01-01

The equipment management risk ratings system outlined here offers two significant departures from current practice: risk classifications are based on intrinsic device risks, and the risk rating system is based on engineering endpoints. Intrinsic device risks are categorized as physical, clinical and technical, and these flow from the incoming equipment assessment process. Engineering risk management is based on verification of engineering endpoints such as clinical measurements or energy delivery. This practice eliminates the ambiguity associated with ranking risk in terms of physiologic and higher-level outcome endpoints such as no significant hazards, low significance, injury, or mortality.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications

PubMed Central

Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M.; Leufkens, Hubert

2015-01-01

Background. Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy’s clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. Materials and Methods. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Results. Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Conclusion. Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Implications for Practice: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies. PMID:25948678

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

PubMed

Liberti, Lawrence; Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M; Leufkens, Hubert

2015-06-01

Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies. ©AlphaMed Press.

One-year outcomes after successful chronic total occlusion percutaneous coronary intervention: The impact of dissection re-entry techniques.

PubMed

Wilson, W M; Walsh, S J; Bagnall, A; Yan, A T; Hanratty, C G; Egred, M; Smith, E; Oldroyd, K G; McEntegart, M; Irving, J; Douglas, H; Strange, J; Spratt, J C

2017-11-01

We aimed to determine clinical outcomes 1 year after successful chronic total occlusion (CTO) PCI and, in particular, whether use of dissection and re-entry strategies affects clinical outcomes. Hybrid approaches have increased the procedural success of CTO percutaneous coronary intervention (PCI) but longer-term outcomes are unknown, particularly in relation to dissection and re-entry techniques. Data were collected for consecutive CTO PCIs performed by hybrid-trained operators from 7 United Kingdom (UK) centres between 2012 and 2014. The primary endpoint (death, myocardial infarction, unplanned target vessel revascularization) was measured at 12 months along with angina status. One-year follow up data were available for 96% of successful cases (n = 805). In total, 85% of patients had a CCS angina class of 2-4 prior to CTO PCI. Final successful procedural strategy was antegrade wire escalation 48%; antegrade dissection and re-entry (ADR) 21%; retrograde wire escalation 5%; retrograde dissection and re-entry (RDR) 26%. Overall, 47% of CTOs were recanalized using dissection and re-entry strategies. During a mean follow up of 11.5 ± 3.8 months, the primary endpoint occurred in 8.6% (n = 69) of patients (10.3% (n = 39/375) in DART group and 7.0% (n = 30/430) in wire-based cases). The majority of patients (88%) had no or minimal angina (CCS class 0 or 1). ADR and RDR were used more frequently in more complex cases with greater disease burden, however, the only independent predictor of the primary endpoint was lesion length. CTO PCI in complex lesions using the hybrid approach is safe, effective and has a low one-year adverse event rate. The method used to recanalize arteries was not associated with adverse outcomes. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Twelve-month results of a prospective, multicentre trial to assess the everolimus-eluting coronary stent system (PROMUS Element): the PLATINUM PLUS all-comers randomised trial.

PubMed

Fajadet, Jean; Neumann, Franz-Josef; Hildick-Smith, David; Petronio, Sonia; Zaman, Azfar; Spence, Mark; Wöhrle, Jochen; Elhadad, Simon; Roberts, David; Hovasse, Thomas; Valdés, Mariano; Silber, Sigmund

2017-01-20

The aim of the study was to compare the safety and efficacy of the platinum-chromium-based everolimus-eluting stent (EES) with a cobalt-chromium EES. We performed a prospective, multicentre, single-blind non-inferiority all-comers study randomising patients with stable or unstable coronary artery disease (2:1) to treatment with the platinum-chromium EES (n=1,952) or the control cobalt-chromium EES (n=1,028) in Europe (PLATINUM PLUS trial). The primary endpoint was target vessel failure (TVF) at 12 months, a composite of target vessel-related cardiac death, myocardial infarction (MI), and ischaemia-driven target vessel revascularisation (TVR). Among 2,980 patients, 33% presented with acute coronary syndromes, and 48% with multivessel disease. At 12 months, the intention-to-treat analysis determined that the platinum-chromium EES was non-inferior to the cobalt-chromium EES for the primary endpoint (86 [4.6%] patients vs. 32 [3.2%], absolute difference 1.4%, 95% confidence interval [CI]: -0.1-2.9; upper limit of the one-sided 95% CI: 2.57%; non-inferiority p=0.012; superiority analysis: hazard ratio [HR] 1.44, 95% CI: 0.96-2.16, p=0.08). In the per protocol analysis, however, the primary endpoint was significantly more common in the platinum-chromium EES (HR 1.64, 95% CI: 1.05-2.55, p=0.03). There were no significant differences in the rates of cardiac death (1.1% vs. 1.0%, p=0.78), MI (1.6% vs. 0.8%, p=0.09), or ischaemia-driven TLR (2.0% vs. 1.6%, p=0.49). The rates of ARC definite or probable stent thrombosis were comparable between platforms (0.8% vs. 0.5%, p=0.44). At one year, the platinum-chromium EES satisfied the pre-specified criteria for non-inferiority relative to the control cobalt-chromium EES in this all-comers trial.

Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial

PubMed Central

James, Stefan; Angiolillo, Dominick J.; Cornel, Jan H.; Erlinge, David; Husted, Steen; Kontny, Frederic; Maya, Juan; Nicolau, Josë C.; Spinar, Jindrich; Storey, Robert F.; Stevens, Susanna R.; Wallentin, Lars

2010-01-01

Aims Patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control. Methods and results We analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76–1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66–1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36–1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81–1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. Ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70–0.91; HR: 0.78, 95% CI: 0.65–0.93; and HR: 0.62, 95% CI: 0.39–1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86–1.12). Conclusion Ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events. PMID:20802246

NAITRE study on the impact of conditional cash transfer on poor pregnancy outcomes in underprivileged women: protocol for a nationwide pragmatic cluster-randomised superiority clinical trial in France

PubMed Central

Bardou, Marc; Crépon, Bruno; Bertaux, Anne-Claire; Godard-Marceaux, Aurélie; Eckman-Lacroix, Astrid; Thellier, Elise; Falchier, Frédérique; Deruelle, Philippe; Doret, Muriel; Carcopino-Tusoli, Xavier; Schmitz, Thomas; Barjat, Thiphaine; Morin, Mathieu; Perrotin, Franck; Hatem, Ghada; Deneux-Tharaux, Catherine; Fournel, Isabelle; Laforet, Laurent; Meunier-Beillard, Nicolas; Duflo, Esther; Le Ray, Isabelle

2017-01-01

Introduction Prenatal care is recommended during pregnancy to improve neonatal and maternal outcomes. Women of lower socioeconomic status (SES) are less compliant to recommended prenatal care and suffer a higher risk of adverse perinatal outcomes. Several attempts to encourage optimal pregnancy follow-up have shown controversial results, particularly in high-income countries. Few studies have assessed financial incentives to encourage prenatal care, and none reported materno-fetal events as the primary outcome. Our study aims to determine whether financial incentives could improve pregnancy outcomes in women with low SES in a high-income country. Methods and analysis This pragmatic cluster-randomised clinical trial includes pregnant women with the following criteria: (1) age above 18 years, (2) first pregnancy visit before 26 weeks of gestation and (3) belonging to a socioeconomically disadvantaged group. The intervention consists in offering financial incentives conditional on attending scheduled pregnancy follow-up consultations. Clusters are 2-month periods with random turnover across centres. A composite outcome of maternal and neonatal morbidity and mortality is the primary endpoint. Secondary endpoints include maternal or neonatal outcomes assessed separately, qualitative assessment of the perception of the intervention and cost-effectiveness analysis for which children will be followed to the end of their first year through the French health insurance database. The study started in June 2016, and based on an expected decrease in the primary endpoint from 18% to 14% in the intervention group, we plan to include 2000 women in each group. Ethics and dissemination Ethics approval was first gained on 28 September 2014. An independent data security and monitoring committee has been established. Results of the main trial and each of the secondary analyses will be submitted for publication in a peer-reviewed journal. Trial registration number NCT02402855; pre-results. PMID:29084796

Substantial improvement of primary cardiovascular prevention by a systematic score-based multimodal approach: A randomized trial: The PreFord-Study.

PubMed

Gysan, Detlef Bernd; Millentrup, Stefanie; Albus, Christian; Bjarnason-Wehrens, Birna; Latsch, Joachim; Gohlke, Helmut; Herold, Gerd; Wegscheider, Karl; Heming, Christian; Seyfarth, Melchior; Predel, Hans-Georg

2017-09-01

Trial design Prospective randomized multicentre interventional study. Methods Individual cardiovascular risk assessment in Ford Company, Germany employees ( n = 4.196), using the European Society of Cardiology-Systematic Coronary Risk Evaluation (ESC-SCORE) for classification into three risk groups. Subjects assigned to ESC high-risk group (ESC-SCORE ≥ 5%), without a history of cardiovascular disease were eligible for randomization to a multimodal 15-week intervention programme (INT) or to usual care and followed up for 36 months. Objectives Evaluation of the long-term effects of a risk-adjusted multimodal intervention in high-risk subjects. Primary endpoint: reduction of ESC-SCORE in INT versus usual care. Secondary endpoints: composite of fatal and non-fatal cardiovascular events and time to first cardiovascular event. intention-to-treat and per-protocol analysis. Results Four hundred and forty-seven subjects were randomized to INT ( n = 224) or to usual care ( n = 223). After 36 months ESC-SCORE development favouring INT was observed (INT: 8.70% to 10.03% vs. usual care: 8.49% to 12.09%; p = 0.005; net difference: 18.50%). Moreover, a significant reduction in the composite cardiovascular events was observed: (INT: n = 11 vs. usual care: n = 27). Hazard ratio of intervention versus control was 0.51 (95% confidence interval 0.25-1.03; p = 0.062) in the intention-to-treat analysis and 0.41 (95% confidence interval 0.18-0.90; p = 0.026) in the per-protocol analysis, respectively. No intervention-related adverse events or side-effects were observed. Conclusions Our results demonstrate the efficiency of identifying cardiovascular high-risk subjects by the ESC-SCORE in order to enrol them to a risk adjusted primary prevention programme. This strategy resulted in a significant improvement of ESC-SCORE, as well as a reduction in predefined cardiovascular endpoints in the INT within 36 months. (ISRCTN 23536103.).

NAITRE study on the impact of conditional cash transfer on poor pregnancy outcomes in underprivileged women: protocol for a nationwide pragmatic cluster-randomised superiority clinical trial in France.

PubMed

Bardou, Marc; Crépon, Bruno; Bertaux, Anne-Claire; Godard-Marceaux, Aurélie; Eckman-Lacroix, Astrid; Thellier, Elise; Falchier, Frédérique; Deruelle, Philippe; Doret, Muriel; Carcopino-Tusoli, Xavier; Schmitz, Thomas; Barjat, Thiphaine; Morin, Mathieu; Perrotin, Franck; Hatem, Ghada; Deneux-Tharaux, Catherine; Fournel, Isabelle; Laforet, Laurent; Meunier-Beillard, Nicolas; Duflo, Esther; Le Ray, Isabelle

2017-10-30

Prenatal care is recommended during pregnancy to improve neonatal and maternal outcomes. Women of lower socioeconomic status (SES) are less compliant to recommended prenatal care and suffer a higher risk of adverse perinatal outcomes. Several attempts to encourage optimal pregnancy follow-up have shown controversial results, particularly in high-income countries. Few studies have assessed financial incentives to encourage prenatal care, and none reported materno-fetal events as the primary outcome. Our study aims to determine whether financial incentives could improve pregnancy outcomes in women with low SES in a high-income country. This pragmatic cluster-randomised clinical trial includes pregnant women with the following criteria: (1) age above 18 years, (2) first pregnancy visit before 26 weeks of gestation and (3) belonging to a socioeconomically disadvantaged group. The intervention consists in offering financial incentives conditional on attending scheduled pregnancy follow-up consultations. Clusters are 2-month periods with random turnover across centres. A composite outcome of maternal and neonatal morbidity and mortality is the primary endpoint. Secondary endpoints include maternal or neonatal outcomes assessed separately, qualitative assessment of the perception of the intervention and cost-effectiveness analysis for which children will be followed to the end of their first year through the French health insurance database. The study started in June 2016, and based on an expected decrease in the primary endpoint from 18% to 14% in the intervention group, we plan to include 2000 women in each group. Ethics approval was first gained on 28 September 2014. An independent data security and monitoring committee has been established. Results of the main trial and each of the secondary analyses will be submitted for publication in a peer-reviewed journal. NCT02402855; pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Boric Acid Is Reproductively Toxic to Adult Xenopus laevis, but Not Endocrine Active.

PubMed

Fort, Douglas J; Fort, Troy D; Mathis, Michael B; Ball, R Wayne

2016-11-01

The potential reproductive and endocrine toxicity of boric acid (BA) in the African clawed frog, Xenopus laevis, was evaluated using a 30-day exposure of adult frogs. Adult female and male frogs established as breeders were exposed to a culture water control and 4 target (nominal) test concentrations [5.0, 7.5, 10.0, and 15 mg boron (B)/L, equivalent to 28.5, 42.8, 57.0, and 85.5 mg BA/L] using flow-through diluter exposure system. The primary endpoints measured were adult survival, growth (weight and snout-vent length [SVL]), necropsy data, reproductive fecundity, and development of progeny (F1) from the exposed frogs. Necropsy endpoints included gonad weight, gonado-somatic index (GSI), ovary profile (oocyte normalcy and stage distribution), sperm count, and dysmorphology. Endocrine endpoints included plasma estradiol (E2), testosterone (T), dihydrotestosteone (DHT), gonadal CYP 19 (aromatase), and gonadal 5α-reductase (5-AR). BA exposure to adult female X. laevis increased the proportion of immature oocytes (< stage II) in the ovaries of females, reduced sperm counts and increased sperm cell dysmorphology frequency in male frogs exposed to 15 mg B/L. No effects on the other general, developmental (F1), or endocrine endpoints were observed. Based on the results of the present study, the no observed adverse effects concentration (NOAEC) for the reproductive endpoints was 10 mg B/L; and 15 mg B/L for reproductive fecundity, F1 embryo larval development, and endocrine function. These results confirmed that although BA is capable of inducing reproductive toxicity at high concentrations, it is not an endocrine disrupting agent. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Culotte stenting for coronary bifurcation lesions with 2nd and 3rd generation everolimus-eluting stents: the CELTIC Bifurcation Study.

PubMed

Walsh, Simon J; Hanratty, Colm G; Watkins, Stuart; Oldroyd, Keith G; Mulvihill, Niall T; Hensey, Mark; Chase, Alex; Smith, Dave; Cruden, Nick; Spratt, James C; Mylotte, Darren; Johnson, Tom; Hill, Jonathan; Hussein, Hafiz M; Bogaerts, Kris; Morice, Marie-Claude; Foley, David P

2018-05-24

The aim of this study was to provide contemporary outcome data for patients with de novo coronary disease and Medina 1,1,1 lesions who were treated with a culotte two-stent technique, and to compare the performance of two modern-generation drug-eluting stent (DES) platforms, the 3-connector XIENCE and the 2-connector SYNERGY. Patients with Medina 1,1,1 bifurcation lesions who had disease that was amenable to culotte stenting were randomised 1:1 to treatment with XIENCE or SYNERGY DES. A total of 170 patients were included. Technical success and final kissing balloon inflation occurred in >96% of cases. Major adverse cardiovascular or cerebrovascular events (MACCE: a composite of death, myocardial infarction [MI], cerebrovascular accident [CVA] and target vessel revascularisation [TVR]) occurred in 5.9% of patients by nine months. The primary endpoint was a composite of death, MI, CVA, target vessel failure (TVF), stent thrombosis and binary angiographic restenosis. At nine months, the primary endpoint occurred in 19% of XIENCE patients and 16% of SYNERGY patients (p=0.003 for non-inferiority for platform performance). MACCE rates for culotte stenting using contemporary everolimus-eluting DES are low at nine months. The XIENCE and SYNERGY stents demonstrated comparable performance for the primary endpoint.

Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis.

PubMed

Falk Delgado, Alberto; Falk Delgado, Anna

2017-08-23

Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07-8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07-0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

PubMed

Anker, Stefan D; Schroeder, Stefan; Atar, Dan; Bax, Jeroen J; Ceconi, Claudio; Cowie, Martin R; Crisp, Adam; Dominjon, Fabienne; Ford, Ian; Ghofrani, Hossein-Ardeschir; Gropper, Savion; Hindricks, Gerhard; Hlatky, Mark A; Holcomb, Richard; Honarpour, Narimon; Jukema, J Wouter; Kim, Albert M; Kunz, Michael; Lefkowitz, Martin; Le Floch, Chantal; Landmesser, Ulf; McDonagh, Theresa A; McMurray, John J; Merkely, Bela; Packer, Milton; Prasad, Krishna; Revkin, James; Rosano, Giuseppe M C; Somaratne, Ransi; Stough, Wendy Gattis; Voors, Adriaan A; Ruschitzka, Frank

2016-05-01

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

Bayesian model selection techniques as decision support for shaping a statistical analysis plan of a clinical trial: An example from a vertigo phase III study with longitudinal count data as primary endpoint

PubMed Central

2012-01-01

Background A statistical analysis plan (SAP) is a critical link between how a clinical trial is conducted and the clinical study report. To secure objective study results, regulatory bodies expect that the SAP will meet requirements in pre-specifying inferential analyses and other important statistical techniques. To write a good SAP for model-based sensitivity and ancillary analyses involves non-trivial decisions on and justification of many aspects of the chosen setting. In particular, trials with longitudinal count data as primary endpoints pose challenges for model choice and model validation. In the random effects setting, frequentist strategies for model assessment and model diagnosis are complex and not easily implemented and have several limitations. Therefore, it is of interest to explore Bayesian alternatives which provide the needed decision support to finalize a SAP. Methods We focus on generalized linear mixed models (GLMMs) for the analysis of longitudinal count data. A series of distributions with over- and under-dispersion is considered. Additionally, the structure of the variance components is modified. We perform a simulation study to investigate the discriminatory power of Bayesian tools for model criticism in different scenarios derived from the model setting. We apply the findings to the data from an open clinical trial on vertigo attacks. These data are seen as pilot data for an ongoing phase III trial. To fit GLMMs we use a novel Bayesian computational approach based on integrated nested Laplace approximations (INLAs). The INLA methodology enables the direct computation of leave-one-out predictive distributions. These distributions are crucial for Bayesian model assessment. We evaluate competing GLMMs for longitudinal count data according to the deviance information criterion (DIC) or probability integral transform (PIT), and by using proper scoring rules (e.g. the logarithmic score). Results The instruments under study provide excellent tools for preparing decisions within the SAP in a transparent way when structuring the primary analysis, sensitivity or ancillary analyses, and specific analyses for secondary endpoints. The mean logarithmic score and DIC discriminate well between different model scenarios. It becomes obvious that the naive choice of a conventional random effects Poisson model is often inappropriate for real-life count data. The findings are used to specify an appropriate mixed model employed in the sensitivity analyses of an ongoing phase III trial. Conclusions The proposed Bayesian methods are not only appealing for inference but notably provide a sophisticated insight into different aspects of model performance, such as forecast verification or calibration checks, and can be applied within the model selection process. The mean of the logarithmic score is a robust tool for model ranking and is not sensitive to sample size. Therefore, these Bayesian model selection techniques offer helpful decision support for shaping sensitivity and ancillary analyses in a statistical analysis plan of a clinical trial with longitudinal count data as the primary endpoint. PMID:22962944

Bayesian model selection techniques as decision support for shaping a statistical analysis plan of a clinical trial: an example from a vertigo phase III study with longitudinal count data as primary endpoint.

PubMed

Adrion, Christine; Mansmann, Ulrich

2012-09-10

A statistical analysis plan (SAP) is a critical link between how a clinical trial is conducted and the clinical study report. To secure objective study results, regulatory bodies expect that the SAP will meet requirements in pre-specifying inferential analyses and other important statistical techniques. To write a good SAP for model-based sensitivity and ancillary analyses involves non-trivial decisions on and justification of many aspects of the chosen setting. In particular, trials with longitudinal count data as primary endpoints pose challenges for model choice and model validation. In the random effects setting, frequentist strategies for model assessment and model diagnosis are complex and not easily implemented and have several limitations. Therefore, it is of interest to explore Bayesian alternatives which provide the needed decision support to finalize a SAP. We focus on generalized linear mixed models (GLMMs) for the analysis of longitudinal count data. A series of distributions with over- and under-dispersion is considered. Additionally, the structure of the variance components is modified. We perform a simulation study to investigate the discriminatory power of Bayesian tools for model criticism in different scenarios derived from the model setting. We apply the findings to the data from an open clinical trial on vertigo attacks. These data are seen as pilot data for an ongoing phase III trial. To fit GLMMs we use a novel Bayesian computational approach based on integrated nested Laplace approximations (INLAs). The INLA methodology enables the direct computation of leave-one-out predictive distributions. These distributions are crucial for Bayesian model assessment. We evaluate competing GLMMs for longitudinal count data according to the deviance information criterion (DIC) or probability integral transform (PIT), and by using proper scoring rules (e.g. the logarithmic score). The instruments under study provide excellent tools for preparing decisions within the SAP in a transparent way when structuring the primary analysis, sensitivity or ancillary analyses, and specific analyses for secondary endpoints. The mean logarithmic score and DIC discriminate well between different model scenarios. It becomes obvious that the naive choice of a conventional random effects Poisson model is often inappropriate for real-life count data. The findings are used to specify an appropriate mixed model employed in the sensitivity analyses of an ongoing phase III trial. The proposed Bayesian methods are not only appealing for inference but notably provide a sophisticated insight into different aspects of model performance, such as forecast verification or calibration checks, and can be applied within the model selection process. The mean of the logarithmic score is a robust tool for model ranking and is not sensitive to sample size. Therefore, these Bayesian model selection techniques offer helpful decision support for shaping sensitivity and ancillary analyses in a statistical analysis plan of a clinical trial with longitudinal count data as the primary endpoint.

Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1.

PubMed

Plotkin, Scott R; Davis, Stephanie D; Robertson, Kent A; Akshintala, Srivandana; Allen, Julian; Fisher, Michael J; Blakeley, Jaishri O; Widemann, Brigitte C; Ferner, Rosalie E; Marcus, Carole L

2016-08-16

Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. © 2016 American Academy of Neurology.

Randomized, double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20 mg/day vortioxetine in adults with major depressive disorder.

PubMed

Nishimura, Akira; Aritomi, Yutaka; Sasai, Kiyofumi; Kitagawa, Tadayuki; Mahableshwarkar, Atul R

2018-02-01

This study assessed the efficacy and safety of vortioxetine in adults with major depressive disorder. In this double-blind, placebo-controlled study, 600 patients with major depressive disorder were randomly assigned (1:1:1:1) to receive vortioxetine 5, 10, or 20 mg, or placebo once daily for 8 weeks. The primary end-point was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8, evaluated by the last-observation-carried-forward method. Secondary end-points included response (≥ 50% decrease in the MADRS total score from baseline) and remission (MADRS total score ≤ 10), Clinical Global Impression Scale-Improvement, and change from baseline in Sheehan Disability Scale. Adverse events were summarized. Vortioxetine failed to show significant differences from placebo in the primary end-point. Nominally significant improvements over placebo were observed for vortioxetine doses of 10 and 20 mg when the primary end-point was evaluated using the mixed model for repeated measures as the secondary analysis, and 10 mg in secondary measures of response and patient functioning. Vortioxetine was well tolerated. Nausea, constipation, dry mouth, dizziness, and insomnia each occurred at a >twofold higher rate than placebo. Discontinuation symptom scores were comparable between all groups after 1 and 2 weeks following withdrawal of the study drug. While vortioxetine failed to meet significance versus placebo in the primary efficacy analysis, there was evidence of efficacy for the 10- and 20-mg doses in secondary analyses. Vortioxetine was safe and well tolerated. Additional studies appear warranted. © 2017 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

Bailout intravenous esmolol for heart rate control in cardiac computed tomography angiography.

PubMed

Aguiar Rosa, Sílvia; Ramos, Ruben; Marques, Hugo; Santos, Rosana; Leal, Cecília; Casado, Helena; Saraiva, Márcia; Figueiredo, Luísa; Cruz Ferreira, Rui

2016-12-01

To evaluate the efficacy and safety of a heart rate (HR) reduction protocol using intravenous esmolol as bailout for failed oral metoprolol regimens in patients undergoing coronary computed tomography angiography (CCTA) with 64-slice multidetector computed tomography (64-MDCT). Patients who underwent cardiac 64-MDCT in a single institution between 2011 and 2014 were analyzed. Those with HR above 60 beats per minute (bpm) on presentation received oral metoprolol (50-200 mg) at least one hour before CCTA. Intravenous esmolol 1-2 mg/kg was administered as a bolus whenever HR remained over 65 bpm just before imaging. The primary efficacy endpoint was HR <65 bpm during CCTA. The primary safety endpoint was symptomatic hypotension or bradycardia up to hospital discharge. During the study period CCTA was performed in 947 cases. In 86% of these, oral metoprolol was the only medication required to successfully reduce HR <60 bpm. Esmolol was used in the remaining 130 patients (14%). For esmolol-treated patients mean baseline and acquisition HR were 74±14 bpm and 63±9 bpm, respectively (p<0.001). The target HR of <65 bpm was achieved in 82 of the 130 esmolol-treated patients (63%). Considering the whole population, esmolol use led to a significant increase in the primary efficacy endpoint from 86% to 95% (p<0.001). Esmolol also resulted in a statistically, but not clinically, significant reduction in systolic blood pressure (144±22 to 115±17 mmHg; p<0.001). The combined primary safety endpoint was only observed in two (1.5%) patients. Despite optimal use of oral beta-blockers, 14% of patients needed intravenous esmolol for HR control. The pre-medication combination of oral metoprolol and on-demand administration of intravenous esmolol was safe and effective and enabled 95% of patients to be imaged with HR below 65 bpm. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

The Barrel vascular reconstruction device for endovascular coiling of wide-necked intracranial aneurysms: a multicenter, prospective, post-marketing study.

PubMed

Gory, Benjamin; Blanc, Raphaël; Turjman, Francis; Berge, Jérôme; Piotin, Michel

2018-02-02

The Barrel vascular reconstruction device (Barrel VRD) is a novel stent with design features that allow endovascular coiling of wide-necked bifurcation aneurysms while preserving adjacent branches, without necessitating dual stent implantation. This study aimed to assess the safety and effectiveness of the Barrel VRD at 12-month follow-up. The Barrel VRD trial is a prospective, multicenter, observational post-marketing registry evaluating the use of the Barrel VRD for treatment of wide-necked bifurcation aneurysms. The primary effectiveness endpoint was successful aneurysm treatment measured by digital subtraction angiography with a Raymond-Roy occlusion grade of 1 or 2 in the absence of retreatment, parent artery stenosis (>50%), or target aneurysm rupture at 12 months. The primary safety endpoint was the absence of neurological death or major stroke at 12 months. Twenty patients were enrolled from December 2013 to December 2014. The device was implanted in 19 patients with 19 aneurysms (8 middle cerebral artery, 4 anterior communicating artery, 1 internal carotid artery terminus, 4 basilar artery aneurysms; mean dome height 5.7±1.91 mm; mean neck length 4.8±1.35 mm, mean dome-to-neck ratio 1.6±2.0). Coiling was performed in all cases. The primary effectiveness endpoint was achieved in 78.9% of subjects (15/19; 12 complete occlusions, 3 neck remnants), and the primary safety endpoint was 5.3% (1/19). This prospective study demonstrates that the Barrel VRD device resulted in ~80% occlusion rates and ~5% rates of neurological complications at 1 year after endovascular treatment of wide-necked bifurcation intracranial aneurysms. REGISTERED CLINICAL TRIAL: NCT02125097;Results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials.

PubMed

Hui, David; Glitza, Isabella; Chisholm, Gary; Yennu, Sriram; Bruera, Eduardo

2013-03-01

Attrition is common among supportive care/palliative oncology clinical trials. However, to the authors' knowledge, few studies to date have documented the reasons and predictors for dropout. In the current study, the authors' objective was to determine the rate, reasons, and factors associated with attrition both before reaching the primary endpoint and at the end of the study. A review of all prospective interventional supportive care/palliative oncology trials conducted in the Department of Palliative Care and Rehabilitation Medicine at The University of Texas MD Anderson Cancer Center in Houston between 1999 and 2011 was performed. Patient and study characteristics and attrition data were extracted. A total of 1214 patients were included in 18 clinical trials. The median age of the patients was 60 years. Approximately 41% had an Eastern Cooperative Oncology Group performance status of ≥ 3, a median Edmonton Symptom Assessment Scale (ESAS) for fatigue of 7 of 10, and a median ESAS for dyspnea of 2 of 10. The attrition rate was 26% (95% confidence interval [95% CI], 23%-28%) for the primary endpoint and 44% (95% CI, 41%-47%) for the end of the study. Common reasons for primary endpoint dropout were symptom burden (21%), patient preference (15%), hospitalization (10%), and death (6%). Primary endpoint attrition was associated with a higher baseline intensity of fatigue (odds ratio [OR], 1.10 per point; P = .01) and a longer study duration (P = .04). End-of-study attrition was associated with higher baseline levels of dyspnea (OR, 1.06; P = .01), fatigue (OR, 1.08; P = .01), Hispanic race (OR, 1.87; P = .002), higher level of education (P = .02), longer study duration (P = .01), and outpatient studies (P = 0.05). The attrition rate was high in supportive care/palliative oncology clinical trials, and was associated with various patient characteristics and a high baseline symptom burden. These findings have implications for future clinical trial design including eligibility criteria and sample size calculation. Copyright © 2012 American Cancer Society.

The impact of community health worker-led home delivery of antiretroviral therapy on virological suppression: a non-inferiority cluster-randomized health systems trial in Dar es Salaam, Tanzania.

PubMed

Geldsetzer, Pascal; Francis, Joel M; Ulenga, Nzovu; Sando, David; Lema, Irene A; Mboggo, Eric; Vaikath, Maria; Koda, Happiness; Lwezaula, Sharon; Hu, Janice; Noor, Ramadhani A; Olofin, Ibironke; Larson, Elysia; Fawzi, Wafaie; Bärnighausen, Till

2017-02-22

Home delivery of antiretroviral therapy (ART) by community health workers (CHWs) may improve ART retention by reducing the time burden and out-of-pocket expenditures to regularly attend an ART clinic. In addition, ART home delivery may shorten waiting times and improve quality of care for those in facility-based care by decongesting ART clinics. This trial aims to determine whether ART home delivery for patients who are clinically stable on ART combined with facility-based care for those who are not stable on ART is non-inferior to the standard of care (facility-based care for all ART patients) in achieving and maintaining virological suppression. This is a non-inferiority cluster-randomized trial set in Dar es Salaam, Tanzania. A cluster is one of 48 healthcare facilities with its surrounding catchment area. 24 clusters were randomized to ART home delivery and 24 to the standard of care. The intervention consists of home visits by CHWs to provide counseling and deliver ART to patients who are stable on ART, while the control is the standard of care (facility-based ART and CHW home visits without ART home delivery). In addition, half of the healthcare facilities in each study arm were randomized to standard counseling during home visits (covering family planning, prevention of HIV transmission, and ART adherence), and half to standard plus nutrition counseling (covering food production and dietary advice). The non-inferiority design applies to the endpoints of the ART home delivery trial; the primary endpoint is the proportion of ART patients at a healthcare facility who are virally suppressed at the end of the study period. The margin of non-inferiority for this primary endpoint was set at nine percentage points. As the number of ART patients in sub-Saharan Africa is expected to rise, this trial provides causal evidence on the effectiveness of a home-based care model that could decongest ART clinics and reduce patients' healthcare expenditures. More broadly, this trial will inform the increasing policy interest in task-shifting of chronic disease care from facility- to community-based healthcare workers. ClinicalTrials.gov: NCT02711293 . Registration date: 16 March 2016.

Disease management in the treatment of patients with chronic heart failure who have universal access to health care: a randomized controlled trial.

PubMed

Kalter-Leibovici, Ofra; Freimark, Dov; Freedman, Laurence S; Kaufman, Galit; Ziv, Arnona; Murad, Havi; Benderly, Michal; Silverman, Barbara G; Friedman, Nurit; Cukierman-Yaffe, Tali; Asher, Elad; Grupper, Avishay; Goldman, Dorit; Amitai, Miriam; Matetzky, Shlomi; Shani, Mordechai; Silber, Haim

2017-05-01

The efficacy of disease management programs in improving the outcome of heart failure patients remains uncertain and may vary across health systems. This study explores whether a countrywide disease management program is superior to usual care in reducing adverse health outcomes and improving well-being among community-dwelling adult patients with moderate-to-severe chronic heart failure who have universal access to advanced health-care services and technologies. In this multicenter open-label trial, 1,360 patients recruited after hospitalization for heart failure exacerbation (38%) or from the community (62%) were randomly assigned to either disease management or usual care. Disease management, delivered by multi-disciplinary teams, included coordination of care, patient education, monitoring disease symptoms and patient adherence to medication regimen, titration of drug therapy, and home tele-monitoring of body weight, blood pressure and heart rate. Patients assigned to usual care were treated by primary care practitioners and consultant cardiologists. The primary composite endpoint was the time elapsed till first hospital admission for heart failure exacerbation or death from any cause. Secondary endpoints included the number of all hospital admissions, health-related quality of life and depression during follow-up. Intention-to-treat comparisons between treatments were adjusted for baseline patient data and study center. During the follow-up, 388 (56.9%) patients assigned to disease management and 387 (57.1%) assigned to usual care had a primary endpoint event. The median (range) time elapsed until the primary endpoint event or end of study was 2.0 (0-5.0) years among patients assigned to disease management, and 1.8 (0-5.0) years among patients assigned to usual care (adjusted hazard ratio, 0.908; 95% confidence interval, 0.788 to 1.047). Hospital admissions were mostly (70%) unrelated to heart failure. Patients assigned to disease management had a better health-related quality of life and a lower depression score during follow-up. This comprehensive disease management intervention was not superior to usual care with respect to the primary composite endpoint, but it improved health-related quality of life and depression. A disease-centered approach may not suffice to make a significant impact on hospital admissions and mortality in patients with chronic heart failure who have universal access to health care. Clinicaltrials.gov identifier: NCT00533013 . Trial registration date: 9 August 2007. Initial protocol release date: 20 September 2007.

Overextended Criteria Donors: Experience of an Italian Transplantation Center.

PubMed

Nure, E; Lirosi, M C; Frongillo, F; Bianco, G; Silvestrini, N; Fiorillo, C; Sganga, G; Agnes, S

2015-09-01

The increasing gap between the number of patients who could benefit from liver transplantation and the number of available donors has fueled efforts to maximize the donor pool using marginal grafts that usually were discarded for transplantation. This study included data of all patients who received decreased donor liver grafts between January 2004 and January 2013 (n = 218) with the use of a prospectively collected database. Patients with acute liver failure, retransplantation, pediatric transplantation, and split liver transplantation were excluded. Donors were classified as standard donor (SD), extended criteria donor (ECD), and overextended criteria donor (OECD). The primary endpoints of the study were early allograft primary dysfunction (PDF), primary nonfunction (PNF), and patient survival (PS), whereas incidence of major postoperative complications was the secondary endpoint. In our series we demonstrated that OECD have similar outcome in terms of survival and incidence of complication after liver transplantation as ideal grafts. Copyright © 2015 Elsevier Inc. All rights reserved.

Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study.

PubMed

Auliac, J B; Chouaid, C; Greillier, L; Greiller, L; Monnet, I; Le Caer, H; Falchero, L; Corre, R; Descourt, R; Bota, S; Berard, H; Schott, R; Bizieux, A; Fournel, P; Labrunie, A; Marin, B; Vergnenegre, A

2014-09-01

Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective. To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC. In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages. 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months. Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

PubMed Central

Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

2015-01-01

Background Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID:26109878

Tools in the assessment of sarcopenia

PubMed Central

Cooper, C; Fielding, R; Visser, M; van Loon, LJ; Rolland, Y; Orwoll, E; Reid, K; Boonen, S; Dere, W; Epstein, S; Mitlak, B; Tsouderos, Y; Sayer, AA; Rizzoli, R; Reginster, JY; Kanis, JA

2013-01-01

Summary This review provides a framework for development of an operational definition of sarcopenia and of the potential endpoints that might be adopted in clinical trials among older adults. Introduction While the clinical relevance of sarcopenia is widely recognized, there is currently no universally accepted definition of the disorder. The development of interventions to alter the natural history of sarcopenia also requires consensus on the most appropriate endpoints for determining outcomes of clinical importance which might be utilised in intervention studies. Methods and results We review current approaches to the definition of sarcopenia, and the methods used for the assessment of various aspects of physical function in older people. The potential endpoints of muscle mass, muscle strength, muscle power and muscle fatigue, as well as the relationships between them, are explored with reference to the availability and practicality of the available methods for measuring these endpoints in clinical trials. Conclusions Based on current evidence, none of the four potential outcomes in question is sufficiently comprehensive to recommend as a uniform single outcome in randomised clinical trials. We propose that sarcopenia may be optimally defined (for the purposes of clinical trial inclusion criteria, as well as epidemiological studies) using a combination of measures of muscle mass and physical performance. The choice of outcome measures for clinical trials in sarcopenia is more difficult; co-primary outcomes, tailored to the specific intervention in question, may be the best way forward in this difficult but clinically important area. PMID:23842964

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial.

PubMed

Derdeyn, Colin P; Chimowitz, Marc I; Lynn, Michael J; Fiorella, David; Turan, Tanya N; Janis, L Scott; Montgomery, Jean; Nizam, Azhar; Lane, Bethany F; Lutsep, Helmi L; Barnwell, Stanley L; Waters, Michael F; Hoh, Brian L; Hourihane, J Maurice; Levy, Elad I; Alexandrov, Andrei V; Harrigan, Mark R; Chiu, David; Klucznik, Richard P; Clark, Joni M; McDougall, Cameron G; Johnson, Mark D; Pride, G Lee; Lynch, John R; Zaidat, Osama O; Rumboldt, Zoran; Cloft, Harry J

2014-01-25

Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. National Institute of Neurological Disorders and Stroke (NINDS) and others. Copyright © 2014 Elsevier Ltd. All rights reserved.

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial

PubMed Central

Derdeyn, Colin P; Chimowitz, Marc I; Lynn, Michael J; Fiorella, David; Turan, Tanya N; Janis, L Scott; Montgomery, Jean; Nizam, Azhar; Lane, Bethany F; Lutsep, Helmi L; Barnwell, Stanley L; Waters, Michael F; Hoh, Brian L; Hourihane, J Maurice; Levy, Elad I; Alexandrov, Andrei V; Harrigan, Mark R; Chiu, David; Klucznik, Richard P; Clark, Joni M; McDougall, Cameron G; Johnson, Mark D; Pride, G Lee; Lynch, John R; Zaidat, Osama O; Rumboldt, Zoran; Cloft, Harry J

2014-01-01

Summary Background Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. Methods We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70–99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. Findings During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (−0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%] of 224 patients vs 10 [4%] of 227 patients; p=0·0009). Interpretation The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. PMID:24168957

Patient navigation for lung cancer screening in an urban safety-net system: Protocol for a pragmatic randomized clinical trial.

PubMed

Gerber, David E; Hamann, Heidi A; Santini, Noel O; Abbara, Suhny; Chiu, Hsienchang; McGuire, Molly; Quirk, Lisa; Zhu, Hong; Lee, Simon J Craddock

2017-09-01

The National Lung Screening Trial demonstrated improved lung cancer mortality with annual low-dose computed tomography (CT) screening, leading to lung cancer screening endorsement by the United States Preventive Services Task Force and coverage by the Centers for Medicare and Medicaid. Adherence to annual CT screens in that trial was 95%, which may not be representative of real-world, particularly medically underserved populations. This pragmatic trial will determine the effect of patient-focused, telephone-based patient navigation on adherence to CT-based lung cancer screening in an urban safety-net population. 340 adults who meet standard eligibility for lung cancer screening (age 55-77years, smoking history≥30 pack-years, quit within 15years if former smoker) are referred through an electronic medical record-based order by physicians in community- and hospital-based primary care settings within the Parkland Health and Hospital System in Dallas County, Texas. Eligible patients are randomized to usual care or patient navigation, which addresses adherence, patient-reported barriers, smoking cessation, and psycho-social concerns related to screening completion. Patients complete surveys and semi-structured interviews at baseline, 6-month, and 18-month follow-ups to assess attitudes toward screening. The primary endpoint of this pragmatic trial is adherence to three sequential, prospectively defined steps in the screening protocol. Secondary endpoints include self-reported tobacco use and other patient-reported outcomes. Results will provide real-world insight into the impact of patient navigation on adherence to CT-based lung cancer screening in a medically underserved population. This study was registered with the NIH ClinicalTrials.gov database (NCT02758054) on April 26, 2016. Copyright © 2017 Elsevier Inc. All rights reserved.

Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial.

PubMed

Heery, Christopher R; Madan, Ravi A; Stein, Mark N; Stadler, Walter M; Di Paola, Robert S; Rauckhorst, Myrna; Steinberg, Seth M; Marté, Jennifer L; Chen, Clara C; Grenga, Italia; Donahue, Renee N; Jochems, Caroline; Dahut, William L; Schlom, Jeffrey; Gulley, James L

2016-10-18

PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM.

Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial

PubMed Central

Heery, Christopher R.; Madan, Ravi A.; Stein, Mark N.; Stadler, Walter M.; Di Paola, Robert S.; Rauckhorst, Myrna; Steinberg, Seth M.; Marté, Jennifer L.; Chen, Clara C.; Grenga, Italia; Donahue, Renee N.; Jochems, Caroline; Dahut, William L.; Schlom, Jeffrey; Gulley, James L.

2016-01-01

PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM. PMID:27486817

Vedolizumab: a review of its use in adult patients with moderately to severely active ulcerative colitis or Crohn's disease.

PubMed

Garnock-Jones, K P

2015-02-01

Vedolizumab (Entyvio™) is a humanized monoclonal antibody α4β7 integrin-receptor antagonist indicated for the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn's disease. This article reviews the pharmacological properties of intravenous infusions of vedolizumab and its clinical efficacy in adult patients with these diseases. In phase III clinical trials, patients with ulcerative colitis had significantly higher rates of clinical response and clinical remission when treated with vedolizumab than when receiving placebo at both 6 and 52 weeks. However, outcomes with vedolizumab in patients with Crohn's disease were mixed. In a study that evaluated both clinical remission rate and CDAI-100 response rate as primary endpoints, only the clinical remission rate at 6 weeks was significantly higher with vedolizumab than placebo. In another trial, there was no significant between-group difference in the clinical remission rate in TNF-antagonist failure patients at 6 weeks (primary endpoint), although there was a significant difference at 10 weeks. In the Crohn's disease study that included maintenance treatment, vedolizumab was significantly more effective at 52 weeks than placebo in both endpoints (clinical remission was the only primary endpoint in the maintenance study). Vedolizumab was generally well tolerated in these trials. As vedolizumab is a specific α4β7 integrin antagonist, with gut-specific effects, it is unlikely to be associated with the development of progressive multifocal leukoencephalopathy, a risk observed with the less selective α4β7/α4β1 integrin antagonist natalizumab. Vedolizumab is a useful addition to the treatment options available for patients with moderately to severely active ulcerative colitis and Crohn's disease.

Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.

PubMed

Johansen, Odd Erik; Neubacher, Dietmar; von Eynatten, Maximilian; Patel, Sanjay; Woerle, Hans-Juergen

2012-01-10

This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments. This was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis. Of 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]). These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM. © 2012 Johansen et al; licensee BioMed Central Ltd.

Development and validation of optimal cut-off value in inter-arm systolic blood pressure difference for prediction of cardiovascular events.

PubMed

Hirono, Akira; Kusunose, Kenya; Kageyama, Norihito; Sumitomo, Masayuki; Abe, Masahiro; Fujinaga, Hiroyuki; Sata, Masataka

2018-01-01

An inter-arm systolic blood pressure difference (IAD) is associated with cardiovascular disease. The aim of this study was to develop and validate the optimal cut-off value of IAD as a predictor of major adverse cardiac events in patients with arteriosclerosis risk factors. From 2009 to 2014, 1076 patients who had at least one cardiovascular risk factor were included in the analysis. We defined 700 randomly selected patients as a development cohort to confirm that IAD was the predictor of cardiovascular events and to determine optimal cut-off value of IAD. Next, we validated outcomes in the remaining 376 patients as a validation cohort. The blood pressure (BP) of both arms measurements were done simultaneously using the ankle-brachial blood pressure index (ABI) form of automatic device. The primary endpoint was the cardiovascular event and secondary endpoint was the all-cause mortality. During a median period of 2.8 years, 143 patients reached the primary endpoint in the development cohort. In the multivariate Cox proportional hazards analysis, IAD was the strong predictor of cardiovascular events (hazard ratio: 1.03, 95% confidence interval: 1.01-1.05, p=0.005). The receiver operating characteristic curve revealed that 5mmHg was the optimal cut-off point of IAD to predict cardiovascular events (p<0.001). In the validation cohort, the presence of a large IAD (IAD ≥5mmHg) was significantly associated with the primary endpoint (p=0.021). IAD is significantly associated with future cardiovascular events in patients with arteriosclerosis risk factors. The optimal cut-off value of IAD is 5mmHg. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease.

PubMed

Bernay, F; Bland, J M; Häggström, J; Baduel, L; Combes, B; Lopez, A; Kaltsatos, V

2010-01-01

Spironolactone, an aldosterone antagonist, has been demonstrated to decrease mortality in human patients when added to other cardiac therapies. Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Between February 2003 and March 2005, 221 dogs were recruited in Europe. Nine dogs were excluded from analysis, leaving 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). Double-blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac-related death, euthanasia, or severe worsening of MR. Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22-0.90; log rank test, P = .017). Risk of cardiac-related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13-0.76; P = .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD.

Urate predicts rate of clinical decline in Parkinson disease

PubMed Central

Ascherio, Alberto; LeWitt, Peter A.; Xu, Kui; Eberly, Shirley; Watts, Arthur; Matson, Wayne R.; Marras, Connie; Kieburtz, Karl; Rudolph, Alice; Bogdanov, Mikhail B.; Schwid, Steven R.; Tennis, Marsha; Tanner, Caroline M.; Beal, M. Flint; Lang, Anthony E.; Oakes, David; Fahn, Stanley; Shoulson, Ira; Schwarzschild, Michael A.

2009-01-01

Context The risk of Parkinson disease (PD) and its rate of progression may decline with increasing blood urate, a major antioxidant. Objective To determine whether serum and cerebrospinal fluid (CSF) concentrations of urate predict clinical progression in patients with PD. Design, Setting, and Participants 800 subjects with early PD enrolled in the DATATOP trial. Pre-treatment urate was measured in serum for 774 subjects and in CSF for 713. Main Outcome Measures Treatment-, age- and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the pre-specified primary endpoint. Results The HR of progressing to endpoint decreased with increasing serum urate (HR for 1 standard deviation increase = 0.82; 95% CI = 0.73 to 0.93). In analyses stratified by α-tocopherol treatment (2,000 IU/day), a decrease in the HR for the primary endpoint was seen only among subjects not treated with α-tocopherol (HR = 0.75; 95% CI = 0.62 to 0.89, versus those treated HR = 0.90; 95% CI = 0.75 to 1.08). Results were similar for the rate of change in the United Parkinson Disease Rating Scale (UPDRS). CSF urate was also inversely related to both the primary endpoint (HR for highest versus lowest quintile = 0.65; 95% CI: 0.54 to 0.96) and to the rate of change in UPDRS. As with serum urate, these associations were present only among subjects not treated with α-tocopherol. Conclusion Higher serum and CSF urate at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate and PD and the rationale for considering CNS urate elevation as a potential strategy to slow PD progression. PMID:19822770

Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R

Endpoint-based parallel data processing with non-blocking collective instructions in a PAMI of a parallel computer is disclosed. The PAMI is composed of data communications endpoints, each including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task. The compute nodes are coupled for data communications through the PAMI. The parallel application establishes a data communications geometry specifying a set of endpoints that are used in collective operations of the PAMI by associating with the geometry a list of collective algorithms valid for use with themore » endpoints of the geometry; registering in each endpoint in the geometry a dispatch callback function for a collective operation; and executing without blocking, through a single one of the endpoints in the geometry, an instruction for the collective operation.« less

[PHARMAGRIPS: structured pharmaceutical counseling in the self-medication of the common cold. A randomised controlled study (RCT)].

PubMed

Laven, Anna; Schäfer, Julia; Läer, Stephanie

2014-06-01

Many minor ailments are treated in Germany by self-medication. Most drugs dispensed by pharmacy staff are those for the common cold, general pain and gastrointestinal disorders. Whilst pharmacists express their need for further training in counseling on side effects, interactions and contraindications, they tend to receive feedback from patients to the effect that the drugs used have not worked. From July to October 2013 we carried out a prospective, single-blind, quasi-randomised controlled study on the effect of training on structured pharmaceutical advice in self-medication of the common cold (PHARMAGRIPS Study). Using a controlled, interventional study design we investigated whether it is possible to improve the pharmaceutical counseling in self-medication within a short time, by using an appropriate teaching method. The counseling should be made in a systematic way and refer to evidence-based content in order to avoid incorrect advice. We enrolled 86 pharmacists and assigned them randomly into the study protocol. Of those, 56 completed the study as planned and were analysed. In this study, we reviewed the structure of the average pharmaceutical consultation and added evidence-based content from the Cochrane Reviews on common cold. We then integrated this structured consultation in a methodical modem training program consisting of e-learning and live classes which we evaluated scientifically. For this purpose, we conducted telephone interviews with the participating pharmacists by using standardized case report forms. The case report forms contained the questions that the participants were supposed to ask. For every question asked, the participant received a certain amount of points, 18 in total. The training was stated to be successful at the primary endpoint when an improvement of at least 3.5 out of 18 points was achieved on average. The secondary endpoints were related to various aspects of the interview process (medical history, limits of self-medication, evidence-based drug selection and integration of customer input in the consultation interaction). The training group improved in the primary endpoint by an average of 5.93 points (p < 0.001) and compared to the control group significantly in all secondary endpoints, with one participant managing to achieve the full score. The participants recognized the importance and practical relevance of the exercise in a short time and were able to implement even integrate complex content in their consultations and to give the customer appropriate advice.

PATCH: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial.

PubMed

de Gans, Koen; de Haan, Rob J; Majoie, Charles B; Koopman, Maria M; Brand, Anneke; Dijkgraaf, Marcel G; Vermeulen, Marinus; Roos, Yvo B

2010-03-18

Patients suffering from intracerebral haemorrhage have a poor prognosis, especially if they are using antiplatelet therapy. Currently, no effective acute treatment option for intracerebral haemorrhage exists. Limiting the early growth of intracerebral haemorrhage volume which continues the first hours after admission seems a promising strategy. Because intracerebral haemorrhage patients who are on antiplatelet therapy have been shown to be particularly at risk of early haematoma growth, platelet transfusion may have a beneficial effect. The primary objective is to investigate whether platelet transfusion improves outcome in intracerebral haemorrhage patients who are on antiplatelet treatment. The PATCH study is a prospective, randomised, multi-centre study with open treatment and blind endpoint evaluation. Patients will be randomised to receive platelet transfusion within six hours or standard care. The primary endpoint is functional health after three months. The main secondary endpoints are safety of platelet transfusion and the occurrence of haematoma growth. To detect an absolute poor outcome reduction of 20%, a total of 190 patients will be included. To our knowledge this is the first randomised controlled trial of platelet transfusion for an acute haemorrhagic disease.

A multicentre European registry to evaluate the Direct Flow Medical transcatheter aortic valve system for the treatment of patients with severe aortic stenosis.

PubMed

Naber, Christoph K; Pyxaras, Stylianos A; Ince, Hüseyin; Frambach, Peter; Colombo, Antonio; Butter, Christian; Gatto, Fernando; Hink, Ulrich; Nickenig, Georg; Bruschi, Giuseppe; Brueren, Guus; Tchétché, Didier; Den Heijer, Peter; Schillinger, Wolfgang; Scholtz, Smita; Van der Heyden, Jan; Lefèvre, Thierry; Gilard, Martine; Kuck, Karl-Heinz; Schofer, Joachim; Divchev, Dimitar; Baumgartner, Helmut; Asch, Federico; Wagner, Daniel; Latib, Azeem; De Marco, Federico; Kische, Stephan

2016-12-10

Our aim was to assess the clinical outcomes of the Direct Flow Medical Transcatheter Aortic Valve System (DFM-TAVS), when used in routine clinical practice. This is a prospective, open-label, multicentre, post-market registry of patients treated with DFM-TAVS according to approved commercial indications. Echocardiographic and angiographic data were evaluated by an independent core laboratory and adverse events were adjudicated and classified according to VARC-2 criteria by an independent clinical events committee. The primary endpoint was freedom from all-cause mortality at 30 days post procedure. Secondary endpoints included procedural, early safety and efficacy endpoints at 30 days. Two hundred and fifty patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) with the DFM-TAVS were enrolled in 21 European centres. The primary endpoint, freedom from all-cause mortality at 30 days, was met in 98% (245/250) of patients. Device success was 83.8%. Moderate or severe aortic regurgitation was reported in 3% of patients, and none/trace regurgitation in 73% of patients. Post-procedural permanent pacemaker implantation was performed in 30 patients (12.0%). The DFM-TAVS was associated with good short-term outcomes in this real-world registry. The low pacemaker and aortic regurgitation rates confirm the advantages of this next-generation transcatheter heart valve (THV).

Endpoints in medical communication research, proposing a framework of functions and outcomes.

PubMed

de Haes, Hanneke; Bensing, Jozien

2009-03-01

The evidence base of medical communication has been underdeveloped and the field was felt to be in need for thorough empirical investigation. Studying medical communication can help to clarify what happens during medical encounters and, subsequently, whether the behavior displayed is effective. However, before effectiveness can be established, one should argue what functions or goals the communication has and what outcomes are relevant in medical communication research. In the present paper, we first suggest the six function model of medical communication based on the integration of earlier models. The model distinguishes (1) fostering the relationship, (2) gathering information, (3) information provision, (4) decision making, (5) enabling disease and treatment-related behavior, and (6) responding to emotions. Secondly, a framework for endpoints in such research is presented. Immediate, intermediate and long-term outcomes are distinguished on the one hand and patient-, provider- and process- or context-related outcomes on the other. Based on this framework priorities can be defined and a tentative hierarchy proposed. Health is suggested to be the primary goal of medical communication as are patient-related outcomes. Dilemmas are described. Finally, in medical communication research, theory is advocated to link health care provider behavior or skills to outcomes and to connect intermediate outcomes to long-term ones. By linking specific communication elements to concrete endpoints within the six function model of medical communication, communication will become better integrated within the process of medical care. This is helpful to medical teachers and motivational to medical students. This approach can provide the place to medical communication it deserves in the center of medical care.

Advanced topics in evidence-based urologic oncology: surrogate endpoints.

PubMed

Lavallée, Luke T; Montori, Victor M; Canfield, Stephen E; Breau, Rodney H

2011-01-01

Clinical trials often report surrogate endpoint data. A surrogate endpoint is a biological marker or clinical sign that can be substituted for a patient-important outcome. Using surrogate endpoints correctly may facilitate and expedite clinical trials and may improve medical decisions. However, rigorous criteria must be met for an endpoint to be considered a valid surrogate. The purpose of this article is to review the topic of surrogate endpoints in the context of a urologic encounter. Copyright © 2011 Elsevier Inc. All rights reserved.

A comparison of water quality criteria for the Great Lakes based on human and wildlife health

USGS Publications Warehouse

Ludwig, James P.; Giesy, John P.; Summer, Cheryl L.; Bowerman, William; Aulerich, Richard J.; Bursian, Steven J.; Auman, Heidi J.; Jones, Paul D.; Williams, Lisa L.; Tillitt, Donald E.; Gilbertson, Michael

1993-01-01

Water quality criteria (WQC) can be derived in several ways. The usual techniques involve hazard and risk assessment procedures. For non-persistent, non-biomagnified compounds and elements, WQC are experimentally derived from their acute and chronic toxicity to aquatic organisms. For those persistent chlorinated hydrocarbons (PCHs) that are bioaccumulated and biomagnified, these traditional techniques have not been effective, partly because effects higher in the food web were not considered. Polychlorinated biphenyls (PCBs) are the bioaccumulative synthetic chemicals of primary toxicological significance to the Great Lakes biota which have caused widespread injury to wildlife. In the Laurentian Great Lakes, the primary emphasis of hazard assessments has been on the potential for adverse effects in humans who eat fish. The primary regulatory endpoint of traditional hazard and risk assessments underlying current WQC are the probabilities of additional cancers occurring in the human population. The analysis presented here indicates that this is not adequate to restore sensitive wildlife species that are highly exposed to PCBs, especially those that have suffered serious population declines. Because WQC are legal instruments, the methods of deriving WQC have large implications for remediation, litigation, and damage assessments. Here WQC are derived for six species based on the responses of wildlife in the field or produced by feeding fish to surrogate species, rather than projecting a potential of increased cancer rates in humans. If the most sensitive wildlife species are restored and protected for very sensitive reproductive endpoints, then all components of the ecosystem, including human health, should be more adequately protected. The management of Great Lakes wildlife requires an understanding of the injury and causal relationships to persistent toxic substances.

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

PubMed

van der Heijde, Désirée; Deodhar, Atul; Wei, James C; Drescher, Edit; Fleishaker, Dona; Hendrikx, Thijs; Li, David; Menon, Sujatha; Kanik, Keith S

2017-08-01

To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis). In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored. Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16. Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications. NCT01786668. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R

Methods, apparatuses, and computer program products for endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface (`PAMI`) of a parallel computer are provided. Embodiments include establishing by a parallel application a data communications geometry, the geometry specifying a set of endpoints that are used in collective operations of the PAMI, including associating with the geometry a list of collective algorithms valid for use with the endpoints of the geometry. Embodiments also include registering in each endpoint in the geometry a dispatch callback function for a collective operation and executing without blocking, through a single onemore » of the endpoints in the geometry, an instruction for the collective operation.« less

Thromboelastometry versus standard coagulation tests versus restrictive protocol to guide blood transfusion prior to central venous catheterization in cirrhosis: study protocol for a randomized controlled trial.

PubMed

Rocha, Leonardo Lima; Pessoa, Camila Menezes Souza; Neto, Ary Serpa; do Prado, Rogerio Ruscitto; Silva, Eliezer; de Almeida, Marcio Dias; Correa, Thiago Domingos

2017-02-27

Liver failure patients have traditionally been empirically transfused prior to invasive procedures. Blood transfusion is associated with immunologic and nonimmunologic reactions, increased risk of adverse outcomes and high costs. Scientific evidence supporting empirical transfusion is lacking, and the best approach for blood transfusion prior to invasive procedures in cirrhotic patients has not been established so far. The aim of this study is to compare three transfusion strategies (routine coagulation test-guided - ordinary or restrictive, or thromboelastometry-guided) prior to central venous catheterization in critically ill patients with cirrhosis. Design and setting: a double-blinded, parallel-group, single-center, randomized controlled clinical trial in a tertiary private hospital in São Paulo, Brazil. adults (aged 18 years or older) admitted to the intensive care unit with cirrhosis and an indication for central venous line insertion. Patients will be randomly assigned to three groups for blood transfusion strategy prior to central venous catheterization: standard coagulation tests-based, thromboelastometry-based, or restrictive. The primary efficacy endpoint will be the proportion of patients transfused with any blood product prior to central venous catheterization. The primary safety endpoint will be the incidence of major bleeding. Secondary endpoints will be the proportion of transfusion of fresh frozen plasma, platelets and cryoprecipitate; infused volume of blood products; hemoglobin and hematocrit before and after the procedure; intensive care unit and hospital length of stay; 28-day and hospital mortality; incidence of minor bleeding; transfusion-related adverse reactions; and cost analysis. This study will evaluate three strategies to guide blood transfusion prior to central venous line placement in severely ill patients with cirrhosis. We hypothesized that thromboelastometry-based and/or restrictive protocols are safe and would significantly reduce transfusion of blood products in this population, leading to a reduction in costs and transfusion-related adverse reactions. In this manner, this trial will add evidence in favor of reducing empirical transfusion in severely ill patients with coagulopathy. ClinicalTrials.gov, identifier: NCT02311985 . Retrospectively registered on 3 December 2014.

76 FR 1620 - Trials to Verify and Describe Clinical Benefit of Midodrine Hydrochloride; Establishment of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-11

... a surrogate endpoint that is reasonably likely to predict clinical benefit or based on a clinical endpoint other than survival or irreversible morbidity. Approval of PROAMATINE was based on trials... surrogate endpoints are ``subject to the requirement that the applicant study the drug further to verify and...

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T).

PubMed

Tanaka, Yoshiya; Takeuchi, Tsutomu; Harigai, Masayoshi; Yamanaka, Hisashi; Nakano, Toshikazu; Akagi, Koshiro; Ukyo, Yoshifumi; Hsu, Benjamin

2018-04-13

To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

Progressive resistance training in head and neck cancer patients undergoing concomitant chemoradiotherapy

PubMed Central

Lonkvist, Camilla K.; Vinther, Anders; Zerahn, Bo; Rosenbom, Eva; Deshmukh, Atul S.; Hojman, Pernille

2017-01-01

Objectives Patients with head and neck squamous cell carcinoma undergoing concomitant chemoradiotherapy (CCRT) frequently experience weight loss, especially loss of lean body mass (LBM), and reduced functional performance. This study investigated whether a 12‐week hospital‐based progressive resistance training (PRT) program during CCRT is feasible in the clinical setting before planning initiation of a larger randomized study which is the long‐term goal. Study design Prospective pilot study. Methods Twelve patients receiving CCRT were planned to attend a 12‐week PRT program. Primary endpoint was feasibility measured as attendance to training sessions. Secondary endpoints included changes in functional performance, muscle strength, and body composition measured by Dual‐energy X‐ray Absorptiometry (DXA) scans. Furthermore, sarcomeric protein content, pentose phosphate pathway (PPP) activity, and glycolysis were determined in muscle biopsies. Results Twelve patients with p16 positive oropharyngeal cancer were enrolled. The primary endpoint was met with 9 of the 12 patients completing at least 25 of 36 planned training sessions. The mean attendance rate was 77%. Functional performance was maintained during the treatment period and increased during follow‐up (p < 0.01). Strength was regained after an initial dip during treatment, paralleling responses in LBM and sarcomeric protein content. LBM began to increase immediately after treatment. The PPP was upregulated after the treatment period, whilst glycolysis remained unchanged. No adverse events were related to PRT and in questionnaires, patients emphasized the social and psychological benefits of attendance. Conclusion Progressive resistance training is feasible and safe during CCRT for head and neck cancer, and is associated with high patient satisfaction. Level of Evidence 2C. PMID:29094074

Coping with missing data in phase III pivotal registration trials: Tolvaptan in subjects with kidney disease, a case study.

PubMed

Ouyang, John; Carroll, Kevin J; Koch, Gary; Li, Junfang

2017-07-01

Missing data cause challenging issues, particularly in phase III registration trials, as highlighted by the European Medicines Agency (EMA) and the US National Research Council. We explore, as a case study, how the issues from missing data were tackled in a double-blind phase III trial in subjects with autosomal dominant polycystic kidney disease. A total of 1445 subjects were randomized in a 2:1 ratio to receive active treatment (tolvaptan), or placebo. The primary outcome, the rate of change in total kidney volume, favored tolvaptan (P < .0001). The key secondary efficacy endpoints of clinical progression of disease and rate of decline in kidney function also favored tolvaptan. However, as highlighted by Food and Drug Administration and EMA, the interpretation of results was hampered by a high number of unevenly distributed dropouts, particularly early dropouts. In this paper, we outline the analyses undertaken to address the issue of missing data thoroughly. "Tipping point analyses" were performed to explore how extreme and detrimental outcomes among subjects with missing data must be to overturn the positive treatment effect attained in those subjects who had complete data. Nonparametric rank-based analyses were also performed accounting for missing data. In conclusion, straightforward and transparent analyses directly taking into account missing data convincingly support the robustness of the preplanned analyses on the primary and secondary endpoints. Tolvaptan was confirmed to be effective in slowing total kidney volume growth, which is considered an efficacy endpoint by EMA, and in lessening the decline in renal function in patients with autosomal dominant polycystic kidney disease. Copyright © 2017 John Wiley & Sons, Ltd.

Inhaled Colistin in Patients with Bronchiectasis and Chronic Pseudomonas aeruginosa Infection

PubMed Central

Foweraker, Juliet E.; Wilkinson, Peter; Kenyon, Robert F.; Bilton, Diana

2014-01-01

Rationale: Chronic infection with Pseudomonas aeruginosa is associated with an increased exacerbation frequency, a more rapid decline in lung function, and increased mortality in patients with bronchiectasis. Objectives: To perform a randomized placebo-controlled study assessing the efficacy and safety of inhaled colistin in patients with bronchiectasis and chronic P. aeruginosa infection. Methods: Patients with bronchiectasis and chronic P. aeruginosa infection were enrolled within 21 days of completing a course of antipseudomonal antibiotics for an exacerbation. Participants were randomized to receive colistin (1 million IU; n = 73) or placebo (0.45% saline; n = 71) via the I-neb twice a day, for up to 6 months. Measurements and Main Results: The primary endpoint was time to exacerbation. Secondary endpoints included time to exacerbation based on adherence recorded by the I-neb, P. aeruginosa bacterial density, quality of life, and safety parameters. All analyses were on the intention-to-treat population. Median time (25% quartile) to exacerbation was 165 (42) versus 111 (52) days in the colistin and placebo groups, respectively (P = 0.11). In adherent patients (adherence quartiles 2–4), the median time to exacerbation was 168 (65) versus 103 (37) days in the colistin and placebo groups, respectively (P = 0.038). P. aeruginosa density was reduced after 4 (P = 0.001) and 12 weeks (P = 0.008) and the St. George’s Respiratory Questionnaire total score was improved after 26 weeks (P = 0.006) in the colistin versus placebo patients, respectively. There were no safety concerns. Conclusions: Although the primary endpoint was not reached, this study shows that inhaled colistin is a safe and effective treatment in adherent patients with bronchiectasis and chronic P. aeruginosa infection. Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596) PMID:24625200

Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.

PubMed

Baas, Jara M; Krens, Lisanne L; Bos, Monique M; Portielje, Johanneke E A; Batman, Erdogan; van Wezel, Tom; Morreau, Hans; Guchelaar, Henk-Jan; Gelderblom, Hans

2015-09-01

Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.

T-wave area as biomarker of clinical response to cardiac resynchronization therapy.

PubMed

Végh, Eszter M; Engels, Elien B; van Deursen, Caroline J M; Merkely, Béla; Vernooy, Kevin; Singh, Jagmeet P; Prinzen, Frits W

2016-07-01

There is increasing evidence that left bundle branch block (LBBB) morphology on the electrocardiogram is a positive predictor for response to cardiac resynchronization therapy (CRT). We previously demonstrated that the vectorcardiography (VCG)-derived T-wave area predicts echocardiographic CRT response in LBBB patients. In the present study, we investigate whether the T-wave area also predicts long-term clinical outcome to CRT. This is a retrospective study consisting of 335 CRT recipients. Primary endpoint were the composite of heart failure (HF) hospitalization, heart transplantation, left ventricular assist device implantation or death during a 3-year follow-up period. HF hospitalization and death alone were secondary endpoints. The patient subgroup with a large T-wave area and LBBB 36% reached the primary endpoint, which was considerably less (P < 0.01) than for patients with LBBB and a small T-wave area or non-LBBB patients with a small or large T-wave area (48, 57, and 51%, respectively). Similar differences were observed for the secondary endpoints, HF hospitalization (31 vs. 51, 51, and 38%, respectively, P < 0.01) and death (19 vs. 42, 34, and 42%, respectively, P < 0.01). In multivariate analysis, a large T-wave area and LBBB were the only independent predictors of the combined endpoint besides high creatinine levels and use of diuretics. T-wave area may be useful as an additional biomarker to stratify CRT candidates and improve selection of those most likely to benefit from CRT. A large T-wave area may derive its predictive value from reflecting good intrinsic myocardial properties and a substrate for CRT. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

PubMed Central

Seymour, Lesley; Ivy, S. Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

2010-01-01

The optimal design of phase II studies continues to be the subject of vigorous debate, especially with regards to studies of newer molecularly targeted agents. The observations that many new therapeutics ‘fail’ in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials further emphasizes the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force(CTD-TF)of the NCI Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on Phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations regarding aspects of phase II trial design which are the subject of frequent debate such as endpoints(response vs. progression free survival), randomization(single arm designs vs. randomization), inclusion of biomarkers, biomarker based patient enrichment strategies, and statistical design(e.g. two stage designs vs. multiple-group adaptive designs). While these recommendations in general encourage the use of progression-free survival as the primary endpoint, the use of randomization, the inclusion of biomarkers and the incorporation of newer designs, we acknowledge that objective response as an endpoint, and single arm designs, remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on the characteristic specific to the situation. PMID:20215557

Surrogate endpoints for overall survival in lung cancer trials: a review.

PubMed

Fiteni, Frédéric; Westeel, Virginie; Bonnetain, Franck

2017-05-01

Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS. Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials. Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia

PubMed Central

MacDonald, Thomas M; Ford, Ian; Nuki, George; Mackenzie, Isla S; De Caterina, Raffaele; Findlay, Evelyn; Hallas, Jesper; Hawkey, Christopher J; Ralston, Stuart; Walters, Matthew; Webster, John; McMurray, John; Perez Ruiz, Fernando; Jennings, Claudine G

2014-01-01

Introduction Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST). Methods and analysis FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists’ Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3. Ethics and dissemination FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal. Trial Registration number FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728). PMID:25011991

SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.

PubMed

Rochlitz, Christoph; Bigler, Martin; von Moos, Roger; Bernhard, Jürg; Matter-Walstra, Klazien; Wicki, Andreas; Zaman, Khalil; Anchisi, Sandro; Küng, Marc; Na, Kyung-Jae; Bärtschi, Daniela; Borner, Markus; Rordorf, Tamara; Rauch, Daniel; Müller, Andreas; Ruhstaller, Thomas; Vetter, Marcus; Trojan, Andreas; Hasler-Strub, Ursula; Cathomas, Richard; Winterhalder, Ralph

2016-10-10

Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab. This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3-5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010. Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15-35 %) and arm B (24 % [16/68]; 95 % CI 13-34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46-0.69) and 50 % (37/74; 95 % CI 0.39-0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7-11.3) in arm A and 8.5 months (95 % CI 6.5-11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent. This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3-5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.

The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial.

PubMed

Eisen, Alon; Cannon, Christopher P; Blazing, Michael A; Bohula, Erin A; Park, Jeong-Gun; Murphy, Sabina A; White, Jennifer A; Giugliano, Robert P; Braunwald, Eugene

2016-12-21

To examine the efficacy and safety of ezetimibe added to statin in patients with prior coronary artery bypass graft surgery (CABG) following hospitalization for an acute coronary syndrome (ACS). In the IMPROVE-IT trial, post-ACS patients with mean low density lipoprotein cholesterol (LDL-C) of 93.8 mg/dL at presentation were randomized to simvastatin/ezetimibe or simvastatin/placebo. The primary endpoint was cardiovascular death, major coronary event or stroke, and the median follow-up was 6 years. Efficacy and safety endpoints were examined by prior CABG status. Among 18 134 patients, 1684 (9.3%) had a prior CABG (median age 69 years, 82% male). During the trial, the median time-weighted LDL-C level was 55.0 mg/dL with simvastatin/ezetimibe vs. 69.9 mg/dL with simvastatin/placebo in patients with prior CABG (P < 0.001), and it was 53.6 mg/dL vs. 69.5 mg/dL, respectively, in patients without prior CABG (P < 0.001). The rate of the primary endpoint was higher in patients with vs. without prior CABG [56% vs. 32%, adj. hazard ratio 1.45, 95% confidence interval (CI) 1.33-1.58]. Patients with prior CABG receiving simvastatin/ezetimibe had an 8.8% (95% CI 3.1-14.6%) lower absolute risk over simvastatin/placebo in the primary endpoint, whereas patients without prior CABG had a 1.3% (95% CI 0-2.6%) lower absolute risk (P-interaction = 0.02). There were no between-group significant differences in safety endpoints. The clinical benefit of adding ezetimibe to statin appears to be enhanced in patients with prior CABG, supporting the use of intensive lipid lowering therapy in these high-risk patients following ACS. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

A non-randomized confirmatory trial of segmentectomy for clinical T1N0 lung cancer with dominant ground glass opacity based on thin-section computed tomography (JCOG1211).

PubMed

Aokage, Keiju; Saji, Hisashi; Suzuki, Kenji; Mizutani, Tomonori; Katayama, Hiroshi; Shibata, Taro; Watanabe, Syunichi; Asamura, Hisao

2017-05-01

Lobectomy has been the standard surgery for even stage I lung cancer since the validity of limited resection for stage I lung cancer was denied by the randomized study reported in 1995. The aim of this non-randomized confirmatory going on since September 2013 is to confirm the efficacy of a segmentectomy for clinical T1N0 lung cancer with dominant ground glass opacity based on thin-slice computed tomography. A total of 390 patients from 42 Japanese institutions are recruited within 4 years. The primary endpoint of this study is a 5-year relapse-free survival in all of the patients who undergo a segmentectomy for a lung nodule. The secondary endpoints are overall survival, annual relapse-free survival, disease-free survival, proportion of local relapse, postoperative pulmonary function, proportion of segmentectomy completion, proportion of R0 resection completion by segmentectomy, adverse events, and serious adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000011819 ( http://www.umin.ac.jp/ctr/ ). Patient's accrual has been already finished in November, 2015 and the primary analysis will be performed in 2021. This study is one of the pivotal trial of lung segmentectomy for early lung cancer. The result will provide a clear evidence for our daily clinics and will be possible contribution to preserving pulmonary function for lung cancer patients.

Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

PubMed

Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

2017-12-01

Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

Preoperative computer simulation for planning of vascular access surgery in hemodialysis patients.

PubMed

Zonnebeld, Niek; Huberts, Wouter; van Loon, Magda M; Delhaas, Tammo; Tordoir, Jan H M

2017-03-06

The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients. Unfortunately, 20-40% of all constructed AVFs fail to mature (FTM), and are therefore not usable for hemodialysis. AVF maturation importantly depends on postoperative blood volume flow. Predicting patient-specific immediate postoperative flow could therefore support surgical planning. A computational model predicting blood volume flow is available, but the effect of blood flow predictions on the clinical endpoint of maturation (at least 500 mL/min blood volume flow, diameter of the venous cannulation segment ≥4 mm) remains undetermined. A multicenter randomized clinical trial will be conducted in which 372 patients will be randomized (1:1 allocation ratio) between conventional healthcare and computational model-aided decision making. All patients are extensively examined using duplex ultrasonography (DUS) during preoperative assessment (12 venous and 11 arterial diameter measurements; 3 arterial volume flow measurements). The computational model will predict patient-specific immediate postoperative blood volume flows based on this DUS examination. Using these predictions, the preferred AVF configuration is recommended for the individual patient (radiocephalic, brachiocephalic, or brachiobasilic). The primary endpoint is FTM rate at six weeks in both groups, secondary endpoints include AVF functionality and patency rates at 6 and 12 months postoperatively. ClinicalTrials.gov (NCT02453412), and ToetsingOnline.nl (NL51610.068.14).

Performance of Crohn's disease Clinical Trial Endpoints based upon Different Cutoffs for Patient Reported Outcomes or Endoscopic Activity: Analysis of EXTEND Data.

PubMed

Feagan, Brian; Sandborn, William J; Rutgeerts, Paul; Levesque, Barrett G; Khanna, Reena; Huang, Bidan; Zhou, Qian; Maa, Jen-Fue; Wallace, Kori; Lacerda, Ana; Thakkar, Roopal B; Robinson, Anne M

2018-04-23

Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation. This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups. Increased stringency of Week 12 clinical endpoints compared to CDAI<150 to SF≤3.0/1.5&AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects. This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Clinical outcome of renal artery stenting for hypertension and chronic kidney disease up to 12 months in the J-RAS Study – prospective, single-arm, multicenter clinical study.

PubMed

Fujihara, Masahiko; Yokoi, Yoshiaki; Abe, Takaaki; Soga, Yoshimitsu; Yamashita, Takehiro; Miyashita, Yusuke; Nakamura, Masato; Yokoi, Hiroyoshi; Ito, Sadayoshi

2015-01-01

Atherosclerotic renal artery stenosis (ARAS) causes renovascular hypertension (HTN) and impairs renal function, leading to chronic kidney disease (CKD). The J-RAS study was a prospective, multicenter study to assess the clinical outcome of renal artery stenting for up to 1 year in Japanese patients with ARAS. One hundred and forty-nine patients were enrolled between November 2010 and January 2013. The patients were classified into an HTN (n=121) group and a CKD (n=108) group in the primary analysis. The primary efficacy endpoints were change in blood pressure for the HTN group and change in estimated glomerular filtration rate (eGFR) for the CKD group at 1 months. The primary safety endpoint was freedom from major cardiovascular or renal events at 12 months. In the HTN group, the mean systolic blood pressure (SBP) significantly decreased from 161.6 ± 21 mmHg at baseline to 137.0 ± 21 mmHg (P<0.0001). In the CKD group, there was no significant difference in eGFR from 40.7 ± 10 ml·min(-1)·1.73 m(-2)at baseline to 40.8 ± 13 ml·min(-1)·1.73 m(-2)(P=0.32). The primary safety endpoint was 89.4% at 12 months. In the J-RAS trial, significant SBP reduction was seen in the HTN group, and stabilization of renal function in the CKD group. Renal artery stenting for ARAS is safe and effective in Japanese patients.

Impedance-based cellular assay technologies: recent advances, future promise.

PubMed

McGuinness, Ryan

2007-10-01

Cell-based assays are continuing to grow in importance in the drug discovery workflow. Their early introduction holds the promise of limiting attrition in the later, more costly phases of the process. This article reviews recent advances in the development of impedance technologies for label-free cell-based assays. These systems are capable of monitoring endogenous receptor activation, and thus generate more physiologically relevant measures of pharmacological endpoints. Primary cells can be investigated as well, thus producing disease relevant information. Label-free assays significantly decrease assay development efforts and avoid many complications inherent in recombinant readout systems. Impedance-based systems have great potential to advance the utility of cell-based assays as they are applied to drug discovery and pharmacology.

Design and Methodology of the Trial to Assess Chelation Therapy (TACT)

PubMed Central

Lamas, Gervasio A.; Goertz, Christine; Boineau, Robin; Mark, Daniel B.; Rozema, Theodore; Nahin, Richard L.; Drisko, Jeanne A.; Lee, Kerry L.

2011-01-01

The Trial to Assess Chelation Therapy (TACT) is an NIH-sponsored, randomized, double blind, placebo-controlled, 2×2 factorial clinical trial testing the benefits and risks of 40 infusions of a multi-component Na2EDTA-chelation solution compared with placebo, and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow 1708 patients for an average of approximately 4 years. The primary endpoint is a composite of all cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900 patient substudy will examine quality of life outcomes. The trial is designed to have >85% power to detect a 25% relative reduction in the primary endpoint for each treatment factor. Enrollment began in September 2003 and completed in October 2010. PMID:22172430

The impact of phosphate-balanced crystalloid infusion on acid-base homeostasis (PALANCE study): study protocol for a randomized controlled trial.

PubMed

Pagel, Judith-Irina; Hulde, Nikolai; Kammerer, Tobias; Schwarz, Michaela; Chappell, Daniel; Burges, Alexander; Hofmann-Kiefer, Klaus; Rehm, Markus

2017-07-10

This study aims to investigate the effects of a modified, balanced crystalloid including phosphate in a perioperative setting in order to maintain a stable electrolyte and acid-base homeostasis in the patient. This is a single-centre, open-label, randomized controlled trial involving two parallel groups of female patients comparing a perioperative infusion regime with sodium glycerophosphate and Jonosteril® (treatment group) or Jonosteril® (comparator) alone. The primary endpoint is to maintain a stable concentration of weak acids [A - ] according to the Stewart approach of acid-base balance. Secondary endpoints are measurement of serum phosphate levels, other acid-base parameters such as the strong ion difference (SID), the onset and severity of postoperative nausea and vomiting (PONV), electrolyte levels and their excretion in the urine, monitoring of renal function and glycocalyx components, haemodynamics, amounts of catecholamines and other vasopressors used and the safety of the infusion regime. Perioperative fluid replacement with the use of currently available crystalloid preparations still fail to maintain a stable acid-base balance and experts agree that common balanced solutions are still not ideal. This study aims to investigate the effectivity and safety of a new crystalloid solution by adding sodium glycerophosphate to a standardized crystalloid preparation in order to maintain a balanced perioperative acid-base homeostasis. EudraCT number 201002422520 . Registered on 30 November 2010.

Surrogate Endpoints and Risk Adaptive Strategies in Previously Untreated Follicular Lymphoma.

PubMed

Narkhede, Mayur S; Cheson, Bruce D

2018-05-05

Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma with an estimated 3.18 cases per 100,000 people. Despite the prolongation of survival with chemoimmunotherapy, variability in response to initial treatment and outcome still exists. Whereas prolonging overall survival is important, it is generally an unreasonable primary endpoint in the front-line setting. The long follow-up needed and the influence of subsequent therapies creates a potential bias. Thus, clinical trials require approximately 5 to 8 years from activation to completion and analysis of outcomes. This duration results in enormous cost and a delay in developing newer therapies. Thus, there is a need to identify markers or surrogate endpoints that can be used in clinical trials to expedite the development of new treatments. This review will discuss various clinical, radiologic, and laboratory measures used to assess outcomes and overall survival in patients with untreated follicular lymphoma, and gauge their utility in clinical trials as surrogate endpoints. Copyright © 2018 Elsevier Inc. All rights reserved.

Endpoints and cutpoints in head and neck oncology trials: methodical background, challenges, current practice and perspectives.

PubMed

Hezel, Marcus; von Usslar, Kathrin; Kurzweg, Thiemo; Lörincz, Balazs B; Knecht, Rainald

2016-04-01

This article reviews the methodical and statistical basics of designing a trial, with a special focus on the process of defining and choosing endpoints and cutpoints as the foundations of clinical research, and ultimately that of evidence-based medicine. There has been a significant progress in the treatment of head and neck cancer in the past few decades. Currently available treatment options can have a variety of different goals, depending e.g. on tumor stage, among other factors. The outcome of a specific treatment in clinical trials is measured using endpoints. Besides classical endpoints, such as overall survival or organ preservation, other endpoints like quality of life are becoming increasingly important in designing and conducting a trial. The present work is based on electronic research and focuses on the solid methodical and statistical basics of a clinical trial, on the structure of study designs and on the presentation of various endpoints.

Treatment Paradigms for Advanced Non‐Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design

PubMed Central

Borghaei, Hossein

2017-01-01

Abstract Based on the positive results of various clinical trials, treatment options for non‐small cell lung cancer (NSCLC) have expanded greatly over the last 25 years. While regulatory approvals of chemotherapeutic agents for NSCLC have largely been based on improvements in overall survival, recent approvals of many targeted agents for NSCLC (afatinib, crizotinib, ceritinib, osimertinib) have been based on surrogate endpoints such as progression‐free survival and objective response. As such, selection of appropriate clinical endpoints for examining the efficacy of investigational agents for NSCLC is of vital importance in clinical trial design. This review provides an overview of clinical trial endpoints previously utilized for approved agents for NSCLC and highlights the key efficacy results for these trials. Trends for more recent approvals in NSCLC, including those for the immunotherapeutic agents nivolumab and pembrolizumab, are also discussed. The results of a correlative analysis of endpoints from 18 clinical trials that supported approvals of investigational agents in clinical trials for NSCLC are also presented. Implications for Practice. While improving survival remains the ultimate goal of oncology clinical trials, overall survival may not always be the most feasible or appropriate endpoint to assess patient response. Recently, several investigational agents, both targeted agents and immunotherapies, have gained U.S. Food and Drug Administration approval in non‐small cell lung cancer based on alternate endpoints such as progression‐free survival or response rate. An understanding of the assessment of response and trial endpoint choice is important for future oncology clinical trial design. PMID:28408617

Automatic streak endpoint localization from the cornerness metric

NASA Astrophysics Data System (ADS)

Sease, Brad; Flewelling, Brien; Black, Jonathan

2017-05-01

Streaked point sources are a common occurrence when imaging unresolved space objects from both ground- and space-based platforms. Effective localization of streak endpoints is a key component of traditional techniques in space situational awareness related to orbit estimation and attitude determination. To further that goal, this paper derives a general detection and localization method for streak endpoints based on the cornerness metric. Corners detection involves searching an image for strong bi-directional gradients. These locations typically correspond to robust structural features in an image. In the case of unresolved imagery, regions with a high cornerness score correspond directly to the endpoints of streaks. This paper explores three approaches for global extraction of streak endpoints and applies them to an attitude and rate estimation routine.

An entropy-based nonparametric test for the validation of surrogate endpoints.

PubMed

Miao, Xiaopeng; Wang, Yong-Cheng; Gangopadhyay, Ashis

2012-06-30

We present a nonparametric test to validate surrogate endpoints based on measure of divergence and random permutation. This test is a proposal to directly verify the Prentice statistical definition of surrogacy. The test does not impose distributional assumptions on the endpoints, and it is robust to model misspecification. Our simulation study shows that the proposed nonparametric test outperforms the practical test of the Prentice criterion in terms of both robustness of size and power. We also evaluate the performance of three leading methods that attempt to quantify the effect of surrogate endpoints. The proposed method is applied to validate magnetic resonance imaging lesions as the surrogate endpoint for clinical relapses in a multiple sclerosis trial. Copyright © 2012 John Wiley & Sons, Ltd.

PreSSUB II: The prehospital stroke study at the Universitair Ziekenhuis Brussel II

PubMed Central

Espinoza, Alexis Valenzuela; Van Hooff, Robbert-Jan; De Smedt, Ann; Moens, Maarten; Yperzeele, Laetitia; Nieboer, Koenraad; Hubloue, Ives; De Keyser, Jacques; Dupont, Alain; De Wit, Liesbet; Putman, Koen; Brouns, Raf

2015-01-01

Rationale Stroke is a time-critical medical emergency requiring specialized treatment. Prehospital delay contributes significantly to delayed or missed treatment opportunities. In-ambulance telemedicine can bring stroke expertise to the prehospital arena and facilitate this complex diagnostic and therapeutic process. Aims This study evaluates the efficacy, safety, feasibility, reliability and cost-effectiveness of in-ambulance telemedicine for patients with suspicion of acute stroke. We hypothesize that this approach will reduce the delay to in-hospital treatment by streamlining the diagnostic process and that prehospital stroke care will be improved by expert stroke support via telemedicine during the ambulance transportation. Design PreSSUB II is an interventional, prospective, randomized, open-blinded, end-point, single-center trial comparing standard emergency care by the Paramedic Intervention Team of the Universitair Ziekenhuis Brussel (control) with standard emergency care complemented with in-ambulance teleconsultation service by stroke experts (PreSSUB). Study Outcomes The primary efficacy endpoint is the call-to-brain imaging time. Secondary endpoints for the efficacy analysis include the prevalence of medical events diagnosed and corrected during in-ambulance teleconsultation, the proportion of patients with ischemic stroke receiving recanalization therapy, the assessment of disability, functional status, quality of life and overall well-being. Mortality at 90 days after stroke is the primary safety endpoint. Secondary safety analysis will involve the registration of any adverse event. Other analyses include assessment of feasibility and reliability and a health economic evaluation. PMID:27847888

Lung Allocation Score: A Single-Center Simulation.

PubMed

Rosso, L; Palleschi, A; Tosi, D; Mendogni, P; Righi, I; Carrinola, R; Montoli, M; Damarco, F; Rossetti, V; Morlacchi, L C; Nosotti, M

2016-03-01

The lung allocation score (LAS) was introduced in the United States in May 2005 with the main goal of reducing the waiting list mortality of patients with end-stage lung diseases, but also to enhance the lung transplant benefit and improve the management of urgent candidates. Several papers have reported that LAS resulted in a reduction of the waiting list mortality but no significant survival benefit was noted. We evaluate the usefulness of LAS as a predictor for lung transplantation outcome in 123 patients listed for lung transplantation in an Italian center. Primary endpoints were waiting list mortality and posttransplant mortality at 1 year; secondary endpoints included perioperative circulatory support, cardiopulmonary bypass, primary graft dysfunction, and long-term survival after transplantation. We observed the absence of correlation between LAS and waiting list mortality. The LAS did not affect the long-term survival in our population. High LAS was predictive of primary graft dysfunction of grade 3 in the first 72 hours after transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study).

PubMed

Starling, Amaal J; Tepper, Stewart J; Marmura, Michael J; Shamim, Ejaz A; Robbins, Matthew S; Hindiyeh, Nada; Charles, Andrew C; Goadsby, Peter J; Lipton, Richard B; Silberstein, Stephen D; Gelfand, Amy A; Chiacchierini, Richard P; Dodick, David W

2018-05-01

Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75 ± 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p < 0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381.

An Update on ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcriptomics on primary cell cultures, and developmental assays in zebrafish embryos. Almost all of the compounds being examined in Phase 1 of ToxCast™ have been tested in traditional toxicology tests, including developmental toxicity, multi-generation studies, and sub-chronic and chronic rodent bioassays Lessons learned to date for ToxCast: Large amounts of quality HTS data can be economically obtained. Large scale data sets will be required to understand potential for biological activity. Value in having multiple assays with overlapping coverage of biological pathways and a variety of methodologies Concentration-response will be important for ultimate interpretation Data transparency will be important for acceptance. Metabolic capabilities and coverage of developmental toxicity pathways will need additional attention. Need to define the gold standard Partnerships are needed to bring critical mass and expertise.

The influence of non-DNA-targeted effects on carbon ion–induced low-dose hyper-radiosensitivity in MRC-5 cells

PubMed Central

Ye, Fei; Ning, Jing; Liu, Xinguo; Jin, Xiaodong; Wang, Tieshan; Li, Qiang

2016-01-01

Low-dose hyper-radiosensitivity (LDHRS) is a hot topic in normal tissue radiation protection. However, the primary causes for LDHRS still remain unclear. In this study, the impact of non-DNA-targeted effects (NTEs) on high-LET radiation–induced LDHRS was investigated. Human normal lung fibroblast MRC-5 cells were irradiated with high-LET carbon ions, and low-dose biological effects (in terms of various bio-endpoints, including colony formation, DNA damage and micronuclei formation) were detected under conditions with and without gap junctional intercellular communication (GJIC) inhibition. LDHRS was observed when the radiation dose was <0.2 Gy for all bio-endpoints under investigation, but vanished when the GJIC was suppressed. Based on the probability of cells being hit and micro-dose per cell calculation, we deduced that the LDHRS phenomenon came from the combined action of direct hits and NTEs. We concluded that GJIC definitely plays an important role in cytotoxic substance spreading in high-LET carbon ion–induced LDHRS. PMID:26559335

On the Use of Local Assessments for Monitoring Centrally Reviewed Endpoints with Missing Data in Clinical Trials*

PubMed Central

Brummel, Sean S.; Gillen, Daniel L.

2014-01-01

Due to ethical and logistical concerns it is common for data monitoring committees to periodically monitor accruing clinical trial data to assess the safety, and possibly efficacy, of a new experimental treatment. When formalized, monitoring is typically implemented using group sequential methods. In some cases regulatory agencies have required that primary trial analyses should be based solely on the judgment of an independent review committee (IRC). The IRC assessments can produce difficulties for trial monitoring given the time lag typically associated with receiving assessments from the IRC. This results in a missing data problem wherein a surrogate measure of response may provide useful information for interim decisions and future monitoring strategies. In this paper, we present statistical tools that are helpful for monitoring a group sequential clinical trial with missing IRC data. We illustrate the proposed methodology in the case of binary endpoints under various missingness mechanisms including missing completely at random assessments and when missingness depends on the IRC’s measurement. PMID:25540717

Use of outcome measures in pulmonary hypertension clinical trials.

PubMed

Parikh, Kishan S; Rajagopal, Sudarshan; Arges, Kristine; Ahmad, Tariq; Sivak, Joseph; Kaul, Prashant; Shah, Svati H; Tapson, Victor; Velazquez, Eric J; Douglas, Pamela S; Samad, Zainab

2015-09-01

To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice. Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined. We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014. Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients). The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures. Copyright © 2015 Elsevier Inc. All rights reserved.

[Efficiency of a postoperative treatment after rotator cuff repair with a continuous passive motion device (CPM)].

PubMed

Michael, J W-P; König, D P; Imhoff, A B; Martinek, V; Braun, S; Hübscher, M; Koch, C; Dreithaler, B; Bernholt, J; Preis, S; Loew, M; Rickert, M; Speck, M; Bös, L; Bidner, A; Eysel, P

2005-01-01

The main objective of this study was to prove that a postoperative combined continuous passive motion (CPM) and physiotherapy treatment protocol (CPM group) can achieve 90 degrees active abduction in the shoulder joint earlier than physiotherapy alone (PT group). The indication was a complete tear of the rotator cuff. The study was conducted under in-patient and out-patient conditions. 55 patients were included in this study. The prospective, randomized multicenter study design complies with DIN EN 540. The primary endpoint was the time span until 90 degrees active abduction was achieved by the patients. Patients in the CPM group reached the primary endpoint on average 12 days earlier than the control group. This difference was statistically significant (p = 0.0292). Analyzing the secondary endpoints, e. g., pain and disablement, the results in the CPM group showed again advantages of the combined treatment protocol (CPM + physiotherapy). The postoperative treatment of a total tear of the rotator cuff with a combined continuous passive motion and physiotherapy protocol provided a significantly earlier range of motion in the shoulder joint than physiotherapy alone. There was no report of CPM-related adverse effects.

Effectiveness and cost-effectiveness of knowledge transfer and behavior modification interventions in type 2 diabetes mellitus patients--the INDICA study: a cluster randomized controlled trial.

PubMed

Ramallo-Fariña, Yolanda; García-Pérez, Lidia; Castilla-Rodríguez, Iván; Perestelo-Pérez, Lilisbeth; Wägner, Ana María; de Pablos-Velasco, Pedro; Domínguez, Armando Carrillo; Cortés, Mauro Boronat; Vallejo-Torres, Laura; Ramírez, Marcos Estupiñán; Martín, Pablo Pedrianes; García-Puente, Ignacio; Salinero-Fort, Miguel Ángel; Serrano-Aguilar, Pedro Guillermo

2015-04-09

Type 2 diabetes mellitus is a chronic disease whose health outcomes are related to patients and healthcare professionals' decision-making. The Diabetes Intervention study in the Canary Islands (INDICA study) aims to evaluate the effectiveness and cost-effectiveness of educational interventions supported by new technology decision tools for type 2 diabetes patients and primary care professionals in the Canary Islands. The INDICA study is an open, community-based, multicenter, clinical controlled trial with random allocation by clusters to one of three interventions or to usual care. The setting is primary care where physicians and nurses are invited to participate. Patients with diabetes diagnosis, 18-65 years of age, and regular users of mobile phone were randomly selected. Patients with severe comorbidities were excluded. The clusters are primary healthcare practices with enough professionals and available places to provide the intervention. The calculated sample size was 2,300 patients. Patients in group 1 are receiving an educational group program of eight sessions every 3 months led by trained nurses and monitored by means of logs and a web-based platform and tailored semi-automated SMS for continuous support. Primary care professionals in group 2 are receiving a short educational program to update their diabetes knowledge, which includes a decision support tool embedded into the electronic clinical record and a monthly feedback report of patients' results. Group 3 is receiving a combination of the interventions for patients and professionals. The primary endpoint is the change in HbA1c in 2 years. Secondary endpoints are cardiovascular risk factors, macrovascular and microvascular diabetes complications, quality of life, psychological outcomes, diabetes knowledge, and healthcare utilization. Data is being collected from interviews, questionnaires, clinical examinations, and records. Generalized linear mixed models with repeated time measurements will be used to analyze changes in outcomes. The cost-effectiveness analysis, from the healthcare services perspective, involves direct medical costs per quality-adjusted life year gained and two periods, a 'within-trial' period and a lifetime Markov model. Deterministic and probabilistic sensitivity analyses are planned. This ongoing trial aims to set up the implementation of evidence-based programs in the clinical setting for chronic patients. Clinical Trial.gov NCT01657227.

International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design.

PubMed

Maron, David J; Hochman, Judith S; O'Brien, Sean M; Reynolds, Harmony R; Boden, William E; Stone, Gregg W; Bangalore, Sripal; Spertus, John A; Mark, Daniel B; Alexander, Karen P; Shaw, Leslee; Berger, Jeffrey S; Ferguson, T Bruce; Williams, David O; Harrington, Robert A; Rosenberg, Yves

2018-07-01

Prior trials comparing a strategy of optimal medical therapy with or without revascularization have not shown that revascularization reduces cardiovascular events in patients with stable ischemic heart disease (SIHD). However, those trials only included participants in whom coronary anatomy was known prior to randomization and did not include sufficient numbers of participants with significant ischemia. It remains unknown whether a routine invasive approach offers incremental value over a conservative approach with catheterization reserved for failure of medical therapy in patients with moderate or severe ischemia. The ISCHEMIA trial is a National Heart, Lung, and Blood Institute supported trial, designed to compare an initial invasive or conservative treatment strategy for managing SIHD patients with moderate or severe ischemia on stress testing. Five thousand one-hundred seventy-nine participants have been randomized. Key exclusion criteria included estimated glomerular filtration rate (eGFR) <30 mL/min, recent myocardial infarction (MI), left ventricular ejection fraction <35%, left main stenosis >50%, or unacceptable angina at baseline. Most enrolled participants with normal renal function first underwent blinded coronary computed tomography angiography (CCTA) to exclude those with left main coronary artery disease (CAD) and without obstructive CAD. All randomized participants receive secondary prevention that includes lifestyle advice and pharmacologic interventions referred to as optimal medical therapy (OMT). Participants randomized to the invasive strategy underwent routine cardiac catheterization followed by revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, when feasible, as selected by the local Heart Team to achieve optimal revascularization. Participants randomized to the conservative strategy undergo cardiac catheterization only for failure of OMT. The primary endpoint is a composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. Assuming the primary endpoint will occur in 16% of the conservative group within 4 years, estimated power exceeds 80% to detect an 18.5% reduction in the primary endpoint. Major secondary endpoints include the composite of CV death and nonfatal MI, net clinical benefit (primary and secondary endpoints combined with stroke), angina-related symptoms and disease-specific quality of life, as well as a cost-effectiveness assessment in North American participants. Ancillary studies of patients with advanced chronic kidney disease and those with documented ischemia and non-obstructive coronary artery disease are being conducted concurrently. ISCHEMIA will provide new scientific evidence regarding whether an invasive management strategy improves clinical outcomes when added to optimal medical therapy in patients with SIHD and moderate or severe ischemia. Copyright © 2018 Elsevier Inc. All rights reserved.

Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.

PubMed

Goette, Andreas; Merino, Jose L; Ezekowitz, Michael D; Zamoryakhin, Dmitry; Melino, Michael; Jin, James; Mercuri, Michele F; Grosso, Michael A; Fernandez, Victor; Al-Saady, Naab; Pelekh, Natalya; Merkely, Bela; Zenin, Sergey; Kushnir, Mykola; Spinar, Jindrich; Batushkin, Valeriy; de Groot, Joris R; Lip, Gregory Y H

2016-10-22

Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434. Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA 2 DS 2 -VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status. ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. Daiichi Sankyo provided financial support for the study. Copyright © 2016 Elsevier Ltd. All rights reserved.

Scar Characterization to Predict Life-Threatening Arrhythmic Events and Sudden Cardiac Death in Patients With Cardiac Resynchronization Therapy: The GAUDI-CRT Study.

PubMed

Acosta, Juan; Fernández-Armenta, Juan; Borràs, Roger; Anguera, Ignasi; Bisbal, Felipe; Martí-Almor, Julio; Tolosana, Jose M; Penela, Diego; Andreu, David; Soto-Iglesias, David; Evertz, Reinder; Matiello, María; Alonso, Concepción; Villuendas, Roger; de Caralt, Teresa M; Perea, Rosario J; Ortiz, Jose T; Bosch, Xavier; Serra, Luis; Planes, Xavier; Greiser, Andreas; Ekinci, Okan; Lasalvia, Luis; Mont, Lluis; Berruezo, Antonio

2018-04-01

The aim of this study was to analyze whether scar characterization could improve the risk stratification for life-threatening ventricular arrhythmias and sudden cardiac death (SCD). Among patients with a cardiac resynchronization therapy (CRT) indication, appropriate defibrillator (CRT-D) therapy rates are low. Primary prevention patients with a class I indication for CRT were prospectively enrolled and assigned to CRT-D or CRT pacemaker according to physician's criteria. Pre-procedure contrast-enhanced cardiac magnetic resonance was obtained and analyzed to identify scar presence or absence, quantify the amount of core and border zone (BZ), and depict BZ distribution. The presence, mass, and characteristics of BZ channels in the scar were recorded. The primary endpoint was appropriate defibrillator therapy or SCD. 217 patients (39.6% ischemic) were included. During a median follow-up of 35.5 months (12 to 62 months), the primary endpoint occurred in 25 patients (11.5%) and did not occur in patients without myocardial scar. Among patients with scar (n = 125, 57.6%), those with implantable cardioverter-defibrillator (ICD) therapies or SCD exhibited greater scar mass (38.7 ± 34.2 g vs. 17.9 ± 17.2 g; p < 0.001), scar heterogeneity (BZ mass/scar mass ratio) (49.5 ± 13.0 vs. 40.1 ± 21.7; p = 0.044), and BZ channel mass (3.6 ± 3.0 g vs. 1.8 ± 3.4 g; p = 0.018). BZ mass (hazard ratio: 1.06 [95% confidence interval: 1.04 to 1.08]; p < 0.001) and BZ channel mass (hazard ratio: 1.21 [95% confidence interval: 1.10 to 1.32]; p < 0.001) were the strongest predictors of the primary endpoint. An algorithm based on scar mass and the absence of BZ channels identified 148 patients (68.2%) without ICD therapy/SCD during follow-up with a 100% negative predictive value. The presence, extension, heterogeneity, and qualitative distribution of BZ tissue of myocardial scar independently predict appropriate ICD therapies and SCD in CRT patients. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Assessing the validity of surrogate endpoints in the context of a controversy about the measurement of effectiveness of hepatitis C virus treatment.

PubMed

Dobler, Claudia C; Morgan, Rebecca L; Falck-Ytter, Yngve; Montori, Victor M; Murad, M Hassan

2018-04-01

Surrogate endpoints are often used in clinical trials, as they allow for indirect measures of outcomes (eg, shorter trials with less participants). Improvements in surrogate endpoints (eg, reduction in low density lipoprotein cholesterol, normalisation of glycated haemoglobin) achieved with an intervention are, however, not always associated with improvements in patient-important outcomes. The common tendency in evidence-based medicine is to view results based on surrogate endpoints as less certain than results based on long term, final patient-important outcomes and rate them as 'lower quality evidence'. However, careful appraisal of the validity of a surrogate endpoint as a measure of the final, patient-important outcome is more useful than an automatic judgement. In this guide, we use a contemporary and currently highly debated example of the surrogate endpoint 'sustained viral response' (ie, viral eradication considered to represent successful treatment) in patients treated for chronic hepatitis C virus. We demonstrate how the validity of a surrogate endpoint can be critically appraised to assess the quality of the evidence (ie, the certainty in estimates) and the implications for decision-making. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.

PubMed

Wickström, Kerstin; Moseley, Jane

2017-05-01

To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.

Coronary artery disease severity and long-term cardiovascular risk in patients with myocardial infarction: a Danish nationwide register-based cohort study

PubMed Central

Özcan, Cengiz; Deleskog, Anna; Schjerning Olsen, Anne-Marie; Nordahl Christensen, Helene; Lock Hansen, Morten; Hilmar Gislason, Gunnar

2018-01-01

Abstract Aim Long-term prognostic impact of coronary artery disease (CAD) severity in stable post-myocardial infarction (MI) patients is not well known. We examined the impact of CAD severity and co-morbidity on the long-term (1 year and beyond) risk of cardiovascular events post-MI. Methods and results From nationwide administrative and clinical registers, we identified 55 747 MI patients, during 2004–2010, who had not experienced subsequent MI, stroke, or death within 7 days post-discharge. The risk for primary composite endpoint (MI, stroke, or cardiovascular death) was estimated for the first 365 days after MI (index MI) and from day 366 to study completion (stable post-MI population), corresponding to a mean follow-up of 3.6 (2.2) years. Risk was assessed using cumulative incidence, multivariable adjusted logistic regression and Cox proportional-hazards models. The 1-year cumulative incidence for primary endpoint was 20.0% [95% confidence interval (CI), (19.6–20.3)]. Correspondingly, the 4-year cumulative incidence for primary endpoint was 21.0% (95% CI, 20.6–21.4) in patients without events on the first year. In multivariable models with no significant stenosis as reference, CAD severity was the most important risk factor for cardiovascular events the first 365 days [left main stenosis (LMS): odds ratio and 95% CI, 4.37, 3.69–5.17; 3-vessel disease (VD), 4.18, 3.66–4.77; 2-VD, 3.23, 2.81–3.72; 1-VD, 2.12,–1.85–2.43] and remained from day 366 to study completion [LMS: hazard ratio and 95% CI, 1.91, 1.64–2.22; 3-VD, 1.85,1.65–2.07; 2-VD, 1.55, 1.38–1.74; 1-VD, 1.30, 1.16–1.45]. Conclusion Despite contemporary treatment at baseline, stable post-MI patients’ 4-year outcome was similar to 1-year outcome after MI, and CAD severity remained a critical risk factor the first year and thereafter. PMID:28444162

Angiographic outcomes following stenting or coronary artery bypass surgery of the left main coronary artery: fifteen-month outcomes from the synergy between PCI with TAXUS express and cardiac surgery left main angiographic substudy (SYNTAX-LE MANS).

PubMed

Morice, Marie-Claude; Feldman, Ted E E; Mack, Michael J; Ståhle, Elisabeth; Holmes, David R; Colombo, Antonio; Morel, Marie-Angèle; van den Brand, Marcel; Serruys, Patrick W; Mohr, Friedrich; Carrié, Didier; Fournial, Gérard; James, Stefan; Leadley, Katrin; Dawkins, Keith D; Kappetein, A Pieter

2011-10-30

The SYNTAX-LE MANS substudy prospectively evaluated 15-month angiographic and clinical outcomes in patients with treated left main (LM) disease. In the SYNTAX trial, 1,800 patients with three-vessel and/or LM disease were randomised to either CABG or PCI; of these, 271 LM patients were prospectively assigned to receive a 15-month angiogram. The primary endpoint for the CABG arm was the ratio of ≥50% to <100% obstructed/occluded grafts bypassing LM lesions to the number placed. The primary endpoint for the PCI arm was the proportion of patients with ≤50% diameter stenosis ('patent' stents) of treated LM lesions. Per protocol, no formal comparison between CABG and PCI arms was intended based on the differing primary endpoints. Available 15-month angiograms were analysed for 114 CABG and 149 PCI patients. At 15 months, 9.9% (26/263) of CABG grafts were 100% occluded and an additional 5.7% (15/263) were ≥50% to <100% occluded. Overall, 27.2% (31/114) of patients had ≥1 obstructed/occluded graft. The 15-month CABG MACCE rate was 8.8% (10/114) and MACCE at 15 months was not significantly associated with graft obstruction/occlusion (p=0.85). In the PCI arm, 92.4% (134/145) of patients had ≤50% diameter LM stenosis at 15 months (89.7% [87/97] distal LM lesions and 97.9% [47/48] non-distal LM lesions). The 15-month PCI MACCE rate was 12.8% (20/156) and this was significantly associated with lack of stent patency at 15 months (p<0.001), mainly due to repeat revascularisation. At 15 months, 15.6% (41/263) of grafts were at least 50% obstructed but this was not significantly associated with MACCE; 92.4% (134/145) of patients had stents that remained patent at 15 months, and stent restenosis was significantly associated with MACCE, predominantly due to revascularisation.

The predictive value of multiple electrode platelet aggregometry for postoperative bleeding complications in patients undergoing coronary artery bypass graft surgery

PubMed Central

Woźniak, Karolina; Hryniewiecki, Tomasz; Kruk, Mariusz; Różański, Jacek; Kuśmierczyk, Mariusz

2016-01-01

Introduction Postoperative bleeding is one of the most serious complications of cardiac surgery and requires transfusion of blood or blood products. Acetylsalicylic acid (ASA) and clopidogrel (CLO) are the two most commonly used antiplatelet agents; when used in combination (i.e., as dual antiplatelet therapy [DAPT]), they exert a synergistic effect. Dual antiplatelet therapy, however, significantly increases the risk of postoperative bleeding. The effect of antiplatelet therapy can be monitored by platelet aggregation testing. One of the most commonly methods used for assessing platelet reactivity is multiple electrode aggregometry (MEA) which can be performed with the use of Multiplate analyzer. Although the method has long been used in interventional cardiology to assess the effect of antiplatelet therapy, it is not available at cardiac surgery departments as a standard diagnostic procedure. The aim of the study was to establish the frequency of bleeding complications following coronary artery bypass graft (CABG) surgery in patients on single antiplatelet therapy (SAPT) and patients on DAPT and to determine the usefulness of routine measurement of platelet responsiveness before CABG surgery in patients receiving antiplatelet therapy. Material and methods A consecutive cohort of 200 patients referred for elective surgical treatment of stable coronary artery disease was enrolled (100 consecutive patients on SAPT [ASA 75 mg/day] and 100 consecutive patients on DAPT [ASA 75 mg/day + CLO 75 mg/day]). All subjects continued their antiplatelet therapy until the day before surgery. For each subject, platelet aggregation testing in the form of an ASPI test and an ADP test was performed on the Multiplate analyzer. Each subject underwent coronary artery bypass grafting surgery. For the primary and secondary endpoints in our study we adopted the definition provided in ‘Standardised Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report from the Bleeding Academic Research Consortium’ (‘Circulation’, 2011) for BARC type 4 bleeding (i.e. CABG-related bleeding). Results An ROC curve was constructed for the ASPI test and ADP test for a total of 200 patients. No significant correlations were demonstrated between the ASPI test results and either the primary endpoint or the secondary endpoints. A correlation was found between the ADP test results and the composite primary endpoint and each of the secondary endpoints. The primary endpoint of major postoperative bleeding occurred in 16 subjects. From the ROC curve, we established the optimal cut-off value for the ADP test of 26 U at sensitivity of 72%, specificity of 69%, positive predictive value of 69.90%, and negative predictive value of 71.13%. Conclusions In patients on antiplatelet therapy, an ADP test result of < 26 U is strongly predictive of serious bleeding complications after CABG surgery. The MEA ADP test allows to identify the group of patients at an increased risk of postoperative bleeding. PMID:27212971

Genotoxic effect of a binary mixture of dicamba- and glyphosate-based commercial herbicide formulations on Rhinella arenarum (Hensel, 1867) (Anura, Bufonidae) late-stage larvae.

PubMed

Soloneski, Sonia; Ruiz de Arcaute, Celeste; Larramendy, Marcelo L

2016-09-01

The acute toxicity of two herbicide formulations, namely, the 57.71 % dicamba (DIC)-based Banvel(®) and the 48 % glyphosate (GLY)-based Credit(®), alone as well as the binary mixture of these herbicides was evaluated on late-stage Rhinella arenarum larvae (stage 36) exposed under laboratory conditions. Mortality was used as an endpoint for determining acute lethal effects, whereas the single-cell gel electrophoresis (SCGE) assay was employed as genotoxic endpoint to study sublethal effects. Lethality studies revealed LC5096 h values of 358.44 and 78.18 mg L(-1) DIC and GLY for Banvel(®) and Credit(®), respectively. SCGE assay revealed, after exposure for 96 h to either 5 and 10 % of the Banvel(®) LC5096 h concentration or 5 and 10 % of the Credit(®) LC5096 h concentration, an equal significant increase of the genetic damage index (GDI) regardless of the concentration of the herbicide assayed. The binary mixtures of 5 % Banvel(®) plus 5 % Credit(®) LC5096 h concentrations and 10 % Banvel(®) plus 10 % Credit(®) LC5096 h concentrations induced equivalent significant increases in the GDI in regard to GDI values from late-stage larvae exposed only to Banvel(®) or Credit(®). This study represents the first experimental evidence of acute lethal and sublethal effects exerted by DIC on the species, as well as the induction of primary DNA breaks by this herbicide in amphibians. Finally, a synergistic effect of the mixture of GLY and DIC on the induction of primary DNA breaks on circulating blood cells of R. arenarum late-stage larvae could be demonstrated.

Chelation therapy and cardiovascular disease: connecting scientific silos to benefit cardiac patients.

PubMed

Peguero, Julio G; Arenas, Ivan; Lamas, Gervasio A

2014-08-01

Medical practitioners have treated atherosclerotic disease with chelation therapy for over 50 years. Lack of strong of evidence led conventional practitioners to abandon its use in the 1960s and 1970s. This relegated chelation therapy to complementary and alternative medicine practitioners, who reported good anecdotal results. Concurrently, the epidemiologic evidence linking xenobiotic metals with cardiovascular disease and mortality gradually accumulated, suggesting a plausible role for chelation therapy. On the basis of the continued use of chelation therapy without an evidence base, the National Institutes of Health released a Request for Applications for a definitive trial of chelation therapy. The Trial to Assess Chelation Therapy (TACT) was formulated as a 2 × 2 factorial randomized controlled trial of intravenous EDTA-based chelation vs. placebo and high-dose oral multivitamins and multiminerals vs. oral placebo. The composite primary endpoint was death, reinfarction, stroke, coronary revascularization, or hospitalization for angina. A total of 1708 post-MI patients who were 50 years or older with a creatinine of 2.0 or less were enrolled and received 55,222 infusions of disodium EDTA or placebo with a median follow-up of 55 months. Patients were on evidence-based post-MI medications including statins. EDTA proved to be safe. EDTA chelation therapy reduced cardiovascular events by 18%, with a 5-year number needed to treat (NNT) of 18. Prespecified subgroup analysis revealed a robust benefit in patients with diabetes mellitus with a 41% reduction in the primary endpoint (5-year NNT = 6.5), and a 43% 5-year relative risk reduction in all-cause mortality (5-year NNT = 12). The magnitude of benefit is such that it suggests urgency in replication and implementation, which could, due to the excellent safety record, occur simultaneously. Copyright © 2014 Elsevier Inc. All rights reserved.

Clinical Evidence Supporting US Food and Drug Administration Approval of Otolaryngologic Prescription Drug Indications, 2005-2014.

PubMed

Rathi, Vinay K; Wang, Bo; Ross, Joseph S; Downing, Nicholas S; Kesselheim, Aaron S; Gray, Stacey T

2017-04-01

Objective The US Food and Drug Administration (FDA) approves indications for prescription drugs based on premarket pivotal clinical studies designed to demonstrate safety and efficacy. We characterized the pivotal studies supporting FDA approval of otolaryngologic prescription drug indications. Study Design Retrospective cross-sectional analysis. Setting Publicly available FDA documents. Subjects Recently approved (2005-2014) prescription drug indications for conditions treated by otolaryngologists or their multidisciplinary teams. Drugs could be authorized for treatment of otolaryngologic disease upon initial approval (original indications) or thereafter via supplemental applications (supplemental indications). Methods Pivotal studies were categorized by enrollment, randomization, blinding, comparator type, and primary endpoint. Results Between 2005 and 2014, the FDA approved 48 otolaryngologic prescription drug indications based on 64 pivotal studies, including 21 original indications (19 drugs, 31 studies) and 27 supplemental indications (18 drugs, 33 studies). Median enrollment was 299 patients (interquartile range, 198-613) for original indications and 197 patients (interquartile range, 64-442) for supplemental indications. Most indications were supported by ≥1 randomized study (original: 20/21 [95%], supplemental: 21/27 [78%]) and ≥1 double-blinded study (original: 14/21 [67%], supplemental: 17/27 [63%]). About half of original indications (9/21 [43%]) and one-quarter of supplemental indications (7/27 [26%]) were supported by ≥1 active-controlled study. Nearly half (original: 8/21 [38%], supplemental: 14/27 [52%]) of all indications were approved based exclusively on studies using surrogate markers as primary endpoints. Conclusion The quality of clinical evidence supporting FDA approval of otolaryngologic prescription drug indications varied widely. Otolaryngologists should consider limitations in premarket evidence when helping patients make informed treatment decisions about newly approved drugs.

A prospective randomised trial comparing the novel ridaforolimus-eluting BioNIR stent to the zotarolimus-eluting Resolute stent: six-month angiographic and one-year clinical results of the NIREUS trial.

PubMed

Paradies, Valeria; Ben-Yehuda, Ori; Jonas, Michael; Banai, Shmuel; Iñiguez, Andres; Perlman, Gidon Y; Kandzari, David E; Stone, Gregg W; Smits, Pieter C

2018-05-20

The aim of this study was to evaluate the efficacy and safety of the BioNIR stent compared with the Resolute Integrity stent for the treatment of coronary artery disease. This first-in-human, multicentre, single-blind randomised non-inferiority trial was performed in Europe and Israel. Patients with stable coronary artery disease or acute coronary syndromes were randomly assigned to treatment with BioNIR or Resolute Integrity stents in a 2:1 fashion. The primary endpoint was angiographic in-stent late lumen loss (LLL) at six months. Three hundred and two patients were randomised, of whom 261 (86.0%) underwent six-month angiographic follow-up. The BioNIR stent was non-inferior to the Resolute Integrity stent for the primary endpoint of in-stent LLL at six months (0.04±0.30 mm vs. 0.03±0.31 mm, respectively, pnoninferiority<0.0001). At 12-month follow-up, target lesion failure occurred in 3.4% in the BioNIR group and 5.9% in the Resolute Integrity group (p=0.22). Rates of MACE were similar between the BioNIR and Resolute Integrity groups (4.3% vs. 5.9%, respectively, p=0.45). The BioNIR stent was non-inferior to the Resolute Integrity stent for the primary endpoint of angiographic in-stent LLL at six months. Clinical outcomes at one year were comparable between the two groups.

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

PubMed

Tedesco-Silva, Helio; Pescovitz, Mark D; Cibrik, Diane; Rees, Michael A; Mulgaonkar, Shamkant; Kahan, Barry D; Gugliuzza, Kristene K; Rajagopalan, P R; Esmeraldo, Ronaldo de M; Lord, Hélène; Salvadori, Maurizio; Slade, Jennifer M

2006-12-27

Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

Depressive symptoms and outcomes in patients with heart failure: data from the COACH study.

PubMed

Lesman-Leegte, Ivonne; van Veldhuisen, Dirk J; Hillege, Hans L; Moser, Debra; Sanderman, Robbert; Jaarsma, Tiny

2009-12-01

To study the prognostic value of depressive symptoms on heart failure (HF) readmission and mortality, in a large and clinically relevant population of hospitalized HF patients adjusted for disease severity by B-type natriuretic peptide (BNP) level. We studied 958 patients enrolled after hospitalization for HF; 37% female; mean age 71 +/- 11 years; New York Heart Association class II (51%) or III/IV (49%). Left ventricular ejection fraction: 33% +/- 14%, and median BNP level: 454 pg/mL (75% CI, 195-876 pg/mL). In total, 377 patients (39%) had depressive symptoms [Centre for Epidemiological Studies Depression Scale (CES-D) score >or=16] and 200 (21%) had severe depressive symptoms (score >or=24). During 18 months of follow-up, 386 (40%) patients reached the primary endpoint of death or readmission for HF. In multivariate analyses, CES-D was significantly associated with the primary endpoint [hazard ratio (HR) 1.13, P = 0.02], and also with both individual components of the primary endpoint [HF readmission (HR 1.165, P = 0.02) and mortality (HR 1.169, P = 0.02)]. Patients with severe depressive symptoms had a >40% higher risk for HF readmission or death. In patients with HF, depression is independently associated with poor outcomes. These findings highlight the need for continued exploration of whether improvements in depression lead to better cardiovascular outcomes. The study was registered at clinical trial (www.trialregister.nl): NCT 98675639.

RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kachnic, Lisa A., E-mail: lisa.kachnic@bmc.org; Winter, Kathryn; Myerson, Robert J.

2013-05-01

Purpose: A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811. Methods and Materials: T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤3 cm or 54more » Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigator’s ability to perform DP-IMRT. Results: Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations. Conclusions: Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.« less

Is there an additional benefit of serial NT-proBNP measurements in patients with stable chronic heart failure receiving individually optimized therapy?

PubMed

Franke, Jennifer; Frankenstein, Lutz; Schellberg, Dieter; Bajrovic, Amer; Wolter, Jan Sebastian; Ehlermann, Philipp; Doesch, Andreas O; Nelles, Manfred; Katus, Hugo A; Zugck, Christian

2011-12-01

The role of serial NT-proBNP measurements in patients suffering from chronic systolic heart failure (CHF) who already receive individually optimized pharmacotherapy is still unresolved. NT-proBNP was assessed at baseline and at 6 months follow-up in 504 stable CHF patients treated with individually optimized pharmacotherapy. After assessment of clinical stability at 6 months, patients were followed up for at least 1 year. The combined primary endpoint was defined as death, hospitalization due to cardiac reasons or heart transplantation in 1-year follow-up. We stratified our patients according to two principles: first, a percent change of value (CV) between the first and second measurement of NT-proBNP and secondly, the transformed logarithm of NT-proBNP measured at 6 months. During the follow-up period of 1 year, 50 patients (9.9%) reached the combined primary endpoint. Stratification according to percentage CV was less accurate in predicting endpoint-free survival compared to a classification in categories of lnNT-proBNP measured at 6 months (ROC AUC = 0.615; 95% CI 0.525-0.70 vs. ROC AUC = 0.790; 95% CI 0.721-0.856, respectively). When entered into proportional hazard regression analysis, lnNT-proBNP measured at 6 months remained an independent predictor of the combined primary endpoint with an associated HR of 2.53 (95% CI 1.385-4.280). To date, this is the largest analysis of serial NT-proBNP measurements in patients with CHF receiving individually optimized medical therapy. These data suggest that a single NT-proBNP measurement after 6 months in stable clinical conditions may have higher predictive value than stratification of change in serial measurements.

A Pharmacokinetics Phase 1 Bioequivalence Study of the Trastuzumab Biosimilar MYL-1401O vs EU-Trastuzumab and US-Trastuzumab.

PubMed

Waller, Cornelius F; Vutikullird, Apinya; Lawrence, Tracey E; Shaw, Andrew; Liu, Mark Shiyao; Baczkowski, Mark; Sharma, Rajiv; Barve, Abhijit; Goyal, Parag; Donnelly, Charles; Sengupta, Nilanjan; Pennella, Eduardo J

2018-06-21

Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2-overexpressing breast cancer. MYL-1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL-1401O, reference EU-trastuzumab, and US-trastuzumab. This single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study was conducted in healthy adult male volunteers. Subjects were randomized 1:1:1 to receive a single 8 mg kg -1 dose of MYL-1401O, EU-trastuzumab, or US-trastuzumab as a 90-minute intravenous infusion. Primary objective was to assess PK similarity among all three products. Primary endpoints assessed were peak serum concentration (Cmax), area under the serum concentration-time curve from time of dosing to time of last quantifiable concentration (AUC 0-last ), and AUC from time of dosing to infinity (AUC 0-∞ ). Secondary endpoints included time of Cmax (tmax), elimination rate constant (λz), half-life (t ½ ), safety, and immunogenicity. Of 132 subjects enrolled (44/treatment), 120 (MYL-1401O, n=42; EU-trastuzumab, n=41; US-trastuzumab, n=37) were included in the PK analysis. The 90% CIs of the ratios of geometric means for the primary endpoints were bounded within the predefined bioequivalence criterion of 80% to 125%. Secondary endpoints tmax, λz, and t ½ were similar among groups. All treatment-emergent adverse events were mild or moderate, similar across groups, and no serious adverse events were reported. No treatment-related antidrug antibodies were detected. MYL-1401O was well tolerated, and demonstrated PK and safety profiles similar to EU-trastuzumab and US-trastuzumab in healthy volunteers (ClinicalTrials.gov, NCT02594761). This article is protected by copyright. All rights reserved.

Effects of remote monitoring on clinical outcomes and use of healthcare resources in heart failure patients with biventricular defibrillators: results of the MORE-CARE multicentre randomized controlled trial.

PubMed

Boriani, Giuseppe; Da Costa, Antoine; Quesada, Aurelio; Ricci, Renato Pietro; Favale, Stefano; Boscolo, Gabriele; Clementy, Nicolas; Amori, Valentina; Mangoni di S Stefano, Lorenza; Burri, Haran

2017-03-01

The aim of this study was to evaluate the clinical efficacy and safety of remote monitoring in patients with heart failure implanted with a biventricular defibrillator (CRT-D) with advanced diagnostics. The MORE-CARE trial is an international, prospective, multicentre, randomized controlled trial. Within 8 weeks of de novo implant of a CRT-D, patients were randomized to undergo remote checks alternating with in-office follow-ups (Remote arm) or in-office follow-ups alone (Standard arm). The primary endpoint was a composite of death and cardiovascular (CV) and device-related hospitalization. Use of healthcare resources was also evaluated. A total of 865 eligible patients (mean age 66 ± 10 years) were included in the final analysis (437 in the Remote arm and 428 in the Standard arm) and followed for a median of 24 (interquartile range = 15-26) months. No significant difference was found in the primary endpoint between the Remote and Standard arms [hazard ratio 1.02, 95% confidence interval (CI) 0.80-1.30, P = 0.89] or in the individual components of the primary endpoint (P > 0.05). For the composite endpoint of healthcare resource utilization (i.e. 2-year rates of CV hospitalizations, CV emergency department admissions, and CV in-office follow-ups), a significant 38% reduction was found in the Remote vs. Standard arm (incidence rate ratio 0.62, 95% CI 0.58-0.66, P < 0.001) mainly driven by a reduction of in-office visits. In heart failure patients implanted with a CRT-D, remote monitoring did not reduce mortality or risk of CV or device-related hospitalization. Use of healthcare resources was significantly reduced as a result of a marked reduction of in-office visits without compromising patient safety. NCT00885677. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial.

PubMed

Wali, Ramesh K; Bianchi, Laura; Kupfer, Sonia; De La Cruz, Mart; Jovanovic, Borko; Weber, Christopher; Goldberg, Michael J; Rodriguez, L M; Bergan, Raymond; Rubin, David; Tull, Mary Beth; Richmond, Ellen; Parker, Beth; Khan, Seema; Roy, Hemant K

2018-01-01

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. ClinicalTrials.gov NCT00828984.

Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial

PubMed Central

Wali, Ramesh K.; Bianchi, Laura; Kupfer, Sonia; De La Cruz, Mart; Jovanovic, Borko; Weber, Christopher; Goldberg, Michael J.; Rodriguez, L. M.; Bergan, Raymond; Rubin, David; Tull, Mary Beth; Richmond, Ellen; Parker, Beth; Khan, Seema

2018-01-01

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. Trial registration: ClinicalTrials.gov NCT00828984 PMID:29617381

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis.

PubMed

Cremolini, Chiara; Antoniotti, Carlotta; Pietrantonio, Filippo; Berenato, Rosa; Tampellini, Marco; Baratelli, Chiara; Salvatore, Lisa; Marmorino, Federica; Borelli, Beatrice; Nichetti, Federico; Bironzo, Paolo; Sonetto, Cristina; Bartolomeo, Maria Di; Braud, Filippo de; Loupakis, Fotios; Falcone, Alfredo; Di Maio, M

2017-07-01

The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R 2 ). Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R 2 =0.539, p < 0.001) and poor correlation (R=0.169, R 2 =0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

COMET: a multicomponent home-based disease-management programme versus routine care in severe COPD.

PubMed

Kessler, Romain; Casan-Clara, Pere; Koehler, Dieter; Tognella, Silvia; Viejo, Jose Luis; Dal Negro, Roberto W; Díaz-Lobato, Salvador; Reissig, Karina; Rodríguez González-Moro, José Miguel; Devouassoux, Gilles; Chavaillon, Jean-Michel; Botrus, Pierre; Arnal, Jean-Michel; Ancochea, Julio; Bergeron-Lafaurie, Anne; De Abajo, Carlos; Randerath, Winfried J; Bastian, Andreas; Cornelissen, Christian G; Nilius, Georg; Texereau, Joëlle B; Bourbeau, Jean

2018-01-01

The COPD Patient Management European Trial (COMET) investigated the efficacy and safety of a home-based COPD disease management intervention for severe COPD patients.The study was an international open-design clinical trial in COPD patients (forced expiratory volume in 1 s <50% of predicted value) randomised 1:1 to the disease management intervention or to the usual management practices at the study centre. The disease management intervention included a self-management programme, home telemonitoring, care coordination and medical management. The primary end-point was the number of unplanned all-cause hospitalisation days in the intention-to-treat (ITT) population. Secondary end-points included acute care hospitalisation days, BODE (body mass index, airflow obstruction, dyspnoea and exercise) index and exacerbations. Safety end-points included adverse events and deaths.For the 157 (disease management) and 162 (usual management) patients eligible for ITT analyses, all-cause hospitalisation days per year (mean±sd) were 17.4±35.4 and 22.6±41.8, respectively (mean difference -5.3, 95% CI -13.7 to -3.1; p=0.16). The disease management group had fewer per-protocol acute care hospitalisation days per year (p=0.047), a lower BODE index (p=0.01) and a lower mortality rate (1.9% versus 14.2%; p<0.001), with no difference in exacerbation frequency. Patient profiles and hospitalisation practices varied substantially across countries.The COMET disease management intervention did not significantly reduce unplanned all-cause hospitalisation days, but reduced acute care hospitalisation days and mortality in severe COPD patients. Copyright ©ERS 2018.

Navigating the fine line between benefit and risk in chronic atrial fibrillation: rationale and design of the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY).

PubMed

Carrington, Melinda J; Ball, Jocasta; Horowitz, John D; Marwick, Thomas H; Mahadevan, Gnanadevan; Wong, Chiew; Abhayaratna, Walter P; Haluska, Brian; Thompson, David R; Scuffham, Paul A; Stewart, Simon

2013-06-20

Health outcomes associated with atrial fibrillation (AF) continue to be poor and standard management often does not provide clinical stability. The Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY) compares the efficacy of a post-discharge, nurse-led, multi-disciplinary programme to optimise AF management with usual care. SAFETY is a prospective, multi-centre, randomised controlled trial with blinded-endpoint adjudication. A target of 320 hospitalised patients with a chronic form of AF will be randomised (stratified by "rate" versus "rhythm" control) to usual post-discharge care or the SAFETY Intervention (SI). The SI involves home-based assessment, extensive clinical profiling and the application of optimal gold-standard pharmacology which is individually tailored according to a "traffic light" framework based on clinical stability, risk profile and therapeutic management. The primary endpoint is event-free survival from all-cause death or unplanned readmission during 18-36 months follow-up. Secondary endpoints include rate of recurrent hospital stay, treatment success (i.e. maintenance of rhythm or rate control and/or application of anti-thrombotic therapy without a bleeding event) and cost-efficacy. With study recruitment to be completed in early 2012, the results of this study will be available in early 2014. If positive, SAFETY will represent a potentially cost-effective and readily applicable strategy to improve health outcomes in high risk individuals discharged from hospital with chronic AF. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Integration of technology-based outcome measures in clinical trials of Parkinson and other neurodegenerative diseases.

PubMed

Artusi, Carlo Alberto; Mishra, Murli; Latimer, Patricia; Vizcarra, Joaquin A; Lopiano, Leonardo; Maetzler, Walter; Merola, Aristide; Espay, Alberto J

2018-01-01

We sought to review the landscape of past, present, and future use of technology-based outcome measures (TOMs) in clinical trials of neurodegenerative disorders. We systematically reviewed PubMed and ClinicalTrials.gov for published and ongoing clinical trials in neurodegenerative disorders employing TOMs. In addition, medical directors of selected pharmaceutical companies were surveyed on their companies' ongoing efforts and future plans to integrate TOMs in clinical trials as primary, secondary, or exploratory endpoints. We identified 164 published clinical trials indexed in PubMed that used TOMs as outcome measures in Parkinson disease (n = 132) or other neurodegenerative disorders (n = 32). The ClinicalTrials.gov search yielded 42 clinical trials using TOMs, representing 2.7% of ongoing trials. Sensor-based technology accounted for over 75% of TOMs applied. Gait and physical activity were the most common targeted domains. Within the next 5 years, 83% of surveyed pharmaceutical companies engaged in neurodegenerative disorders plan to deploy TOMs in clinical trials. Although promising, TOMs are underutilized in clinical trials of neurodegenerative disorders. Validating relevant endpoints, standardizing measures and procedures, establishing a single platform for integration of data and algorithms from different devices, and facilitating regulatory approvals should advance TOMs integration into clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Some controversial multiple testing problems in regulatory applications.

PubMed

Hung, H M James; Wang, Sue-Jane

2009-01-01

Multiple testing problems in regulatory applications are often more challenging than the problems of handling a set of mathematical symbols representing multiple null hypotheses under testing. In the union-intersection setting, it is important to define a family of null hypotheses relevant to the clinical questions at issue. The distinction between primary endpoint and secondary endpoint needs to be considered properly in different clinical applications. Without proper consideration, the widely used sequential gate keeping strategies often impose too many logical restrictions to make sense, particularly to deal with the problem of testing multiple doses and multiple endpoints, the problem of testing a composite endpoint and its component endpoints, and the problem of testing superiority and noninferiority in the presence of multiple endpoints. Partitioning the null hypotheses involved in closed testing into clinical relevant orderings or sets can be a viable alternative to resolving the illogical problems requiring more attention from clinical trialists in defining the clinical hypotheses or clinical question(s) at the design stage. In the intersection-union setting there is little room for alleviating the stringency of the requirement that each endpoint must meet the same intended alpha level, unless the parameter space under the null hypothesis can be substantially restricted. Such restriction often requires insurmountable justification and usually cannot be supported by the internal data. Thus, a possible remedial approach to alleviate the possible conservatism as a result of this requirement is a group-sequential design strategy that starts with a conservative sample size planning and then utilizes an alpha spending function to possibly reach the conclusion early.

A web-based endpoint adjudication system for interim analyses in clinical trials.

PubMed

Nolen, Tracy L; Dimmick, Bill F; Ostrosky-Zeichner, Luis; Kendrick, Amy S; Sable, Carole; Ngai, Angela; Wallace, Dennis

2009-02-01

A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal. For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required. We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data. The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However, once these issues were resolved, the reviewers found the system user-friendly and easy to navigate. Web-based data adjudication depends upon expeditious data collection and verification. Further, ability to use web-based technologies, in addition to clinical expertise, must be considered in selecting EAC members. The automated nature of this system makes it a practical mechanism for ensuring timely endpoint adjudication. The authors believe a similar approach could be useful for handling endpoint adjudication for future clinical trials.

A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor.

PubMed

Vincenti, Flavio; Budde, Klemens; Merville, Pierre; Shihab, Fuad; Peddi, V Ram; Shah, Malay; Wyburn, Kate; Cassuto-Viguier, Elisabeth; Weidemann, Alexander; Lee, Misun; Flegel, Teresa; Erdman, Jay; Wang, Xuegong; Lademacher, Christopher

2018-05-09

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive five doses of ASP0113 (5 mg; n=75) or placebo (n=74) on Days 30/60/90/120/180 post transplant, and received prophylactic valganciclovir/ganciclovir 10-100 days post transplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; p=0.307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Derivation of aquatic predicted no-effect concentration (PNEC) for ibuprofen and sulfamethoxazole based on various toxicity endpoints and the associated risks.

PubMed

Huang, Qiusen; Bu, Qingwei; Zhong, Wenjue; Shi, Kaichong; Cao, Zhiguo; Yu, Gang

2018-02-01

For pharmaceuticals, the ecological risk assessment based on traditional endpoints of toxicity could not be properly protective in the long run since the mode of action could vary because they are intended for different therapeutic uses. In this study, the predicted no-effect concentrations (PNECs) of two selected pharmaceuticals, ibuprofen (IBU) and sulfamethoxazole (SMX), were derived based on either traditional endpoints of survival and growth data or some nonlethal endpoints such as reproduction, biochemical and molecular data. The PNECs of IBU based on biochemical-cellular and reproduction data were 0.018 and 0.026 μg L -1 that were significantly lower than those derived from other endpoints, while the lowest PNEC for SMX derived from growth data with the concentration of 0.89 μg L -1 . Ecological risk assessment was performed for IBU and SMX to the aquatic environment by applying hazard quotient and probabilistic distribution based quotient (DBQs) methods. The results showed that the probability of DBQs of IBU exceeding 0.1 was 11.2%, while for SMX the probability was 0.9% that could be neglected. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hyberbaric oxygen as sole treatment for severe radiation - induced haemorrhagic cystitis

PubMed Central

Dellis, Athanasios; Papatsoris, Athanasios; Kalentzos, Vasileios; Deliveliotis, Charalambos; Skolarikos, Andreas

2017-01-01

ABSTRACT Purpose To examine the safety and efficacy of hyperbaric oxygen as the primary and sole treatment for severe radiation-induced haemorrhagic cystitis. Materials and methods Hyperbaric oxygen was prospectively applied as primary treatment in 38 patients with severe radiation cystitis. Our primary endpoint was the incidence of complete and partial response to treatment, while the secondary endpoints included the duration of response, the correlation of treatment success-rate to the interval between the onset of haematuria and initiation of therapy, blood transfusion need and total radiation dose, the number of sessions to success, the avoidance of surgery and the overall survival. Results All patients completed therapy without complications with a mean follow-up of 29.33 months. Median number of sessions needed was 33. Complete and partial response rate was 86.8% and 13.2%, respectively. All 33 patients with complete response received therapy within 6 months of the haematuria onset. One patient needed cystectomy, while 33 patients were alive at the end of follow-up. Conclusions Our study suggests the early primary use of hyperbaric oxygen for radiation-induced severe cystitis as an effective and safe treatment option. PMID:28338304

Amitraz

EPA Science Inventory

Amitraz (CAS 33089-61-1) is a formamidine insecticide and acaricide used on crops, livestock, and pets. Neurotoxicity is the primary endpoint of concern for short-term exposures in nontarget species. Amitraz has hepatic, reproductive, and developmental effects with longer-term...

Primary and submovement control of aiming in C6 tetraplegics following posterior deltoid transfer

PubMed Central

2014-01-01

Background Upper limb motor control in fast, goal-directed aiming is altered in tetraplegics following posterior-deltoid musculotendinous transfer. Specifically, movements have similar end-point accuracy but longer duration and lower peak velocity than those of age-matched, neurotypical controls. Here, we examine in detail the interplay between primary movement and submovement phases in five C6 tetraplegic and five control participants. Methods Aiming movements were performed in two directions (20 cm away or toward), with or without vision. Trials that contained a submovement phase (i.e., discontinuity in velocity, acceleration or jerk) were identified. Discrete kinematic variables were then extracted on the primary and submovements phases. Results The presence of submovements did not differ between the tetraplegic (68%) and control (57%) groups, and almost all submovements resulted from acceleration and jerk discontinuities. Tetraplegics tended to make a smaller amplitude primary movement, which had lower peak velocity and greater spatial variability at peak velocity. This was followed by a larger amplitude and longer duration secondary submovement. Peak velocity of primary movement was not related to submovement incidence. Together, the primary and submovement phases of both groups were equally effective in reducing end-point error. Conclusions C6 tetraplegic participants exhibit some subtle differences in measures of motor behaviour compared to control participants, but importantly feedforward and feedback processes work effectively in combination to achieve accurate goal-directed aiming. PMID:25055852

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

PubMed

MacDonald, Thomas M; Ford, Ian; Nuki, George; Mackenzie, Isla S; De Caterina, Raffaele; Findlay, Evelyn; Hallas, Jesper; Hawkey, Christopher J; Ralston, Stuart; Walters, Matthew; Webster, John; McMurray, John; Perez Ruiz, Fernando; Jennings, Claudine G

2014-07-10

Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST). FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3. FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal. FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial.

PubMed

Bousser, Marie-Germaine; Amarenco, Pierre; Chamorro, Angel; Fisher, Marc; Ford, Ian; Fox, Kim M; Hennerici, Michael G; Mattle, Heinrich P; Rothwell, Peter M; de Cordoüe, Agnès; Fratacci, Marie-Dominique

2011-06-11

Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event. This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1·05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730. 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28·3 months (SD 7·7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1·02, 95% CI 0·94-1·12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1·11, 95% CI 1·02-1·21), but no significant differences in other safety endpoints. The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost. Servier, France. Copyright © 2011 Elsevier Ltd. All rights reserved.

Evaluation of selective cyclooxygenase-2 inhibitor-induced small bowel injury: randomized cross-over study compared with loxoprofen in healthy subjects.

PubMed

Mizukami, Kazuhiro; Murakami, Kazunari; Yamauchi, Mika; Matsunari, Osamu; Ogawa, Ryo; Nakagawa, Yoshifumi; Okimoto, Tadayoshi; Kodama, Masaaki; Fujioka, Toshio

2013-05-01

Non-steroidal anti-inflammatory drugs have the potential to injure the mucosa of the upper digestive tract and small bowel, whereas celecoxib (a selective cyclooxygenase-2 inhibitor) has less influence on the entire digestive tract mucosa. The present study was conducted to compare the extents of small bowel mucosal injury induced by celecoxib and loxoprofen (the most frequently used non-steroidal anti-inflammatory drugs in Japan). Ten healthy adult males were given celecoxib (200 mg/day, Group C) and loxoprofen (180 mg/day, Group L) in a cross-over design for 14 days, and the influence of each drug on small bowel mucosa was evaluated by comparing pre- and post-treatment capsule endoscopy findings. We measured the percentage of patients with small bowel mucosal injury following administration of these drugs as primary endpoint. Additionally, mean number of small bowel mucosal injuries per subject was analyzed as secondary endpoint. The percentage of subjects experiencing small bowel mucosal injury as primary endpoint was 10% in Group C and 70% in Group L after treatment. This magnitude of the difference of between Group C and Group L was statistically significant (P = 0.031). The number of small bowel mucosal injuries as secondary endpoint differed significantly between the two groups, and the influence of celecoxib on small bowel injury was less than that of loxoprofen. These results indicate that celecoxib has less influence on small bowel mucosa than loxoprofen and can be used safely. © 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.

PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy.

PubMed

Nuebling, Georg; Hensler, Mira; Paul, Sabine; Zwergal, Andreas; Crispin, Alexander; Lorenzl, Stefan

2016-08-01

To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1 mg/d rasagiline or placebo. The combined primary endpoint included symptom progression as measured by the PSP rating scale (PSP-RS) and the requirement of L-dopa rescue medication. Secondary endpoints included Schwab and England Activities of Daily Living (SEADL), Montgomery-Åsberg Depression Rating Scale, Mini Mental State Examination, Frontal Assessment Battery and posturographic measurements. Of the 44 patients randomized, 26 completed the trial per protocol. Rasagiline was well tolerated, with a slight increase of known side effects (hallucinations, ventricular extrasystoles). No effect on the primary endpoint (p = 0.496) was detected. Symptom progression averaged at 11.2 (rasagiline) and 10.8 (placebo) points per year (ΔPSP-RS). No difference was seen in SEADL, depression, cognitive function, frontal executive function and posturographic measurements. Post hoc analyses of PSP-RS subdomains indicate a potential beneficial effect in the "limb motor" subdomain, whereas performance appeared lower in the "mentation" and "history" subdomains in the treatment group. While rasagiline is well tolerated in PSP, a beneficial effect on overall symptom progression was not detected. Post hoc analyses suggest the implementation of more specific endpoints in future studies.

Effectiveness, immunogenicity and safety of 23-valent pneumococcal polysaccharide vaccine revaccinations in the elderly: a systematic review.

PubMed

Remschmidt, Cornelius; Harder, Thomas; Wichmann, Ole; Bogdan, Christian; Falkenhorst, Gerhard

2016-11-25

In many industrialized countries routine vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) is recommended to prevent pneumococcal disease in the elderly. However, vaccine-induced immunity wanes after a few years, and there are controversies around revaccination with PPSV-23. Here, we systematically assessed the effectiveness and safety of PPSV-23 revaccination. We conducted a systematic literature review in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from inception to June 2015. We included all study types that compared effectiveness, immunogenicity and/or safety of PPSV-23 as a primary vs. a revaccination dose in persons aged 50 years and older. With respect to immunogenicity, we calculated the ratio of geometric mean antibody concentrations and opsonophagocytic indexes at identical time-points after primary and revaccination. Additionally, we compared rates and severity of adverse events (AEs) after primary and revaccination. We included 14 observational studies. 10 studies had a prospective design and analysed data on (i) the same individuals after a first and a second dose of PPSV-23 given 1 to 10 years later (n = 5) or (ii) two groups consisting of participants receiving PPSV-23 who were either vaccine-naïve or had received a first PPSV-23 dose 3 to 13 years earlier (n = 5). Three studies used electronic data bases to compare AEs after primary vs. revaccination doses of PPSV-23 after 1 to 10 years and one study had a cross-sectional design. Number of participants in the non-register-based and register-based studies ranged from 29 to 1414 and 360 to 316,000, respectively. 11 out of 14 included studies were at high risk of bias, three studies had an unclear risk of bias. None of the studies reported data on clinical effectiveness. Immunogenicity studies revealed that during the first two months antibody levels tended to be lower after revaccination as compared to primary vaccination. Thereafter, no obvious differences in antibody levels were observed. Compared to primary vaccination, revaccination was associated with an increased risk of local and systemic AEs, which, however, were usually mild and self-limiting. The risk and severity of AEs appeared to decrease with longer intervals between primary and revaccination. Data comparing the effectiveness of primary vs. revaccination with PPSV-23 are still lacking, because there are no studies with clinical endpoints. Data from observational studies indicates that revaccination with PPSV-23 is likely to induce long-term antibody levels that are comparable to those after primary vaccination. Given the high disease burden and the waning of vaccine-induced immunity, revaccination with PPSV-23 could be considered in the elderly. The increased risk of local and systemic AEs can likely be mitigated when giving revaccination at least five years after the primary dose. Adequately powered randomized controlled trials using clinical endpoints are urgently needed.

The Medical and Endovascular Treatment of Atherosclerotic Renal Artery Stenosis (METRAS) study: rationale and study design.

PubMed

Rossi, G P; Seccia, T M; Miotto, D; Zucchetta, P; Cecchin, D; Calò, L; Puato, M; Motta, R; Caielli, P; Vincenzi, M; Ramondo, G; Taddei, S; Ferri, C; Letizia, C; Borghi, C; Morganti, A; Pessina, A C

2012-08-01

It is unclear whether revascularization of renal artery stenosis (RAS) by means of percutaneous renal angioplasty and stenting (PTRAS) is advantageous over optimal medical therapy. Hence, we designed a randomized clinical trial based on an optimized patient selection strategy and hard experimental endpoints. Primary objective of this study is to determine whether PTRAS is superior or equivalent to optimal medical treatment for preserving glomerular filtration rate (GFR) in the ischemic kidney as assessed by 99mTcDTPA sequential renal scintiscan. Secondary objectives of this study are to establish whether the two treatments are equivalent in lowering blood pressure, preserving overall renal function and regressing target organ damage, preventing cardiovascular events and improving quality of life. The study is designed as a prospective multicentre randomized, un-blinded two-arm study. Eligible patients will have clinical and angio-CT evidence of RAS. Inclusion criteria is RAS affecting the main renal artery or its major branches either >70% or, if <70, with post-stenotic dilatation. Renal function will be assessed with 99mTc-DTPA renal scintigraphy. Patients will be randomized to either arms considering both resistance index value in the ischemic kidney and the presence of unilateral/bilateral stenosis. Primary experimental endpoint will be the GFR of the ischemic kidney, assessed as quantitative variable by 99TcDTPA, and the loss of ischemic kidney defined as a categorical variable.

Real-world use of the second-generation cobalt-chromium sirolimus-eluting stents: 12-month results from the prospective multicentre FOCUS registry.

PubMed

Zhang, Feng; Ge, Junbo; Qian, Juying; Ge, Lei; Zhou, Jun

2012-12-20

The FOCUS registry is a prospective, multicentre, web-based programme designed to collect clinical outcome data from real-world patients receiving the second-generation cobalt-chromium sirolimus-eluting stent (CoCr-SES). From March 2009 to February 2010, a total of 5,084 patients from 83 centres who were eligible to receive CoCr-SES were enrolled in the FOCUS registry. The primary endpoint was 12-month major adverse cardiac events (MACE, defined as the composite of cardiac death, myocardial infarction [MI], and target vessel revascularisation [TVR]). One-year data were available for 5,013 (98.6%) of the 5,084 patients enrolled. The primary endpoint occurred in 174 (3.47%) of 5,013 patients, consisting of 43 (0.86%) cardiac deaths, 132 (2.63%) MI, and 46 (0.92%) TVR. According to the Academic Research Consortium definition, definite and probable stent thrombosis (ST) occurred in 0.52% (26/5,013) of patients, including 19 cases of early ST and 7 of late ST. The 12-month MACE rates were 3.73% and 2.60% for extended-use and standard-use patients, respectively (p=0.065). The second-generation CoCr-SES was associated with low rates of 12-month MACE and ST in a broad spectrum of patients, thereby confirming the clinical safety and efficacy of this stent in a real-world setting.

A proof-of-concept trial of protein kinase C iota inhibition with auranofin for the paclitaxel-induced acute pain syndrome.

PubMed

Jatoi, Aminah; Grudem, Megan E; Dockter, Travis J; Block, Matthew S; Villasboas, Jose C; Tan, Angelina; Deering, Erin; Kasi, Pashtoon M; Mansfield, Aaron S; Botero, Juliana Perez; Okuno, Scott H; Smith, Deanne R; Fields, Alan P

2017-03-01

Paclitaxel causes the paclitaxel-induced acute pain (PIAP) syndrome. Based on preclinical data, we hypothesized that the protein kinase C (PKC) iota inhibitor, auranofin (a gold salt used for other pain conditions), palliates this pain. In a randomized, double-blinded manner, patients who had suffered this syndrome were assigned a one-time dose of auranofin 6 mg orally on day #2 of the chemotherapy cycle (post-paclitaxel) versus placebo. Patients completed the Brief Pain Inventory and a pain diary on days 2 through 8 and at the end of the cycle. The primary endpoint was pain scores, as calculated by area under the curve, in response to "Please rate your pain by circling the one number that best describes your pain at its worse in the last 24 hours." Thirty patients were enrolled. For the primary endpoint, mean area under the curve of 55 units (standard deviation 19) and 61 units (standard deviation 22) were observed in auranofin-treated and placebo-exposed patients, respectively (p = 0.44). On day 8 and at the end of the cycle, pain scores in auranofin-treated patients were more favorable, although differences were not statistically significant. In the dose schedule studied, auranofin did not palliate the PIAP syndrome, but delayed beneficial trends suggest further study for this indication.

Anatomy of an experimental two-link flexible manipulator under end-point control

NASA Technical Reports Server (NTRS)

Oakley, Celia M.; Cannon, Robert H., Jr.

1990-01-01

The design and experimental implementation of an end-point controller for two-link flexible manipulators are presented. The end-point controller is based on linear quadratic Gaussian (LQG) theory and is shown to exhibit significant improvements in trajectory tracking over a conventional controller design. To understand the behavior of the manipulator structure under end-point control, a strobe sequence illustrating the link deflections during a typical slew maneuver is included.

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

PubMed

Brain, Etienne G C; Mertens, Cécile; Girre, Véronique; Rousseau, Frédérique; Blot, Emmanuel; Abadie, Sophie; Uwer, Lionel; Bourbouloux, Emmanuelle; Van Praagh-Doreau, Isabelle; Mourey, Loic; Kirscher, Sylvie; Laguerre, Brigitte; Fourme, Emmanuelle; Luneau, Sylvia; Genève, Jean; Debled, Marc

2011-10-01

Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderly women <85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis.

PubMed

Davis, Stephanie D; Ratjen, Felix; Brumback, Lyndia C; Johnson, Robin C; Filbrun, Amy G; Kerby, Gwendolyn S; Panitch, Howard B; Donaldson, Scott H; Rosenfeld, Margaret

2016-05-01

The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint. Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials. Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0). iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Variability in the reporting of renal function endpoints in immunosuppression trials in renal transplantation: time for consensus?

PubMed

Knight, Simon R; Hussain, Samia

2016-12-01

Early measures of graft function are increasingly used to assess efficacy in clinical trials of kidney transplant immunosuppression. This study aimed to assess the variability and quality of reporting of these endpoints in contemporary trials. Data regarding renal function endpoints were extracted from 213 reports from randomized controlled trials comparing immunosuppressive interventions in renal transplant recipients published between 2010 and 2014. A total of 174 (81.7%) reports included a measure of renal function; in 44 (20.7%), this was the primary endpoint. A total of 103 manuscripts (48.4%) reported serum creatinine, 142 (66.6%) reported estimated glomerular filtration rate (eGFR), and 26 (12.2%) reported measured GFR. Formulas used for GFR estimation were modification of diet in renal disease (42.3%), Cockroft-Gault (23.5%), Nankivell (15.0%), and CKD-EPI (0.9%). Six studies (2.8%) did not report the formula used to estimate GFR. A total of 13.9% of endpoints had missing data. In 10 studies, disagreement was found in the significance of findings using different measures of renal function. There is a great deal of variability in the reporting of renal function endpoints, with a significant proportion of studies using underperforming or inappropriate estimates. There is a need for consensus as to the best tool for monitoring and reporting renal function post-transplant, and in particular for use in clinical trials and registries. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Challenges in translating endpoints from trials to observational cohort studies in oncology

PubMed Central

Ording, Anne Gulbech; Cronin-Fenton, Deirdre; Ehrenstein, Vera; Lash, Timothy L; Acquavella, John; Rørth, Mikael; Sørensen, Henrik Toft

2016-01-01

Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues – including previously unrecognized concerns – by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints. PMID:27354827

Interactive web-based learning modules prior to general medicine advanced pharmacy practice experiences.

PubMed

Isaacs, Alex N; Walton, Alison M; Nisly, Sarah A

2015-04-25

To implement and evaluate interactive web-based learning modules prior to advanced pharmacy practice experiences (APPEs) on inpatient general medicine. Three clinical web-based learning modules were developed for use prior to APPEs in 4 health care systems. The aim of the interactive modules was to strengthen baseline clinical knowledge before the APPE to enable the application of learned material through the delivery of patient care. For the primary endpoint, postassessment scores increased overall and for each individual module compared to preassessment scores. Postassessment scores were similar among the health care systems. The survey demonstrated positive student perceptions of this learning experience. Prior to inpatient general medicine APPEs, web-based learning enabled the standardization and assessment of baseline student knowledge across 4 health care systems.

Progression-free survival as a primary endpoint in clinical trials of metastatic colorectal cancer

PubMed Central

Gill, S.; Berry, S.; Biagi, J.; Butts, C.; Buyse, M.; Chen, E.; Jonker, D.; Mărginean, C.; Samson, B.; Stewart, J.; Thirlwell, M.; Wong, R.; Maroun, J.A.

2011-01-01

In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the “gold standard”—the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer. PMID:21969810

Design of the heart failure endpoint evaluation of AII-antagonist losartan (HEAAL) study in patients intolerant to ACE-inhibitor.

PubMed

Konstam, Marvin A; Poole-Wilson, Philip A; Dickstein, Kenneth; Drexler, Helmut; Justice, Steven J; Komajda, Michel; Malbecq, William; Martinez, Felipe A; Neaton, James D; Riegger, Gunter A J; Guptha, Soneil

2008-09-01

In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors. To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n = 3834) with symptomatic heart failure and an ejection fraction < or = 40% who are intolerant of ACE-inhibitor treatment. This paper presents the rationale, trial design, and baseline characteristics of the study population. The study, which completed recruitment on 31 March 2005, is event-driven and is estimated to accrue the target of 1710 adjudicated primary events during the latter half of 2008. The results of HEAAL should facilitate selection of an optimal dosing regimen for losartan in patients with symptomatic heart failure who are intolerant of ACE-inhibitors.

Impact of Medication Adherence on Mortality and Cardiovascular Morbidity: Protocol for a Population-Based Cohort Study

PubMed Central

2018-01-01

Background Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, such as coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. CVD is the leading threat to global health, whether measured by mortality, morbidity, or economic cost. Long-term administration of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers improves survival in patients with stablished coronary heart disease. Nevertheless, adherence to prescribed medication is poor for long-term drug treatment. Objective We aim to assess the relationship between adherences to the four pharmacological groups recommended for secondary prevention and the clinical outcomes of cardiovascular morbidity and mortality in patients with established CHD according to the level of adherence to these drugs in a population of incident cases of acute coronary syndrome (ACS). Methods Population-based cohort study of patients with a first episode of ACS during 2006-2015 in the Information System for Research in Primary Care (SIDIAP) database. We will estimate adherence to these drugs. The primary endpoint is a composite of all-cause mortality, ACS, and ischaemic stroke. Bivariate analyses will be performed estimating odds ratios for categorical variables and mean differences for continuous variables. Hazard ratios for adherences will be calculated for outcome events using Cox proportional hazard regression models, and proportionality of hazards assumption will be tested. Results We expect to estimate adherence to all four study treatments, the incidence of MACE, and to analyze if this incidence is associated with the level of drug adherence. Conclusions We expect to find that adherent patients have a lower risk of the primary endpoints compared with nonadherent patients. Trial Registration This study protocol was classified as EPA-OD by the AEMPS (IJG-EST-2017-01-2017-01, 07/04/2017) and registered in the EU PAS register (EUPAS19017, 09/05/2017). PMID:29523501

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression

PubMed Central

2012-01-01

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

Should palonosetron be a preferred 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting? An updated systematic review and meta-analysis.

PubMed

Chow, Ronald; Warr, David G; Navari, Rudolph M; Tsao, May; Popovic, Marko; Chiu, Leonard; Milakovic, Milica; Lam, Henry; DeAngelis, Carlo

2018-05-23

Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of palonosetron relative to other 5-HT 3 RAs. A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints-complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT 3 RAs for 10 of the 19 assessed endpoints. Only one endpoint-emesis in the overall phase-had noticeable more favorable data for palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. Palonosetron seems to be more efficacious and safe than other 5-HT 3 RAs-statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating palonosetron as the 5-HT 3 RA of choice.

Randomised controlled trial comparing hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors: a pilot study

PubMed Central

MacLaughlan David, Shannon; Salzillo, Sandra; Bowe, Patrick; Scuncio, Sandra; Malit, Bridget; Raker, Christina; Gass, Jennifer S; Granai, C O; Dizon, Don S

2013-01-01

Objectives To compare the efficacy of hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors, and to evaluate the feasibility of conducting a clinical trial comparing a drug with a complementary or alternative method (CAM). Design Prospective randomised trial. Setting Breast health centre of a tertiary care centre. Participants 15 women with a personal history of breast cancer or an increased risk of breast cancer who reported at least one daily hot flash. Interventions Gabapentin 900 mg daily in three divided doses (control) compared with standardised hypnotherapy. Participation lasted 8 weeks. Outcome measures The primary endpoints were the number of daily hot flashes and hot flash severity score (HFSS). The secondary endpoint was the Hot Flash Related Daily Interference Scale (HFRDIS). Results 27 women were randomised and 15 (56%) were considered evaluable for the primary endpoint (n=8 gabapentin, n=7 hypnotherapy). The median number of daily hot flashes at enrolment was 4.5 in the gabapentin arm and 5 in the hypnotherapy arm. HFSS scores were 7.5 in the gabapentin arm and 10 in the hypnotherapy arm. After 8 weeks, the median number of daily hot flashes was reduced by 33.3% in the gabapentin arm and by 80% in the hypnotherapy arm. The median HFSS was reduced by 33.3% in the gabapentin arm and by 85% in the hypnotherapy arm. HFRDIS scores improved by 51.6% in the gabapentin group and by 55.2% in the hypnotherapy group. There were no statistically significant differences between groups. Conclusions Hypnotherapy and gabapentin demonstrate efficacy in improving hot flashes. A definitive trial evaluating traditional interventions against CAM methods is feasible, but not without challenges. Further studies aimed at defining evidence-based recommendations for CAM are necessary. Trial registration clinicaltrials.gov (NCT00711529). PMID:24022390

Light-Driven Contact Hearing Aid for Broad-Spectrum Amplification: Safety and Effectiveness Pivotal Study.

PubMed

Gantz, Bruce J; Perkins, Rodney; Murray, Michael; Levy, Suzanne Carr; Puria, Sunil

2017-03-01

Demonstrate safety and effectiveness of the light-driven contact hearing aid to support FDA clearance. A single-arm, open-label investigational-device clinical trial. Two private-practice and one hospital-based ENT clinics. Forty-three subjects (86 ears) with mild-to-severe bilateral sensorineural hearing impairment. Bilateral amplification delivered via a light-driven contact hearing aid comprising a Tympanic Lens (Lens) with a customized platform to directly drive the umbo and a behind-the-ear sound processor (Processor) that encodes sound into light pulses to wirelessly deliver signal and power to the Lens. The primary safety endpoint was a determination of "no change" (PTA4 < 10 dB) in residual unaided hearing at the 120-day measurement interval. The primary efficacy endpoint was improvement in word recognition using NU-6 at the 30-day measurement interval over the baseline unaided case. Secondary efficacy endpoints included functional gain from 2 to 10 kHz and speech-in-noise improvement over the baseline unaided case using both omnidirectional and directional microphones. The results for the 86 ears in the study determined a mean change of -0.40 dB in PTA4, indicating no change in residual hearing (p < 0.0001). There were no serious device- or procedure-related adverse events, or unanticipated adverse events. Word recognition aided with the Earlens improved significantly (p < 0.0001) over the unaided performance, by 35% rationalized arcsine units on average. Mean functional gain was 31 dB across 2 to 10 kHz. The average speech-recognition threshold improvement over the unaided case for the Hearing in Noise Test was 0.75 dB (p = 0.028) and 3.14 dB (p < 0.0001) for the omnidirectional and directional microphone modes, respectively. The safety and effectiveness data supported a de novo 510(k) submission that received clearance from the FDA.

Autonomic nervous system activity as risk predictor in the medical emergency department: a prospective cohort study.

PubMed

Eick, Christian; Rizas, Konstantinos D; Meyer-Zürn, Christine S; Groga-Bada, Patrick; Hamm, Wolfgang; Kreth, Florian; Overkamp, Dietrich; Weyrich, Peter; Gawaz, Meinrad; Bauer, Axel

2015-05-01

To evaluate heart rate deceleration capacity, an electrocardiogram-based marker of autonomic nervous system activity, as risk predictor in a medical emergency department and to test its incremental predictive value to the modified early warning score. Prospective cohort study. Medical emergency department of a large university hospital. Five thousand seven hundred thirty consecutive patients of either sex in sinus rhythm, who were admitted to the medical emergency department of the University of Tübingen, Germany, between November 2010 and March 2012. None. Deceleration capacity of heart rate was calculated within the first minutes after emergency department admission. The modified early warning score was assessed from respiratory rate, heart rate, systolic blood pressure, body temperature, and level of consciousness as previously described. Primary endpoint was intrahospital mortality; secondary endpoints included transfer to the ICU as well as 30-day and 180-day mortality. One hundred forty-two patients (2.5%) reached the primary endpoint. Deceleration capacity was highly significantly lower in nonsurvivors than survivors (2.9 ± 2.1 ms vs 5.6 ± 2.9 ms; p < 0.001) and yielded an area under the receiver-operator characteristic curve of 0.780 (95% CI, 0.745-0.813). The modified early warning score model yielded an area under the receiver-operator characteristic curve of 0.706 (0.667-0.750). Implementing deceleration capacity into the modified early warning score model led to a highly significant increase of the area under the receiver-operator characteristic curve to 0.804 (0.770-0.835; p < 0.001 for difference). Deceleration capacity was also a highly significant predictor of 30-day and 180-day mortality as well as transfer to the ICU. Deceleration capacity is a strong and independent predictor of short-term mortality among patients admitted to a medical emergency department.

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype

PubMed Central

Seegers, Joachim; Vos, Marc A.; Flevari, Panagiota; Willems, Rik; Sohns, Christian; Vollmann, Dirk; Lüthje, Lars; Kremastinos, Dimitrios T.; Floré, Vincent; Meine, Mathias; Tuinenburg, Anton; Myles, Rachel C.; Simon, Dirk; Brockmöller, Jürgen; Friede, Tim; Hasenfuß, Gerd; Lehnart, Stephan E.; Zabel, Markus

2012-01-01

Aims The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca2+, Na+, K+) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes. Methods and results Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis. Conclusion The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. Clinicaltrials.gov identifier: NCT01209494. PMID:22117037

Long term results of a randomized trial in locally advanced rectal cancer: No benefit from adding a brachytherapy boost

PubMed Central

Appelt, Ane L; Vogelius, Ivan R; Pløen, John; Rafaelsen, Søren R; Lindebjerg, Jan; Havelund, Birgitte M; Bentzen, Søren M; Jakobsen, Anders

2014-01-01

Purpose/Objective(s) Mature data on tumor control and survival are presented from a randomized trial of the addition of a brachytherapy boost to long-course neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer. Methods and Materials Between March 2005 and November 2008, 248 patients withT3-4N0-2M0 rectal cancer were prospectively randomized to either long-course preoperative CRT (50.4Gy in 28 fractions, peroral UFT and L-leucovorin) alone or the same CRT schedule plus a brachytherapy boost (10Gy in 2 fractions). Primary trial endpoint was pathological complete response (pCR) at time of surgery; secondary endpoints included overall survival (OS), progression-free survival (PFS) and freedom from locoregional failure. Results Results for the primary endpoint have previously been reported. This analysis presents survival data for the 224 patients in the Danish part of the trial. 221 patients (111 control arm, 110 brachytherapy boost arm) had data available for analysis, with a median follow-up of 5.4 years. Despite a significant increase in tumor response at the time of surgery, no differences in 5-year OS (70.6% vs 63.6%, HR=1.24, p=0.34) and PFS (63.9% vs 52.0%, HR=1.22, p=0.32) were observed. Freedom from locoregional failure at 5 years were 93.9% and 85.7% (HR=2.60, 1.00–6.73, p=0.06) in the standard and in the brachytherapy arm, respectively. There was no difference in the prevalence of stoma. Explorative analysis based on stratification for tumor regression grade and resection margin status indicated the presence of response migration. Conclusions Despite increased pathological tumor regression at the time of surgery, we observed no benefit on late outcome. Improved tumor regression does not necessarily lead to a relevant clinical benefit when the neoadjuvant treatment is followed by high-quality surgery. PMID:25015203

An information-theoretic approach to surrogate-marker evaluation with failure time endpoints.

PubMed

Pryseley, Assam; Tilahun, Abel; Alonso, Ariel; Molenberghs, Geert

2011-04-01

Over the last decades, the evaluation of potential surrogate endpoints in clinical trials has steadily been growing in importance, not only thanks to the availability of ever more potential markers and surrogate endpoints, also because more methodological development has become available. While early work has been devoted, to a large extent, to Gaussian, binary, and longitudinal endpoints, the case of time-to-event endpoints is in need of careful scrutiny as well, owing to the strong presence of such endpoints in oncology and beyond. While work had been done in the past, it was often cumbersome to use such tools in practice, because of the need for fitting copula or frailty models that were further embedded in a hierarchical or two-stage modeling approach. In this paper, we present a methodologically elegant and easy-to-use approach based on information theory. We resolve essential issues, including the quantification of "surrogacy" based on such an approach. Our results are put to the test in a simulation study and are applied to data from clinical trials in oncology. The methodology has been implemented in R.

A unified framework for the evaluation of surrogate endpoints in mental-health clinical trials.

PubMed

Molenberghs, Geert; Burzykowski, Tomasz; Alonso, Ariel; Assam, Pryseley; Tilahun, Abel; Buyse, Marc

2010-06-01

For a number of reasons, surrogate endpoints are considered instead of the so-called true endpoint in clinical studies, especially when such endpoints can be measured earlier, and/or with less burden for patient and experimenter. Surrogate endpoints may occur more frequently than their standard counterparts. For these reasons, it is not surprising that the use of surrogate endpoints in clinical practice is increasing. Building on the seminal work of Prentice(1) and Freedman et al.,(2) Buyse et al. (3) framed the evaluation exercise within a meta-analytic setting, in an effort to overcome difficulties that necessarily surround evaluation efforts based on a single trial. In this article, we review the meta-analytic approach for continuous outcomes, discuss extensions to non-normal and longitudinal settings, as well as proposals to unify the somewhat disparate collection of validation measures currently on the market. Implications for design and for predicting the effect of treatment in a new trial, based on the surrogate, are discussed. A case study in schizophrenia is analysed.

Ecosystem services as assessment endpoints for ecological risk assessment.

PubMed

Munns, Wayne R; Rea, Anne W; Suter, Glenn W; Martin, Lawrence; Blake-Hedges, Lynne; Crk, Tanja; Davis, Christine; Ferreira, Gina; Jordan, Steve; Mahoney, Michele; Barron, Mace G

2016-07-01

Ecosystem services are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future. Those outputs include food and drinking water, clean air and water, and pollinated crops. The need to protect the services provided by natural systems has been recognized previously, but ecosystem services have not been formally incorporated into ecological risk assessment practice in a general way in the United States. Endpoints used conventionally in ecological risk assessment, derived directly from the state of the ecosystem (e.g., biophysical structure and processes), and endpoints based on ecosystem services serve different purposes. Conventional endpoints are ecologically important and susceptible entities and attributes that are protected under US laws and regulations. Ecosystem service endpoints are a conceptual and analytical step beyond conventional endpoints and are intended to complement conventional endpoints by linking and extending endpoints to goods and services with more obvious benefit to humans. Conventional endpoints can be related to ecosystem services even when the latter are not considered explicitly during problem formulation. To advance the use of ecosystem service endpoints in ecological risk assessment, the US Environmental Protection Agency's Risk Assessment Forum has added generic endpoints based on ecosystem services (ES-GEAE) to the original 2003 set of generic ecological assessment endpoints (GEAEs). Like conventional GEAEs, ES-GEAEs are defined by an entity and an attribute. Also like conventional GEAEs, ES-GEAEs are broadly described and will need to be made specific when applied to individual assessments. Adoption of ecosystem services as a type of assessment endpoint is intended to improve the value of risk assessment to environmental decision making, linking ecological risk to human well-being, and providing an improved means of communicating those risks. Integr Environ Assess Manag 2016;12:522-528. Published 2015 SETAC. This article is a US Government work and, as such, is in the public domain in the USA. Published 2015 SETAC. This article is a US Government work and, as such, is in the public domain in the USA.

Assessing cancer drugs for reimbursement: methodology, relationship between effect size and medical need.

PubMed

de Sahb-Berkovitch, Rima; Woronoff-Lemsi, Marie-Christine; Molimard, Mathieu

2010-01-01

Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an "improvement of medical service rendered" (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as the endpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versus the comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensive in quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these issues, the roundtable recommends the possibility of early scientific opinions by the office of the Transparency Commission in order to discuss comparators and the relevance of responder subgroups. It also recommends the possibility of granting a temporary ASMR, on condition of subsequent confirmation by production of data, when reimbursement appears justified in a subpopulation of the MA for which only subgroup analysis is available. © 2010 Société Française de Pharmacologie et de Thérapeutique.

Edaravone and its clinical development for amyotrophic lateral sclerosis.

PubMed

Takei, Koji; Watanabe, Kazutoshi; Yuki, Satoshi; Akimoto, Makoto; Sakata, Takeshi; Palumbo, Joseph

2017-10-01

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

[Which information is given during the purchase of an HIV self-test in a Caen pharmacy? A Comprehensive transversal and observational study using surveys, without modification of practice].

PubMed

Guitton, S; Rabiaza, A

2018-04-16

HIV infection affects about 150,000 people in France. In total, 30,000 of them are unaware of their serostatus. In this context, HIV self-testing has arrived in France in September 2015. The aim of our study was to analyze the level of application of the recommendations during the purchase of an HIV self-test. Our primary hypothesis was that the delivered information is poor. We realized a comprehensive transversal and observational study with surveys without modification of practice in all Caen pharmacies. The primary endpoint was the seller's assessment of the presence or possibility of an emergency situation requiring a post-exposure prophylaxis and suitability assessment of self-testing for the patient's case. Seven pharmacies out of the 41 visited (17.07%) validated our primary endpoint. In all pharmacies, 43.9% had HIV self-tests available for sale. The availabality of the self-tests is linked to the main endpoint (P<0.005). In total, 31.71% of the vendors redirected the patient to another method of screening (general practitioner, sexual health clinic…). The delivered information about HIV self-tests is poor. Improving it would put the pharmacist at the heart of the HIV screening strategy. The introduction of training for the professionnals in our region could be interesting to improve the dispensing of the self-tests. Copyright © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Basal values and changes of liver stiffness predict the risk of disease progression in compensated advanced chronic liver disease.

PubMed

Pons, Mònica; Simón-Talero, Macarena; Millán, Laura; Ventura-Cots, Meritxell; Santos, Begoña; Augustin, Salvador; Genescà, Joan

2016-10-01

Transient elastography has been proposed as a tool to predict the risk of decompensation in patients with chronic liver disease. We aimed to identify risk groups of disease progression, using a combination of baseline liver stiffness measurement (LSM) and its change over time (delta-LSM) in patients with compensated advanced chronic liver disease (cACLD). Ninety-four patients with baseline LSM ≥10kPa, Child-Pugh score 5 and without previous decompensation were included. A second LSM was performed during follow-up and data on liver function and liver-related events were collected. The primary endpoint was a composite that included death, liver decompensation and impairment in at least 1 point in Child-Pugh score. After a median follow-up of 43.6 months, 15% of patients presented the primary endpoint. Multivariate analysis identified baseline LSM (OR 1.12, P=0.002) and delta-LSM (OR 1.02, P=0.048) as independent predictors of the primary endpoint. A high risk group represented by patients with baseline LSM ≥21kPa and delta-LSM ≥10% (risk of progression 47.1%, 95% CI: 23-71%) was identified, while patients with LSM <21kPa and delta-LSM <10% presented zero risk of progression (P=0.03). Simple classification rules using baseline LSM and delta-LSM identify cACLD patients at low or high risk of disease progression. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Surrogate and clinical endpoints for studies in peripheral artery occlusive disease: Are statistics the brakes?

PubMed

Waliszewski, Matthias W; Redlich, Ulf; Breul, Victor; Tautenhahn, Jörg

2017-04-30

The aim of this review is to present the available clinical and surrogate endpoints that may be used in future studies performed in patients with peripheral artery occlusive disease (PAOD). Importantly, we describe statistical limitations of the most commonly used endpoints and offer some guidance with respect to study design for a given sample size. The proposed endpoints may be used in studies using surgical or interventional revascularization and/or drug treatments. Considering recently published study endpoints and designs, the usefulness of these endpoints for reimbursement is evaluated. Based on these potential study endpoints and patient sample size estimates with different non-inferiority or tests for difference hypotheses, a rating relative to their corresponding reimbursement values is attempted. As regards the benefit for the patients and for the payers, walking distance and the ankle brachial index (ABI) are the most feasible endpoints in a relatively small study samples given that other non-vascular impact factors can be controlled. Angiographic endpoints such as minimal lumen diameter (MLD) do not seem useful from a reimbursement standpoint despite their intuitiveness. Other surrogate endpoints, such as transcutaneous oxygen tension measurements, have yet to be established as useful endpoints in reasonably sized studies with patients with critical limb ischemia (CLI). From a reimbursement standpoint, WD and ABI are effective endpoints for a moderate study sample size given that non-vascular confounding factors can be controlled.

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.

PubMed

Giugliano, Robert P; Pedersen, Terje R; Park, Jeong-Gun; De Ferrari, Gaetano M; Gaciong, Zbigniew A; Ceska, Richard; Toth, Kalman; Gouni-Berthold, Ioanna; Lopez-Miranda, Jose; Schiele, François; Mach, François; Ott, Brian R; Kanevsky, Estella; Pineda, Armando Lira; Somaratne, Ransi; Wasserman, Scott M; Keech, Anthony C; Sever, Peter S; Sabatine, Marc S

2017-10-28

LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. Amgen. Copyright © 2017 Elsevier Ltd. All rights reserved.

Flagged uniform particle splitting for variance reduction in proton and carbon ion track-structure simulations

NASA Astrophysics Data System (ADS)

Ramos-Méndez, José; Schuemann, Jan; Incerti, Sebastien; Paganetti, Harald; Schulte, Reinhard; Faddegon, Bruce

2017-08-01

Flagged uniform particle splitting was implemented with two methods to improve the computational efficiency of Monte Carlo track structure simulations with TOPAS-nBio by enhancing the production of secondary electrons in ionization events. In method 1 the Geant4 kernel was modified. In method 2 Geant4 was not modified. In both methods a unique flag number assigned to each new split electron was inherited by its progeny, permitting reclassification of the split events as if produced by independent histories. Computational efficiency and accuracy were evaluated for simulations of 0.5-20 MeV protons and 1-20 MeV u-1 carbon ions for three endpoints: (1) mean of the ionization cluster size distribution, (2) mean number of DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) classified with DBSCAN, and (3) mean number of SSBs and DSBs classified with a geometry-based algorithm. For endpoint (1), simulation efficiency was 3 times lower when splitting electrons generated by direct ionization events of primary particles than when splitting electrons generated by the first ionization events of secondary electrons. The latter technique was selected for further investigation. The following results are for method 2, with relative efficiencies about 4.5 times lower for method 1. For endpoint (1), relative efficiency at 128 split electrons approached maximum, increasing with energy from 47.2  ±  0.2 to 66.9  ±  0.2 for protons, decreasing with energy from 51.3  ±  0.4 to 41.7  ±  0.2 for carbon. For endpoint (2), relative efficiency increased with energy, from 20.7  ±  0.1 to 50.2  ±  0.3 for protons, 15.6  ±  0.1 to 20.2  ±  0.1 for carbon. For endpoint (3) relative efficiency increased with energy, from 31.0  ±  0.2 to 58.2  ±  0.4 for protons, 23.9  ±  0.1 to 26.2  ±  0.2 for carbon. Simulation results with and without splitting agreed within 1% (2 standard deviations) for endpoints (1) and (2), within 2% (1 standard deviation) for endpoint (3). In conclusion, standard particle splitting variance reduction techniques can be successfully implemented in Monte Carlo track structure codes.

IN SILICO MODELLING OF HAZARDOUS ENDPOINTS: CURRENT PROBLEMS AND PROSPECTIVES

EPA Science Inventory

The primary hurdles for Quantitative Structure-Activity Relationships (QSARs) to overcome their acceptance for regulatory purposes will be discussed. They include (a) the development of more mechanistic representations of chemical structure, (b) the classification of toxicity pa...

A systematic comparison of recurrent event models for application to composite endpoints.

PubMed

Ozga, Ann-Kathrin; Kieser, Meinhard; Rauch, Geraldine

2018-01-04

Many clinical trials focus on the comparison of the treatment effect between two or more groups concerning a rarely occurring event. In this situation, showing a relevant effect with an acceptable power requires the observation of a large number of patients over a long period of time. For feasibility issues, it is therefore often considered to include several event types of interest, non-fatal or fatal, and to combine them within a composite endpoint. Commonly, a composite endpoint is analyzed with standard survival analysis techniques by assessing the time to the first occurring event. This approach neglects that an individual may experience more than one event which leads to a loss of information. As an alternative, composite endpoints could be analyzed by models for recurrent events. There exists a number of such models, e.g. regression models based on count data or Cox-based models such as the approaches of Andersen and Gill, Prentice, Williams and Peterson or, Wei, Lin and Weissfeld. Although some of the methods were already compared within the literature there exists no systematic investigation for the special requirements regarding composite endpoints. Within this work a simulation-based comparison of recurrent event models applied to composite endpoints is provided for different realistic clinical trial scenarios. We demonstrate that the Andersen-Gill model and the Prentice- Williams-Petersen models show similar results under various data scenarios whereas the Wei-Lin-Weissfeld model delivers effect estimators which can considerably deviate under commonly met data scenarios. Based on the conducted simulation study, this paper helps to understand the pros and cons of the investigated methods in the context of composite endpoints and provides therefore recommendations for an adequate statistical analysis strategy and a meaningful interpretation of results.

A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation.

PubMed

Abraham, William T; Kuck, Karl-Heinz; Goldsmith, Rochelle L; Lindenfeld, JoAnn; Reddy, Vivek Y; Carson, Peter E; Mann, Douglas L; Saville, Benjamin; Parise, Helen; Chan, Rodrigo; Wiegn, Phi; Hastings, Jeffrey L; Kaplan, Andrew J; Edelmann, Frank; Luthje, Lars; Kahwash, Rami; Tomassoni, Gery F; Gutterman, David D; Stagg, Angela; Burkhoff, Daniel; Hasenfuß, Gerd

2018-05-05

The authors sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak VO 2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. The difference in peak VO 2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O 2 /kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172). Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial.

PubMed

Shah, P L; Slebos, D-J; Cardoso, P F G; Cetti, E; Voelker, K; Levine, B; Russell, M E; Goldin, J; Brown, M; Cooper, J D; Sybrecht, G W

2011-09-10

Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. Broncus Technologies. Copyright © 2011 Elsevier Ltd. All rights reserved.

2-Year Outcomes of High Bleeding Risk Patients After Polymer-Free Drug-Coated Stents.

PubMed

Garot, Philippe; Morice, Marie-Claude; Tresukosol, Damras; Pocock, Stuart J; Meredith, Ian T; Abizaid, Alexandre; Carrié, Didier; Naber, Christoph; Iñiguez, Andres; Talwar, Suneel; Menown, Ian B A; Christiansen, Evald H; Gregson, John; Copt, Samuel; Hovasse, Thomas; Lurz, Philipp; Maillard, Luc; Krackhardt, Florian; Ong, Paul; Byrne, Jonathan; Redwood, Simon; Windhövel, Ute; Greene, Samantha; Stoll, Hans-Peter; Urban, Philip

2017-01-17

A 1-year follow-up, polymer-free metallic stent coated with biolimus-A9 followed by 1-month dual antiplatelet therapy is safer and more effective than a bare-metal stent (BMS) for patients with high risk of bleeding. This study analyzed 2-year outcomes to determine whether these benefits are maintained. In a prospective, multicenter, double-blind trial, we randomized 2,466 high bleeding risk patients to receive a drug-coated stent (DCS) or a BMS followed by 1-month dual antiplatelet therapy. The primary safety endpoint was a composite of cardiac death, myocardial infarction, or stent thrombosis. The primary efficacy endpoint was clinically driven target lesion revascularization. At 2 years, the primary safety endpoint had occurred in 147 DCS and 180 BMS patients (15.3%) (hazard ratio: 0.80; 95% confidence interval: 0.64 to 0.99; p = 0.039). Clinically driven target lesion revascularization occurred for 77 DCS and 136 BMS patients (12.0%) (hazard ratio: 0.54; 95% confidence interval: 0.41 to 0.72; p < 0.0001). Major bleeding occurred in 8.9% of DCS and 9.2% of BMS patients (p = 0.95), and a coronary thrombotic event (myocardial infarction and/or stent thrombosis) occurred in 8.2% of DCS and 10.6% of BMS patients (p = 0.045). One-year mortality was 27.1% for a major bleed and 26.3% for a thrombotic event. At 2 years, multivariate correlates of major bleeding were age >75 years, anemia, raised plasma creatinine, and planned long-term anticoagulation. Correlates of the primary safety endpoint were age, anemia, congestive heart failure, multivessel disease, number of stents implanted, and use of a BMS rather than a DCS. Safety and efficacy benefits of DCS over BMS were maintained for 2 years in high bleeding risk patients. Rates of major bleeding and coronary thrombotic events were no different and were associated with a substantial and comparable mortality risk. (A Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug Coated Stent Versus the Gazelle Bare Metal Stent in Patients With High Risk of Bleeding [LEADERS FREE]; NCT01623180). Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials

PubMed Central

Laporte, Silvy; Squifflet, Pierre; Baroux, Noémie; Fossella, Frank; Georgoulias, Vassilis; Pujol, Jean-Louis; Douillard, Jean-Yves; Kudoh, Shinzohy; Pignon, Jean-Pierre; Quinaux, Emmanuel; Buyse, Marc

2013-01-01

Objectives To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Design Meta-analysis of individual patient data from randomised trials. Setting Five randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC. Participants 2331 patients with advanced NSCLC. Primary and secondary outcome measures Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS. Results The median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata. Conclusions These analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation. PMID:23485717

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities.

PubMed

Schmidt, Béla Z; Lehmann, Martin; Gutbier, Simon; Nembo, Erastus; Noel, Sabrina; Smirnova, Lena; Forsby, Anna; Hescheler, Jürgen; Avci, Hasan X; Hartung, Thomas; Leist, Marcel; Kobolák, Julianna; Dinnyés, András

2017-01-01

Neurotoxicity and developmental neurotoxicity are important issues of chemical hazard assessment. Since the interpretation of animal data and their extrapolation to man is challenging, and the amount of substances with information gaps exceeds present animal testing capacities, there is a big demand for in vitro tests to provide initial information and to prioritize for further evaluation. During the last decade, many in vitro tests emerged. These are based on animal cells, human tumour cell lines, primary cells, immortalized cell lines, embryonic stem cells, or induced pluripotent stem cells. They differ in their read-outs and range from simple viability assays to complex functional endpoints such as neural crest cell migration. Monitoring of toxicological effects on differentiation often requires multiomics approaches, while the acute disturbance of neuronal functions may be analysed by assessing electrophysiological features. Extrapolation from in vitro data to humans requires a deep understanding of the test system biology, of the endpoints used, and of the applicability domains of the tests. Moreover, it is important that these be combined in the right way to assess toxicity. Therefore, knowledge on the advantages and disadvantages of all cellular platforms, endpoints, and analytical methods is essential when establishing in vitro test systems for different aspects of neurotoxicity. The elements of a test, and their evaluation, are discussed here in the context of comprehensive prediction of potential hazardous effects of a compound. We summarize the main cellular characteristics underlying neurotoxicity, present an overview of cellular platforms and read-out combinations assessing distinct parts of acute and developmental neurotoxicology, and highlight especially the use of stem cell-based test systems to close gaps in the available battery of tests.

Systematic Review and Meta-analysis of Major Cardiovascular Outcomes for Radial Versus Femoral Access in Patients with Acute Coronary Syndrome

PubMed Central

Ruiz-Rodriguez, Ernesto; Asfour, Ahmed; Lolay, Georges; Ziada, Khaled M.; Abdel-Latif, Ahmed K.

2016-01-01

Objectives Radial artery access (RA) for left heart catheterization and percutaneous coronary interventions (PCIs) has been demonstrated to be safe and effective. Despite consistent data showing less bleeding complications compared with femoral artery access (FA), it continues to be underused in the United States, particularly in patients with acute coronary syndrome (ACS) in whom aggressive anticoagulation and platelet inhibition regimens are needed. This systematic review and meta-analysis aims to compare major cardiovascular outcomes and safety endpoints in patients with ACS managed with PCI using radial versus femoral access. Methods Randomized controlled trials and cohort studies comparing RA versus FA in patients with ACS were analyzed. Our primary outcomes were mortality, major adverse cardiac event, major bleeding, and access-related complications. A fixed-effects model was used for the primary analyses. Results Fifteen randomized controlled trials and 17 cohort studies involving 44,854 patients with ACS were identified. Compared with FA, RA was associated with a reduction in major bleeding (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.33–0.61; P < 0.001), access-related complications (OR 0.27, 95% CI 0.18–0.39; P < 0.001), mortality (OR 0.64, 95% CI 0.54–0.75; P < 0.001), and major adverse cardiac event (OR 0.70, 95% CI 0.57–0.85; P < 0.001). These significant reductions were consistent across different study designs and clinical presentations. Conclusions Based on this large meta-analysis, RA for primary PCI in the setting of ACS is associated with reduction in cardiac and safety endpoints when compared with FA in both urgent and elective procedures. This should encourage a wider adoption of this technique among centers and interventional cardiologists. PMID:26741877

A multicenter, primary-care-based, open-label study to assess the success of converting opioid-experienced patients with chronic moderate-to-severe pain to morphine sulfate and naltrexone hydrochloride extended-release capsules using a standardized conversion guide.

PubMed

Setnik, Beatrice; Roland, Carl L; Sommerville, Kenneth W; Pixton, Glenn C; Berke, Robert; Calkins, Anne; Goli, Veeraindar

2015-01-01

To evaluate the conversion of opioid-experienced patients with chronic moderate-to-severe pain to extended-release morphine sulfate with sequestered naltrexone hydrochloride (MSN) using a standardized conversion guide. This open-label, single-arm study was conducted in 157 primary care centers in the United States. A total of 684 opioid-experienced adults with chronic moderate-to-severe pain were converted to oral administration of MSN from transdermal fentanyl and oral formulations of hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and other morphine products using a standardized conversion guide. The primary endpoint was the percentage of patients achieving a stable MSN dose within a 6-week titration phase. Secondary endpoints included duration of time to stable dose, number of titration steps, safety and efficacy measures, and investigator assessment of conversion guide utility. Of the 684 patients, 51.3% were converted to a stable dose of MSN (95% confidence interval: 47.5%, 55.1%). The mean (standard deviation) number of days to stable dose was 20 (8.94), and number of titration steps to stable dose was 2.4 (1.37). The majority of adverse events were mild/moderate and consistent with opioid therapy. Mean pain scores at stable dose decreased from baseline. Investigators were generally satisfied with the conversion guide and, in 94% of cases, reported they would use it again. Conversion to MSN treatment using the standardized MSN conversion guide was an attainable goal in approximately half of the population of opioid-experienced patients with chronic moderate-to-severe pain. Investigators found the guide to be a useful tool to assist conversion of opioid-experienced patients to MSN.

REmote SUpervision to Decrease HospitaLization RaTe. Unified and integrated platform for data collected from devices manufactured by different companies: Design and rationale of the RESULT study.

PubMed

Tajstra, Mateusz; Sokal, Adam; Gwóźdź, Arkadiusz; Wilczek, Marcin; Gacek, Adam; Wojciechowski, Konrad; Gadula-Gacek, Elżbieta; Adamowicz-Czoch, Elżbieta; Chłosta-Niepiekło, Katarzyna; Milewski, Krzysztof; Rozentryt, Piotr; Kalarus, Zbigniew; Gąsior, Mariusz; Poloński, Lech

2017-07-01

The number of patients with heart failure implantable cardiac electronic devices (CIEDs) is growing. Hospitalization rate in this group is very high and generates enormous costs. To avoid the need for hospital treatment, optimized monitoring and follow-up is crucial. Remote monitoring (RM) has been widely put into practice in the management of CIEDs but it may be difficult due to the presence of differences in systems provided by device manufacturers and loss of gathered data in case of device reimplantation. Additionally, conclusions derived from studies about usefulness of RM in clinical practice apply to devices coming only from a single company. An integrated monitoring platform allows for more comprehensive data analysis and interpretation. Therefore, the primary objective of Remote Supervision to Decrease Hospitalization Rate (RESULT) study is to evaluate the impact of RM on the clinical status of patients with ICDs or CRT-Ds using an integrated platform. Six hundred consecutive patients with ICDs or CRT-Ds implanted will be prospectively randomized to either a traditional or RM-based follow-up model. The primary clinical endpoint will be a composite of all-cause mortality or hospitalization for cardiovascular reasons within 12 months after randomization. The primary technical endpoint will be to construct and evaluate a unified and integrated platform for the data collected from RM devices manufactured by different companies. This manuscript describes the design and methodology of the prospective, randomized trial designed to determine whether remote monitoring using an integrated platform for different companies is safe, feasible, and efficacious (ClinicalTrials.gov Identifier: NCT02409225). © 2016 Wiley Periodicals, Inc.

Pulsed electromagnetic fields for postmenopausal osteoporosis and concomitant lumbar osteoarthritis in southwest China using proximal femur bone mineral density as the primary endpoint: study protocol for a randomized controlled trial.

PubMed

Liu, Hui-Fang; He, Hong-Chen; Yang, Lin; Yang, Zhou-Yuan; Yao, Ke; Wu, Yuan-Chao; Yang, Xi-Biao; He, Cheng-Qi

2015-06-10

Osteoporosis (OP) and osteoarthritis (OA) are prevalent skeletal disorders among postmenopausal women. Coexistence is common especially that of postmenopausal osteoporosis (PMO) and lumbar OA. An hypothesis has been raised that OP and OA might share the same pathogenic mechanism, and pulsed electromagnetic fields (PEMFs) were reported to have anti-osteoporosis and anti-osteoarthritis properties, but this suggestion was based primarily on biomarker data. Therefore, whether these two effects could take place simultaneously has not yet been investigated. This randomized controlled trial (RCT) is designed to explore the effect of PEMFs for PMO and concomitant lumbar OA. The study will include PMO patients (postmenopausal women; aged between 50 and 70 years; have been postmenopausal for at least 5 years and diagnosed with OP using proximal femur T-score) with concomitant lumbar OA (patients with confounding disorders like diabetes, hypertension, hyperlipidemia, and previous fracture history, etcetera, will be excluded) will be randomly assigned to two arms: PEMFs group and sham PEMFs group. There will be 25 participants in each arm (50 in total) and the outcome assessment, including the primary endpoint (proximal femur bone mineral density), will be performed at 5 weeks, 3 months and 6 months after enrollment. PMO and lumbar OA are prominent public health problem, especially for postmenopausal women. We hope this RCT will provide scientific evidence to primary care of the postmenopausal women regarding the use of these nonpharmaceutical, noninvasive modalities, PEMFs, in managing PMO and lumbar OA. Chinese Clinical Trial Registry: ChiCTR-TRC-14005156 (28 August 2014).

Rationale and design of the extracranial carotid artery aneurysm registry.

PubMed

Welleweerd, J C; Bots, M L; Kappelle, L J; Rinkel, G J; Ruigrok, Y M; Baas, A F; van der Worp, H B; Vergouwen, M D; Bleys, R L; Hendrikse, J; Lo, T H; Moll, F L; de Borst, G J

2015-02-06

Aneurysms of the extracranial carotid artery (ECAA) are rare. Although most ECAA are identified in asymptomatic patients, serious neurological complications may occur. Current literature on treatment outcome contains mainly case reports and small case series with incomplete data and lack of long--term follow--up. There is clear lack on natural follow--up data, and there is no clear treatment algorithm. An international web--based registry to collect data on patients with ECAA is designed to provide clinical guidance on this scarce pathology. The Carotid Aneurysm Registry (CAR) is open for inclusion of all patients with a fusiform or saccular ECAA. Patients with primary or secondary ECAA can be enrolled in CAR independent of the type of treatment (conservative or invasive). CAR participation does not interfere with the local physician's treatment policy. Follow--up and imaging can also be scheduled according to local clinical practice. The primary endpoint of the CAR in conservative patients is occurrence of symptoms related to the aneurysm at 30 days, one, three, and five years. The primary endpoint in invasively treated patients is freedom from symptoms of the aneurysm at 30 days, one, three, and five years. Analyses will relate outcome to etiology, imaging characteristics, ECAA growth patterns, and (if applicable) revascularization technique applied. The aim of the registry is to prospectively collect follow--up data on patients with an ECAA, being either treated conservatively or by invasive aneurysm exclusion strategies. The CAR database will be used to address diagnostic and therapeutic research questions. Collecting and analyzing the data gained from the registry could be the first step towards development of treatment guidelines and expert consensus for the management of ECAA.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial.

PubMed

Kimura, Genjiro; Kasahara, Masato; Ueshima, Kenji; Tanaka, Sachiko; Yasuno, Shinji; Fujimoto, Akira; Sato, Toshiya; Imamoto, Miyuki; Kosugi, Shinji; Nakao, Kazuwa

2017-06-01

Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m 2 in Group A and by 2.6 ml/min/1.73 m 2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

Study to determine the clinical significance of HEmolysis During Orbital AtheRectomy (CLEAR study).

PubMed

Staniloae, Cezar S; Korabathina, Ravikiran; Lane, Thomas A; Dattilo, Raymond; Church, Kevin J; Mody, Kanika P; Mayeda, Guy S

2011-02-01

To evaluate the incidence of clinically evident hemolysis associated with orbital atherectomy used to treat severe peripheral artery disease. The observational CLEAR study enrolled 31 subjects (16 men; mean age 71 ± 10 years, range 44-92) with claudication (58.1%) or critical limb ischemia (38.7%) who underwent orbital atherectomy with the Diamondback 360 system at 4 US centers. The 42 lesions in 31 limbs were located in the superficial femoral (n = 19, 45.2%), popliteal (n = 8, 19.0%), and tibial arteries (n = 15, 35.8%). The majority of lesions (34, 81.0%) were de novo; moderate or severe calcification was identified in 90.5% of cases. Lesion and procedural parameters were analyzed at a core laboratory. Blood samples were collected during and post procedure and analyzed for markers of hemolysis. The primary endpoint was the occurrence of clinically significant hemolysis. The secondary endpoints included the occurrence of any clinical symptoms/signs potentially related to hemolysis. Statistical analysis was performed to identify predictors for hemolysis. Laboratory evidence of hemolysis was seen in 11 (35.5%) subjects. No one met the clinical event criteria, and so the primary endpoint of the study was not reached. The secondary endpoints were hypertensive crisis (1, 3.2%) and transient hemoglobinuria (3, 9.7%). Lower glomerular filtration rates, calcified plaque, long atherectomy runs, and solid crown selection were independent predictors of hemolysis. There was no clinically significant hemolysis after orbital atherectomy. The results of this study will enable users to predict conditions that predispose to high levels of red cell hemolysis following orbital atherectomy and to take appropriate measures to limit its occurrence.

Long-term renal outcome in patients with malignant hypertension: a retrospective cohort study

PubMed Central

2012-01-01

Background Malignant hypertension is frequently complicated by renal insufficiency. Although the survival of this hypertensive emergency has improved, recent data on renal outcome and its predictors are lacking. We assessed renal outcome and its predictors in patients with malignant hypertension. Methods Retrospective analysis of patients admitted with malignant hypertension in Amsterdam, the Netherlands between August 1992–January 2010. Follow-up data on vital status, renal function and blood pressure (BP) were obtained from the outpatient department and from general practitioners. The primary composite endpoint was end-stage renal disease (ESRD) defined as the start of kidney replacement therapy (KRT) or ≥ 50% decline of estimated glomerular filtration rate (eGFR). The secondary endpoint was all cause mortality. Results A total of 120 patients admitted with malignant hypertension were included. After a median follow-up period of 67 months (IQR 28 to 108 months) the primary endpoint was reached by 37 (31%) patients, whereas 18 patients (15%) reached the secondary endpoint. Twenty-nine (24%) patients started KRT and 8 patients (7%) had an eGFR decline ≥ 50%. After the acute phase (> 3 months after admission), initial serum creatinine and follow-up BP were the main predictors of future ESRD with hazard ratios of 6.1 (95% CI, 2.2–17) for patients with initial serum creatinine ≥ 175 μmol /L and 4.3 (95% CI, 1.4–14) for patients with uncontrolled hypertension. Conclusions Progressive renal function decline leading to ESRD remains a major threat to patients with malignant hypertension. BP control during follow-up was an important modifiable predictor of renal outcome. PMID:22846257

Efficacy and safety of sitagliptin as compared with glimepiride in Japanese patients with type 2 diabetes mellitus aged ≥ 60 years (START-J trial).

PubMed

Terauchi, Yasuo; Yamada, Yuichiro; Ishida, Hitoshi; Ohsugi, Mitsuru; Kitaoka, Masafumi; Satoh, Jo; Yabe, Daisuke; Shihara, Nobuyuki; Seino, Yutaka

2017-08-01

The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus (T2DM) for 1 year as compared with glimepiride. Patients aged ≥60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 52. Secondary efficacy endpoints included self-monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [CI] -0.02 to 0.24; P = .087) (1.2 mmol/mol [-0.2 to 2.6]). The upper limit of the CI was below the predefined non-inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non-inferiority of sitagliptin to glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non-serious hypoglycaemia than glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-type KRAS Metastatic Colorectal Cancer

PubMed Central

Cutsem, Eric Van; Eng, Cathy; Nowara, Elzbieta; Świeboda-Sadlej, Anna; Tebbutt, Niall C.; Mitchell, Edith; Davidenko, Irina; Stephenson, Joe; Elez, Elena; Prenen, Hans; Deng, Hongjie; Tang, Rui; McCaffery, Ian; Oliner, Kelly S.; Chen, Lisa; Gansert, Jennifer; Loh, Elwyn; Smethurst, Dominic; Tabernero, Josep

2015-01-01

Purpose Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8,10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. PMID:24919569

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol for a controlled clinical trial developed by consensus of an international study group. Part two: design of the study.

PubMed

Bauhofer, A; Lorenz, W; Stinner, B; Rothmund, M; Koller, M; Sitter, H; Celik, I; Farndon, J R; Fingerhut, A; Hay, J M; Lefering, R; Lorijn, R; Nyström, P O; Schäfer, H; Schein, M; Solomkin, J; Troidl, H; Volk, H D; Wittmann, D H; Wyatt, J

2001-04-01

Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). This part describes the design of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). The trial design includes the following elements for a prototype protocol: * The study population is restricted to patients with colorectal cancer, including a left sided resection and an increased perioperative risk (ASA 3 and 4). * Patients are allocated by random to the control or treatment group. * The double blinding strategy of the trial is assessed by psychometric indices. * An endpoint construct with quality of life (EORTC QLQ-C30) and a recovery index (modified Mc Peek index) are used as primary endpoints. Qualitative analysis of clinical relevance of the endpoints is performed by both patients and doctors. * Statistical analysis uses an area under the curve (AUC) model for improvement of quality of life on leaving hospital and two and six months after operation. A confirmatory statistical model with quality of life as the first primary endpoint in the hierarchic test procedure is used. Expectations of patients and surgeons and the negative affect are analysed by social psychological scales. This study design differs from other trials on preoperative prophylaxis and postoperative recovery, and has been developed to try a new concept and avoid previous failures.

The effect of individualized nutritional counseling on muscle mass and treatment outcome in patients with metastatic colorectal cancer undergoing chemotherapy: a randomized controlled trial protocol.

PubMed

van der Werf, Anne; Blauwhoff-Buskermolen, Susanne; Langius, Jacqueline A E; Berkhof, Johannes; Verheul, Henk M W; de van der Schueren, Marian A E

2015-03-05

A low muscle mass is prevalent in patients with metastatic colorectal cancer (mCRC) and has been associated with poor treatment outcome. Chemotherapeutic treatment has an additional unfavorable effect on muscle mass. Sufficient protein intake and physical activity are known to induce muscle protein anabolism in healthy individuals, however it is unclear whether optimal nutrition is effective to preserve muscle mass in patients with mCRC during first-line chemotherapy as well. We hypothesize that individual nutritional counseling by a trained dietitian during first-line chemotherapy is effective in preserving muscle mass and may improve clinical outcomes in patients with mCRC. In this multi-center single-blind randomized controlled trial, patients with mCRC scheduled for first-line combination chemotherapy consisting of oxaliplatin and fluoropyrimidine, with or without bevacizumab (n = 110), will be randomized to receive either individualized nutritional counseling by a trained dietitian to achieve a sufficient dietary intake and an adequate physical activity level, or usual care. Outcome measures will be assessed at baseline and after two and four months of treatment. The primary endpoint will be the change in skeletal muscle area (measured by CT-scan) at the first treatment evaluation. Secondary endpoints will be quality of life, physical functioning, treatment toxicity, treatment intensity and survival. Statistical analyses include one-sided t-tests for the primary endpoint and mixed models and the Kaplan-Meier method for secondary endpoints. This randomized controlled trial will provide evidence whether individualized nutritional counseling during chemotherapy is effective in preventing loss of muscle mass in patients with mCRC. ClinicalTrials.gov NCT01998152 ; Netherlands Trial Register NTR4223.

A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.

PubMed

Ostrowitzki, Susanne; Lasser, Robert A; Dorflinger, Ernest; Scheltens, Philip; Barkhof, Frederik; Nikolcheva, Tania; Ashford, Elizabeth; Retout, Sylvie; Hofmann, Carsten; Delmar, Paul; Klein, Gregory; Andjelkovic, Mirjana; Dubois, Bruno; Boada, Mercè; Blennow, Kaj; Santarelli, Luca; Fontoura, Paulo

2017-12-08

Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.

The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy

PubMed Central

Constantine, Ginger D.; Simon, James A.; Pickar, James H.; Archer, David F.; Kushner, Harvey; Bernick, Brian; Gasper, Gina; Graham, Shelli; Mirkin, Sebastian

2017-01-01

Abstract Objective: To evaluate the safety and efficacy of TX-004HR vaginal estradiol soft-gel capsules for moderate-to-severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Methods: In this randomized, double-blind, placebo-controlled, phase 3 study, postmenopausal women with a self-identified most bothersome symptom of dyspareunia received 4, 10, or 25 μg TX-004HR or placebo for 12 weeks. Four co-primary efficacy endpoints were change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH, and severity of dyspareunia. Secondary endpoints included severity of vaginal dryness and vulvar and/or vaginal itching or irritation. Endometrial histology and adverse events (AEs) were included in the safety endpoints. Results: In all, 764 women were randomized (modified intent-to-treat population, n = 747; mean age 59 y). Compared with placebo, all three doses of TX-004HR significantly improved the four co-primary endpoints (P < 0.0001 for all, except dyspareunia with 4 μg, P = 0.0149). Changes in cytology, pH, and dyspareunia were also significant at weeks 2, 6, and 8. Vaginal dryness and vaginal itching/irritation improved. Sex hormone binding globulin concentrations did not change with treatment. TX-004HR was well-tolerated, with no clinically meaningful differences in treatment-emergent AEs versus placebo, and no treatment-related serious AEs or deaths. Conclusions: TX-004HR (4, 10, and 25 μg) was safe, well-tolerated, and effective for treating moderate-to-severe dyspareunia within 2 weeks with minimal systemic estrogen exposure. This novel product may be a potential new treatment option for women experiencing postmenopausal vulvar and vaginal atrophy. PMID:27922936

Association between in-hospital acute hypertensive episodes and outcomes in older trauma patients.

PubMed

Saliba, Lina; Stawicki, Stanislaw Peter; Thongrong, Cattleya; Bergese, Sergio Daniel; Papadimos, Thomas John; Gerlach, Anthony Thomas

2014-08-01

Although chronic hypertension is associated with long-term complications, few studies directly examine the effects of in-hospital acute hypertensive episodes in trauma patients. The aim was to determine whether there is an association between in-hospital acute hypertension and morbidity. We included trauma patients between 45 and 89 years who presented to a level I trauma center between January and September 2008. Patients were classified as either experiencing or not experiencing acute hypertensive episode(s) as defined by systolic blood pressure ≥180, or diastolic blood pressure ≥110 mmHg, or at least two readings of systolic blood pressure ≥160 or diastolic blood pressure ≥100 mmHg. The primary outcome was a composite endpoint of myocardial infarction, stroke, venous thromboembolism, new-onset atrial fibrillation, or acute kidney injury. At least one acute hypertensive episode occurred in 42.6% (69/162) of patients. A total of 10.5% patients developed the composite endpoint, 17.4% in the acute hypertensive episode group compared to 5.4% in the non-hypertensive group, p = 0.012. Patients in the acute hypertensive group were more likely to require an intensive care unit admission compared to the non-hypertensive group (33.3 versus 14.0%, p = 0.004). Of the 17 patients who developed an acute hypertensive episode and met the primary endpoint, 10 were on home antihypertensive medications. Of those, four were restarted on all medications initially, three on some, two were started on new medications, and one was not resumed on home medications. Development of acute hypertensive episode(s) in older trauma patients was associated with an increase in the composite endpoint. Prospective studies are needed.

A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients.

PubMed

Fogelman, David R; Morris, J; Xiao, L; Hassan, M; Vadhan, S; Overman, M; Javle, S; Shroff, R; Varadhachary, G; Wolff, R; Vence, L; Maitra, A; Cleeland, C; Wang, X S

2017-06-01

Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients. Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy. Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker. Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome.

Phase 2 trial of neoadjuvant chemotherapy and transoral endoscopic surgery with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck.

PubMed

Weiss, Jared M; Grilley-Olson, Juneko E; Deal, Allison Mary; Zevallos, Jose P; Chera, Bhishamjit S; Paul, Jennifer; Knowles, Mary Fleming; Usenko, Dmitriy; Weissler, Mark C; Patel, Samip; Hayes, David N; Hackman, Trevor

2018-05-09

The objective of this study was to demonstrate the feasibility and efficacy of induction chemotherapy, surgery, and pathology-guided adjuvant therapy to treat transorally resectable squamous head and neck cancer. Patients had squamous head and neck cancer that was resectable by the transoral route and advanced-stage disease (American Joint Committee on Cancer stage III-IV, T3-T4 tumors, and/or positive lymph nodes). They received treatment with weekly carboplatin at an area under the curve of 2, plus paclitaxel 135 mg/m 2 , and daily lapatinib 1000mg for 6 weeks followed by surgical resection. Pathology that revealed margins <5 mm, extracapsular extension, N2a of N2b lymph node status, perineural invasion, or lymphovascular space invasion resulted in adjuvant radiotherapy concurrent with weekly cisplatin. Pathology with N2c/N3 lymph node status or positive margins resulted in radiation with bolus cisplatin. The primary endpoint was the clinical response rate to induction chemotherapy, and a key secondary endpoint was feasibility. Toxicity was modest, and 37 of 40 patients completed study procedures as planned. The clinical response rate was 93%, the pathologic complete response rate was 36%, and the clinical response did not predict for a pathologic complete response. No patient on study follow-up has recurred or died. Twenty-nine of 39 patients who underwent surgery avoided radiation. Speech and swallowing function were well preserved. The study met both its primary efficacy endpoint and the secondary feasibility endpoint. Neoadjuvant, systemic therapy and surgical resection followed by risk-adapted adjuvant therapy resulted in high response rates and excellent long-term outcomes and should be further studied. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

A randomized trial of telemedicine efficacy and safety for nonacute headaches.

PubMed

Müller, Kai I; Alstadhaug, Karl B; Bekkelund, Svein I

2017-07-11

To evaluate long-term treatment efficacy and safety of one-time telemedicine consultations for nonacute headaches. We randomized, allocated, and consulted nonacute headache patients via telemedicine (n = 200) or in a traditional manner (n = 202) in a noninferiority trial. Efficacy endpoints, assessed by questionnaires at 3 and 12 months, included change from baseline in Headache Impact Test-6 (HIT-6) (primary endpoint) and pain intensity (visual analogue scale [VAS]) (secondary endpoint). The primary safety endpoint, assessed via patient records, was presence of secondary headache within 12 months after consultation. We found no differences between telemedicine and traditional consultations in HIT-6 ( p = 0.84) or VAS ( p = 0.64) over 3 periods. The absolute difference in HIT-6 from baseline was 0.3 (95% confidence interval [CI] -1.26 to 1.82, p = 0.72) at 3 months and 0.2 (95% CI -1.98 to 1.58, p = 0.83) at 12 months. The absolute change in VAS was 0.4 (95% CI -0.93 to 0.22, p = 0.23) after 3 months and 0.3 (95% CI -0.94 to 0.29, p = 0.30) at 12 months. We found one secondary headache in each group at 12 months. The estimated number of consultations needed to miss one secondary headache with the use of telemedicine was 20,200. Telemedicine consultation for nonacute headache is as efficient and safe as a traditional consultation. NCT02270177. This study provides Class III evidence that a one-time telemedicine consultation for nonacute headache is noninferior to a one-time traditional consultation regarding long-term treatment outcome and safety. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Deep sedation versus general anesthesia in percutaneous edge-to-edge mitral valve reconstruction using the MitraClip system.

PubMed

de Waha, Suzanne; Seeburger, Joerg; Ender, Joerg; Desch, Steffen; Eitel, Ingo; Reinhardt, Adrian; Pöss, Janine; Fuernau, Georg; Noack, Thilo; Merk, Denis Rouven; Schuler, Gerhard; Sievers, Hans-Hinrich; Mohr, Friedrich-Wilhelm; Thiele, Holger

2016-06-01

Percutaneous edge-to-edge mitral valve reconstruction (PMVR) has emerged as a treatment option in patients with severe mitral regurgitation not considered suitable candidates for surgery. The majority of PMVR procedures are performed under general anesthesia (GA), although deep sedation (DS) appears to be an attractive alternative. We thus sought to assess the impact on intensive care unit (ICU) length of stay, efficacy, and safety of DS in comparison to GA in patients undergoing PMVR using the MitraClip(®) system. Sixty consecutive patients underwent PMVR procedures at two centers. The first 30 patients were treated by GA followed by 30 patients undergoing DS under different settings. The primary clinical endpoint was ICU length of stay. The primary efficacy endpoint included procedural success and procedural duration. The safety endpoint was defined as a composite of death, stroke, cardiogenic shock, moderate and severe bleeding as well as pneumonia. The ICU length of stay was significantly shorter in the DS group in comparison to GA patients (p = 0.001). The hospital length of stay did not differ following DS in comparison to GA (p = 0.96). Procedural success was high in both groups (100 versus 96.7 %, p = 0.34) at similar procedural duration time (p = 0.60). No difference between GA and DS was observed with respect to the occurrence of the combined safety endpoint (p = 0.47). In comparison to GA, DS reduces the ICU length of stay in PMVR without negative effects on safety and efficacy. Prospective randomized trials are needed to confirm these findings.

Upper airway stabilization by osteopathic manipulation of the sphenopalatine ganglion versus sham manipulation in OSAS patients: a proof-of-concept, randomized, crossover, double-blind, controlled study.

PubMed

Jacq, Olivier; Arnulf, Isabelle; Similowski, Thomas; Attali, Valérie

2017-12-20

Osteopathic manipulative treatment (OMT) of the sphenopalatine ganglion (SPG) is used empirically for the treatment of rhinitis and snoring and is thought to increase pharyngeal stability. This trial was designed to study the effects of this treatment on pharyngeal stability evaluated by critical closing pressure in obstructive sleep apnoea syndrome. This single-centre, randomized, crossover, double-blind study compared active manipulation and sham manipulation of the SPG. Randomization was computer-generated. Patients each received one active manipulation and one sham manipulation at an interval of 21 days and were evaluated 30 min and 48 h after each session administered by a qualified osteopath. Neither the patients, nor the investigator performing the evaluations were informed about the order of the two techniques (double-blind). The primary endpoint was the percentage of responding patients presenting increased pharyngeal stability defined by a variation of critical closing pressure (Pcrit) of at least -4 cmH 2 O at 30 min. Secondary endpoints were the variation of Pcrit in absolute values, sleepiness and snoring. Others endpoints were lacrimation (Schirmer's test), induced pain, sensations experienced during OMT. Ten patients were included and nine (57 [50; 58] years, comprising 7 men, with an apnoea-hypopnoea index of 31.0 [25.5; 33.2]/h; (values are median [quartiles])) were analysed. Seven patients were analysed for the primary endpoint and nine patients were analysed for secondary endpoints. Five patients responded after active manipulation versus no patients after sham manipulation (p = 0.0209). Active manipulation induced more intense pain (p = 0.0089), increased lacrimation (ns) and more tactile, nociceptive and gustatory sensations (13 versus 1) compared to sham manipulation. No significant difference was observed for the other endpoints. Osteopathic manipulative treatment of the SPG may improve pharyngeal stability in obstructive sleep apnoea syndrome. This trial validates the feasibility of the randomized, controlled, double-blind methodology for evaluation of this osteopathic treatment. Studies on a larger sample size must specify the efficacy on the apnoea-hypopnoea index. The study was retrospectively registered in the clinicaltrial.gov registry under reference NCT01193738 on 1st September 2010 (first inclusion May 19, 2010).

Soluble ST2 protein in the short-term prognosis after hospitalisation in chronic systolic heart failure.

PubMed

Wojtczak-Soska, Karolina; Sakowicz, Agata; Pietrucha, Tadeusz; Lelonek, Małgorzata

2014-01-01

The prognosis in patients with chronic heart failure (CHF) is poor. ST2 protein is a promising prognostic biomarker for CHF. ST2 belongs to the cardioprotective signalling pathway involving interleukin-33 and its concentration in the serum depends on the biomechanical stress of cardiomyocytes (biomechanical strain). To determine the prognostic value of ST2 in short term follow-up after hospitalisation among patients with CHF. The study included 167 patients (mean age 62 years, 83% men) in stable NYHA class I-III with left ventricular ejection fraction (LVEF) of ≤ 45% (average 29.65%, ranges 13-45%). We analysed 58 variables including: demographics, co-morbidities, resting ECG, echocardiographic and coronary arteriography data, basic laboratory tests including N-terminal prohormone B-type natriuretic peptide (NT-proBNP), serum concentration of soluble form of ST2 (sST2) using quantitative ELISA test ST2 Kit (Medical and Biological Laboratories; Japan) and adverse cardiovascular events during a one year observation. In the study, the primary endpoint (death) and the composite endpoint (hospitalisation for HF worsening, worsening in NYHA functional class, the need to increase the dose of diuretics, and/or death in a one year observation) were determined. Patients who died (n = 24; 14.55%) were in more advanced NYHA class, had prolonged QRS duration, higher levels of sST2, NT-proBNP, and lower estimated glomerular filtration rate. From multivariate analysis, the independent variable for the primary endpoint was NT-proBNP (OR = 1.00012; 95% CI 1.00002-1.00022; p = 0.018). 93 (56%) patients reached the composite endpoint. Multivariate analysis revealed that fasting glucose (OR = 1.343; 95% CI 1.041-1.732; p = 0.023) and sST2 (OR = 3.593; 95% CI 1.427-9.05; p = 0.007) independently enhanced the risk of composite endpoint occurrence in a one year observation. In patients with CHF with LVEF ≤ 45%, the prognostic value of sST2 protein in a short-term observation of one year was confirmed. sST2 protein was an independent variable for the composite endpoint, which consisted of worsening NYHA functional class, hospitalisation for worsening of HF, the need to increase the dose of diuretics, and/or death.

Randomized controlled trial of perioperative antimicrobial therapy based on the results of preoperative bile cultures in patients undergoing biliary reconstruction.

PubMed

Okamura, Kunishige; Tanaka, Kimitaka; Miura, Takumi; Nakanishi, Yoshitsugu; Noji, Takehiro; Nakamura, Toru; Tsuchikawa, Takahiro; Okamura, Keisuke; Shichinohe, Toshiaki; Hirano, Satoshi

2017-07-01

The high frequency of surgical site infections (SSIs) after hepato-pancreato-biliary (HPB) surgery is a problem that needs to be addressed. This prospective, randomized, controlled study examined whether perioperative prophylactic use of antibiotics based on preoperative bile culture results in HPB surgery could decrease SSI. Participants comprised 126 patients who underwent HPB (bile duct, gallbladder, ampullary, or pancreatic) cancer surgery with biliary reconstruction at Hokkaido University Hospital between August 2008 and March 2013 (UMIN Clinical Trial Registry #00001278). Before surgery, subjects were randomly allocated to a targeted group administered antibiotics based on bile culture results or a standard group administered cefmetazole. The primary endpoint was SSI rates within 30 days after surgery. Secondary endpoint was SSI rates for each operative procedure. Of the 126 patients, 124 were randomly allocated (targeted group, n = 62; standard group, n = 62). Frequency of SSI after surgery was significantly lower in the targeted group (27 patients, 43.5%) than in the standard group (44 patients, 71.0%; P = 0.002). Among patients who underwent pancreaticoduodenectomy and hepatectomy, SSI occurred significantly less frequently in the targeted group (P = 0.001 and P = 0.025, respectively). This study demonstrated that preoperative bile culture-targeted administration of prophylactic antibiotics decreased SSIs following HBP surgery with biliary reconstruction. © 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

DarT: The embryo test with the Zebrafish Danio rerio--a general model in ecotoxicology and toxicology.

PubMed

Nagel, Roland

2002-01-01

The acute fish test is an animal test whose ecotoxicological relevance is worthy of discussion. The primary aim of protection in ecotoxicology is the population and not the individual. Furthermore the concentration of pollutants in the environment is normally not in the lethal range. Therefore the acute fish test covers solely the situation after chemical spills. Nevertheless, acute fish toxicity data still belong to the base set used for the assessment of chemicals. The embryo test with the zebrafish Danio rerio (DarT) is recommended as a substitute for the acute fish test. For validation an international laboratory comparison test was carried out. A summary of the results is presented in this paper. Based on the promising results of testing chemicals and waste water the test design was validated by the DIN-working group "7.6 Fischei-Test". A normed test guideline for testing waste water with fish is available. The test duration is short (48 h) and within the test different toxicological endpoints can be examined. Endpoints from the embryo test are suitable for QSAR-studies. Besides the use in ecotoxicology the introduction as a toxicological model was investigated. Disturbance of pigmentation and effects on the frequency of heart-beat were examined. A further important application is testing of teratogenic chemicals. Based on the results DarT could be a screening test within preclinical studies.

Angiographic and Clinical Impact of Successful Manual Thrombus Aspiration in Diabetic Patients Undergoing Primary PCI

PubMed Central

2014-01-01

Background. Diabetes mellitus is associated with worse angiographic and clinical outcomes after percutaneous coronary intervention (PCI). Aim. To investigate the impact of manual thrombus aspiration on in-stent restenosis (ISR) and clinical outcome in patients treated by bare-metal stent (BMS) implantation for ST-segment elevation myocardial infarction (STEMI). Methods. 100 diabetic patients were prospectively enrolled. They were randomly assigned to undergo either standard primary PCI (group A, 50 patients) or PCI with thrombus aspiration using Export catheter (group B, 50 patients). The primary endpoint was the rate of eight-month ISR. The secondary endpoint included follow-up for major adverse cardiac events (MACE). Results. Mean age of the study cohort was 59.86 ± 8.3 years, with 64 (64%) being males. Baseline characteristics did not differ between both groups. Eight-month angiogram showed that group B patients had significantly less late lumen loss (0.17 ± 0.35 versus 0.60 ± 0.42 mm, P < 0.001), with lower incidence of ISR (4% versus 16.6%, P < 0.001). There was a trend towards lower rate of MACE in the same group of patients. Conclusion. In diabetic patients undergoing primary PCI, manual thrombus aspiration (compared with standard PCI) was associated with better ISR rate after BMS implantation. PMID:24804102

Issues Surrounding Clinical Trial Endpoints in Solid Malignancies With a Focus on Metastatic Non-Small Cell Lung Cancer

PubMed Central

Garon, Edward B

2013-01-01

Summary Relative to best supportive care alone, cytotoxic chemotherapy has an established role in prolonging overall survival (OS) in patients with or without previous treatment for metastatic non-small cell lung cancer (NSCLC). OS has been the principal endpoint influencing regulatory decisions regarding targeted therapies for metastatic NSCLC, including the vascular endothelial growth factor monoclonal antibody bevacizumab in the frontline setting and the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib in patients after prior treatment. Progression-free survival (PFS), another common endpoint in oncology clinical trials, has been discussed as a potential surrogate for OS in metastatic NSCLC. A number of phase III clinical trials of investigational targeted agents for treatment of metastatic NSCLC are ongoing, with OS designated as the primary endpoint in some cases and PFS in others. Both endpoints have been developed largely to evaluate outcomes in unselected populations in which a fraction of patients are anticipated to derive significant benefit. New approaches are being considered for the evaluation of targeted agents. Recent high profile trials have been designed to assess PFS using a randomized discontinuation design and disease control rate after 8 weeks of treatment. With a series of recent advances towards increasingly personalized biomarker-directed anticancer therapies, the appropriateness of the traditional regulatory approach has been questioned. PMID:22795702

Associations of common variants at ALDH2 gene and the risk of stroke in patients with coronary artery diseases undergoing percutaneous coronary intervention.

PubMed

You, Ling; Li, Chenze; Zhao, Jinzhao; Wang, Dao Wen; Cui, Wei

2018-05-01

Limited data are available about the role of common variants at the aldehyde dehydrogenase 2 gene (ALDH2) on the clinical outcome in Chinese patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI). In the present study, a total of 1089 patients were consecutively enrolled from January 2012 and July 2013. Six common variants at ALDH2 gene, including rs2339840, rs4648328, rs4767939, rs11066028, rs16941669, and rs671, were selected to test the associations of those polymorphisms with the cardiovascular outcome in patients with CHD after PCI. The clinical endpoints included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The composite of clinical endpoints was defined as the primary endpoint, and every endpoint alone was considered as the secondary endpoints. The median follow-up time was 38.27 months. Our results showed that the common variant rs2339840 was independently associated with a lower risk of stroke in patients with CHD after PCI (codominant model, HR = 0.32, 95% CI, 0.11-0.91, P = .074 for heterozygotes; HR = 0.25, 95% CI, 0.06-1.14, P = .033 for homozygotes; dominant model, HR = 0.32, 95% CI, 0.14-0.74, P = .007). However, no significant associations were found between other 5 single nucleotide polymorphisms (SNPs) and the clinical endpoints. For the first time, the common variant rs2339840 was reported to be a protective factor against stroke in CHD patients with PCI.

Study design and rationale for Optimal aNtiplatelet pharmacotherapy guided by bedSIDE genetic or functional TESTing in elective percutaneous coronary intervention patients (ONSIDE TEST): a prospective, open-label, randomised parallel-group multicentre trial (NCT01930773).

PubMed

Kołtowski, Łukasz; Aradi, Daniel; Huczek, Zenon; Tomaniak, Mariusz; Sibbing, Dirk; Filipiak, Krzysztof J; Kochman, Janusz; Balsam, Paweł; Opolski, Grzegorz

2016-01-01

High platelet reactivity (HPR) and presence of CYP2C19 loss-of-function alleles are associated with higher risk for periprocedural myocardial infarction in clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI). It is unknown whether personalised treatment based on platelet function testing or genotyping can prevent such complications. The ONSIDE-TEST is a multicentre, prospective, open-label, randomised controlled clinical trial aiming to assess if optimisation of antiplatelet therapy based on either phenotyping or genotyping is superior to conventional care. Patients will be randomised into phenotyping, genotyping, or control arms. In the phenotyping group, patients will be tested with the VerifyNow P2Y12 assay before PCI, and patients with a platelet reactivity unit greater than 208 will be switched over to prasugrel, while others will continue on clopidogrel therapy. In the genotyping group, carriers of the *2 loss-of-function allele will receive prasugrel for PCI, while wild-type subjects will be treated with clopidogrel. Patients in the control arm will be treated with standard-dose clopidogrel. The primary endpoint of the study is the prevalence of periprocedural myocardial injury within 24 h after PCI in the controls as compared to the phenotyping and genotyping group. Secondary endpoints include cardiac death, myocardial infarction, definite or probable stent thrombosis, or urgent repeat revascularisation within 30 days of PCI. Primary safety outcome is Bleeding Academic Research Consortium (BARC) type 3 and 5 bleeding during 30 days of PCI. The ONSIDE TEST trial is expected to verify the clinical utility of an individualised antiplatelet strategy in preventing periprocedural myocardial injury by either phenotyping or genotyping. ClinicalTrials.gov: NCT01930773.

Phase II study of palonosetron, aprepitant and dexamethasone to prevent nausea and vomiting induced by multiple-day emetogenic chemotherapy.

PubMed

Ioroi, Takeshi; Furukawa, Junya; Kume, Manabu; Hirata, Sachi; Utsubo, Yuko; Mizuta, Naomi; Miyake, Hideaki; Fujisawa, Masato; Hirai, Midori

2018-05-01

This study aimed to determine the antiemetic efficacy and safety of palonosetron, aprepitant and dexamethasone in patients with testicular germ cell tumours (TGCTs) receiving 5-day cisplatin-based combination chemotherapy. In this open-label, single-arm, single-centre study, the antiemetic therapy consisted of palonosetron 0.75 mg on day 1, aprepitant 125 mg on day 1 and 80 mg on days 2-7 and dexamethasone 6.6 mg on days 1-7. The primary endpoint was complete response (CR; no vomiting/retching or rescue medication) in the overall period (0-240 h), and secondary endpoints included complete protection (CP; defined as CR and no more than mild nausea) and total control (TC; defined as CR and no nausea). The incidence and severity of nausea were assessed on the basis of the Common Terminology Criteria for Adverse Events v4.0 and a subjective rating scale completed by patients. Twenty-five patients were enrolled and evaluated for safety, and 24 patients were evaluated for efficacy. CR was achieved in 62.5% of patients (95% confidence interval [CI] = 40.6-81.2, p = 0.043) in the overall period. CP and TC were achieved in 62.5% (95% CI = 40.6-81.2) and 25.0% of patients (95% CI = 9.8-46.7), respectively, in the overall period. The primary adverse drug reaction was hiccups (48.0%). The events were expected, and none was grade 3 or 4. The examined combination antiemetic therapy was effective and well-tolerated in patients with TGCTs receiving 5-day cisplatin-based combination chemotherapy.

Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement.

PubMed

Reginster, J-Y; Reiter-Niesert, S; Bruyère, O; Berenbaum, F; Brandi, M-L; Branco, J; Devogelaer, J-P; Herrero-Beaumont, G; Kanis, J; Maggi, S; Maheu, E; Richette, P; Rizzoli, R; Cooper, C

2015-12-01

The European Society on Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO) organised a working group to evaluate the need for updating the current European guideline on clinical investigation of drugs used in the treatment of osteoarthritis (OA). Areas of potential attention were identified and the need for modifications, update or clarification was examined. Proposals were then developed based on literature reviews and through a consensus process. It was agreed that the current guideline overall still reflects the current knowledge in OA, although two possible modifications were identified. The first relates to the number and timing of measurements required as primary endpoints during clinical trials of symptom-relieving drugs, either drugs with rapid onset of action or slow acting drugs. The suggested modifications are intended to take into consideration the time related clinical need and expected time response to these drugs - i.e., a more early effect for the first category in addition to the maintenance of effect, a more continuous benefit over the long-term for the latter - in the timing of assessments. Secondly, values above which a benefit over placebo should be considered clinically relevant were considered. Based on literature reviews, the most consensual values were determined for primary endpoints of both symptom-relieving drugs (i.e., pain intensity on a visual analogue scale (VAS)) and disease-modifying drugs (i.e., radiographic joint-space narrowing). This working document might be considered by the European regulatory authorities in a future update of the guideline for the registration of drugs in OA. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Overview of ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

In 2007, EPA launched ToxCast™ in order to develop a cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time. Using data from state-of-the-art high throughput screening (HTS) bioassays developed in the pharmaceutical industry, ToxCast™ is building computational models to forecast the potential human toxicity of chemicals. These hazard predictions will provide EPA regulatory programs with science-based information helpful in prioritizing chemicals for more detailed toxicological evaluations, and lead to more efficient use of animal testing. In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcriptomics on primary cell cultures, and developmental assays in zebrafish embryos. Almost all of the compounds being examined in Phase 1 of ToxCast™ have been tested in traditional toxicology tests, including developmental toxicity, multi-generation studies, and sub-chronic and chronic rodent bioassays. ToxRefDB, a relational database being created to house this information, will contain nearly $1B worth of toxicity studies in animals when completed. ToxRefDB is integrated into a more comprehensive data management system developed by NCCT called ACToR (Aggregated Computational Toxicology

Safety and effectiveness of the Phoenix Atherectomy System in lower extremity arteries: Early and midterm outcomes from the prospective multicenter EASE study.

PubMed

Davis, Thomas; Ramaiah, Venkatesh; Niazi, Khusrow; Martin Gissler, Hans; Crabtree, Tami

2017-12-01

Objectives To evaluate the novel Phoenix Atherectomy System as percutaneous treatment of de novo and restenotic infrainguinal arterial lesions. Methods This prospective, multicenter, nonrandomized investigational device exemption trial was conducted across 16 US and German centers between August 2010 and April 2013. Intention-to-treat enrollment was 128 patients (mean age: 71.8 years, 59% male) with 149 lesions (mean length: 34 mm, mean diameter stenosis: 89.5%), and the primary analysis per-protocol population consisted of 105 patients with 123 lesions. The primary efficacy endpoint, technical success, was the achievement of acute debulking with a post-atherectomy residual diameter stenosis ≤50% (before adjunctive therapy). The primary safety endpoint was the major adverse event (MAE) rate through 30 days. Results For the primary analysis per-protocol population, the rate of lesion technical success was 95.1% (117/123), with the lower limit of the 95% CI 90.6%, meeting the prospectively established target performance goal of ≥86%. After post-atherectomy adjunctive therapy, residual stenosis was ≤30% for 99.2% (122/123) of lesions (mean final diameter stenosis 10.5%). Improvement of ≥1 Rutherford class occurred for 74.5% of patients through 30 days and for 80% through six months. MAEs were experienced by 5.7% (6/105) of patients through 30 days (with the upper limit of the 95% CI 11.0%, meeting the target performance goal of <20%), and 16.8% through six months. Six-month freedom from TLR and TVR was 88.0% and 86.1%, respectively. Conclusions Based on the high rate of technical success and the low rates of MAEs through six months, the Phoenix Atherectomy System is safe and effective for the debulking of lower-extremity arterial lesions. ClinicalTrials.gov identifier NCT01541774.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

PubMed

Bartunek, Jozef; Terzic, Andre; Davison, Beth A; Filippatos, Gerasimos S; Radovanovic, Slavica; Beleslin, Branko; Merkely, Bela; Musialek, Piotr; Wojakowski, Wojciech; Andreka, Peter; Horvath, Ivan G; Katz, Amos; Dolatabadi, Dariouch; El Nakadi, Badih; Arandjelovic, Aleksandra; Edes, Istvan; Seferovic, Petar M; Obradovic, Slobodan; Vanderheyden, Marc; Jagic, Nikola; Petrov, Ivo; Atar, Shaul; Halabi, Majdi; Gelev, Valeri L; Shochat, Michael K; Kasprzak, Jaroslaw D; Sanz-Ruiz, Ricardo; Heyndrickx, Guy R; Nyolczas, Noémi; Legrand, Victor; Guédès, Antoine; Heyse, Alex; Moccetti, Tiziano; Fernandez-Aviles, Francisco; Jimenez-Quevedo, Pilar; Bayes-Genis, Antoni; Hernandez-Garcia, Jose Maria; Ribichini, Flavio; Gruchala, Marcin; Waldman, Scott A; Teerlink, John R; Gersh, Bernard J; Povsic, Thomas J; Henry, Timothy D; Metra, Marco; Hajjar, Roger J; Tendera, Michal; Behfar, Atta; Alexandre, Bertrand; Seron, Aymeric; Stough, Wendy Gattis; Sherman, Warren; Cotter, Gad; Wijns, William

2017-03-01

Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

Outcomes Definitions and Statistical Tests in Oncology Studies: A Systematic Review of the Reporting Consistency.

PubMed

Rivoirard, Romain; Duplay, Vianney; Oriol, Mathieu; Tinquaut, Fabien; Chauvin, Franck; Magne, Nicolas; Bourmaud, Aurelie

2016-01-01

Quality of reporting for Randomized Clinical Trials (RCTs) in oncology was analyzed in several systematic reviews, but, in this setting, there is paucity of data for the outcomes definitions and consistency of reporting for statistical tests in RCTs and Observational Studies (OBS). The objective of this review was to describe those two reporting aspects, for OBS and RCTs in oncology. From a list of 19 medical journals, three were retained for analysis, after a random selection: British Medical Journal (BMJ), Annals of Oncology (AoO) and British Journal of Cancer (BJC). All original articles published between March 2009 and March 2014 were screened. Only studies whose main outcome was accompanied by a corresponding statistical test were included in the analysis. Studies based on censored data were excluded. Primary outcome was to assess quality of reporting for description of primary outcome measure in RCTs and of variables of interest in OBS. A logistic regression was performed to identify covariates of studies potentially associated with concordance of tests between Methods and Results parts. 826 studies were included in the review, and 698 were OBS. Variables were described in Methods section for all OBS studies and primary endpoint was clearly detailed in Methods section for 109 RCTs (85.2%). 295 OBS (42.2%) and 43 RCTs (33.6%) had perfect agreement for reported statistical test between Methods and Results parts. In multivariable analysis, variable "number of included patients in study" was associated with test consistency: aOR (adjusted Odds Ratio) for third group compared to first group was equal to: aOR Grp3 = 0.52 [0.31-0.89] (P value = 0.009). Variables in OBS and primary endpoint in RCTs are reported and described with a high frequency. However, statistical tests consistency between methods and Results sections of OBS is not always noted. Therefore, we encourage authors and peer reviewers to verify consistency of statistical tests in oncology studies.

Outcomes Definitions and Statistical Tests in Oncology Studies: A Systematic Review of the Reporting Consistency

PubMed Central

Rivoirard, Romain; Duplay, Vianney; Oriol, Mathieu; Tinquaut, Fabien; Chauvin, Franck; Magne, Nicolas; Bourmaud, Aurelie

2016-01-01

Background Quality of reporting for Randomized Clinical Trials (RCTs) in oncology was analyzed in several systematic reviews, but, in this setting, there is paucity of data for the outcomes definitions and consistency of reporting for statistical tests in RCTs and Observational Studies (OBS). The objective of this review was to describe those two reporting aspects, for OBS and RCTs in oncology. Methods From a list of 19 medical journals, three were retained for analysis, after a random selection: British Medical Journal (BMJ), Annals of Oncology (AoO) and British Journal of Cancer (BJC). All original articles published between March 2009 and March 2014 were screened. Only studies whose main outcome was accompanied by a corresponding statistical test were included in the analysis. Studies based on censored data were excluded. Primary outcome was to assess quality of reporting for description of primary outcome measure in RCTs and of variables of interest in OBS. A logistic regression was performed to identify covariates of studies potentially associated with concordance of tests between Methods and Results parts. Results 826 studies were included in the review, and 698 were OBS. Variables were described in Methods section for all OBS studies and primary endpoint was clearly detailed in Methods section for 109 RCTs (85.2%). 295 OBS (42.2%) and 43 RCTs (33.6%) had perfect agreement for reported statistical test between Methods and Results parts. In multivariable analysis, variable "number of included patients in study" was associated with test consistency: aOR (adjusted Odds Ratio) for third group compared to first group was equal to: aOR Grp3 = 0.52 [0.31–0.89] (P value = 0.009). Conclusion Variables in OBS and primary endpoint in RCTs are reported and described with a high frequency. However, statistical tests consistency between methods and Results sections of OBS is not always noted. Therefore, we encourage authors and peer reviewers to verify consistency of statistical tests in oncology studies. PMID:27716793

Infection after primary hip arthroplasty

PubMed Central

2011-01-01

Background and purpose The aim of the present study was to assess incidence of and risk factors for infection after hip arthroplasty in data from 3 national health registries. We investigated differences in risk patterns between surgical site infection (SSI) and revision due to infection after primary total hip arthroplasty (THA) and hemiarthroplasty (HA). Materials and methods This observational study was based on prospective data from 2005–2009 on primary THAs and HAs from the Norwegian Arthroplasty Register (NAR), the Norwegian Hip Fracture Register (NHFR), and the Norwegian Surveillance System for Healthcare–Associated Infections (NOIS). The Norwegian Patient Register (NPR) was used for evaluation of case reporting. Cox regression analyses were performed with revision due to infection as endpoint for data from the NAR and the NHFR, and with SSI as the endpoint for data from the NOIS. Results The 1–year incidence of SSI in the NOIS was 3.0% after THA (167/5,540) and 7.3% after HA (103/1,416). The 1–year incidence of revision due to infection was 0.7% for THAs in the NAR (182/24,512) and 1.5% for HAs in the NHFR (128/8,262). Risk factors for SSI after THA were advanced age, ASA class higher than 2, and short duration of surgery. For THA, the risk factors for revision due to infection were male sex, advanced age, ASA class higher than 1, emergency surgery, uncemented fixation, and a National Nosocomial Infection Surveillance (NNIS) risk index of 2 or more. For HAs inserted after fracture, age less than 60 and short duration of surgery were risk factors of revision due to infection. Interpretation The incidences of SSI and revision due to infection after primary hip replacements in Norway are similar to those in other countries. There may be differences in risk pattern between SSI and revision due to infection after arthroplasty. The risk patterns for revision due to infection appear to be different for HA and THA. PMID:22066562

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

PubMed Central

Bartunek, Jozef; Terzic, Andre; Davison, Beth A.; Filippatos, Gerasimos S.; Radovanovic, Slavica; Beleslin, Branko; Merkely, Bela; Musialek, Piotr; Wojakowski, Wojciech; Andreka, Peter; Horvath, Ivan G.; Katz, Amos; Dolatabadi, Dariouch; El Nakadi, Badih; Arandjelovic, Aleksandra; Edes, Istvan; Seferovic, Petar M.; Obradovic, Slobodan; Vanderheyden, Marc; Jagic, Nikola; Petrov, Ivo; Atar, Shaul; Halabi, Majdi; Gelev, Valeri L.; Shochat, Michael K.; Kasprzak, Jaroslaw D.; Sanz-Ruiz, Ricardo; Heyndrickx, Guy R.; Nyolczas, Noémi; Legrand, Victor; Guédès, Antoine; Heyse, Alex; Moccetti, Tiziano; Fernandez-Aviles, Francisco; Jimenez-Quevedo, Pilar; Bayes-Genis, Antoni; Hernandez-Garcia, Jose Maria; Ribichini, Flavio; Gruchala, Marcin; Waldman, Scott A.; Teerlink, John R.; Gersh, Bernard J.; Povsic, Thomas J.; Henry, Timothy D.; Metra, Marco; Hajjar, Roger J.; Tendera, Michal; Behfar, Atta; Alexandre, Bertrand; Seron, Aymeric; Stough, Wendy Gattis; Sherman, Warren; Cotter, Gad; Wijns, William

2017-01-01

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted. PMID:28025189

Fourier-transform infrared spectroscopy as a novel approach to providing effect-based endpoints in duckweed toxicity testing.

PubMed

Hu, Li-Xin; Ying, Guang-Guo; Chen, Xiao-Wen; Huang, Guo-Yong; Liu, You-Sheng; Jiang, Yu-Xia; Pan, Chang-Gui; Tian, Fei; Martin, Francis L

2017-02-01

Traditional duckweed toxicity tests only measure plant growth inhibition as an endpoint, with limited effects-based data. The present study aimed to investigate whether Fourier-transform infrared (FTIR) spectroscopy could enhance the duckweed (Lemna minor L.) toxicity test. Four chemicals (Cu, Cd, atrazine, and acetochlor) and 4 metal-containing industrial wastewater samples were tested. After exposure of duckweed to the chemicals, standard toxicity endpoints (frond number and chlorophyll content) were determined; the fronds were also interrogated using FTIR spectroscopy under optimized test conditions. Biochemical alterations associated with each treatment were assessed and further analyzed by multivariate analysis. The results showed that comparable x% of effective concentration (ECx) values could be achieved based on FTIR spectroscopy in comparison with those based on traditional toxicity endpoints. Biochemical alterations associated with different doses of toxicant were mainly attributed to lipid, protein, nucleic acid, and carbohydrate structural changes, which helped to explain toxic mechanisms. With the help of multivariate analysis, separation of clusters related to different exposure doses could be achieved. The present study is the first to show successful application of FTIR spectroscopy in standard duckweed toxicity tests with biochemical alterations as new endpoints. Environ Toxicol Chem 2017;36:346-353. © 2016 SETAC. © 2016 SETAC.

Challenges in early clinical development of adjuvanted vaccines.

PubMed

Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

2015-06-08

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. Copyright © 2015 Elsevier Ltd. All rights reserved.

Communicating ecological importance in a risk-based world: linking numeric nutrient criteria to waterbody expectations

NASA Astrophysics Data System (ADS)

Kaufman, G.; Crawford, T. N.

2016-12-01

To protect the integrity of US waters, the Clean Water Act calls for the development of water quality standards. One key component of standards is limits for pollutants, known as water quality criteria. A cornerstone of deriving water quality criteria is determining how nutrients and other chemicals affect the goals for a waterbody set by a state or tribe, known as designated uses. By establishing a quantifiable and predictable relationship between nutrients and nutrient sensitive organisms and processes, known as assessment endpoints, researchers can help policy makers to address the consequences of pollution in a risk-based, understandable way tied to the goals for a waterbody. Furthermore, public buy-in and effectiveness of criteria can be enhanced by using endpoints to show the connection between nutrient pollution and the uses of waters that are important to the public. This talk will communicate the work done by the US Environmental Protection Agency in cooperation with state, federal, and academic partners to explore the connections between biological and ecological responses and nutrient pollution to derive numeric nutrient criteria in estuarine and coastal waters. The presentation will examine the variety of endpoints that have been used in the work of various research efforts and assessment frameworks. Examples will also be given of numeric nutrient criteria development using assessment endpoints and some of the key decisions that were made during endpoint selection and criteria development will be discussed. Aspects of those decisions that will be presented include development of selection factors for endpoints, data considerations when selecting endpoints, and spatial and temporal representation of endpoints for criteria development. Promising endpoints and future research needs will also be highlighted.

Communicating ecological importance in a risk-based world: linking numeric nutrient criteria to waterbody expectations

NASA Astrophysics Data System (ADS)

Kaufman, G.; Crawford, T. N.

2016-02-01

To protect the integrity of US waters, the Clean Water Act calls for the development of water quality standards. One key component of standards is limits for pollutants, known as water quality criteria. A cornerstone of deriving water quality criteria is determining how nutrients and other chemicals affect the goals for a waterbody set by a state or tribe, known as designated uses. By establishing a quantifiable and predictable relationship between nutrients and nutrient sensitive organisms and processes, known as assessment endpoints, researchers can help policy makers to address the consequences of pollution in a risk-based, understandable way tied to the goals for a waterbody. Furthermore, public buy-in and effectiveness of criteria can be enhanced by using endpoints to show the connection between nutrient pollution and the uses of waters that are important to the public. This talk will communicate the work done by the US Environmental Protection Agency in cooperation with state, federal, and academic partners to explore the connections between biological and ecological responses and nutrient pollution to derive numeric nutrient criteria in estuarine and coastal waters. The presentation will examine the variety of endpoints that have been used in the work of various research efforts and assessment frameworks. Examples will also be given of numeric nutrient criteria development using assessment endpoints and some of the key decisions that were made during endpoint selection and criteria development will be discussed. Aspects of those decisions that will be presented include development of selection factors for endpoints, data considerations when selecting endpoints, and spatial and temporal representation of endpoints for criteria development. Promising endpoints and future research needs will also be highlighted.

The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors.

PubMed

Grossberg, George T; Manes, Facundo; Allegri, Ricardo F; Gutiérrez-Robledo, Luis Miguel; Gloger, Sergio; Xie, Lei; Jia, X Daniel; Pejović, Vojislav; Miller, Michael L; Perhach, James L; Graham, Stephen M

2013-06-01

Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). Extended-release memantine was efficacious, safe, and well tolerated in this population.

The PREDIMED trial, Mediterranean diet and health outcomes: How strong is the evidence?

PubMed

Guasch-Ferré, M; Salas-Salvadó, J; Ros, E; Estruch, R; Corella, D; Fitó, M; Martínez-González, M A

2017-07-01

To address potential controversies on the health benefits of the Mediterranean diet (MedDiet) after PREDIMED, a randomized trial of MedDiet for primary cardiovascular prevention. We have focused on: a) the PREDIMED study design, b) analysis of PREDIMED data and c) interpretation of its results. Regarding the design of the trial, its early termination and between-group differences in the intensity of the intervention are potential causes of concern. The planned duration was 6 years but the trial was prematurely stopped when an interim analysis at 4.8-year provided sufficient evidence of benefit for the two MedDiets. In the MedDiet groups supplemented with extra-virgin olive oil or mixed-nuts, the primary composite endpoint (myocardial infarction, stroke, or cardiovascular death) was reduced by 30% and 28% respectively, as compared with the control group. Final results did not change after taking into account the different intensity of educational efforts during the trial. Other potential doubts related to data analysis (e.g., intention to treat versus a per-protocol approach, and consequences of dropouts) should not be causes of concern. Finally, we addressed alternative interpretations of the effect on all-cause mortality. The protocol-defined primary endpoint was a composite cardiovascular endpoint, not all-cause mortality. To analyze total mortality, we would have needed a much larger sample size and longer follow-up. Therefore, the PREDIMED results cannot be used to draw firm conclusions on MedDiets and all-cause mortality. The PREDIMED study was designed to overcome three major problems of previous nutritional research: a) residual confounding, addressed by using a randomized design; b) single-nutrient approaches, by randomizing an overall dietary pattern; and c) the limitations of assessing only intermediate risk markers, by using hard clinical end-points. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

An Imaging Biomarker for Assessing Hepatic Function in Patients with Primary Sclerosing Cholangitis.

PubMed

Schulze, Jennifer; Lenzen, Henrike; Hinrichs, Jan B; Ringe, Burckhardt; Manns, Michael P; Wacker, Frank; Ringe, Kristina I

2018-05-15

We aimed to evaluate the potential of hepatobiliary phase magnetic resonance imaging (MRI) as parameter for assessment of hepatocellular function in patients with primary sclerosing cholangitis (PSC). We collected data from 111 patients (83 male, 28 female; median, 44 years old), from March 2012 through March 2016, with a confirmed diagnosis of PSC who underwent MRI evaluation before and after injection (hepatobiliary phase) of a hepatocyte-specific contrast agent (gadoxetate disodium). Signal intensities were measured in each liver segment. Mean relative enhancement values were calculated and correlated with findings from liver functions tests, prognostic scoring systems (model for end-stage liver disease [MELD] score; Mayo risk score; Amsterdam-Oxford-PSC score), abnormalities detected by endoscopic retrograde cholangiopancreatography (using the Amsterdam cholangiographic classification system), and clinical endpoints (liver transplantation, cholangiocarcinoma, liver-related death). Our primary aim was to associate relative enhancement values with liver function and patient outcomes. Most patients had moderate-stage disease and had intermediate levels of risk (median MELD score, 8 and median Mayo score, 0.27). Clinical endpoints were reached by 21 patients (6 developed cholangiocarcinoma, 8 underwent liver transplantation, and 7 patients died). The highest levels of correlations were observed for relative enhancement 20 min after contrast injection and level of alkaline phosphatase (r= -0.636), bilirubin (r= -0.646), albumin (r= 0.538); as well as international normalized ratio (r=0.456); MELD score (r= -0.587); Mayo risk score (r= -0.535), and Amsterdam-Oxford model score (r= -0.595) (P<.0001). Relative enhancement correlated with all clinical endpoints (all P<.05). A cutoff relative enhancement value of 0.65 identified patients with a clinical endpoint with 73.9% sensitivity 92.9% specificity (area under the receiver operating characteristic curve, 0.901; likelihood ratio, 10.34; P<.0001). In an analysis of 111 patients with PSC, we found MRI-measured relative enhancement, using a hepatocyte-specific contrast agent, to identify patients with clinical outcomes with 73.9% sensitivity 92.9% specificity. Long-term, multicenter studies are needed to further evaluate this marker of PSC progression. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial

PubMed Central

Husted, Steen; James, Stefan K.; Bach, Richard G.; Becker, Richard C.; Budaj, Andrzej; Heras, Magda; Himmelmann, Anders; Horrow, Jay; Katus, Hugo A.; Lassila, Riita; Morais, Joao; Nicolau, José C.; Steg, Ph. Gabriel; Storey, Robert F.; Wojdyla, Daniel; Wallentin, Lars

2014-01-01

Aims The aim of this study was to assess the relationship between sex and clinical outcomes and treatment-related complications in patients with ST-elevation or non-ST-elevation acute coronary syndromes (ACS) randomized to treatment with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial. Methods The associations between sex subgroup and the primary composite outcomes, secondary outcomes, and major bleeding endpoints as well as interaction of sex subgroup with treatment effects were analysed using Cox proportional-hazards models. Results Sex was not significantly associated with the probability of the primary composite endpoint [adjusted hazard ratio (HR): 1.02 (0.91−1.16)], or other adverse cardiovascular endpoints. Ticagrelor was similarly more effective than clopidogrel in reducing rates of the primary endpoint in women 11.2 vs. 13.2% [adjusted HR: 0.88 (0.74−1.06)] and men 9.4 vs. 11.1% [adjusted HR: 0.86 (0.76−0.97)] (interaction P-value 0.78), all-cause death in women 5.8 vs. 6.8% [adjusted HR: 0.90 (0.69−1.16)] and men 4.0 vs. 5.7% [adjusted HR: 0.80 (0.67−0.96)] (interaction P-value 0.49), and definite stent thrombosis in women 1.2 vs. 1.4% [adjusted HR: 0.71 (0.36−1.38)] and men 1.4 vs. 2.1% [adjusted HR: 0.63 (0.45−0.89)] (interaction P-value 0.78). The treatments did not differ for PLATO-defined overall major bleeding complications in women [adjusted HR: 1.01 (0.83−1.23)] or men [adjusted HR: 1.10 (0.98−1.24)]. Sex had no significant association with these outcomes (interactions P = 0.43−0.88). Conclusion Female sex is not an independent risk factor for adverse clinical outcomes in moderate-to-high risk ACS patients. Ticagrelor has a similar efficacy and safety profile in men and women. PMID:24682844

Electronic surveillance and using administrative data to identify healthcare associated infections.

PubMed

Gastmeier, Petra; Behnke, Michael

2016-08-01

Traditional surveillance of healthcare associated infections (HCAI) is time consuming and error-prone. We have analysed literature of the past year to look at new developments in this field. It is divided into three parts: new algorithms for electronic surveillance, the use of administrative data for surveillance of HCAI, and the definition of new endpoints of surveillance, in accordance with an automatic surveillance approach. Most studies investigating electronic surveillance of HCAI have concentrated on bloodstream infection or surgical site infection. However, the lack of important parameters in hospital databases can lead to misleading results. The accuracy of administrative coding data was poor at identifying HCAI. New endpoints should be defined for automatic detection, with the most crucial step being to win clinicians' acceptance. Electronic surveillance with conventional endpoints is a successful method when hospital information systems implemented key changes and enhancements. One requirement is the access to systems for hospital administration and clinical databases.Although the primary source of data for HCAI surveillance is not administrative coding data, these are important components of a hospital-wide programme of automated surveillance. The implementation of new endpoints for surveillance is an approach which needs to be discussed further.

[Selection of "surrogate" and "endpoints" evaluation of the efficacy of medical interventions].

PubMed

Lazebnik, L B; Gusein-Zade, M G; Efremov, L I

2011-01-01

With the advent of new medical technologies and medicines, as well as due to changes in disease patterns and demographic problems rises the need for continued increases in health spending. Increased costs can be totally inadequate, if it has been done without studying the effectiveness of medical interventions, based on the results of evidence-based medicine and economic of their feasibility. To evaluate the clinical effectiveness of medical interventions have been recently used specific criteria, so called points of clinical efficacy (surrogate and endpoints), that allow to conclude feasibility or harmfulness of the introduction or application of the intervention in clinical practice. The endpoint is reliable indicator the effectiveness of medical intervention. Surrogate point--is a biomarker that is intended to replace the endpoint and is a predictor of the effectiveness of medical intervention. The use of surrogate points has several advantages such as simple in identification and measurement, as well as more higher in compare with endpoints the vents frequency, that can significantly reduce the size of the selection and duration and cost of clinical trials, respectively. Finally, the surrogate points allow to evaluate treatment effect in situations where the use of endpoints is difficult or is unethical.

Link prediction based on nonequilibrium cooperation effect

NASA Astrophysics Data System (ADS)

Li, Lanxi; Zhu, Xuzhen; Tian, Hui

2018-04-01

Link prediction in complex networks has become a common focus of many researchers. But most existing methods concentrate on neighbors, and rarely consider degree heterogeneity of two endpoints. Node degree represents the importance or status of endpoints. We describe the large-degree heterogeneity as the nonequilibrium between nodes. This nonequilibrium facilitates a stable cooperation between endpoints, so that two endpoints with large-degree heterogeneity tend to connect stably. We name such a phenomenon as the nonequilibrium cooperation effect. Therefore, this paper proposes a link prediction method based on the nonequilibrium cooperation effect to improve accuracy. Theoretical analysis will be processed in advance, and at the end, experiments will be performed in 12 real-world networks to compare the mainstream methods with our indices in the network through numerical analysis.

A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

PubMed

Erman, Milton K; Zammit, Gary; Rubens, Robert; Schaefer, Kendyl; Wessel, Thomas; Amato, David; Caron, Judy; Walsh, James K

2008-06-15

To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. LPS and SE were significantly different than placebo for all active treatments (p < 0.05 for all). Significant differences from placebo were noted in the 3 objective sleep maintenance measures (WASO, WTDS, and NAW) for eszopiclone 3 mg (p < 0.05), which was not the case for zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

Phase II cancer clinical trials for biomarker-guided treatments.

PubMed

Jung, Sin-Ho

2018-01-01

The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.

The open abdomen and temporary abdominal closure systems--historical evolution and systematic review.

PubMed

Quyn, A J; Johnston, C; Hall, D; Chambers, A; Arapova, N; Ogston, S; Amin, A I

2012-08-01

Several techniques for temporary abdominal closure have been developed. We systematically review the literature on temporary abdominal closure to ascertain whether the method can be tailored to the indication. Medline, Embase, the Cochrane Central Register of Controlled Trials and relevant meeting abstracts until December 2009 were searched using the following headings: open abdomen, laparostomy, VAC (vacuum assisted closure), TNP (topical negative pressure), fascial closure, temporary abdominal closure, fascial dehiscence and deep wound dehiscence. The data were analysed by closure technique and aetiology. The primary end-points included delayed fascial closure and in-hospital mortality. The secondary end-points were intra-abdominal complications. The search identified 106 papers for inclusion. The techniques described were VAC (38 series), mesh/sheet (30 series), packing (15 series), Wittmann patch (eight series), Bogotá bag (six series), dynamic retention sutures (three series), zipper (15 series), skin only and locking device (one series each). The highest facial closure rates were seen with the Wittmann patch (78%), dynamic retention sutures (71%) and VAC (61%). Temporary abdominal closure has evolved from simple packing to VAC based systems. In the absence of sepsis Wittmann patch and VAC offered the best outcome. In its presence VAC had the highest delayed primary closure and the lowest mortality rates. However, due to data heterogeneity only limited conclusions can be drawn from this analysis. © 2012 The Authors. Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.

[Questions about the ADVANCE study].

PubMed

Jean, Guillaume; Chazot, Charles

2012-06-01

The symptoms of secondary hyperparathyroidism (SHPT) were substantially changed by the availability of cinacalcet (CC). The recent ADVANCE study, which was a prospective randomized trial comparing two treatment strategies-CC plus low doses of calcitriol analogues (CA) versus higher doses of CA without CC-reports the absence of difference in the primary endpoint, i.e. coronary artery calcification score progression after 12 months. The progression of coronary calcification was related to the initial hypercalcemia and hyperphosphataemia, and low serum PTH level. What was the rationale for defining SHPT with only serum PTH value of more than 300 pg/mL or more than 150 pg/mL associated with a high Ca×P product? Why was this coronary score chosen as the primary endpoint and why was a seemingly short observational period used? Is it correct to consider all forms of SHPT equivalent in terms of set point, response to conventional treatment, or vascular and bone consequences? Why are the biological values of patients not provided? Were the CAs, dialysate calcium, and PTH assay values really equal? Why were only calcium-based phosphate binders used? The main controversial point of the study was to consider all HPT cases as equivalent and able to be treated by one fixed strategy. Therefore, the nephrologist community should conduct relevant independent studies in order to improve the diagnosis and treatment of SHPT. Copyright © 2011 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

A Double-Blind Placebo-Controlled Randomized Clinical Trial With Magnesium Oxide to Reduce Intrafraction Prostate Motion for Prostate Cancer Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lips, Irene M., E-mail: i.m.lips@umcutrecht.nl; Gils, Carla H. van; Kotte, Alexis N.T.J.

2012-06-01

Purpose: To investigate whether magnesium oxide during external-beam radiotherapy for prostate cancer reduces intrafraction prostate motion in a double-blind, placebo-controlled randomized trial. Methods and Materials: At the Department of Radiotherapy, prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker-based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. The primary outcome was the proportion of patients with clinically relevant intrafraction prostate motion, defined as the proportion of patients who demonstrated in {>=}50% of the fractions an intrafraction motion outside a range of 2 mm. Secondarymore » outcome measures included quality of life and acute toxicity. Results: In total, 46 patients per treatment arm were enrolled. The primary endpoint did not show a statistically significant difference between the treatment arms with a percentage of patients with clinically relevant intrafraction motion of 83% in the magnesium oxide arm as compared with 80% in the placebo arm (p = 1.00). Concerning the secondary endpoints, exploratory analyses demonstrated a trend towards worsened quality of life and slightly more toxicity in the magnesium oxide arm than in the placebo arm; however, these differences were not statistically significant. Conclusions: Magnesium oxide is not effective in reducing the intrafraction prostate motion during external-beam radiotherapy, and therefore there is no indication to use it in clinical practice for this purpose.« less

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study).

PubMed

Shaddy, Robert; Canter, Charles; Halnon, Nancy; Kochilas, Lazaros; Rossano, Joseph; Bonnet, Damien; Bush, Christopher; Zhao, Ziqiang; Kantor, Paul; Burch, Michael; Chen, Fabian

2017-11-01

Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Extended Follow-Up | Division of Cancer Prevention

Cancer.gov

NCI supports the continued follow-up of participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to strengthen the PLCO as a valuable resource for molecular epidemiologic research as well as provide long-term data on the trial’s primary endpoints. |

LIFE AFTER COMPETITIVE EXCLUSION: AN ALTERNATIVE STRATEGY FOR A COMPETITIVE INFERIOR

EPA Science Inventory

Experimental manipulations in the rocky intertidal have demonstrated that in the absence of predation (Paine 1966, 1974) or physical disturbance (Dayton 1971) a competitive dominant species can monopolize the primary space, thereby excluding competitors. he endpoint of this compe...

Ecological risk assessment of bisphenol A in surface waters of China based on both traditional and reproductive endpoints.

PubMed

Guo, Lei; Li, Zhengyan; Gao, Pei; Hu, Hong; Gibson, Mark

2015-11-01

Bisphenol A (BPA) occurs widely in natural waters with both traditional and reproductive toxicity to various aquatic species. The water quality criteria (WQC), however, have not been established in China, which hinders the ecological risk assessment for the pollutant. This study therefore aims to derive the water quality criteria for BPA based on both acute and chronic toxicity endpoints and to assess the ecological risk in surface waters of China. A total of 15 acute toxicity values tested with aquatic species resident in China were found in published literature, which were simulated with the species sensitivity distribution (SSD) model for the derivation of criterion maximum concentration (CMC). 18 chronic toxicity values with traditional endpoints were simulated for the derivation of traditional criterion continuous concentration (CCC) and 12 chronic toxicity values with reproductive endpoints were for reproductive CCC. Based on the derived WQC, the ecological risk of BPA in surface waters of China was assessed with risk quotient (RQ) method. The results showed that the CMC, traditional CCC and reproductive CCC were 1518μgL(-1), 2.19μgL(-1) and 0.86μgL(-1), respectively. The acute risk of BPA was negligible with RQ values much lower than 0.1. The chronic risk was however much higher with RQ values of between 0.01-3.76 and 0.03-9.57 based on traditional and reproductive CCC, respectively. The chronic RQ values on reproductive endpoints were about threefold as high as those on traditional endpoints, indicating that ecological risk assessment based on traditional effects may not guarantee the safety of aquatic biota. Copyright © 2015 Elsevier Ltd. All rights reserved.

Surrogate endpoints for cancer screening trials: general principles and an illustration using the UK Flexible Sigmoidoscopy Screening Trial.

PubMed

Cuzick, Jack; Cafferty, Fay H; Edwards, Robert; Møller, Henrik; Duffy, Stephen W

2007-01-01

Cancer screening is aimed primarily at reducing deaths. Thus, site-specific cancer mortality is the appropriate endpoint for evaluating screening interventions. However, it is also the most demanding endpoint, requiring follow-up and a large numbers of patients order to have adequate power. Therefore, it is highly desirable to have surrogate endpoints that can reliably predict mortality reductions many years earlier. We here review a range of surrogate markers in terms of their potential advantages and pitfalls, and argue that a measure which weights incident cancers according to their predicted mortality has many advantages over other measures and should be used more routinely. Application to the UK Flexible Sigmoidoscopy Screening Trial data suggests that predicted colorectal cancer mortality, based on stage-specific incidence, is a more powerful endpoint than actual mortality and could advance the analysis time by about three years. Total colorectal cancer incidence as a surrogate endpoint provides little advance in the analysis time over actual mortality. The approach requires reliable prognostic data, (e.g. stage), for both the study cohort and a representative sample of the whole population. The routine collection of such data should be a priority for cancer registries. Surrogate endpoints should not replace a long-term analysis based directly on mortality, but can provide reliable early indicators which can be useful both for monitoring ongoing screening programmes and for making policy decisions.

Developing ecosystem services-based assessment endpoints for determining ecological risks to estuarine environments

EPA Science Inventory

Current U.S. EPA ecological risk assessment (ERA) guidance defines an assessment endpoint (AE) as an explicit expression of the environmental value that is to be protected, and recommends that AEs are selected based on ecological relevance, susceptibility to known or potential st...

A PHYSIOLOGICALLY BASED COMPUTATIONAL MODEL OF THE BPG AXIS IN FATHEAD MINNOWS: PREDICTING EFFECTS OF ENDOCRINE DISRUPTING CHEMICAL EXPOSURE ON REPRODUCTIVE ENDPOINTS

EPA Science Inventory

This presentation describes development and application of a physiologically-based computational model that simulates the brain-pituitary-gonadal (BPG) axis and other endpoints important in reproduction such as concentrations of sex steroid hormones, 17-estradiol, testosterone, a...

IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies

PubMed Central

Loher, Phillipe; Londin, Eric R.; Rigoutsos, Isidore

2014-01-01

For many years it was believed that each mature microRNA (miRNA) existed as a single entity with fixed endpoints and a ‘static’ and unchangeable primary sequence. However, recent evidence suggests that mature miRNAs are more ‘dynamic’ and that each miRNA precursor arm gives rise to multiple isoforms, the isomiRs. Here we report on our identification of numerous and abundant isomiRs in the lymphoblastoid cell lines (LCLs) of 452 men and women from five different population groups. Unexpectedly, we find that these isomiRs exhibit an expression profile that is population-dependent and gender-dependent. This is important as it indicates that the LCLs of each gender/population combination have their own unique collection of mature miRNA transcripts. Moreover, each identified isomiR has its own characteristic abundance that remains consistent across biological replicates indicating that these are not degradation products. The primary sequences of identified isomiRs differ from the known miRBase miRNA either at their 5´-endpoint (leads to a different ‘seed’ sequence and suggests a different targetome), their 3´-endpoint, or both simultaneously. Our analysis of Argonaute PAR-CLIP data from LCLs supports the association of many of these newly identified isomiRs with the Argonaute silencing complex and thus their functional roles through participation in the RNA interference pathway. PMID:25229428

A Phase IIIb, Multicentre, Randomised, Parallel-Group, Placebo-Controlled, Double-Blind Study to Investigate the Efficacy and Safety of OROS Hydromorphone in Subjects with Moderate-to-Severe Chronic Pain Induced by Osteoarthritis of the Hip or the Knee

PubMed Central

Vojtaššák, Jozef; Vojtaššák, Jozef; Jacobs, Adam; Rynn, Leonie; Waechter, Sandra; Richarz, Ute

2011-01-01

Background. Opioid analgesics are included in treatment guidelines for the symptomatic management of osteoarthritis (OA). Starting with a low dose of opioid and slowly titrating to a higher dose may help avoid intolerable side effects. Methods. Subjects aged ≥40 years, with moderate to severe pain induced by OA of the hip or knee not adequately controlled by previous non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol treatment, were enrolled. Subjects received OROS hydromorphone 4 mg or placebo once-daily. The dose was titrated every 3-4 days in case of unsatisfactory pain control during the 4-week titration phase. A 12 week maintenance phase followed. The primary efficacy endpoint was the change in “pain on average” measured on the Brief Pain Inventory (BPI) scale from baseline to the end of the maintenance phase. Results. 139 subjects received OROS hydromorphone and 149 subjects received placebo. All efficacy endpoints showed similar improvements from baseline to end of study in the 2 groups. The safety results were consistent with the safety profile of OROS hydromorphone. Conclusion.The study did not meet the primary endpoint; although many subjects' pain was not adequately controlled at inclusion, their pain may have improved with continued paracetamol or NSAID treatment. PMID:22110921

IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies.

PubMed

Loher, Phillipe; Londin, Eric R; Rigoutsos, Isidore

2014-09-30

For many years it was believed that each mature microRNA (miRNA) existed as a single entity with fixed endpoints and a 'static' and unchangeable primary sequence. However, recent evidence suggests that mature miRNAs are more 'dynamic' and that each miRNA precursor arm gives rise to multiple isoforms, the isomiRs. Here we report on our identification of numerous and abundant isomiRs in the lymphoblastoid cell lines (LCLs) of 452 men and women from five different population groups. Unexpectedly, we find that these isomiRs exhibit an expression profile that is population-dependent and gender-dependent. This is important as it indicates that the LCLs of each gender/population combination have their own unique collection of mature miRNA transcripts. Moreover, each identified isomiR has its own characteristic abundance that remains consistent across biological replicates indicating that these are not degradation products. The primary sequences of identified isomiRs differ from the known miRBase miRNA either at their 5´-endpoint (leads to a different 'seed' sequence and suggests a different targetome), their 3´-endpoint, or both simultaneously. Our analysis of Argonaute PAR-CLIP data from LCLs supports the association of many of these newly identified isomiRs with the Argonaute silencing complex and thus their functional roles through participation in the RNA interference pathway.

Evaluating the use of plerixafor in stem cell mobilisation - an economic analysis of the PHANTASTIC trial.

PubMed

Martin, Antony P; Richards, Sarah; Haycox, Alan; Houten, Rachel; McLeod, Claire; Braithwaite, Barbara; Clark, Jack O; Bell, Joanne; Clark, Richard E

2016-10-01

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor-mobilised patients achieved the composite primary endpoint of ≥4 × 10(6) CD34+ cells kg(-1) in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Profiling clinical cancer research across the Atlantic: a review of research and its characteristics presented at ASCO and ESMO Congresses during the last decade.

PubMed

Pentheroudakis, George; Krikelis, Dimitrios; Cervantes, Andres; Vermorken, Jan; Pavlidis, Nicholas

2012-10-01

The comparison of clinical cancer research characteristics across the Atlantic and their evolution over time have not been studied to date. We collected oral presentations on breast, lung and colorectal cancer at ASCO (n=506) and ESMO (n=239) Congresses in years 2000-2010. EU-originated research constituted 52% of all ASCO presentations while US-research 26.7% of ESMO Congress presentations. Industry sponsorship was reported in 24.8% of ASCO vs. 31.8% of ESMO Congress trials. ASCO-presented trials were larger with longer follow-up periods but were blinded less often. ESMO-presented trials used Event-Free Survival (EFS, 38.1%) and Surrogate (18.4%) primary endpoints and reported positive primary endpoints (65%) more often than ASCO-presented trials. Interim analysis resulted in discontinuation of a trial more often at ASCO Congress (8.3% vs. 3.2%). ASCO Congress-presented research was more often published (69.2% vs. 59.8% at ESMO) at higher impact factor journals. Strong trends over the decade were seen for more frequent industry sponsorship, blinded design, larger sample size, early interim discontinuation, use of EFS endpoints and biomarker evaluation. Cancer clinical research is a complex scientific activity with common global but also distinct characteristics at the two sides of the Atlantic. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Stent and surgery for symptomatic carotid stenosis. SPACE study results].

PubMed

Ringleb, P A; Hacke, W

2007-10-01

The SPACE trial compared risk and effectiveness of stent-supported angioplasty (CAS) vs carotid endarterectomy (CEA) using a noninferiority design in patients with symptomatic stenoses. Intention-to-treat analysis of the entire study population of 1,214 patients showed that primary endpoint events (ipsilateral stroke or death between randomisation and day 30) occurred in 6.92% of the CAS group and 6.45% of the CEA group. The 95% confidence interval (CI) of the absolute risk difference ranged from -1.94% to +2.87%, therefore the noninferiority was not proven. The same was true for the analysis of protocols. No significant differences between the two treatment methods were found in primary or any of the secondary endpoints. There were also no differences in short-term prevention. The endpoint 'ipsilateral ischemic stroke or vascular death between randomisation and 6 months' occurred in 7.4% of the CAS and 6.5% of the CEA patients (odds ratio 1.16, 95% confidence interval 0.74-1.82). Instent restenoses were significantly more common in the CAS group (4.6% vs 2.2%, odds ratio 2.14, 95% CI 1.10-4.18). Surgery remains the gold standard in treatment of patients with symptomatic carotid artery stenosis. Stent-supported angioplasty can be an alternative only in the hands of an experienced interventionalist with proven low periprocedural complication rate.

Pre-hospital ticagrelor in patients with ST-segment elevation myocardial infarction with long transport time to primary PCI facility.

PubMed

Lupi, Alessandro; Schaffer, Alon; Lazzero, Maurizio; Tessitori, Massimo; De Martino, Leonardo; Rognoni, Andrea; Bongo, Angelo S; Porto, Italo

2016-12-01

Pre-hospital ticagrelor, given less than 1h before coronary intervention (PCI), failed to improve coronary reperfusion in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI. It is unknown whether a longer interval from ticagrelor administration to primary PCI might reveal any improvement of coronary reperfusion. We retrospectively compared 143 patients, pre-treated in spoke centers or ambulance with ticagrelor at least 1.5h before PCI (Pre-treatment Group), with 143 propensity score-matched controls treated with ticagrelor in the hub before primary PCI (Control Group) extracted from RENOVAMI, a large observational Italian registry of more than 1400 STEMI patients enrolled from Jan. 2012 to Oct. 2015 (ClinicalTrials.gov id: NCT01347580). The median time from ticagrelor administration and PCI was 2.08h (95% CI 1.66-2.84) in the Pre-treatment Group and 0.56h (95% CI 0.33-0.76) in the Control Group. TIMI flow grade before primary PCI in the infarct related artery was the primary endpoint. The primary endpoint, baseline TIMI flow grade, was significantly higher in Pre-treatment Group (0.88±1.14 vs 0.53±0.86, P=0.02). However in-hospital mortality, in-hospital stent thrombosis, bleeding rates and other clinical and angiographic outcomes were similar in the two groups. In a real world STEMI network, pre-treatment with ticagrelor in spoke hospitals or in ambulance loading at least 1.5h before primary PCI is safe and might improve pre-PCI coronary reperfusion, in comparison with ticagrelor administration immediately before PCI. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson's disease.

PubMed

Schapira, A H V; Stocchi, F; Borgohain, R; Onofrj, M; Bhatt, M; Lorenzana, P; Lucini, V; Giuliani, R; Anand, R

2013-02-01

Safinamide is an α-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action in Phase III clinical development as a once-daily add-on to dopamine agonist (DA) therapy for early Parkinson's disease (PD). Study 017 was a 12-month, randomized, double-blind, placebo-controlled pre-planned extension study to the previously reported Study 015. Patients received safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to 'intervention', defined as increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post hoc analyses were performed on each separate dose group. Of the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled safinamide and placebo groups, respectively (log-rank test; P = 0.3342). In post hoc analyses, patients receiving safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and a delay in median time to intervention of 9 days (P < 0.05; 240- to 540-day analysis). The pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that safinamide 100 mg/day may be effective as add-on treatment to DA in PD. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial).

PubMed

Hasegawa, Seiki; Okada, Morihito; Tanaka, Fumihiro; Yamanaka, Takeharu; Soejima, Toshinori; Kamikonya, Norihiko; Tsujimura, Tohru; Fukuoka, Kazuya; Yokoi, Kohei; Nakano, Takashi

2016-06-01

We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM). Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume >1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy). Primary endpoints were macroscopic complete resection (MCR) rate for EPP and treatment-related mortality for TMT. Forty-two eligible patients were enrolled: median age 64.5 (range 43-74) years; M:F = 39:3, clinical stage I:II:III = 14:13:15; histological type epithelioid were sarcomatoid; biphasic; others = 28:1:9:4. Of 42 patients, 30 completed EPP with MCR and 17 completed TMT. The trial met the primary endpoints, with an MCR rate of 71 % (30/42) and treatment-related mortality of 9.5 % (4/42). Overall median survival time and 2-year survival rate for 42 registered patients were 19.9 months and 42.9 %, respectively. Two-year relapse-free survival rate of 30 patients who completed EPP with MCR was 37.0 %. This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory.

Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy

PubMed Central

Krauss, Gregory L.; Wechsler, Robert T.; Wang, Xue-Feng; DiVentura, Bree; Brandt, Christian; Trinka, Eugen; O'Brien, Terence J.; Laurenza, Antonio; Patten, Anna; Bibbiani, Francesco

2015-01-01

Objective: To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE). Methods: In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel uptitrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving ≥50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored. Results: Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (−38.4% vs −76.5%; p < 0.0001) and greater 50% PGTC seizure responder rate (39.5% vs 64.2%; p = 0.0019). During maintenance, 12.3% of placebo-treated patients and 30.9% of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%). Conclusions: Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE. Classification of evidence: This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE. PMID:26296511

Impact of Prior Cancer on Eligibility for Lung Cancer Clinical Trials

PubMed Central

Laccetti, Andrew L.; Xuan, Lei; Halm, Ethan A.; Pruitt, Sandi L.

2014-01-01

Background In oncology clinical trials, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of such patients. We determined the prevalence and characteristics of this practice in lung cancer clinical trials and estimated impact on trial accrual. Methods We reviewed lung cancer clinical trials sponsored or endorsed by the Eastern Oncology Cooperative Group for exclusion criteria related to a prior cancer diagnosis. We estimated prevalence of prior primary cancer diagnoses among lung cancer patients using Surveillance Epidemiology and End Results (SEER)-Medicare linked data. We assessed the association between trial characteristics and prior cancer exclusion using chi-square analysis. All statistical tests were two-sided. Results Fifty-one clinical trials (target enrollment 13072 patients) were included. Forty-one (80%) excluded patients with a prior cancer diagnosis as follows: any prior (14%), within five years (43%), within two or three years (7%), or active cancer (16%). In SEER-Medicare data (n = 210509), 56% of prior cancers were diagnosed within five years before the lung cancer diagnosis. Across trials, the estimated number and proportion of patients excluded because of prior cancer ranged from 0–207 and 0%-18%. Prior cancer was excluded in 94% of trials with survival primary endpoints and 73% of trials with nonsurvival primary endpoints (P = .06). Conclusions A substantial proportion of patients are reflexively excluded from lung cancer clinical trials because of prior cancer. This inclusion criterion is applied widely across studies, including more than two-thirds of trials with nonsurvival endpoints. More research is needed to understand the basis and ramifications of this exclusion policy. PMID:25253615

A prospective, randomized study of the patency period of the plastic antireflux biliary stent: an interim analysis.

PubMed

Leong, Quan Wai; Shen, Mira L; Au, Kim W; Luo, Derek; Lau, James Y; Wu, Justin C; Chan, Francis K; Sung, Joseph J

2016-02-01

There is as yet no ideal design of a plastic biliary stent with the longest patency period. To study the safety and effective patency period of a new plastic antireflux biliary stent in the clinical setting. We conducted a prospective, randomized trial to compare the patency of 2 similar plastic biliary stents, one of which has an antiduodenobiliary reflux property. The study was conducted at 2 separate tertiary centers in 2 countries. Patients with inoperable distal malignant biliary obstruction were recruited. One of the 2 types of plastic stents under study was randomly chosen and inserted in the common bile duct of the study subjects. The subjects were followed until the end of study or occlusion occurrence. Our primary endpoint was the time to stent occlusion in days, with stent-related adverse events and all-cause mortality the secondary endpoints. A total of 16 subjects were recruited for the study; 7 were allocated to group A (ordinary Tannenbaum stent) and 9 to group B (antireflux biliary stent). Five of 7 subjects (71%) in group B had stent occlusion within 8 days, and the primary end point was reached in all 7 subjects within 30 days, whereas the primary endpoint was not reached within 30 days in any of the subjects in group A. Our data showed a significantly shorter stent patency period in group B compared with group A (P < .003). Small sample size. Routine use of antireflux plastic biliary stents in the palliative management of malignant biliary obstructions cannot be recommended at present. (Clinical trial registration number: NCT01142921.). Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Partial splenic embolization to permit continuation of systemic chemotherapy.

PubMed

Luz, Jose Hugo M; Luz, Paula M; Marchiori, Edson; Rodrigues, Leonardo A; Gouveia, Hugo R; Martin, Henrique S; Faria, Igor M; Souza, Roberto R; Gil, Roberto de Almeida; Palladino, Alexandre de M; Pimenta, Karina B; de Souza, Henrique S

2016-10-01

Systemic chemotherapy treatments, commonly those that comprise oxaliplatin, have been linked to the appearance of distinctive liver lesions that evolves to portal hypertension, spleen enlargement, platelets sequestration, and thrombocytopenia. This outcome can interrupt treatment or force dosage reduction, decreasing efficiency of cancer therapy. We conducted a prospective phase II study for the evaluation of partial splenic embolization in patients with thrombocytopenia that impeded systemic chemotherapy continuation. From August 2014 through July 2015, 33 patients underwent partial splenic embolization to increase platelets count and allow their return to treatment. Primary endpoint was the accomplishment of a thrombocyte level superior to 130 × 10 9 /L and the secondary endpoints were the return to chemotherapy and toxicity. Partial splenic embolization was done 36 times in 33 patients. All patients presented gastrointestinal cancer and colorectal malignancy was the commonest primary site. An average of 6.4 cycles of chemotherapy was done before splenic embolization and the most common regimen was Folfox. Mean platelet count prior to embolization was 69 × 10 9 /L. A total of 94% of patients achieved primary endpoint. All patients in need reinitiated treatment and median time to chemotherapy return was 14 days. No grade 3 or above adverse events were identified. Aiming for a 50% to 70% infarction area may be sufficient to achieve success without the complications associated with more extensive infarction. Combined with the better safety profile, partial splenic embolization is an excellent option in the management of thrombocytopenia, enabling the resumption of systemic chemotherapy with minimal procedure-related morbidity. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

A double-blind, crossover, randomized comparison of granisetron and ramosetron for the prevention of acute and delayed cisplatin-induced emesis in patients with gastrointestinal cancer: is patient preference a better primary endpoint?

PubMed

Koizumi, Wasaburo; Tanabe, Satoshi; Nagaba, Shizuka; Higuchi, Katsuhiko; Nakayama, Norisuke; Saigenji, Katsunori; Nonaka, Miwa; Yago, Kazuo

2003-12-01

Serotonin receptor antagonists are recommended by the American Society of Clinical Oncology for the prevention of acute and delayed chemotherapy-induced emesis. However, the most effective agent in this class of antiemetic drugs for preventing emesis has not been clearly defined. We therefore performed a double-blind, crossover, randomized, controlled trial comparing the efficacy of granisetron and ramosetron, using patient preference as the primary endpoint. Thirty patients receiving two courses of combined chemotherapy (including > or =60 mg/m(2) cisplatin) for gastric or esophageal cancer were randomly assigned to the granisetron-ramosetron group (treatment phase 1: granisetron, 3 mg; treatment phase 2: ramosetron, 0.3 mg) or the ramosetron-granisetron group (treatment phase 1: ramosetron, 0.3 mg; treatment phase 2: granisetron, 3 mg). All patients received methylprednisolone sodium, 250 mg i.v., during each treatment phase. The efficacy of granisetron and ramosetron was similar in terms of the suppression of emesis and appetite status. However, the majority of patients (19/30, 63.3%) expressed a preference for granisetron, as compared with 9 patients (30.0%) who preferred ramosetron; 2 patients (6.7%) had no preference (chi(2) test: p = 0.008; Fisher's exact test: p = 0.015). (1) A significant proportion of patients prefer granisetron over ramosetron for the prevention of chemotherapy-induced emesis. (2) Granisetron and ramosetron possess similar effectiveness for the suppression of emesis. (3) The variable of 'patient preference' should be accepted as a primary endpoint of antiemetic drug efficacy. Copyright 2003 S. Karger AG, Basel

High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy.

PubMed

Fernández-Juárez, Gema; Villacorta Perez, Javier; Luño Fernández, José Luis; Martinez-Martinez, Ernesto; Cachofeiro, Victoria; Barrio Lucia, Vicente; Tato Ribera, Ana M; Mendez Abreu, Angel; Cordon, Alfredo; Oliva Dominguez, Jesus Angel; Praga Terente, Manuel

2017-05-01

Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria. Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death. The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers. Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers. © 2016 Asian Pacific Society of Nephrology.

A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study).

PubMed

Holland, Thomas L; O'Riordan, William; McManus, Alison; Shin, Elliot; Borghei, Ali; File, Thomas M; Wilcox, Mark H; Torres, Antoni; Dryden, Matthew; Lodise, Thomas; Oguri, Toyoko; Corey, G Ralph; McLeroth, Patrick; Shukla, Rajesh; Huang, David B

2018-05-01

Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, -5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier NCT02607618.). Copyright © 2018 American Society for Microbiology.

Association of Lp-PLA2-A and early recurrence of vascular events after TIA and minor stroke.

PubMed

Lin, Jinxi; Zheng, Hongwei; Cucchiara, Brett L; Li, Jiejie; Zhao, Xingquan; Liang, Xianhong; Wang, Chunxue; Li, Hao; Mullen, Michael T; Johnston, S Claiborne; Wang, Yilong; Wang, Yongjun

2015-11-03

To determine the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) measured in the acute period and the short-term risk of recurrent vascular events in patients with TIA or minor stroke. We measured Lp-PLA2 activity (Lp-PLA2-A) in a subset of 3,201 participants enrolled in the CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) trial. Participants with TIA or minor stroke were enrolled within 24 hours of symptom onset and randomized to single or dual antiplatelet therapy. In the current analysis, the primary outcome was defined as the composite of ischemic stroke, myocardial infarction, or death within 90 days. The composite endpoint occurred in 299 of 3,021 participants (9.9%). The population average Lp-PLA2-A level was 209 ± 59 nmol/min/mL (95% confidence interval [CI] 207-211). Older age, male sex, and current smoking were associated with higher Lp-PLA2-A levels. Lp-PLA2-A was significantly associated with the primary endpoint (adjusted hazard ratio 1.07, 95% CI 1.01-1.13 for every 30 nmol/min/mL increase). Similar results were seen for ischemic stroke alone. Adjustment for low-density lipoprotein cholesterol attenuated the association between Lp-PLA2-A and the primary endpoint (adjusted hazard ratio 1.04, 95% CI 0.97-1.11 for every 30 nmol/min/mL increase). Higher levels of Lp-PLA2-A in the acute period are associated with increased short-term risk of recurrent vascular events. © 2015 American Academy of Neurology.

Long-term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy.

PubMed

Vollmar, A C; Fox, P R

2016-01-01

Dilated cardiomyopathy (DCM) is a common cause of morbidity and mortality in the Irish Wolfhound (IW). However, the benefit of medical treatment in IW dogs with preclinical DCM, atrial fibrillation (AF), or both has not been demonstrated. Compare the time to develop congestive heart failure (CHF) or sudden death in IW dogs with preclinical DCM, AF, or both receiving monotherapy with pimobendan, methyldigoxin, or benazepril hydrochloride. Seventy-five client-owned IW dogs. Irish Wolfhound dogs were prospectively randomized to receive pimobendan (Vetmedin®), benazepril HCl (Fortekor®), or methyldigoxin (Lanitop®) monotherapy in a 1:1:1 ratio in a blinded clinical trial. The prospectively defined composite primary endpoint was onset of CHF or sudden death. To assure stringent evaluation of treatment effect, data from dogs complying with the study protocol were analyzed. Sixty-six IW fulfilling the study protocol included 39 males, 27 females; median (interquartile range) age, 4.0 years (3.0-5.0 years) and weight, 70.0 kg (63.0-75.0 kg). Primary endpoint was reached in 5 of 23 (21.7%) IW receiving pimobendan, 11 of 22 (50.0%) receiving benazepril HCl, and 9 of 21 (42.9%) receiving methyldigoxin. Median time to primary endpoint was significantly longer for pimobendan (1,991 days; 65.4 months) compared to methyldigoxin (1,263 days; 41.5 months; P = .031) or benazepril HCl-(997 days; 32.8 months; P = .008) treated dogs. In IW dogs with preclinical DCM, AF or both, pimobendan monotherapy significantly prolonged time to onset of CHF or sudden death than did monotherapy with benazepril HCl or methyldigoxin. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Disease Management Plus Recommended Care versus Recommended Care Alone for Ambulatory COPD Patients.

PubMed

Kalter-Leibovici, Ofra; Benderly, Michal; Freedman, Laurence S; Kaufman, Galit; Molcho Falkenberg Luft, Tchiya; Murad, Havi; Olmer, Liraz; Gluch, Meri; Segev, David; Gilad, Avi; Elkrinawi, Said; Cukierman-Yaffe, Tali; Chen, Baruch; Jacobson, Orit; Key, Calanit; Shani, Mordechai; Fink, Gershon

2018-03-01

The efficacy of disease management programs in the treatment of patients with chronic obstructive pulmonary disease (COPD) remains uncertain. To study the effect of disease management (DM) added to recommended care (RC) in ambulatory COPD patients. In this trial, 1,202 COPD patients (age >40 years), with moderate to very severe airflow limitation were randomly assigned either to DM plus RC (study intervention) or to RC alone (control intervention). RC included follow-up by pulmonologists; inhaled long-acting bronchodilators and corticosteroids; smoking cessation intervention; nutritional advice and psychosocial support when indicated, and supervised physical activity sessions. DM, delivered by trained nurses during patients' visits to the designated COPD centers and remote contacts with the patients between these visits, included patient self-care education; monitoring patients' symptoms and adherence to treatment; provision of advice in case of acute disease exacerbation, and coordination of care vis-à-vis other healthcare providers. The primary composite endpoint was first hospital admission for respiratory symptoms or death from any cause. During 3,537 patient-years, 284 (47.2%) patients in the control group and 264 (44.0%) in the study intervention group had a primary endpoint event. The median (range) time elapsed until a primary endpoint event was 1.0 (0-4.0) years among patients assigned to the study intervention and 1.1 (0-4.1) years among patients assigned to the control intervention; adjusted hazard ratio, 0.92 (95%CI: 0.77 to 1.08). DM added to RC was not superior to RC alone in delaying first hospital admission or death among ambulatory COPD patients. Clinical trial registration available at www.clinicaltrials.gov, ID NCT00982384.

Impact of the introduction of a standardised ICD programming protocol: real-world data from a single centre.

PubMed

Sunderland, Nicholas; Kaura, Amit; Li, Anthony; Kamdar, Ravi; Petzer, Ed; Dhillon, Para; Murgatroyd, Francis; Scott, Paul A

2016-09-01

Randomised trials have shown that empiric ICD programming, using long detection times and high detection zones, reduces device therapy in ICD recipients. However, there is less data on its effectiveness in a "real-world" setting, especially secondary prevention patients. Our aim was to evaluate the introduction of a standardised programming protocol in a real-world setting of unselected ICD recipients. We analysed 270 consecutive ICD recipients implanted in a single centre-135 implanted prior to protocol implementation (physician-led group) and 135 after (standardised group). The protocol included long arrhythmia detection times (30/40 or equivalent) and high rate detection zones (primary prevention lower treatment zone 200 bpm). Programming in the physician-led group was at the discretion of the implanter. The primary endpoint was time-to-any therapy (ATP or shocks). Secondary endpoints were time-to-inappropriate therapy and time-to-appropriate therapy. The safety endpoints were syncopal episodes, hospital admissions and death. At 12 months follow-up, 47 patients had received any ICD therapy (physician-led group, n = 31 vs. standardised group, n = 16). There was a 47 % risk reduction in any device therapy (p = 0.04) and an 86 % risk reduction in inappropriate therapy (p = 0.009) in the standardised compared to the physician-led group. There was a non-significant 30 % risk reduction in appropriate therapy (p = 0.32). Results were consistent across primary and secondary prevention patients. There were no significant differences in the rates of syncope, hospitalisation, and death. In unselected patients in a real-world setting, introduction of a standardised programming protocol, using long detection times and high detection zones, significantly reduces the burden of ICD therapy without an increase in adverse outcomes.

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

PubMed

Merrill, J T; van Vollenhoven, R F; Buyon, J P; Furie, R A; Stohl, W; Morgan-Cox, M; Dickson, C; Anderson, P W; Lee, C; Berclaz, P-Y; Dörner, T

2016-02-01

To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. NCT01205438. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition.

PubMed

Gilbert, Peter B; Gabriel, Erin E; Huang, Ying; Chan, Ivan S F

2015-09-01

A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the "principal effects" or "causal effect predictiveness (CEP)" surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the "surrogate paradox"). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis, and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency.

Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition

PubMed Central

Gilbert, Peter B.; Gabriel, Erin E.; Huang, Ying; Chan, Ivan S.F.

2015-01-01

A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the “principal effects” or “causal effect predictiveness (CEP)” surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the “surrogate paradox”). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis, and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency. PMID:26722639

A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome.

PubMed

Adhikari, Narayan; Biswas, Ahitagni; Gogia, Ajay; Sahoo, Ranjit Kumar; Garg, Ajay; Nehra, Ashima; Sharma, Mehar Chand; Bhasker, Suman; Singh, Manmohan; Sreenivas, Vishnubhatla; Chawla, Rohan; Joshi, Garima; Kumar, Lalit; Chander, Subhash

2018-04-09

The treatment of primary CNS lymphoma (PCNSL) comprises high dose methotrexate (HDMTX) based chemotherapy followed by whole brain radiotherapy (WBRT), the major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in PCNSL in the Indian setting. We screened 32 patients and enrolled 22 eligible patients with PCNSL from 2015 to 2017 in a prospective phase II trial. The patients underwent five 2-weekly cycles of induction chemotherapy with rituximab, methotrexate, vincristine, procarbazine. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4 Gy/13 fractions/2.5 weeks while those with partial response (PR), stable or progressive disease (SD or PD) were given standard dose WBRT 45 Gy/25 fractions/5 weeks. Thereafter two cycles of consolidation chemotherapy with cytarabine were given. The primary endpoints of the study were assessment of response rate (RR) and progression free survival (PFS). The secondary endpoints of the study were assessment of overall survival (OS), toxicity profile of treatment and serial changes in quality of life and neuropsychological parameters. Out of 19 patients who completed HDMTX based chemotherapy, 10 (52.63%) patients achieved CR, 8 (42.11%) patients had PR and 1 patient had PD. After a median follow-up period of 11.25 months, the estimated median OS was 19 months. The actuarial rates of PFS and OS were respectively 94.1 and 68.2% at 1 year and 50.2 and 48.5% at 2 years. Three patients in reduced dose WBRT arm had recurrence and two of them died of progressive disease, whereas there was no recurrence or disease related death in standard dose WBRT arm. On univariate analysis of PFS, age ≤ 50 years and use of standard dose WBRT (45 Gy) led to significantly improved outcome (p value 0.03 and 0.02 respectively). In patients with PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression and early death. Trial Registration No CTRI/2015/10/006268.

[Detection of endpoint for segmentation between consonants and vowels in aphasia rehabilitation software based on artificial intelligence scheduling].

PubMed

Deng, Xingjuan; Chen, Ji; Shuai, Jie

2009-08-01

For the purpose of improving the efficiency of aphasia rehabilitation training, artificial intelligence-scheduling function is added in the aphasia rehabilitation software, and the software's performance is improved. With the characteristics of aphasia patient's voice as well as with the need of artificial intelligence-scheduling functions under consideration, the present authors have designed a set of endpoint detection algorithm. It determines the reference endpoints, then extracts every word and ensures the reasonable segmentation points between consonants and vowels, using the reference endpoints. The results of experiments show that the algorithm is able to attain the objects of detection at a higher accuracy rate. Therefore, it is applicable to the detection of endpoint on aphasia-patient's voice.

Osteoporosis improvement: a large-scale randomized controlled trial of patient and primary care physician education.

PubMed

Solomon, Daniel H; Katz, Jeffrey N; Finkelstein, Joel S; Polinski, Jennifer M; Stedman, Margaret; Brookhart, M Alan; Arnold, Marilyn; Gauthier, Suzanne; Avorn, Jerry

2007-11-01

We conducted a randomized controlled trial within the setting of a large drug benefit plan for Medicare beneficiaries. Primary care physicians and their patients were randomized to usual care, patient intervention only, physician intervention only, or both interventions. There was no difference in the probability of the primary composite endpoint (BMD test or osteoporosis medication) or in either of its components comparing the combined intervention group with usual care (risk ratio = 1.04; 95% CI, 0.85-1.26). Fractures from osteoporosis are associated with substantial morbidity, mortality, and cost. However, only a minority of at-risk older adults receives screening and/or treatment for this condition. We evaluated the effect of educational interventions for osteoporosis targeting at-risk patients, primary care physicians, or both. We conducted a randomized controlled trial within the setting of a large drug benefit plan for Medicare beneficiaries. Primary care physicians and their patients were randomized to usual care, patient intervention only, physician intervention only, or both interventions. The at-risk patients were women >or=65 yr of age, men and women >or=65 yr of age with a prior fracture, and men and women >or=65 yr of age who used oral glucocorticoids. The primary outcome studied was a composite of either undergoing a BMD test or initiating a medication used for osteoporosis. The secondary outcome was a hip, humerus, spine, or wrist fracture. We randomized 828 primary care physicians and their 13,455 eligible at-risk patients into four study arms. Physician and patient characteristics were very similar across all four groups. Across all four groups, the rate of the composite outcome was 10.3 per 100 person-years and did not differ between the usual care and the combined intervention groups (p = 0.5). In adjusted Cox proportional hazards models, there was no difference in the probability of the primary composite endpoint comparing the combined intervention group with usual care (risk ratio = 1.04; 95% CI, 0.85-1.26). There was also no difference in either of the components of the composite endpoint. The probability of fracture during follow-up was 4.2 per 100 person-years and did not differ by treatment assignment (p = 0.9). In this trial, a relatively brief program of patient and/or physician education did not work to improve the management of osteoporosis. More intensive efforts should be considered for future quality improvement programs for osteoporosis.

Phase I/II study of alectinib in lung cancer with RET fusion gene: study protocol.

PubMed

Takeuchi, Shinji; Murayama, Toshinori; Yoshimura, Kenichi; Kawakami, Takahiro; Takahara, Shizuko; Imai, Yasuhito; Kuribayashi, Yoshikazu; Nagase, Katsuhiko; Goto, Koichi; Nishio, Makoto; Hasegawa, Yoshinori; Satouchi, Miyako; Kiura, Katsuyuki; Seto, Takashi; Yano, Seiji

2017-01-01

The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients. This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

QSAR modeling of cumulative environmental end-points for the prioritization of hazardous chemicals.

PubMed

Gramatica, Paola; Papa, Ester; Sangion, Alessandro

2018-01-24

The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

GAME (Goals - Activity - Motor Enrichment): protocol of a single blind randomised controlled trial of motor training, parent education and environmental enrichment for infants at high risk of cerebral palsy.

PubMed

Morgan, Catherine; Novak, Iona; Dale, Russell C; Guzzetta, Andrea; Badawi, Nadia

2014-10-07

Cerebral palsy is the most common physical disability of childhood and early detection is possible using evidence based assessments. Systematic reviews indicate early intervention trials rarely demonstrate efficacy for improving motor outcomes but environmental enrichment interventions appear promising. This study is built on a previous pilot study and has been designed to assess the effectiveness of a goal - oriented motor training and enrichment intervention programme, "GAME", on the motor outcomes of infants at very high risk of cerebral palsy (CP) compared with standard community based care. A two group, single blind randomised controlled trial (n = 30) will be conducted. Eligible infants are those diagnosed with CP or designated "at high risk of CP" on the basis of the General Movements Assessment and/or abnormal neuroimaging. A physiotherapist and occupational therapist will deliver home-based GAME intervention at least fortnightly until the infant's first birthday. The intervention aims to optimize motor function and engage parents in developmental activities aimed at enriching the home learning environment. Primary endpoint measures will be taken 16 weeks after intervention commences with the secondary endpoint at 12 months and 24 months corrected age. The primary outcome measure will be the Peabody Developmental Motor Scale second edition. Secondary outcomes measures include the Gross Motor Function Measure, Bayley Scales of Infant and Toddler Development, Affordances in the Home Environment for Motor Development - Infant Scale, and the Canadian Occupational Performance Measure. Parent well-being will be monitored using the Depression Anxiety and Stress Scale. This paper presents the background, design and intervention protocol of a randomised trial of a goal driven, motor learning approach with customised environmental interventions and parental education for young infants at high risk of cerebral palsy. This trial is registered on the Australian New Zealand Clinical Trial register: ACTRN12611000572965.

Efficacy of community-based physiotherapy networks for patients with Parkinson's disease: a cluster-randomised trial.

PubMed

Munneke, Marten; Nijkrake, Maarten J; Keus, Samyra Hj; Kwakkel, Gert; Berendse, Henk W; Roos, Raymund Ac; Borm, George F; Adang, Eddy M; Overeem, Sebastiaan; Bloem, Bastiaan R

2010-01-01

Many patients with Parkinson's disease are treated with physiotherapy. We have developed a community-based professional network (ParkinsonNet) that involves training of a selected number of expert physiotherapists to work according to evidence-based recommendations, and structured referrals to these trained physiotherapists to increase the numbers of patients they treat. We aimed to assess the efficacy of this approach for improving health-care outcomes. Between February, 2005, and August, 2007, we did a cluster-randomised trial with 16 clusters (defined as community hospitals and their catchment area). Clusters were randomly allocated by use of a variance minimisation algorithm to ParkinsonNet care (n=8) or usual care (n=8). Patients were assessed at baseline and at 8, 16, and 24 weeks of follow-up. The primary outcome was a patient preference disability score, the patient-specific index score, at 16 weeks. Health secondary outcomes were functional mobility, mobility-related quality of life, and total societal costs over 24 weeks. Analysis was by intention to treat. This trial is registered, number NCT00330694. We included 699 patients. Baseline characteristics of the patients were comparable between the ParkinsonNet clusters (n=358) and usual-care clusters (n=341). The primary endpoint was similar for patients within the ParkinsonNet clusters (mean 47.7, SD 21.9) and control clusters (48.3, 22.4). Health secondary endpoints were also similar for patients in both study groups. Total costs over 24 weeks were lower in ParkinsonNet clusters compared with usual-care clusters (difference euro727; 95% CI 56-1399). Implementation of ParkinsonNet networks did not change health outcomes for patients living in ParkinsonNet clusters. However, health-care costs were reduced in ParkinsonNet clusters compared with usual-care clusters. ZonMw; Netherlands Organisation for Scientific Research; Dutch Parkinson's Disease Society; National Parkinson Foundation; Stichting Robuust. Copyright 2010 Elsevier Ltd. All rights reserved.

The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models

EPA Science Inventory

The second phase of the MicroArray Quality Control (MAQC-II) project evaluated common practices for developing and validating microarray-based models aimed at predicting toxicological and clinical endpoints. Thirty-six teams developed classifiers for 13 endpoints - some easy, som...

Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence.

PubMed

Montezuma-Rusca, Jairo M; Powers, John H; Follmann, Dean; Wang, Jing; Sullivan, Brigit; Williamson, Peter R

2016-01-01

Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM. We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias. Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM. Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis.

An Evaluation of Culture Results during Treatment for Tuberculosis as Surrogate Endpoints for Treatment Failure and Relapse

PubMed Central

Phillips, Patrick P. J.; Fielding, Katherine; Nunn, Andrew J.

2013-01-01

It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial. PMID:23667677

An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse.

PubMed

Phillips, Patrick P J; Fielding, Katherine; Nunn, Andrew J

2013-01-01

It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial.

Patients' preferences for selection of endpoints in cardiovascular clinical trials.

PubMed

Chow, Robert D; Wankhedkar, Kashmira P; Mete, Mihriye

2014-01-01

To reduce the duration and overall costs of cardiovascular trials, use of the combined endpoints in trial design has become commonplace. Though this methodology may serve the needs of investigators and trial sponsors, the preferences of patients or potential trial subjects in the trial design process has not been studied. To determine the preferences of patients in the design of cardiovascular trials. Participants were surveyed in a pilot study regarding preferences among various single endpoints commonly used in cardiovascular trials, preference for single vs. composite endpoints, and the likelihood of compliance with a heart medication if patients similar to them participated in the trial design process. One hundred adult English-speaking patients, 38% male, from a primary care ambulatory practice located in an urban setting. Among single endpoints, participants rated heart attack as significantly more important than death from other causes (4.53 vs. 3.69, p=0.004) on a scale of 1-6. Death from heart disease was rated as significantly more important than chest pain (4.73 vs. 2.47, p<0.001), angioplasty/PCI/CABG (4.73 vs. 2.43, p<0.001), and stroke (4.73 vs. 2.43, p<0.001). Participants also expressed a slight preference for combined endpoints over single endpoint (43% vs. 57%), incorporation of the opinions of the study patient population into the design of trials (48% vs. 41% for researchers), and a greater likelihood of medication compliance if patient preferences were considered during trial design (67% indicated a significant to major effect). Patients are able to make judgments and express preferences regarding trial design. They prefer that the opinions of the study population rather than the general population be incorporated into the design of the study. This novel approach to study design would not only incorporate patient preferences into medical decision making, but it also has the potential to improve compliance with cardiovascular medications.

A vision-based end-point control for a two-link flexible manipulator. M.S. Thesis

NASA Technical Reports Server (NTRS)

Obergfell, Klaus

1991-01-01

The measurement and control of the end-effector position of a large two-link flexible manipulator are investigated. The system implementation is described and an initial algorithm for static end-point positioning is discussed. Most existing robots are controlled through independent joint controllers, while the end-effector position is estimated from the joint positions using a kinematic relation. End-point position feedback can be used to compensate for uncertainty and structural deflections. Such feedback is especially important for flexible robots. Computer vision is utilized to obtain end-point position measurements. A look-and-move control structure alleviates the disadvantages of the slow and variable computer vision sampling frequency. This control structure consists of an inner joint-based loop and an outer vision-based loop. A static positioning algorithm was implemented and experimentally verified. This algorithm utilizes the manipulator Jacobian to transform a tip position error to a joint error. The joint error is then used to give a new reference input to the joint controller. The convergence of the algorithm is demonstrated experimentally under payload variation. A Landmark Tracking System (Dickerson, et al 1990) is used for vision-based end-point measurements. This system was modified and tested. A real-time control system was implemented on a PC and interfaced with the vision system and the robot.

Enhancing activities of daily living of chronic stroke patients in primary health care by modified constraint-induced movement therapy (HOMECIMT): study protocol for a cluster randomized controlled trial

PubMed Central

2013-01-01

Background Stroke leads to constant rehabilitation needs even at the chronic stage. However, although many stroke patients receive physical or occupational therapy in primary health care, treatment prescriptions do not generally specify therapeutic goals; in particular, participation is not established as an explicit therapeutic goal in the ambulatory setting. The primary aim of this study is to evaluate the efficacy of a therapy regimen for chronic stroke patients (modified ‘constraint-induced movement therapy (CIMT) at home’) with impaired hand or arm function with regard to the prerequisites of participation in everyday activities: a sufficient arm and hand function. ‘CIMT at home’ will be compared with conventional physical and occupational therapy (‘therapy as usual’). Methods/design The study is a parallel cluster randomized controlled trial with therapy practices as clusters (n = 48). After written consent from the patients (n = 144), the therapists will be randomly assigned to treat either the intervention or the control group. Blinded external assessors will evaluate the patients using standardized outcome measures before and after the intervention, and six months later. The two coprimary endpoint assessments of arm and hand function as prerequisites for participation (defined as equal involvement in activities of daily living) are the motor activity log (quality of arm and hand use) and the Wolf motor function test (arm and hand function). These assessments are made four weeks post-treatment and relativized to baseline performance. Changes in primary outcomes will be analyzed with mixed models, which consider the hierarchical structure of the data and will be adjusted to the baseline measurements and sex. The primary analysis will be the comparison of the two randomized groups, with respect to the adjusted averages for each of the two coprimary endpoints. To keep an overall significance level of 5%, the two endpoints will be tested at the significance level of 5% each in hierarchical order. Discussion A modification of the CIMT, feasible in the patients’ homes (CIMT at home), appears to be a promising therapeutic approach in the ambulatory care of chronic stroke patients. With proven efficacy and practicality, a participation-oriented, stroke-specific treatment would be available in primary care. Trial registration ClinicalTrials.gov NCT01343602 PMID:24124993

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials.

PubMed

Edland, Steven D; Ard, M Colin; Sridhar, Jaiashre; Cobia, Derin; Martersteck, Adam; Mesulam, M Marsel; Rogalski, Emily J

2016-09-01

Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al . [ Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al . [ Pharmaceutical Statistics 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology.

PubMed

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types.

Modeling of delays in PKPD: classical approaches and a tutorial for delay differential equations.

PubMed

Koch, Gilbert; Krzyzanski, Wojciech; Pérez-Ruixo, Juan Jose; Schropp, Johannes

2014-08-01

In pharmacokinetics/pharmacodynamics (PKPD) the measured response is often delayed relative to drug administration, individuals in a population have a certain lifespan until they maturate or the change of biomarkers does not immediately affects the primary endpoint. The classical approach in PKPD is to apply transit compartment models (TCM) based on ordinary differential equations to handle such delays. However, an alternative approach to deal with delays are delay differential equations (DDE). DDEs feature additional flexibility and properties, realize more complex dynamics and can complementary be used together with TCMs. We introduce several delay based PKPD models and investigate mathematical properties of general DDE based models, which serve as subunits in order to build larger PKPD models. Finally, we review current PKPD software with respect to the implementation of DDEs for PKPD analysis.

Identifying unmet clinical need in hypertrophic cardiomyopathy using national electronic health records.

PubMed

Pujades-Rodriguez, Mar; Guttmann, Oliver P; Gonzalez-Izquierdo, Arturo; Duyx, Bram; O'Mahony, Constantinos; Elliott, Perry; Hemingway, Harry

2018-01-01

To evaluate unmet clinical need in unselected hypertrophic cardiomyopathy (HCM) patients to determine the risk of a wide range of subsequent cardiovascular disease endpoints and safety endpoints relevant for trial design. Population based cohort (CALIBER, linked primary care, hospital and mortality records in England, period 1997-2010), all people diagnosed with HCM were identified and matched by age, sex and general practice with ten randomly selected people without HCM. Random-effects Poisson models were used to assess the associations between HCM and cardiovascular diseases and bleeding. Among 3,290,455 eligible people a diagnosis of hypertrophic cardiomyopathy was found in 4 per 10,000. Forty-one percent of the 1,160 individuals with hypertrophic cardiomyopathy were women and the median age was 57 years. The median follow-up was 4.0 years. Compared to general population controls, people with HCM had higher risk of ventricular arrhythmia (incidence rate ratio = 23.53, [95% confidence interval 12.67-43.72]), cardiac arrest or sudden cardiac death (6.33 [3.69-10.85]), heart failure (4.31, [3.30-5.62]), and atrial fibrillation (3.80 [3.04-4.75]). HCM was also associated with a higher incidence of myocardial infarction ([MI] 1.90 [1.27-2.84]) and coronary revascularisation (2.32 [1.46-3.69]).The absolute Kaplan-Meier risks at 3 years were 8.8% for the composite endpoint of cardiovascular death or heart failure, 8.4% for the composite of cardiovascular death, stroke or myocardial infarction, and 1.5% for major bleeding. Our study identified major unmet need in HCM and highlighted the importance of implementing improved cardiovascular prevention strategies to increase life-expectancy of the contemporary HCM population. They also show that national electronic health records provide an effective method for identifying outcomes and clinically relevant estimates of composite efficacy and safety endpoints essential for trial design in rare diseases.

The Rate of Visual Field Change in the Ocular Hypertension Treatment Study

PubMed Central

De Moraes, Carlos Gustavo V.; Gardiner, Stuart K.; Liebmann, Jeffrey M.; Cioffi, George A.; Ritch, Robert; Gordon, Mae O.; Kass, Michael A.

2012-01-01

Purpose. To assess the rate of change of visual field (VF) mean deviation (MD) in the Ocular Hypertension Treatment Study (OHTS). Methods. OHTS data were filtered to exclude eyes that had fewer than 10 reliable VFs or less than 5 years of follow-up or that reached a nonglaucomatous endpoint. The rate of change of MD (MDR) was calculated for each eye. Differences were sought between groups of eyes differing in primary open angle glaucoma (POAG) outcome, how POAG was determined, and original randomization. Results. In total, 2609 eyes (1379 participants) met the selection criteria. The mean MDR was −0.08 ± 0.20 dB/y (±SD). POAG eyes (n = 359) had significantly worse MDRs (−0.26 ± 0.36 dB/y) than non-POAG eyes (n = 2250; −0.05 ± 0.14 dB/y; P < 0.001). Eyes that reached POAG endpoints based on only VF change (n = 74; −0.29 ± 0.31 dB/y) or only optic disc change (n = 158; −0.12 ± 0.19 dB/y) had significantly worse MDRs than non-POAG eyes (both P < 0.001). Eyes that reached POAG endpoints for both VF and optic disc change (n = 127) deteriorated more rapidly (−0.42 ± 0.46 dB/y) than eyes showing only VF change (P = 0.017) or only optic disc change (P < 0.001). There was not a significant association between MDR and original OHTS randomization (observe vs. treat, P = 0.168). Conclusions. Eyes that develop POAG have significantly worse MDRs than eyes that do not. Eyes that reached endpoints due to both VF and optic disc change had worse MDRs than eyes displaying change in only one of these. MDR was not significantly associated with randomization, suggesting that MDR may not be the best measure of VF change in early-stage POAG. (ClinicalTrials.gov number, NCT00000125.) PMID:22159015

Surrogate outcomes are associated with low methodological quality of studies of rheumatoid arthritis treated with antitumour necrosis factor agents: a systematic review.

PubMed

Nobre, Moacyr Roberto Cuce; da Costa, Frnanda Marques

2012-02-01

Surrogate endpoints may be used as substitutes for, but often do not predict clinically relevant events. Objective To assess the methodological quality of articles that present their conclusions based on clinically relevant or surrogate outcomes in a systematic review of randomised trials and cohort studies of patients with rheumatoid arthritis treated with antitumour necrosis factor (TNF) agents. PubMed, Embase and Cochrane databases were searched. The Jadad score, the percentage of Consolidated Standards Of Reporting Trials (CONSORT) statement items adequately reported and levels-of-evidence (Center for Evidence-based Medicine, Oxford) were used in a descriptive synthesis. Among 88 articles appraised, 27 had surrogate endpoints, mainly radiographic, and 44 were duplicate publications; 74% of articles with surrogate and 39% of articles with clinical endpoints (p=0.006). Fewer articles with surrogate endpoints represented a high level of evidence (Level 1b, 33% vs 62%, p=0.037) and the mean percentage of CONSORT statement items met was also lower for articles with surrogate endpoints (62.5 vs 70.7, p=0.026). Although fewer articles with surrogate endpoints were randomised trials (63% vs 74%, p=0.307) and articles with surrogate endpoints had lower Jadad scores (3.0 vs 3.2, p=0.538), these differences were not statistically significant. Studies of anti-TNF agents that report surrogate outcomes are of lesser methodological quality. As such, inclusion of such studies in evidence syntheses may bias results.

[The endpoint detection of cough signal in continuous speech].

PubMed

Yang, Guoqing; Mo, Hongqiang; Li, Wen; Lian, Lianfang; Zheng, Zeguang

2010-06-01

The endpoint detection of cough signal in continuous speech has been researched in order to improve the efficiency and veracity of manual recognition or computer-based automatic recognition. First, using the short time zero crossing ratio(ZCR) for identifying the suspicious coughs and getting the threshold of short time energy based on acoustic characteristics of cough. Then, the short time energy is combined with short time ZCR in order to implement the endpoint detection of cough in continuous speech. To evaluate the effect of the method, first, the virtual number of coughs in each recording was identified by two experienced doctors using the graphical user interface (GUI). Second, the recordings were analyzed by automatic endpoint detection program under Matlab7.0. Finally, the comparison between these two results showed: The error rate of undetected cough is 2.18%, and 98.13% of noise, silence and speech were removed. The way of setting short time energy threshold is robust. The endpoint detection program can remove most speech and noise, thus maintaining a lower rate of error.

An Update on ToxCast™

EPA Science Inventory

In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcripto...

Motor adaptation to Coriolis force perturbations of reaching movements: endpoint but not trajectory adaptation transfers to the nonexposed arm

NASA Technical Reports Server (NTRS)

Dizio, P.; Lackner, J. R.

1995-01-01

1. Reaching movements made in a rotating room generate Coriolis forces that are directly proportional to the cross product of the room's angular velocity and the arm's linear velocity. Such Coriolis forces are inertial forces not involving mechanical contact with the arm. 2. We measured the trajectories of arm movements made in darkness to a visual target that was extinguished at the onset of each reach. Prerotation subjects pointed with both the right and left arms in alternating sets of eight movements. During rotation at 10 rpm, the subjects reached only with the right arm. Postrotation, the subjects pointed with the left and right arms, starting with the left, in alternating sets of eight movements. 3. The initial perrotary reaching movements of the right arm were highly deviated both in movement path and endpoint relative to the prerotation reaches of the right arm. With additional movements, subjects rapidly regained straight movement paths and accurate endpoints despite the absence of visual or tactile feedback about reaching accuracy. The initial postrotation reaches of the left arm followed straight paths to the wrong endpoint. The initial postrotation reaches of the right arm had paths with mirror image curvature to the initial perrotation reaches of the right arm but went to the correct endpoint. 4. These observations are inconsistent with current equilibrium point models of movement control. Such theories predict accurate reaches under our experimental conditions. Our observations further show independent implementation of movement and posture, as evidenced by transfer of endpoint adaptation to the nonexposed arm without transfer of path adaptation. Endpoint control may occur at a relatively central stage that represents general constraints such as gravitoinertial force background or egocentric direction relative to both arms, and control of path may occur at a more peripheral stage that represents moments of inertia and muscle dynamics unique to each limb. 5. Endpoint and path adaptation occur despite the absence both of mechanical contact cues about the perturbing force and visual or tactile cues about movement accuracy. These findings point to the importance of muscle spindle signals, monitoring of motor commands, and possibly joint and tendon receptors in a detailed trajectory monitoring process. Muscle spindle primary and secondary afferent signals may differentially influence adaptation of movement shape and endpoint, respectively.

Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease.

PubMed

Stone, Gregg W; Sabik, Joseph F; Serruys, Patrick W; Simonton, Charles A; Généreux, Philippe; Puskas, John; Kandzari, David E; Morice, Marie-Claude; Lembo, Nicholas; Brown, W Morris; Taggart, David P; Banning, Adrian; Merkely, Béla; Horkay, Ferenc; Boonstra, Piet W; van Boven, Ad J; Ungi, Imre; Bogáts, Gabor; Mansour, Samer; Noiseux, Nicolas; Sabaté, Manel; Pomar, José; Hickey, Mark; Gershlick, Anthony; Buszman, Pawel; Bochenek, Andrzej; Schampaert, Erick; Pagé, Pierre; Dressler, Ovidiu; Kosmidou, Ioanna; Mehran, Roxana; Pocock, Stuart J; Kappetein, A Pieter

2016-12-08

Patients with obstructive left main coronary artery disease are usually treated with coronary-artery bypass grafting (CABG). Randomized trials have suggested that drug-eluting stents may be an acceptable alternative to CABG in selected patients with left main coronary disease. We randomly assigned 1905 eligible patients with left main coronary artery disease of low or intermediate anatomical complexity to undergo either percutaneous coronary intervention (PCI) with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). Anatomic complexity was assessed at the sites and defined by a Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score of 32 or lower (the SYNTAX score reflects a comprehensive angiographic assessment of the coronary vasculature, with 0 as the lowest score and higher scores [no upper limit] indicating more complex coronary anatomy). The primary end point was the rate of a composite of death from any cause, stroke, or myocardial infarction at 3 years, and the trial was powered for noninferiority testing of the primary end point (noninferiority margin, 4.2 percentage points). Major secondary end points included the rate of a composite of death from any cause, stroke, or myocardial infarction at 30 days and the rate of a composite of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years. Event rates were based on Kaplan-Meier estimates in time-to-first-event analyses. At 3 years, a primary end-point event had occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P=0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval, 0.79 to 1.26; P=0.98 for superiority). The secondary end-point event of death, stroke, or myocardial infarction at 30 days occurred in 4.9% of the patients in the PCI group and in 7.9% in the CABG group (P<0.001 for noninferiority, P=0.008 for superiority). The secondary end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years occurred in 23.1% of the patients in the PCI group and in 19.1% in the CABG group (P=0.01 for noninferiority, P=0.10 for superiority). In patients with left main coronary artery disease and low or intermediate SYNTAX scores by site assessment, PCI with everolimus-eluting stents was noninferior to CABG with respect to the rate of the composite end point of death, stroke, or myocardial infarction at 3 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776 .).

A quantitative analysis of statistical power identifies obesity endpoints for improved in vivo preclinical study design

PubMed Central

Selimkhanov, Jangir; Thompson, W. Clayton; Guo, Juen; Hall, Kevin D.; Musante, Cynthia J.

2017-01-01

The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of key metabolic endpoints. To demonstrate how conclusions can change as a function of study size, we show that a simulated pre-clinical study properly powered for one endpoint may lead to false conclusions based on secondary endpoints. We then propose guidelines for endpoint selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design. PMID:28392555

Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study.

PubMed

Warnecke, Gregor; Van Raemdonck, Dirk; Smith, Michael A; Massard, Gilbert; Kukreja, Jasleen; Rea, Federico; Loor, Gabriel; De Robertis, Fabio; Nagendran, Jayan; Dhital, Kumud K; Moradiellos Díez, Francisco Javier; Knosalla, Christoph; Bermudez, Christian A; Tsui, Steven; McCurry, Kenneth; Wang, I-Wen; Deuse, Tobias; Lesèche, Guy; Thomas, Pascal; Tudorache, Igor; Kühn, Christian; Avsar, Murat; Wiegmann, Bettina; Sommer, Wiebke; Neyrinck, Arne; Schiavon, Marco; Calebrese, Fiorella; Santelmo, Nichola; Olland, Anne; Falcoz, Pierre-Emanuel; Simon, Andre R; Varela, Andres; Madsen, Joren C; Hertz, Marshall; Haverich, Axel; Ardehali, Abbas

2018-05-01

Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage. In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434. Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116 (70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority point estimate -9·1%; 95% CI -∞ to -1·0; p=0·0038; and superiority test p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141 patients (95% CI 91·0-98·4) in the OCS group and 165 patients (100%; 97·8-100·0) in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients (83·1-93·9) for the OCS group compared with 146 (88·1%) of 165 patients (81·8-92·8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%) of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015). The primary safety endpoint was met (0·23 lung graft-related serious adverse events in the OCS group compared with 0·28 events in the control group [point estimate -0·045%; 95% CI -∞ to 0·047; non-inferiority test p=0·020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1). The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation. TransMedics Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Statistical evaluation of the Local Lymph Node Assay.

PubMed

Hothorn, Ludwig A; Vohr, Hans-Werner

2010-04-01

In the Local Lymph Node Assay measured endpoints for each animal, such as cell proliferation, cell counts and/or lymph node weight should be evaluated separately. The primary criterion for a positive response is when the estimated stimulation index is larger than a specified relative threshold that is endpoint- and strain-specific. When the lower confidence limit for ratio-to-control comparisons is larger than a relevance threshold, a biologically relevant increase can be concluded according to the proof of hazard. Alternatively, when the upper confidence limit for ratio-to-control comparisons is smaller than a tolerable margin, harmlessness can be concluded according to a proof of safety. Copyright 2009 Elsevier Inc. All rights reserved.

Determinants for successful marketing authorisation of orphan medicinal products in the EU.

PubMed

Putzeist, Michelle; Heemstra, Harald E; Garcia, Jordi Llinares; Mantel-Teeuwisse, Aukje K; Gispen-De Wied, Christine C; Hoes, Arno W; Leufkens, Hubert G M

2012-04-01

In 2010, the European Regulation for Orphan Medicinal Products (OMPs) was in force for ten years. In this study we assessed possible determinants of applications for OMPs in the EU since 2000 that are associated with a successful marketing authorisation. Our analysis shows that clinical trial characteristics such as demonstrating convincing evidence of a beneficial effect on the primary endpoint, the selection of a clinically relevant endpoint, providing RCT data as pivotal study evidence and the submission of sound dose finding data are critical success factors. In addition, high medical need seems to counterweigh uncertainties about the scientific evidence in the benefit-risk assessment of OMPs. Copyright © 2011 Elsevier Ltd. All rights reserved.

The current role and limitations of surrogate endpoints in advanced prostate cancer.

PubMed

Gomella, Leonard G; Oliver Sartor, A

2014-01-01

The identification of appropriate surrogate endpoints for evaluating cancer therapeutics has been of ongoing interest across various tumor types. Metastatic castrate-resistant prostate cancer (mCRPC) has been a particularly challenging area. As more targeted and novel therapies are being developed in this disease space, an urgent need exists to identify surrogate endpoints in mCRPC. The ability to discern patient benefit in the absence of patient death or other complications would facilitate both drug development and more appropriate patient care. We reviewed the available literature and guidelines used in the development and approval of recent agents for mCRPC. The majority of regulatory approvals of new medications have relied on overall survival (OS) or prevention of complications such as skeletal related events (SRE's). Progression-free survival measures, such as bone scans, computed tomography scans, and prostate-specific antigen related changes, have not been validated nor uniformly accepted as outcome surrogates. All of the successful recent pivotal Phase III trials designed to achieve regulatory approval in mCRPC have used either OS or SRE's as the primary endpoint. There are significant problematic issues that exist associated with defining and implementing surrogate markers in mCRPC beyond survival and complications. Suggestions are made as to how the current situation might be improved. Copyright © 2014 Elsevier Inc. All rights reserved.

Remote preconditioning and major clinical complications following adult cardiovascular surgery: systematic review and meta-analysis.

PubMed

Healy, D A; Khan, W A; Wong, C S; Moloney, M Clarke; Grace, P A; Coffey, J C; Dunne, C; Walsh, S R; Sadat, U; Gaunt, M E; Chen, S; Tehrani, S; Hausenloy, D J; Yellon, D M; Kramer, R S; Zimmerman, R F; Lomivorotov, V V; Shmyrev, V A; Ponomarev, D N; Rahman, I A; Mascaro, J G; Bonser, R S; Jeon, Y; Hong, D M; Wagner, R; Thielmann, M; Heusch, G; Zacharowski, K; Meybohm, P; Bein, B; Tang, T Y

2014-09-01

A number of 'proof-of-concept' trials suggest that remote ischaemic preconditioning (RIPC) reduces surrogate markers of end-organ injury in patients undergoing major cardiovascular surgery. To date, few studies have involved hard clinical outcomes as primary end-points. Randomised clinical trials of RIPC in major adult cardiovascular surgery were identified by a systematic review of electronic abstract databases, conference proceedings and article reference lists. Clinical end-points were extracted from trial reports. In addition, trial principal investigators provided unpublished clinical outcome data. In total, 23 trials of RIPC in 2200 patients undergoing major adult cardiovascular surgery were identified. RIPC did not have a significant effect on clinical end-points (death, peri-operative myocardial infarction (MI), renal failure, stroke, mesenteric ischaemia, hospital or critical care length of stay). Pooled data from pilot trials cannot confirm that RIPC has any significant effect on clinically relevant end-points. Heterogeneity in study inclusion and exclusion criteria and in the type of preconditioning stimulus limits the potential for extrapolation at present. An effort must be made to clarify the optimal preconditioning stimulus. Following this, large-scale trials in a range of patient populations are required to ascertain the role of this simple, cost-effective intervention in routine practice. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Generating Modeling Data From Repeat-Dose Toxicity Reports

PubMed Central

López-Massaguer, Oriol; Pinto-Gil, Kevin; Sanz, Ferran; Amberg, Alexander; Anger, Lennart T; Stolte, Manuela; Ravagli, Carlo

2018-01-01

Abstract Over the past decades, pharmaceutical companies have conducted a large number of high-quality in vivo repeat-dose toxicity (RDT) studies for regulatory purposes. As part of the eTOX project, a high number of these studies have been compiled and integrated into a database. This valuable resource can be queried directly, but it can be further exploited to build predictive models. As the studies were originally conducted to investigate the properties of individual compounds, the experimental conditions across the studies are highly heterogeneous. Consequently, the original data required normalization/standardization, filtering, categorization and integration to make possible any data analysis (such as building predictive models). Additionally, the primary objectives of the RDT studies were to identify toxicological findings, most of which do not directly translate to in vivo endpoints. This article describes a method to extract datasets containing comparable toxicological properties for a series of compounds amenable for building predictive models. The proposed strategy starts with the normalization of the terms used within the original reports. Then, comparable datasets are extracted from the database by applying filters based on the experimental conditions. Finally, carefully selected profiles of toxicological findings are mapped to endpoints of interest, generating QSAR-like tables. In this work, we describe in detail the strategy and tools used for carrying out these transformations and illustrate its application in a data sample extracted from the eTOX database. The suitability of the resulting tables for developing hazard-predicting models was investigated by building proof-of-concept models for in vivo liver endpoints. PMID:29155963

Efficacy and Safety of Once-Daily Minoxidil Foam 5% Versus Twice-Daily Minoxidil Solution 2% in Female Pattern Hair Loss: A Phase III, Randomized, Investigator-Blinded Study.

PubMed

Blume-Peytavi, Ulrike; Shapiro, Jerry; Messenger, Andrew G; Hordinsky, Maria K; Zhang, Paul; Quiza, Carlos; Doshi, Uday; Olsen, Elise A

2016-07-01

A once-daily minoxidil topical foam (MTF) has been developed to treat female pattern hair loss.
Determine noninferiority of once-daily 5% MTF versus twice-daily 2% minoxidil topical solution (MTS) based on the change from baseline in target area hair count (TAHC) at 24 weeks. In a randomized, phase III trial, women with female pattern hair loss received once-daily 5% MTF (n=161) or twice-daily 2% MTS (n=161) for 52 weeks. Primary endpoint was change from baseline in TAHC at 24 weeks. Secondary endpoint was change from baseline in TAHC at 12 weeks. Exploratory endpoints included change in total unit area density and change in overall scalp coverage.
Once-daily 5% MTF increased TAHC from baseline (adjusted mean ± standard error) by 23.9 ± 2.1 hairs/cm² at week 24. Twice-daily 2% MTS increased TAHC 24.2 ± 2.1 hairs/cm² at week 24. The treatment difference was -0.3 hairs/cm² (95% CI = -6.0, 5.4). Since the lower bound of the 95% CI was less than -5.0, the prespecified noninferiority goal was not met. Both treatments were well tolerated.
Once-daily 5% MTF and twice-daily 2% MTS induced hair regrowth in female pattern hair loss, but prespecified noninferiority criteria were not met.
ClinicalTrials.gov identifier: NCT01145625

J Drugs Dermatol. 2016;15(7):883-889.

The Heart Failure Adherence and Retention Trial (HART): Design and Rationale

PubMed Central

Powell, Lynda H.; Calvin, James E.; Mendes de Leon, Carlos F.; Richardson, Dejuran; Grady, Kathleen L.; Flynn, Kristin J.; Rucker-Whitaker, Cheryl S.; Janssen, Imke; Kravitz, Glenda; Eaton, Claudia

2008-01-01

Background Heart failure (HF) is increasing in prevalence and associated with prolonged morbidity, repeat hospitalizations, and high costs. Drug therapies and lifestyle changes can reduce hospitalizations, but non-adherence is high, ranging from 30–80%. There is an urgent need to identify cost-effective ways to improve adherence and reduce hospitalizations. Trial Design HART evaluated the benefit of patient self-management (SM) skills training in combination with HF education, over HF education alone, on the composite endpoints of death/HF hospitalizations and death/all-cause hospitalizations in patients with mild to moderate systolic or diastolic dysfunction. Secondary endpoints included progression of HF, quality of life, adherence to drug and lifestyle regimens, and psychosocial function. The HART cohort was comprised of 902 patients including 47% women, 40% minorities, and 23% with diastolic dysfunction. After a baseline exam, patients were randomized to SM or education control, received 18 treatment contacts over one year, annual follow-ups, and 3-month phone calls to assess primary endpoints. SM treatment was conducted in small groups and aimed to activate the patient to implement HF education through training in problem-solving and 5 SM skills. The education control received HF education in the mail followed by a phone call to check comprehension. Conclusions The significance of HART lies in its ability to determine the clinical value of activating the patient to collaborate in his/her care. Support for the trial hypotheses would encourage interdisciplinary HF treatment, drawing on an evidence base not only from medicine but also from the behavioral sciences. PMID:18760125

Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 μg plus drospirenone 3mg administered in a 24/4 regimen: a pooled analysis.

PubMed

Koltun, William; Maloney, J Michael; Marr, Joachim; Kunz, Michael

2011-04-01

To investigate the effects of an ethinylestradiol (EE) 20 μg/drospirenone (drsp) 3mg combined oral contraceptive (COC) administered in a 24/4 regimen (24 active tablets/4 inert tablets per cycle) for the treatment of moderate acne vulgaris, based on a pooled analysis of two identically designed US studies. Healthy females (n=893) aged 14-45 years with moderate facial acne were randomised to EE 20 μg/drsp 3mg COC (n=451) or placebo (n=442) for six cycles. Primary outcome measures were mean percent change in acne lesion counts and the investigators' assessment of acne from baseline to endpoint. There were significantly greater reductions in the mean percent change from baseline to endpoint in inflammatory, non-inflammatory and total lesion counts in the EE 20 μg/drsp 3mg 24/4 COC group compared with the placebo group (P<0.0001). The odds of women in the EE 20 μg/drsp 3mg 24/4 COC group having 'clear' or 'almost clear' skin as rated by the investigators at endpoint were around three-fold greater than in the placebo group (odds ratio 3.41; 95% CI: 2.15-5.43; P<0.0001). A low-dose COC containing EE 20 μg/drsp 3mg (24/4) more effectively reduced acne lesions than placebo and demonstrated greater improvement in the investigator global assessment of acne. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PLATFORM SESSION "IMMUNOTOXICOLOGY", SOCIETY OF TOXICOLOGY 45TH ANNUAL MEETING, MARCH 5-9, 2006, SAN DIEGO, CA

EPA Science Inventory

For many years the primary endpoints for evaluating the toxicity of xenobiotics were carcinogenicity and mutagenicity. However, it gradually became apparent that exposure to chemicals at levels lower than those shown to be directly carcinogenic may negatively impact other facets...

FACTORS AFFECTING REPRODUCTION AND THE IMPORTANCE OF ADULT SIZE ON REPRODUCTIVE OUTPUT OF THE MIDGE, CHIRONOMUS TENTANS

EPA Science Inventory

Incorporating reproductive endpoints into sediment toxicity tests has become an important consideration in ecological risk assessments. The capacity to assess reproduction was one of the primary objectives underlying the recent development of a life-cycle test with the midge, Ch...

EUTROPHICATION MODELING CAPABILITIES FOR WATER QUALITY AND INTEGRATION TOWARDS ECOLOGICAL ENDPOINTS

EPA Science Inventory

A primary environmental focus for the use of mathematical models is for characterization of sources of nutrients and sediments and their relative loadings from large river basins, and the impact of land uses from smaller sub-basins on water quality in rivers, lakes, and estuaries...

Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA’s ToxRefDB

EPA Science Inventory

As the primary source for regulatory developmental toxicity information, prenatal studies characterize maternal effects and fetal endpoints including malformations, resorptions, and fetal weight reduction. Results from 383 rat and 368 rabbit prenatal studies on 387 chemicals, mo...

[Efficacy of a ketogenic diet in urological cancers patients : A systematic review].

PubMed

Maisch, P; Gschwend, J E; Retz, M

2018-03-01

Beside the classical anticancer treatment tumor patients try to find proactive alternative therapies to fight their disease. Lifestyle changes such as introducing a ketogenic diet is one of the most popular among them. The German Association of Urological Oncology (AUO, Arbeitsgemeinschaft Urologische Onkologie) presents a systematic review investigating the evidence of ketogenic diet in cancer patients. A systematic literature research was conducted in the databases Medline, Livivo, and the Cochrane Library. Only clinical studies of tumor patients receiving chemotherapy while on a ketogenic diet were included. The assessment of the results was performed according to the predefined primary endpoints overall survival and progression-free survival and secondary endpoints quality of life and reduction of adverse effects induced by cytostatics. Nine studies met the inclusion criteria: eight prospective and one retrospective study case series respectively cohort-studies, with a total of 107 patients. Currently there is no evidence of a therapeutic effect of a ketogenic diet in patients with malignant tumors regarding the clinical outcome or quality of life. Based on the current data, a ketogenic diet can not be recommended to cancer patients because prospective, randomized trials are missing.

Efficiency of bowel preparation for capsule endoscopy examination: a meta-analysis.

PubMed

Niv, Yaron

2008-03-07

Good preparation before endoscopic procedures is essential for successful visualization. The small bowel is difficult to evaluate because of its length and complex configuration. A meta-analysis was conducted of studies comparing small bowel visualization by capsule endoscopy with and without preparation. Medical data bases were searched for all studies investigating the preparation for capsule endoscopy of the small bowel up to July 31, 2007. Studies that scored bowel cleanness and measured gastric and small bowel transit time and rate of cecum visualization were included. The primary endpoint was the quality of bowel visualization. The secondary endpoints were transit times and proportion of examinations that demonstrated the cecum, with and without preparation. Meta-analysis was performed with StatDirect Statistical software, version 2.6.1 (http://statsdirect.com). Eight studies met the inclusion criteria. Bowel visualization was scored as "good" in 78% of the examinations performed with preparation and 49% performed without (P<0.0001). There were no significant differences in transit times or in the proportion of examinations that demonstrated the cecum with and without preparation. Capsule endoscopy preparation improves the quality of small bowel visualization, but has no effect on transit times, or demonstration of the cecum.

Efficiency of bowel preparation for capsule endoscopy examination: A meta-analysis

PubMed Central

Niv, Yaron

2008-01-01

Good preparation before endoscopic procedures is essential for successful visualization. The small bowel is difficult to evaluate because of its length and complex configuration. A meta-analysis was conducted of studies comparing small bowel visualization by capsule endoscopy with and without preparation. Medical data bases were searched for all studies investigating the preparation for capsule endoscopy of the small bowel up to July 31, 2007. Studies that scored bowel cleanness and measured gastric and small bowel transit time and rate of cecum visualization were included. The primary endpoint was the quality of bowel visualization. The secondary endpoints were transit times and proportion of examinations that demonstrated the cecum, with and without preparation. Meta-analysis was performed with StatDirect Statistical software, version 2.6.1 (http://statsdirect.com). Eight studies met the inclusion criteria. Bowel visualization was scored as “good” in 78% of the examinations performed with preparation and 49% performed without (P < 0.0001). There were no significant differences in transit times or in the proportion of examinations that demonstrated the cecum with and without preparation. Capsule endoscopy preparation improves the quality of small bowel visualization, but has no effect on transit times, or demonstration of the cecum. PMID:18322940

Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials).

PubMed

Crawford, Jeffrey; Prado, Carla M M; Johnston, Mary Ann; Gralla, Richard J; Taylor, Ryan P; Hancock, Michael L; Dalton, James T

2016-06-01

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm's effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484 , NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1 .

Impact of Medication Adherence on Mortality and Cardiovascular Morbidity: Protocol for a Population-Based Cohort Study.

PubMed

Giner-Soriano, Maria; Sotorra Figuerola, Gerard; Cortés, Jordi; Pera Pujadas, Helena; Garcia-Sangenis, Ana; Morros, Rosa

2018-03-09

Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, such as coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. CVD is the leading threat to global health, whether measured by mortality, morbidity, or economic cost. Long-term administration of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers improves survival in patients with stablished coronary heart disease. Nevertheless, adherence to prescribed medication is poor for long-term drug treatment. We aim to assess the relationship between adherences to the four pharmacological groups recommended for secondary prevention and the clinical outcomes of cardiovascular morbidity and mortality in patients with established CHD according to the level of adherence to these drugs in a population of incident cases of acute coronary syndrome (ACS). Population-based cohort study of patients with a first episode of ACS during 2006-2015 in the Information System for Research in Primary Care (SIDIAP) database. We will estimate adherence to these drugs. The primary endpoint is a composite of all-cause mortality, ACS, and ischaemic stroke. Bivariate analyses will be performed estimating odds ratios for categorical variables and mean differences for continuous variables. Hazard ratios for adherences will be calculated for outcome events using Cox proportional hazard regression models, and proportionality of hazards assumption will be tested. We expect to estimate adherence to all four study treatments, the incidence of MACE, and to analyze if this incidence is associated with the level of drug adherence. We expect to find that adherent patients have a lower risk of the primary endpoints compared with nonadherent patients. This study protocol was classified as EPA-OD by the AEMPS (IJG-EST-2017-01-2017-01, 07/04/2017) and registered in the EU PAS register (EUPAS19017, 09/05/2017). ©Maria Giner-Soriano, Gerard Sotorra Figuerola, Jordi Cortés, Helena Pera Pujadas, Ana Garcia-Sangenis, Rosa Morros. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 09.03.2018.

The Biomarker-Surrogacy Evaluation Schema: a review of the biomarker-surrogate literature and a proposal for a criterion-based, quantitative, multidimensional hierarchical levels of evidence schema for evaluating the status of biomarkers as surrogate endpoints.

PubMed

Lassere, Marissa N

2008-06-01

There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Section 2 is a systematic, historical review of the biomarker-surrogate endpoint literature with special reference to the nomenclature, the systems of classification and statistical methods developed for their evaluation. In Section 3 an explicit, criterion-based, quantitative, multidimensional hierarchical levels of evidence schema - Biomarker-Surrogacy Evaluation Schema - is proposed to evaluate and co-ordinate the multiple dimensions (biological, epidemiological, statistical, clinical trial and risk-benefit evidence) of the biomarker clinical endpoint relationships. The schema systematically evaluates and ranks the surrogacy status of biomarkers and surrogate endpoints using defined levels of evidence. The schema incorporates the three independent domains: Study Design, Target Outcome and Statistical Evaluation. Each domain has items ranked from zero to five. An additional category called Penalties incorporates additional considerations of biological plausibility, risk-benefit and generalizability. The total score (0-15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. The term ;surrogate' is restricted to markers attaining Levels 1 or 2 only. Surrogacy status of markers can then be directly compared within and across different areas of medicine to guide individual, trial-based or drug-development decisions. This schema would facilitate communication between clinical, researcher, regulatory, industry and consumer participants necessary for evaluation of the biomarker-surrogate-clinical endpoint relationship in their different settings.

The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study.

PubMed

Tarlatzis, B; Tavmergen, E; Szamatowicz, M; Barash, A; Amit, A; Levitas, E; Shoham, Z

2006-01-01

The effect of recombinant human LH (r-hLH; lutropin alfa) in women undergoing controlled ovarian stimulation with recombinant human FSH (r-hFSH) prior to IVF was investigated. After down-regulation with the GnRH agonist, buserelin, 114 normo-ovulatory women (aged 18-37 years) received r-hFSH alone until the lead follicle reached a diameter of 14 mm. Patients were then randomized in a double-blind fashion to receive r-hFSH in addition to r-hLH, 75 IU s.c., or placebo daily for a maximum of 10 days prior to oocyte retrieval and IVF. The primary end-point was the number of metaphase II oocytes. There were no significant differences between treatment groups for the primary end-point. Serum estradiol concentrations on the day of HCG administration were significantly higher in the group receiving r-hLH plus r-hFSH than in the group receiving r-hFSH alone (P = 0.0001), but there were no significant differences between the groups in dose and duration of r-hFSH treatment required, oocyte maturation, fertilization rate, pregnancy rate and live birth rate. In this patient population, the addition of r-hLH during the late follicular phase of a long GnRH agonist and r-hFSH stimulation cycle provides no further benefit in terms of oocyte maturation or other end-points.

The Risk of Oxygen during Cardiac Surgery (ROCS) trial: study protocol for a randomized clinical trial.

PubMed

Lopez, Marcos G; Pretorius, Mias; Shotwell, Matthew S; Deegan, Robert; Eagle, Susan S; Bennett, Jeremy M; Sileshi, Bantayehu; Liang, Yafen; Gelfand, Brian J; Kingeter, Adam J; Siegrist, Kara K; Lombard, Frederick W; Richburg, Tiffany M; Fornero, Dane A; Shaw, Andrew D; Hernandez, Antonio; Billings, Frederic T

2017-06-26

Anesthesiologists administer excess supplemental oxygen (hyper-oxygenation) to patients during surgery to avoid hypoxia. Hyper-oxygenation, however, may increase the generation of reactive oxygen species and cause oxidative damage. In cardiac surgery, increased oxidative damage has been associated with postoperative kidney and brain injury. We hypothesize that maintenance of normoxia during cardiac surgery (physiologic oxygenation) decreases kidney injury and oxidative damage compared to hyper-oxygenation. The Risk of Oxygen during Cardiac Surgery (ROCS) trial will randomly assign 200 cardiac surgery patients to receive physiologic oxygenation, defined as the lowest fraction of inspired oxygen (FIO 2 ) necessary to maintain an arterial hemoglobin saturation of 95 to 97%, or hyper-oxygenation (FIO 2  = 1.0) during surgery. The primary clinical endpoint is serum creatinine change from baseline to postoperative day 2, and the primary mechanism endpoint is change in plasma concentrations of F 2 -isoprostanes and isofurans. Secondary endpoints include superoxide production, clinical delirium, myocardial injury, and length of stay. An endothelial function substudy will examine the effects of oxygen treatment and oxidative stress on endothelial function, measured using flow mediated dilation, peripheral arterial tonometry, and wire tension myography of epicardial fat arterioles. The ROCS trial will test the hypothesis that intraoperative physiologic oxygenation decreases oxidative damage and organ injury compared to hyper-oxygenation in patients undergoing cardiac surgery. ClinicalTrials.gov, ID: NCT02361944 . Registered on the 30th of January 2015.

Multicenter Randomized Controlled Trial on Duration of Therapy for Thrombosis in Children and Young Adults (Kids-DOTT): Pilot/Feasibility Phase Findings

PubMed Central

Goldenberg, N.A.; Abshire, T.; Blatchford, P.J.; Fenton, L.Z.; Halperin, J.L.; Hiatt, W.R.; Kessler, C.M.; Kittelson, J.M.; Manco-Johnson, M.J.; Spyropoulos, A.C.; Steg, P.G.; Stence, N.V.; Turpie, A.G.G.; Schulman, S.

2015-01-01

BACKGROUND Randomized controlled trials (RCTs) in pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS Kids-DOTT is a multicenter RCT investigating non-inferiority of a 6-week (shortened) vs. 3-month (conventional) duration of anticoagulation in patients <21 years old with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically-relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded endpoint, parallel-cohort RCT design. RESULTS No eligibility violations or randomization errors occurred. Of enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in pre-specified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Inter-observer agreement between local vs. blinded central determination of venous occlusion by imaging at 6 weeks post-diagnosis was strong (κ-statistic=0.75; 95% confidence interval [CI] 0.48–1.0). Primary efficacy and safety event rates were 3.3% (95% CI 0.3–11.5%) and 1.4% (0.03–7.4%). CONCLUSIONS The P/F phase of Kids-DOTT has demonstrated validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention, and endpoint rates to inform the fully-powered RCT. PMID:26118944

Headache patients' satisfaction with telemedicine: a 12-month follow-up randomized non-inferiority trial.

PubMed

Müller, K I; Alstadhaug, K B; Bekkelund, S I

2017-06-01

We investigated non-acute headache patients' long-term satisfaction with a telemedicine consultation and consultation preferences in northern Norway. We hypothesized that patients were not less satisfied with telemedicine than traditional consultations. We also examined the influence of gender, age and education on satisfaction. For 2.5 years, patients were consecutively screened, recruited and randomly assigned to telemedicine or traditional visits with a consultation at a neurological outpatient department. The primary endpoint was frequency of satisfied patients at 3 and 12 months. Secondary endpoints were satisfaction with consultation, communication, information, diagnosis, advice and prescriptions, and preferred visit form at 12 months. Of 402 participants, 279 (69.4%) answered questionnaires at both 3 and 12 month, and 291 (72.4%) responded at 12 months. The long-term satisfaction of telemedicine patients was 124/145 (85.5%) compared with 118/134 (88.1%) in the traditional group (P = 0.653). The groups did not differ with respect to secondary endpoints, but females were more satisfied with telemedicine communication (P = 0.027). In the telemedicine group, 99/147 (67.3%) were indifferent to the type of consultation. Age and education did not alter the primary results. At 1 year after a specialist evaluation for headache, telemedicine patients did not express less satisfaction than those with traditional consultation. Telemedicine specialist consultations may be a good alternative for headache patients in secondary care. © 2017 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

A randomized trial of peer coach and office staff support to reduce coronary heart disease risk in African-Americans with uncontrolled hypertension.

PubMed

Turner, Barbara J; Hollenbeak, Christopher S; Liang, Yuanyuan; Pandit, Kavita; Joseph, Shelly; Weiner, Mark G

2012-10-01

Adopting features of the Chronic Care Model may reduce coronary heart disease risk and blood pressure in vulnerable populations. We evaluated a peer and practice team intervention on reduction in 4-year coronary heart disease risk and systolic blood pressure. A single blind, randomized, controlled trial in two adjacent urban university-affiliated primary care practices. Two hundred eighty African-American subjects aged 40 to 75 with uncontrolled hypertension. Three monthly calls from trained peer patients with well-controlled hypertension and, on alternate months, two practice staff visits to review a personalized 4-year heart disease risk calculator and slide shows about heart disease risks. All subjects received usual physician care and brochures about healthy cooking and heart disease. Change in 4-year coronary heart disease risk (primary) and change in systolic blood pressure, both assessed at 6 months. At baseline, the 136 intervention and 144 control subjects' mean 4-year coronary heart disease risk did not differ (intervention=5.8 % and control=6.4 %, P=0.39), and their mean systolic blood pressure was the same (140.5 mmHg, p=0.83). Endpoint data for coronary heart disease were obtained for 69 % of intervention and 82 % of control subjects. After multiple imputation for missing endpoint data, the reduction in risk among all 280 subjects favored the intervention, but was not statistically significant (difference -0.73 %, 95 % confidence interval: -1.54 % to 0.09 %, p=0.08). Among the 247 subjects with a systolic blood pressure endpoint (85 % of intervention and 91 % of control subjects), more intervention than control subjects achieved a >5 mmHg reduction (61 % versus 45 %, respectively, p=0.01). After multiple imputation, the absolute reduction in systolic blood pressure was also greater for the intervention group (difference -6.47 mmHg, 95 % confidence interval: -10.69 to -2.25, P=0.003). One patient died in each study arm. Peer patient and office-based behavioral support for African-American patients with uncontrolled hypertension did not result in a significantly greater reduction in coronary heart disease risk but did significantly reduce systolic blood pressure.

Long-Term Results of a Randomized Trial in Locally Advanced Rectal Cancer: No Benefit From Adding a Brachytherapy Boost

DOE Office of Scientific and Technical Information (OSTI.GOV)

Appelt, Ane L., E-mail: ane.lindegaard.appelt@rsyd.dk; Faculty of Health Sciences, University of Southern Denmark, Odense; Vogelius, Ivan R.

Purpose/Objective(s): Mature data on tumor control and survival are presented from a randomized trial of the addition of a brachytherapy boost to long-course neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer. Methods and Materials: Between March 2005 and November 2008, 248 patients with T3-4N0-2M0 rectal cancer were prospectively randomized to either long-course preoperative CRT (50.4 Gy in 28 fractions, per oral tegafur-uracil and L-leucovorin) alone or the same CRT schedule plus a brachytherapy boost (10 Gy in 2 fractions). The primary trial endpoint was pathologic complete response (pCR) at the time of surgery; secondary endpoints included overall survival (OS), progression-free survivalmore » (PFS), and freedom from locoregional failure. Results: Results for the primary endpoint have previously been reported. This analysis presents survival data for the 224 patients in the Danish part of the trial. In all, 221 patients (111 control arm, 110 brachytherapy boost arm) had data available for analysis, with a median follow-up time of 5.4 years. Despite a significant increase in tumor response at the time of surgery, no differences in 5-year OS (70.6% vs 63.6%, hazard ratio [HR] = 1.24, P=.34) and PFS (63.9% vs 52.0%, HR=1.22, P=.32) were observed. Freedom from locoregional failure at 5 years were 93.9% and 85.7% (HR=2.60, P=.06) in the standard and in the brachytherapy arms, respectively. There was no difference in the prevalence of stoma. Explorative analysis based on stratification for tumor regression grade and resection margin status indicated the presence of response migration. Conclusions: Despite increased pathologic tumor regression at the time of surgery, we observed no benefit on late outcome. Improved tumor regression does not necessarily lead to a relevant clinical benefit when the neoadjuvant treatment is followed by high-quality surgery.« less

A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202.

PubMed

Kuyama, Shoichi; Ochi, Nobuaki; Bessho, Akihiro; Hotta, Katsuyuki; Ikeda, Genyo; Kishino, Daizo; Kubo, Toshio; Harada, Daijiro; Fujimoto, Nobukazu; Nakanishi, Masamoto; Umeno, Takahiro; Okada, Toshiaki; Chikamori, Kenichi; Yamagishi, Tomoko; Ohashi, Kadoaki; Ichihara, Eiki; Takigawa, Nagio; Tanimoto, Mitsune; Kiura, Katsuyuki

2017-10-01

S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown. The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40mg/m 2 , twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40mg/m 2 , twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated. Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134days (95% CI: 79-173) and 479days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P<0.01). This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option. Copyright © 2017 Elsevier B.V. All rights reserved.

A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.

PubMed

Pal, Sumanta K; Drabkin, Harry A; Reeves, James A; Hainsworth, John D; Hazel, Susan E; Paggiarino, Dario A; Wojciak, Jon; Woodnutt, Gary; Bhatt, Rupal S

2017-02-15

Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc. A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations. The encouraging OS and favorable safety profile observed with sonepcizumab should prompt further investigation of the agent in combination with VEGF-directed agents or checkpoint inhibitors. Cancer 2017;123:576-582. © 2016 American Cancer Society. © 2016 American Cancer Society.

Acupuncture-Like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Radiation-Induced Xerostomia: Results of RTOG 0537 Phase 3 Study.

PubMed

Wong, Raimond K W; Deshmukh, Snehal; Wyatt, Gwen; Sagar, Stephen; Singh, Anurag K; Sultanem, Khalil; Nguyen-Tân, Phuc F; Yom, Sue S; Cardinale, Joseph; Yao, Min; Hodson, Ian; Matthiesen, Chance L; Suh, John; Thakrar, Harish; Pugh, Stephanie L; Berk, Lawrence

2015-06-01

This report presents the analysis of the RTOG 0537 multicenter randomized study that compared acupuncture-like transcutaneous stimulation (ALTENS) with pilocarpine (PC) for relieving radiation-induced xerostomia. Eligible patients were randomized to twice-weekly 20-minute ALTENS sessions for 24 sessions during 12 weeks or PC (5 mg 3 times daily for 12 weeks). The primary endpoint was the change in the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) scores from baseline to 9 months from randomization (MFR). Secondary endpoints included basal and citric acid primed whole salivary production (WSP), ratios of positive responders (defined as patients with ≥20% reduction in overall radiation-induced xerostomia symptom burden), and the presence of adverse events based on the Common Terminology Criteria for Adverse Events version 3. An intention-to-treat analysis was conducted. One hundred forty-eight patients were randomized. Only 96 patients completed the required XeQOLS and were evaluable at 9 MFR (representing merely 68.6% statistical power). Seventy-six patients were evaluable at 15 MFR. The median change in the overall XeQOLS in ALTENS and PC groups at 9 and 15 MFR were -0.53 and -0.27 (P=.45) and -0.6 and -0.47 (P=.21). The corresponding percentages of positive responders were 81% and 72% (P=.34) and 83% and 63% (P=.04). Changes in WSP were not significantly different between the groups. Grade 3 or less adverse events, mostly consisting of grade 1, developed in 20.8% of patients in the ALTENS group and in 61.6% of the PC group. The observed effect size was smaller than hypothesized, and statistical power was limited because only 96 of the recruited 148 patients were evaluable. The primary endpoint-the change in radiation-induced xerostomia symptom burden at 9 MFR-was not significantly different between the ALTENS and PC groups. There was significantly less toxicity in patients receiving ALTENS. Copyright © 2015 Elsevier Inc. All rights reserved.

Remote monitoring improves outcome after ICD implantation: the clinical efficacy in the management of heart failure (EFFECT) study.

PubMed

De Simone, Antonio; Leoni, Loira; Luzi, Mario; Amellone, Claudia; Stabile, Giuseppe; La Rocca, Vincenzo; Capucci, Alessandro; D'onofrio, Antonio; Ammendola, Ernesto; Accardi, Francesco; Valsecchi, Sergio; Buja, Gianfranco

2015-08-01

Internet-based remote interrogation systems have been shown to reduce emergency department and in-office visits in patients with implantable cardioverter defibrillators (ICDs), resulting in increased efficiency for healthcare providers. Nonetheless, studies sized to demonstrate the impact of remote monitoring on patients' outcome have been lacking. The EFFECT study was a multicentre clinical trial aimed at measuring and comparing the outcome of ICD patients conventionally followed-up by means of in-clinic visits (Standard arm) or by remote monitoring (Remote arm) in the clinical practice of 25 Italian centres. From 2011 to 2013, 987 consecutive patients were enrolled and followed up for at least 12 months. The primary endpoint was the rate of death and cardiovascular hospitalizations. Remote monitoring was adopted by 499 patients. Patients in the Standard and Remote arms did not differ significantly in terms of baseline clinical characteristics, except for a more frequent use of ICD with cardiac resynchronization therapy (CRT-D) in the Remote arm (48 vs. 36%, P < 0.001). One-year rates of the primary combined endpoint were 0.27 events/year for patients in the Standard arm and were 0.15 events/year for those in the Remote arm (incident rate ratio, 0.55; 95% CI, 0.41-0.73; P < 0.001). The endpoint rates in the Standard and Remote arms were 0.27 and 0.08 events/year, respectively, among CRT-D recipients (P < 0.001), and 0.28 vs. 0.21 among ICD patients (P = 0.094). The rates of in-office visits were 1.9 per year in the Standard arm and 1.7 per year in the Remote arm. Compared with the standard follow-up through in-office visits, remote monitoring is associated with reduced death and cardiovascular hospitalizations in patients with ICD in clinical practice. URL: http://clinicaltrials.gov/ Identifier: NCT01723865. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

eEduHeart I: A Multicenter, Randomized, Controlled Trial Investigating the Effectiveness of a Cardiac Web-Based eLearning Platform - Rationale and Study Design.

PubMed

Frederix, Ines; Vandenberk, Thijs; Janssen, Leen; Geurden, Anne; Vandervoort, Pieter; Dendale, Paul

Cardiac telerehabilitation includes, in its most comprehensive format, telemonitoring, telecoaching, social interaction, and eLearning. The specific role of eLearning, however, was seldom assessed. The aim of eEduHeart I is to investigate the medium-term effectiveness of the addition of a cardiac web-based eLearing platform to conventional cardiac care. In this prospective, multicenter randomized, controlled trial, 1,000 patients with coronary artery disease will be randomized 1:1 to an intervention group (receiving 1-month unrestricted access to the cardiac eLearning platform in addition to conventional cardiac care) or to conventional cardiac care alone. The primary endpoint is health-related quality of life, assessed by the HeartQoL questionnaire at the 1- and 3-month follow-ups. Secondary endpoints include pathology-specific knowledge and self-reported eLearning platform user experience. Data on the eLearning platform usage will be gathered through web logging during the study period. eEduHeart I will be one of the first studies to report on the added value of eLearning. If the intervention is proven effective, current cardiac telerehabilitation programs can be augmented by including eLearning, too. The platform can then be used as a model for other chronic diseases in which patient education plays a key role. © 2016 S. Karger AG, Basel.

Characteristics of antimicrobial studies registered in the USA through ClinicalTrials.Gov

PubMed Central

Stockmann, Chris; Sherwin, Catherine M.T.; Ampofo, Krow; Hersh, Adam L.; Pavia, Andrew T.; Byington, Carrie L.; Ward, Robert M.; Spigarelli, Michael G.

2013-01-01

Increasing rates of antimicrobial-resistant infections and the dwindling pipeline of new agents necessitate judicious, evidence-based antimicrobial prescribing. Clinical trials represent a vital resource for establishing evidence of safety and efficacy, which are crucial to guiding antimicrobial treatment decisions. The objective of this study was to comprehensively evaluate the characteristics of antimicrobial research studies registered in ClinicalTrials.gov. Primary outcome measures, funding sources, inclusion criteria and the reporting of study results were evaluated for 16 055 antimicrobial studies registered in ClinicalTrials.gov as of mid 2012. Interventional studies accounted for 93% of registered antimicrobial studies. Clinical trials of drugs (82%) and biologics (9%) were most common. Antibacterial, antiviral and antifungal studies accounted for 43%, 41% and 16% of drug trials, respectively. Among interventional drug trials, 73% featured randomised allocation to study arms and 71% included measures of safety and/or efficacy as primary endpoints. Children were eligible for enrolment in 26% of studies. Among the studies, 60% were sponsored primarily by non-profit organisations, 30% by industry and 10% by the federal government. Only 7% of studies reported results; however, 71% of these were sponsored primarily by industry. Antimicrobial studies commonly incorporated elements of high-quality trial design, including randomisation and safety/efficacy endpoints. Publication of study results and updating of ClinicalTrials.gov should be encouraged for all studies, with particular attention paid to research sponsored by non-profit organisations and governmental agencies. Leveraging the application of these data to guide the careful selection of antimicrobial agents will be essential to preserve their utility for years to come. PMID:23726436

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer

PubMed Central

Alumkal, Joshi J.; Slottke, Rachel; Schwartzman, Jacob; Cherala, Ganesh; Munar, Myrna; Graff, Julie N.; Beer, Tomasz M.; Ryan, Christopher W.; Koop, Dennis R.; Gibbs, Angela; Gao, Lina; Flamiatos, Jason F.; Tucker, Erin; Kleinschmidt, Richard; Mori, Motomi

2014-01-01

Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. We treated 20 patients who had recurrent prostate cancer with 200μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p=0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. Treatment with 200μmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent. PMID:25431127

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

PubMed

Alumkal, Joshi J; Slottke, Rachel; Schwartzman, Jacob; Cherala, Ganesh; Munar, Myrna; Graff, Julie N; Beer, Tomasz M; Ryan, Christopher W; Koop, Dennis R; Gibbs, Angela; Gao, Lina; Flamiatos, Jason F; Tucker, Erin; Kleinschmidt, Richard; Mori, Motomi

2015-04-01

Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. We treated 20 patients who had recurrent prostate cancer with 200 μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. Treatment with 200 μmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Long-Term Outcomes of Non-ST-Elevation Myocardial Infarction Without Creatine Kinase Elevation　- The J-MINUET Study.

PubMed

Ishihara, Masaharu; Nakao, Koichi; Ozaki, Yukio; Kimura, Kazuo; Ako, Junya; Noguchi, Teruo; Fujino, Masashi; Yasuda, Satoshi; Suwa, Satoru; Fujimoto, Kazuteru; Nakama, Yasuharu; Morita, Takashi; Shimizu, Wataru; Saito, Yoshihiko; Hirohata, Atsushi; Morita, Yasuhiro; Inoue, Teruo; Okamura, Atsunori; Uematsu, Masaaki; Hirata, Kazuhito; Tanabe, Kengo; Shibata, Yoshisato; Owa, Mafumi; Tsujita, Kenichi; Funayama, Hiroshi; Kokubu, Nobuaki; Kozuma, Ken; Tobaru, Tetsuya; Oshima, Shigeru; Nakai, Michikazu; Nishimura, Kunihiro; Miyamoto, Yoshihiro; Ogawa, Hisao

2017-06-23

According to troponin-based criteria of myocardial infarction (MI), patients without elevation of creatine kinase (CK), formerly classified as unstable angina (UA), are now diagnosed as non-ST-elevation MI (NSTEMI), but little is known about their outcomes.Methods and Results:Between July 2012 and March 2014, 3,283 consecutive patients with MI were enrolled. Clinical follow-up data were obtained up to 3 years. The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure and urgent revascularization for UA. There were 2,262 patients with ST-elevation MI (STEMI), 563 NSTEMI with CK elevation (NSTEMI+CK) and 458 NSTEMI without CK elevation (NSTEMI-CK). From day 0, Kaplan-Meier curves for the primary endpoint began to diverge in favor of NSTEMI-CK for up to 30 days. The 30-day event rate was significantly lower in patients with NSTEMI-CK (3.3%) than in STEMI (8.6%, P<0.001) and NSTEMI+CK (9.9%, P<0.001). Later, the event curves diverged in favor of STEMI. The event rate from 31 days to 3 years was significantly lower in patients with STEMI (19.8%) than in NSTEMI+CK (33.6%, P<0.001) and NSTEMI-CK (34.2%, P<0.001). Kaplan-Meier curves from 31 days to 3 years were almost identical between NSTEMI+CK and NSTEMI-CK (P=0.91). Despite smaller infarct size and better short-term outcomes, long-term outcomes of NSTEMI-CK after convalescence were as poor as those for NSTEMI+CK and worse than for STEMI.

Questioning the Validity of the 4+/5+ Binge or Heavy Drinking Criterion in College and Clinical Populations

PubMed Central

Pearson, Matthew R.; Kirouac, Megan; Witkiewitz, Katie

2015-01-01

Background and Aims The terms “binge drinking” and “heavy drinking” are both typically operationalized as 4+/5+ standard drinks per occasion for women/men and are commonly used as a proxy for non-problematic (<4/<5) versus problematic (4+/5+) drinking in multiple research contexts. The Food and Drug Administration in the United States (US) recently proposed the 4+/5+ criterion as a primary efficacy endpoint in their guidance for trials examining new medications for alcohol use disorders (AUDs). Internationally, similar cut-offs have been proposed, with the European Medicines Agency having identified reductions in the number of heavy drinking days (defined as 40/60g pure alcohol in women/men) as a primary endpoint for efficacy trials with a harm reduction goal. Analysis and Evidence We question the validity of the 4+/5+ cutoff (and other similar cutoffs) on multiple accounts. The 4+/5+ cutoff has not been shown to have unique predictive validity or clinical utility. The cutoff has been created based on retrospective self-reports and its use demonstrates ecological bias. Given strong evidence that the relationship between alcohol consumption and problems related to drinking is at least monotonic, if not linear, there is little existing evidence to support the 4+/5+ cutoff as a valid marker of problematic alcohol use. Conclusions There is little empirical evidence for the 4+/5+ units per occasion threshold for “binge” or “heavy” drinking in indexing treatment efficacy. Further consideration of an appropriate threshold seems to be warranted. PMID:27605077

A conservative strategy in non-ST-segment elevation myocardial infarction - constraints and prognosis: The situation in Portugal.

PubMed

Moreira, Davide; Marmelo, Bruno; Delgado, Anne; Nunes, Luís; Pipa, João; Santos, Oliveira

2015-05-01

The aim of this study was to assess the impact of a conservative strategy in non-ST-segment elevation myocardial infarction in patients in the Portuguese Registry of Acute Coronary Syndromes. The 3780 patients included in the study over a three-year period were divided into three groups: group 1, patients treated by a conservative strategy during hospitalization; group 2, patients who underwent coronary angiography without percutaneous coronary intervention (PCI); and group 3, patients who underwent PCI. Clinical and procedural data and in-hospital complications were compared. The primary endpoint was defined as in-hospital or one-year mortality and the secondary endpoint as the presence of at least one of the following in-hospital complications: major bleeding according to the GUSTO criteria, need for blood transfusion, invasive ventilation, heart failure or reinfarction. Of the patients analyzed, 16.5% were treated by a conservative strategy. Patients in this group were older, more often women, and had more high-risk factors. A conservative strategy was associated with a higher rate of the primary endpoint - in-hospital mortality (10.6% vs. 1.1% vs. 0.6% in groups 1, 2 and 3, respectively, p<0.001, odds ratio (OR) 6.974, 95% confidence interval [CI]: 2.775-17.527) and one-year mortality (26.1% vs. 6.8% vs. 4.1%, p<0.001, hazard ratio (HR) 2.925, 95% CI: 1.433 -5.974) - and of the secondary endpoint - 37.2% vs. 18.9% vs. 14.6%, p<0.001; OR 1.471 95% CI: 1.043 -2.076. In this patient population, a conservative strategy is an independent predictor of in-hospital mortality, in-hospital complications and one-year mortality. Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Periprocedural use of tirofiban in elective percutaneous coronary intervention for long coronary lesions in stable patients with overlapping drug-eluting stents--the PETITION study: a prospective, randomized, multicenter study.

PubMed

Zhang, Qi; Wang, Xiao Long; Liao, Min Lei; Hu, Jian; Yang, Zhen Kun; Ding, Feng Hua; Zhang, Jian Sheng; Du, Run; Zhu, Tian Qi; Shen, Wei Feng; Zhang, Rui Yan

2015-03-01

Patients are at risk of developing periprocedural myonecrosis after percutaneous coronary intervention (PCI). We investigated whether the use of the platelet glycoprotein (GP) IIb/IIIa receptor inhibitor tirofiban could reduce periprocedural myocardial infarction (PMI) in patients with stable coronary artery disease undergoing elective PCI with overlapping stent implantation for long lesions. A total of 748 stable angina patients with long lesions (≥ 40 mm in length) treated with overlapping stent implantation were randomly assigned to receive tirofiban (tirofiban group; n = 373) or conventional therapy (control group; n = 375). Intravenous tirofiban was initiated before PCI and maintained for 12 hr after the procedure. The primary endpoint was PMI, defined as an elevation in CK-MB > 3 times the upper limit of normal 12 hr after the index procedure. The secondary endpoint was major adverse cardiac events (MACE), including cardiac death, target vessel revascularization, and recurrent MI (re-MI), at one-year of clinical follow-up. The safety end-points included Thrombolysis in Myocardial Infarction (TIMI) major bleeding and stent thrombosis. Despite comparable angiographic and procedural characteristics, in the intention-to-treatment analysis, the primary endpoint was significantly reduced in the tirofiban group (4.0% vs. 11.5%, P < 0.001). Multivariate analysis revealed that the adjunctive use of tirofiban was the only negative predictor of PMI (OR 0.41, 95% CI 0.28-0.81, P < 0.01). At one-year of clinical follow-up, the overall occurrence of MACE was significantly lower in the tirofiban group (13.4% vs. 22.7%, P = 0.001). The rate of TIMI major bleeding and stent thrombosis did not differ significantly between the two groups. Our results show that the adjunctive use of tirofiban reduces the occurrence of PMI and MACE at one year in stable coronary artery disease patients undergoing elective PCI for long lesions with overlapping stent implantation. © 2015 Wiley Periodicals, Inc.

A Randomized Phase 2 Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy–Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fogh, Shannon E., E-mail: Shannon.Fogh@ucsf.edu; Deshmukh, Snehal; Berk, Lawrence B.

Purpose: Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. Methods: The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus <30% or ≥30%) and were then randomized between supportive care, 10 mL of liquid manuka honey 4 times a day, and 2 lozenges (10 mL of dehydrated manuka honey) 4 times a day during concurrent chemotherapy and radiation therapy.more » The primary endpoint was patient-reported pain on swallowing, with the use of an 11-point (0-10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect a 15% relative reduction of change in NRPS score. The secondary endpoints were trend of pain over time, opioid use, clinically graded and patient-reported adverse events, weight loss, dysphagia, nutritional status, and quality of life. Results: 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant (P=.03), with more patients on the supportive care arm taking opioids. Conclusion: Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed.« less

Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study.

PubMed

Böhm, Michael; Borer, Jeffrey; Ford, Ian; Gonzalez-Juanatey, Jose R; Komajda, Michel; Lopez-Sendon, Jose; Reil, Jan-Christian; Swedberg, Karl; Tavazzi, Luigi

2013-01-01

We analysed the effect of ivabradine on outcomes in heart failure (HF) patients on recommended background therapies with heart rates ≥75 bpm and <75 bpm in the SHIFT trial. A cut-off value of ≥75 bpm was chosen by the EMEA for approval for the use of ivabradine in chronic heart failure. The SHIFT population was divided by baseline heart rate ≥75 or <75 bpm. The effect of ivabradine was analysed for primary composite endpoint (cardiovascular death or HF hospitalization) and other endpoints. In the ≥75 bpm group, ivabradine reduced primary endpoint (HR 0.76, 95 % CI 0.68-0.85, P < 0.0001), all-cause mortality (HR 0.83, 95 % CI, 0.72-0.96, P = 0.0109), cardiovascular mortality (HR 0.83, 95 % CI, (0.71-0.97, P = 0.0166), HF death (HR 0.61, 95 % CI, 0.46-0.81, P < 0.0006), and HF hospitalization (HR 0.70, 95 % CI, 0.61-0.80, P < 0.0001). Risk reduction depended on heart rate after 28 days, with the best protection for heart rates <60 bpm or reductions >10 bpm. None of the endpoints was significantly reduced in the <75 bpm group, though there were trends for risk reductions in HF death and hospitalization for heart rate <60 bpm and reductions >10 bpm. Ivabradine was tolerated similarly in both groups. The effect of ivabradine on outcomes is greater in patients with heart rate ≥75 bpm with heart rates achieved <60 bpm or heart rate reductions >10 bpm predicting best risk reduction. Our findings emphasize the importance of identification of high-risk HF patients by high heart rates and their treatment with heart rate-lowering drugs such as ivabradine.

Phase 3 randomised study of the proposed biosimilar adalimumab GP2017 in psoriasis - impact of multiple switches.

PubMed

Blauvelt, A; Lacour, J-P; Fowler, J F; Weinberg, J M; Gospodinov, D; Schuck, E; Jauch-Lembach, J; Balfour, A; Leonardi, C L

2018-06-19

The impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) was assessed following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. This 51-week double-blinded, phase 3 study randomly assigned patients to GP2017 (N=231) or ref-ADMB (N=234) 80 mg subcutaneously at Week 0, then 40 mg biweekly from Week 1. At Week 17, patients were re-randomised to switch (n=126) or continue (n=253) treatment. Primary endpoint: patients achieving Psoriasis Area and Severity Index (PASI)75 at Week 16 (equivalence confirmed if the 95% confidence interval [CI] for the difference in PASI75 between treatments was ±18%). Key secondary endpoint: change from baseline to Week 16 in continuous PASI. Other endpoints: PASI over time, PASI 50/75/90/100, pharmacokinetics, safety, tolerability and immunogenicity for the switched and continued treatment groups. Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66.8% and 65.0%, respectively; 95% CI, -7.46, 11.15) and key secondary (-60.7% and -61.5%, respectively; 95% CI, -3.15, 4.84) endpoints. PASI improved over time and was similar between treatment groups at Week 16, and the switched/continued groups from Weeks 17-51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at Week 16, or the switched/continued groups from Weeks 17-51. No hypersensitivity to adalimumab was reported upon switching. Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Prediction of cardiovascular outcome by estimated glomerular filtration rate and estimated creatinine clearance in the high-risk hypertension population of the VALUE trial.

PubMed

Ruilope, Luis M; Zanchetti, Alberto; Julius, Stevo; McInnes, Gordon T; Segura, Julian; Stolt, Pelle; Hua, Tsushung A; Weber, Michael A; Jamerson, Ken

2007-07-01

Reduced renal function is predictive of poor cardiovascular outcomes but the predictive value of different measures of renal function is uncertain. We compared the value of estimated creatinine clearance, using the Cockcroft-Gault formula, with that of estimated glomerular filtration rate (GFR), using the Modification of Diet in Renal Disease (MDRD) formula, as predictors of cardiovascular outcome in 15 245 high-risk hypertensive participants in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. For the primary end-point, the three secondary end-points and for all-cause death, outcomes were compared for individuals with baseline estimated creatinine clearance and estimated GFR < 60 ml/min and > or = 60 ml/min using hazard ratios and 95% confidence intervals. Coronary heart disease, left ventricular hypertrophy, age, sex and treatment effects were included as covariates in the model. For each end-point considered, the risk in individuals with poor renal function at baseline was greater than in those with better renal function. Estimated creatinine clearance (Cockcroft-Gault) was significantly predictive only of all-cause death [hazard ratio = 1.223, 95% confidence interval (CI) = 1.076-1.390; P = 0.0021] whereas estimated GFR was predictive of all outcomes except stroke. Hazard ratios (95% CIs) for estimated GFR were: primary cardiac end-point, 1.497 (1.332-1.682), P < 0.0001; myocardial infarction, 1.501 (1.254-1.796), P < 0.0001; congestive heart failure, 1.699 (1.435-2.013), P < 0.0001; stroke, 1.152 (0.952-1.394) P = 0.1452; and all-cause death, 1.231 (1.098-1.380), P = 0.0004. These results indicate that estimated glomerular filtration rate calculated with the MDRD formula is more informative than estimated creatinine clearance (Cockcroft-Gault) in the prediction of cardiovascular outcomes.

A Randomized Controlled Trial of the Effects of Febuxostat Therapy on Adipokines and Markers of Kidney Fibrosis in Asymptomatic Hyperuricemic Patients With Diabetic Nephropathy

PubMed Central

Beddhu, Srinivasan; Filipowicz, Rebecca; Wang, Bin; Wei, Guo; Chen, Xiaorui; Roy, Abinash C.; DuVall, Scott L.; Farrukh, Hanadi; Habib, Arsalan N.; Bjordahl, Terrence; Simmons, Debra L.; Munger, Mark; Stoddard, Greg; Kohan, Donald E.; Greene, Tom; Huang, Yufeng

2016-01-01

Background: In observational studies, higher uric acid levels are associated with metabolic syndrome, diabetes, and kidney disease. Objective: The objective of this study is to examine whether reduction of plasma uric acid with febuxostat, a xanthine oxido reductase inhibitor, impacts adipose tissue oxidative stress, adipokines, and markers of systemic inflammation or kidney fibrosis. Design: This was a double-blinded randomized controlled trial. Setting: Academic university setting was used. Patients: Overweight or obese adults with hyperuricemia and type 2 diabetic nephropathy were included. Measurements: Adipose tissue thiobarbituric acid reducing substances (TBARS) and adiponectin concentrations and urinary transforming growth factor–β (TGF-β) were primary endpoints. Plasma C-reactive protein, high molecular weight–adiponectin, interleukin–6, tumor necrosis factor–α, and TBARS and albuminuria were among predefined secondary endpoints. Methods: Participants were randomly assigned to febuxostat (n = 40) or matching placebo (n = 40) and followed for 24 weeks. Results: Baseline plasma uric acid levels were 426 ± 83 µmol/L; 95% completed the study. Estimated glomerular filtration rate (eGFR) declined from 54 ± 17 mL/min/1.73 m2 at baseline to 51 ± 17 mL/min/1.73 m2 at 24 weeks (P = .05). In separate mixed-effects models, compared with placebo, febuxostat reduced uric acid by 50% (P < .001) but had no significant effects on subcutaneous adipose tissue TBARS (−7.4%, 95% confidence interval [CI], 57.4%-101.4%) or adiponectin (6.7%, 95% CI, 26.0%-53.8%) levels or urinary TGF-β/creatinine ratio (18.0%, 95% CI, 10.0%-54.8%) or secondary endpoints. Limitations: Relatively modest sample size and short duration of follow-up. Conclusions: In this population with progressive diabetic nephropathy, febuxostat effectively reduced plasma uric acid. However, no detectable effects were observed for the prespecified primary or secondary endpoints. Trial Registration: The study was registered in clinicaltrials.gov (NCT01350388). PMID:28270924

A Randomized Phase II Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012

PubMed Central

Fogh, Shannon; Deshmukh, Snehal; Berk, Lawrence B.; Dueck, Amylou C.; Roof, Kevin; Yacoub, Sherif; Gergel, Thomas; Stephans, Kevin; Rimner, Andreas; DeNittis, Albert; Pablo, John; Rineer, Justin; Williams, Terence M.; Bruner, Deborah

2017-01-01

Purpose Randomized trials have shown that honey is effective for prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. Methods Patients were stratified by percentage of esophagus receiving specific radiation dose (V60Gy esophagus < or ≥ 30%), then randomized between supportive care, 10 ml of liquid Manuka honey four times a day or 2 lozenges (10 ml of dehydrated Manuka honey) four times a day during concurrent chemotherapy and radiotherapy. The primary endpoint was patient-reported pain on swallowing utilizing an eleven point (0–10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect 15% relative reduction of change in NRPS score. Secondary endpoints were trend of pain over time, opioid use, clinically-graded and patient-reported adverse events, weight loss, dysphagia, nutritional status and quality of life. Results 53 patients were randomized to supportive care, 54 randomized to liquid honey and 56 to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms which was found to be significant (p=0.03) with more patients on the supportive care arm taking opioids. Conclusion Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed. PMID:28244415

A Randomized Phase 2 Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy-Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012.

PubMed

Fogh, Shannon E; Deshmukh, Snehal; Berk, Lawrence B; Dueck, Amylou C; Roof, Kevin; Yacoub, Sherif; Gergel, Thomas; Stephans, Kevin; Rimner, Andreas; DeNittis, Albert; Pablo, John; Rineer, Justin; Williams, Terence M; Bruner, Deborah

2017-03-15

Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus <30% or ≥30%) and were then randomized between supportive care, 10 mL of liquid manuka honey 4 times a day, and 2 lozenges (10 mL of dehydrated manuka honey) 4 times a day during concurrent chemotherapy and radiation therapy. The primary endpoint was patient-reported pain on swallowing, with the use of an 11-point (0-10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect a 15% relative reduction of change in NRPS score. The secondary endpoints were trend of pain over time, opioid use, clinically graded and patient-reported adverse events, weight loss, dysphagia, nutritional status, and quality of life. 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant (P=.03), with more patients on the supportive care arm taking opioids. Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed. Copyright © 2016. Published by Elsevier Inc.

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology

PubMed Central

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types. PMID:23109809

Whole-genome resequencing of Escherichia coli K-12 MG1655 undergoing short-term laboratory evolution in lactate minimal media reveals flexible selection of adaptive mutations

PubMed Central

2009-01-01

Background Short-term laboratory evolution of bacteria followed by genomic sequencing provides insight into the mechanism of adaptive evolution, such as the number of mutations needed for adaptation, genotype-phenotype relationships, and the reproducibility of adaptive outcomes. Results In the present study, we describe the genome sequencing of 11 endpoints of Escherichia coli that underwent 60-day laboratory adaptive evolution under growth rate selection pressure in lactate minimal media. Two to eight mutations were identified per endpoint. Generally, each endpoint acquired mutations to different genes. The most notable exception was an 82 base-pair deletion in the rph-pyrE operon that appeared in 7 of the 11 adapted strains. This mutation conferred an approximately 15% increase to the growth rate when experimentally introduced to the wild-type background and resulted in an approximately 30% increase to growth rate when introduced to a background already harboring two adaptive mutations. Additionally, most endpoints had a mutation in a regulatory gene (crp or relA, for example) or the RNA polymerase. Conclusions The 82 base-pair deletion found in the rph-pyrE operon of many endpoints may function to relieve a pyrimidine biosynthesis defect present in MG1655. In contrast, a variety of regulators acquire mutations in the different endpoints, suggesting flexibility in overcoming regulatory challenges in the adaptation. PMID:19849850

The effect of standard dose multivitamin supplementation on disease progression in HIV-infected adults initiating HAART: a randomized double blind placebo-controlled trial in Uganda.

PubMed

Guwatudde, David; Wang, Molin; Ezeamama, Amara E; Bagenda, Danstan; Kyeyune, Rachel; Wamani, Henry; Manabe, Yukari C; Fawzi, Wafaie W

2015-08-19

Efficacy trials investigating the effect of multivitamin (MV) supplementations among patients on Highly Active Antiretroviral Therapy (HAART) have so far been inconclusive. We conducted a randomized, double blind, placebo controlled trial to determine the effect of one recommended daily allowance (RDA) of MV supplementation on disease progression in patients initiating HAART. Eligible subjects were randomized to receive placebo or MV supplementation including vitamins B-complex, C and E. Participants were followed for up to 18 months. Primary endpoints were: change in CD4 cell count, weight and quality of life (QoL). Secondary endpoints were: i) development of a new or recurrent HIV disease progression event, including all-cause mortality; ii) switching from first- to second-line antiretroviral therapy (ART); and iii) occurrence of an adverse event. Intent-to-treat analysis, using linear regression mixed effects models were used to compare changes over time in the primary endpoints between the study arms. Kaplan-Meier time-to-event analysis and the log-rank test was used to compare HIV disease progression events and all-cause mortality. Four hundred participants were randomized, 200 onto MV and 200 onto placebo. By month 18, the average change in CD4 cell count in the MV arm was 141 cells/uL compared to 147 cells/uL in the placebo arm, a mean difference of -6 · 17 [95 % CI -29 · 3, 16 · 9]. The average change in weight in the MV arm was 3 · 9 kg compared to 3 · 3 kg in the placebo arm, a mean difference of 0 · 54 [95 % CI -0 · 40, 1 · 48]; whereas average change in QoL scores in the MV arm was 6 · 8 compared to 8 · 8 in the placebo arm, a mean difference of -2.16 [95 % CI -4 · 59,0 · 27]. No significant differences were observed in these primary endpoints, or in occurrence of adverse events between the trial arms. One RDA of MV supplementation was safe but did not have an effect on indicators of disease progression among HIV infected adults initiating HAART. Clinical trials NCT01228578 , registered on 15th October 2010.

PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

EPA Science Inventory

Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

The ADDITION-Cambridge trial protocol: a cluster -- randomised controlled trial of screening for type 2 diabetes and intensive treatment for screen-detected patients.

PubMed

Echouffo-Tcheugui, Justin B; Simmons, Rebecca K; Williams, Kate M; Barling, Roslyn S; Prevost, A Toby; Kinmonth, Ann Louise; Wareham, Nicholas J; Griffin, Simon J

2009-05-12

The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, the benefits of such a strategy remain uncertain. The ADDITION-Cambridge study aims to evaluate the effectiveness and cost-effectiveness of (i) a stepwise screening strategy for type 2 diabetes; and (ii) intensive multifactorial treatment for people with screen-detected diabetes in primary care. 63 practices in the East Anglia region participated. Three undertook the pilot study, 33 were allocated to three groups: no screening (control), screening followed by intensive treatment (IT) and screening plus routine care (RC) in an unbalanced (1:3:3) randomisation. The remaining 27 practices were randomly allocated to IT and RC. A risk score incorporating routine practice data was used to identify people aged 40-69 years at high-risk of undiagnosed diabetes. In the screening practices, high-risk individuals were invited to take part in a stepwise screening programme. In the IT group, diabetes treatment is optimised through guidelines, target-led multifactorial treatment, audit, feedback, and academic detailing for practice teams, alongside provision of educational materials for newly diagnosed participants. Primary endpoints are modelled cardiovascular risk at one year, and cardiovascular mortality and morbidity at five years after diagnosis of diabetes. Secondary endpoints include all-cause mortality, development of renal and visual impairment, peripheral neuropathy, health service costs, self-reported quality of life, functional status and health utility. Impact of the screening programme at the population level is also assessed through measures of mortality, cardiovascular morbidity, health status and health service use among high-risk individuals. ADDITION-Cambridge is conducted in a defined high-risk group accessible through primary care. It addresses the feasibility of population-based screening for diabetes, as well as the benefits and costs of screening and intensive multifactorial treatment early in the disease trajectory. The intensive treatment algorithm is based on evidence from studies including individuals with clinically diagnosed diabetes and the education materials are informed by psychological theory. ADDITION-Cambridge will provide timely evidence concerning the benefits of early intensive treatment and will inform policy decisions concerning screening for type 2 diabetes. Current Controlled trials ISRCTN86769081.

Dementia care initiative in primary practice – study protocol of a cluster randomized trial on dementia management in a general practice setting

PubMed Central

Holle, Rolf; Gräßel, Elmar; Ruckdäschel, Stefan; Wunder, Sonja; Mehlig, Hilmar; Marx, Peter; Pirk, Olaf; Butzlaff, Martin; Kunz, Simone; Lauterberg, Jörg

2009-01-01

Background Current guidelines for dementia care recommend the combination of drug therapy with non-pharmaceutical measures like counselling and social support. However, the scientific evidence concerning non-pharmaceutical interventions for dementia patients and their informal caregivers remains inconclusive. Targets of modern comprehensive dementia care are to enable patients to live at home as long and as independent as possible and to reduce the burden of caregivers. The objective of the study is to compare a complex intervention including caregiver support groups and counselling against usual care in terms of time to nursing home placement. In this paper the study protocol is described. Methods/Design The IDA (Initiative Demenzversorgung in der Allgemeinmedizin) project is designed as a three armed cluster-randomized trial where dementia patients and their informal caregivers are recruited by general practitioners. Patients in the study region of Middle Franconia, Germany, are included if they have mild or moderate dementia, are at least 65 years old, and are members of the German AOK (Allgemeine Ortskrankenkasse) sickness fund. In the control group patients receive regular treatment, whereas in the two intervention groups general practitioners participate in a training course in evidence based dementia treatment, recommend support groups and offer counseling to the family caregivers either beginning at baseline or after the 1-year follow-up. The study recruitment and follow-up took place from July 2005 to January 2009. 303 general practitioners were randomized of which 129 recruited a total of 390 patients. Time to nursing home admission within the two year intervention and follow-up period is the primary endpoint. Secondary endpoints are cognitive status, activities of daily living, burden of care giving as well as healthcare costs. For an economic analysis from the societal perspective, data are collected from caregivers as well as by the use of routine data from statutory health insurance and long-term care insurance. Discussion From a public health perspective, the IDA trial is expected to lead to evidence based results on the community effectiveness of non-pharmaceutical support measures for dementia patients and their caregivers in the primary care sector. For health policy makers it is necessary to make their decisions about financing new services based on strong knowledge about the acceptance of measures in the population and their cost-effectiveness. Trial registration ISRCTN68329593 PMID:19500383

The ADDITION-Cambridge trial protocol: a cluster – randomised controlled trial of screening for type 2 diabetes and intensive treatment for screen-detected patients

PubMed Central

Echouffo-Tcheugui, Justin B; Simmons, Rebecca K; Williams, Kate M; Barling, Roslyn S; Prevost, A Toby; Kinmonth, Ann Louise; Wareham, Nicholas J; Griffin, Simon J

2009-01-01

Background The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, the benefits of such a strategy remain uncertain. Methods and design The ADDITION-Cambridge study aims to evaluate the effectiveness and cost-effectiveness of (i) a stepwise screening strategy for type 2 diabetes; and (ii) intensive multifactorial treatment for people with screen-detected diabetes in primary care. 63 practices in the East Anglia region participated. Three undertook the pilot study, 33 were allocated to three groups: no screening (control), screening followed by intensive treatment (IT) and screening plus routine care (RC) in an unbalanced (1:3:3) randomisation. The remaining 27 practices were randomly allocated to IT and RC. A risk score incorporating routine practice data was used to identify people aged 40–69 years at high-risk of undiagnosed diabetes. In the screening practices, high-risk individuals were invited to take part in a stepwise screening programme. In the IT group, diabetes treatment is optimised through guidelines, target-led multifactorial treatment, audit, feedback, and academic detailing for practice teams, alongside provision of educational materials for newly diagnosed participants. Primary endpoints are modelled cardiovascular risk at one year, and cardiovascular mortality and morbidity at five years after diagnosis of diabetes. Secondary endpoints include all-cause mortality, development of renal and visual impairment, peripheral neuropathy, health service costs, self-reported quality of life, functional status and health utility. Impact of the screening programme at the population level is also assessed through measures of mortality, cardiovascular morbidity, health status and health service use among high-risk individuals. Discussion ADDITION-Cambridge is conducted in a defined high-risk group accessible through primary care. It addresses the feasibility of population-based screening for diabetes, as well as the benefits and costs of screening and intensive multifactorial treatment early in the disease trajectory. The intensive treatment algorithm is based on evidence from studies including individuals with clinically diagnosed diabetes and the education materials are informed by psychological theory. ADDITION-Cambridge will provide timely evidence concerning the benefits of early intensive treatment and will inform policy decisions concerning screening for type 2 diabetes. Trial registration Current Controlled trials ISRCTN86769081 PMID:19435491

Tretinoin gel microsphere pump 0.04% plus 5% benzoyl peroxide wash for treatment of acne vulgaris: morning/morning regimen is as effective and safe as morning/evening regimen.

PubMed

Pariser, David; Bucko, Alicia; Fried, Richard; Jarratt, Michael T; Kempers, Steven; Kircik, Leon; Lucky, Anne W; Rafal, Elyse; Rendon, Marta; Weiss, Jonathan; Wilson, David C; Rossi, Ana Beatris; Ramaswamy, Ratna; Nighland, Marge

2010-07-01

Topical tretinoin and benzoyl peroxide (BPO) are often prescribed in combination for the treatment of acne vulgaris; however, these products have not traditionally been administered simultaneously because of the potential for tretinoin degradation by BPO as well as the instability of tretinoin in daylight. The primary objective of this randomized, investigator-blinded, 12-week, phase 4 trial was to determine non-inferiority of a once-daily morning combination regimen of 5% BPO wash + tretinoin gel microsphere (TGM) 0.04% pump versus a sequential regimen (BPO in the morning/TGM in the evening) in patients > or = 12 years old with moderate facial acne vulgaris. The primary efficacy endpoint was the change from baseline in total acne lesions; the primary safety endpoint was the change in cutaneous irritation scores. The 247 participants (mean age: 18.5 years) were randomized to either the morning/morning regimen (n = 123) or the morning/evening regimen (n = 124). The morning/morning regimen was determined to be non-inferior to the morning/evening regimen in reduction of total acne lesions. The tolerability of both regimens was comparable. The morning/morning regimen is a safe and effective treatment option for patients with moderate acne vulgaris.

A new approach for modeling patient overall radiosensitivity and predicting multiple toxicity endpoints for breast cancer patients.

PubMed

Mbah, Chamberlain; De Ruyck, Kim; De Schrijver, Silke; De Sutter, Charlotte; Schiettecatte, Kimberly; Monten, Chris; Paelinck, Leen; De Neve, Wilfried; Thierens, Hubert; West, Catharine; Amorim, Gustavo; Thas, Olivier; Veldeman, Liv

2018-05-01

Evaluation of patient characteristics inducing toxicity in breast radiotherapy, using simultaneous modeling of multiple endpoints. In 269 early-stage breast cancer patients treated with whole-breast irradiation (WBI) after breast-conserving surgery, toxicity was scored, based on five dichotomized endpoints. Five logistic regression models were fitted, one for each endpoint and the effect sizes of all variables were estimated using maximum likelihood (MLE). The MLEs are improved with James-Stein estimates (JSEs). The method combines all the MLEs, obtained for the same variable but from different endpoints. Misclassification errors were computed using MLE- and JSE-based prediction models. For associations, p-values from the sum of squares of MLEs were compared with p-values from the Standardized Total Average Toxicity (STAT) Score. With JSEs, 19 highest ranked variables were predictive of the five different endpoints. Important variables increasing radiation-induced toxicity were chemotherapy, age, SATB2 rs2881208 SNP and nodal irradiation. Treatment position (prone position) was most protective and ranked eighth. Overall, the misclassification errors were 45% and 34% for the MLE- and JSE-based models, respectively. p-Values from the sum of squares of MLEs and p-values from STAT score led to very similar conclusions, except for the variables nodal irradiation and treatment position, for which STAT p-values suggested an association with radiosensitivity, whereas p-values from the sum of squares indicated no association. Breast volume was ranked as the most significant variable in both strategies. The James-Stein estimator was used for selecting variables that are predictive for multiple toxicity endpoints. With this estimator, 19 variables were predictive for all toxicities of which four were significantly associated with overall radiosensitivity. JSEs led to almost 25% reduction in the misclassification error rate compared to conventional MLEs. Finally, patient characteristics that are associated with radiosensitivity were identified without explicitly quantifying radiosensitivity.

Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J-ROCKET AF.

PubMed

Tanahashi, Norio; Hori, Masatsugu; Matsumoto, Masayasu; Momomura, Shin-ichi; Uchiyama, Shinichiro; Goto, Shinya; Izumi, Tohru; Koretsune, Yukihiro; Kajikawa, Mariko; Kato, Masaharu; Ueda, Hitoshi; Iwamoto, Kazuya; Tajiri, Masahiro

2013-11-01

The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively). The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up.

PubMed

Longo, Olimpia; Tripiciano, Antonella; Fiorelli, Valeria; Bellino, Stefania; Scoglio, Arianna; Collacchi, Barbara; Alvarez, Maria Josè Ruiz; Francavilla, Vittorio; Arancio, Angela; Paniccia, Giovanni; Lazzarin, Adriano; Tambussi, Giuseppe; Din, Chiara Tassan; Visintini, Raffaele; Narciso, Pasquale; Antinori, Andrea; D'Offizi, Gianpiero; Giulianelli, Marina; Carta, Maria; Di Carlo, Aldo; Palamara, Guido; Giuliani, Massimo; Laguardia, Maria Elena; Monini, Paolo; Magnani, Mauro; Ensoli, Fabrizio; Ensoli, Barbara

2009-05-26

A randomized, double blind, placebo-controlled phase I vaccine trial based on the native Tat protein was conducted in HIV-infected asymptomatic individuals. The vaccine was administered five times subcute with alum or intradermally without adjuvant at 7.5microg, 15microg or 30microg doses, respectively. The Tat vaccine was well tolerated both locally and systemically and induced and/or maintained Tat-specific T helper (Th)-1 T-cell responses and Th-2 responses in all subjects with a wide spectrum of functional anti-Tat antibodies, rarely seen in HIV-infected subjects. The data indicate the achievement of both the primary (safety) and secondary (immunogenicity) endpoints of the study.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lafata, K; Ren, L; Wu, Q

Purpose: To develop a data-mining methodology based on quantum clustering and machine learning to predict expected dosimetric endpoints for lung SBRT applications based on patient-specific anatomic features. Methods: Ninety-three patients who received lung SBRT at our clinic from 2011–2013 were retrospectively identified. Planning information was acquired for each patient, from which various features were extracted using in-house semi-automatic software. Anatomic features included tumor-to-OAR distances, tumor location, total-lung-volume, GTV and ITV. Dosimetric endpoints were adopted from RTOG-0195 recommendations, and consisted of various OAR-specific partial-volume doses and maximum point-doses. First, PCA analysis and unsupervised quantum-clustering was used to explore the feature-space tomore » identify potentially strong classifiers. Secondly, a multi-class logistic regression algorithm was developed and trained to predict dose-volume endpoints based on patient-specific anatomic features. Classes were defined by discretizing the dose-volume data, and the feature-space was zero-mean normalized. Fitting parameters were determined by minimizing a regularized cost function, and optimization was performed via gradient descent. As a pilot study, the model was tested on two esophageal dosimetric planning endpoints (maximum point-dose, dose-to-5cc), and its generalizability was evaluated with leave-one-out cross-validation. Results: Quantum-Clustering demonstrated a strong separation of feature-space at 15Gy across the first-and-second Principle Components of the data when the dosimetric endpoints were retrospectively identified. Maximum point dose prediction to the esophagus demonstrated a cross-validation accuracy of 87%, and the maximum dose to 5cc demonstrated a respective value of 79%. The largest optimized weighting factor was placed on GTV-to-esophagus distance (a factor of 10 greater than the second largest weighting factor), indicating an intuitively strong correlation between this feature and both endpoints. Conclusion: This pilot study shows that it is feasible to predict dose-volume endpoints based on patient-specific anatomic features. The developed methodology can potentially help to identify patients at risk for higher OAR doses, thus improving the efficiency of treatment planning. R01-184173.« less

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

PubMed

Starling, R C; Stehlik, J; Baran, D A; Armstrong, B; Stone, J R; Ikle, D; Morrison, Y; Bridges, N D; Putheti, P; Strom, T B; Bhasin, M; Guleria, I; Chandraker, A; Sayegh, M; Daly, K P; Briscoe, D M; Heeger, P S

2016-01-01

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced Non-Small Cell Lung Cancer.

PubMed

Hashim, Mahmoud; Pfeiffer, Boris M; Bartsch, Robert; Postma, Maarten; Heeg, Bart

2018-01-01

In previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments. To evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. A systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of R's 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated. In total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% ± 11.2%, 3.2 ± 1.3 months, and 9.6 ± 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.016-0.337) and 0.254 (95% CI 0.074-0.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.081-0.798) and 0.778 (95% CI 0.475-0.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty. Crossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

A comparison of cationic polymerization and esterification for end-point detection in the catalytic thermometric titration of organic bases.

PubMed

J Greenhow, E; Viñas, P

1984-08-01

A systematic comparison has been made of two indicator systems for the non-aqueous catalytic thermometric titration of strong and weak organic bases. The indicator reagents, alpha-methylstyrene and mixtures of acetic anhydride and hydroxy compounds, are shown to give results (for 14 representative bases) which do not diner significantly in coefficient of variation or titration error. Calibration graphs for all the samples, in the range 0.01-0.1 meq, are linear, with correlation coefficients of 0.995 or better. Aniline, benzylamine, n-butylamine, morpholine, pyrrole, l-dopa, alpha-methyl-l-dopa, dl-alpha-alanine, dl-leucine and l-cysteine cannot be determined when acetic anhydride is present in the sample solution, but some primary and second amines can. This is explained in terms of rates of acetylation of the amino groups.

A cluster randomized trial for the implementation of an antibiotic checklist based on validated quality indicators: the AB-checklist.

PubMed

van Daalen, Frederike V; Prins, Jan M; Opmeer, Brent C; Boermeester, Marja A; Visser, Caroline E; van Hest, Reinier M; Hulscher, Marlies E J L; Geerlings, Suzanne E

2015-03-19

Recently we developed and validated generic quality indicators that define 'appropriate antibiotic use' in hospitalized adults treated for a (suspected) bacterial infection. Previous studies have shown that with appropriate antibiotic use a reduction of 13% of length of hospital stay can be achieved. Our main objective in this project is to provide hospitals with an antibiotic checklist based on these quality indicators, and to evaluate the introduction of this checklist in terms of (cost-) effectiveness. The checklist applies to hospitalized adults with a suspected bacterial infection for whom antibiotic therapy is initiated, at first via the intravenous route. A stepped wedge study design will be used, comparing outcomes before and after introduction of the checklist in nine hospitals in the Netherlands. At least 810 patients will be included in both the control and the intervention group. The primary endpoint is length of hospital stay. Secondary endpoints are appropriate antibiotic use measured by the quality indicators, admission to and duration of intensive care unit stay, readmission within 30 days, mortality, total antibiotic use, and costs associated with implementation and hospital stay. Differences in numerical endpoints between the two periods will be evaluated with mixed linear models; for dichotomous outcomes generalized estimating equation models will be used. A process evaluation will be performed to evaluate the professionals' compliance with use of the checklist. The key question for the economic evaluation is whether the benefits of the checklist, which include reduced antibiotic use, reduced length of stay and associated costs, justify the costs associated with implementation activities as well as daily use of the checklist. If (cost-) effective, the AB-checklist will provide physicians with a tool to support appropriate antibiotic use in adult hospitalized patients who start with intravenous antibiotics. Dutch trial registry: NTR4872.

Efficacy and Safety of Insulin Glargine 300 U/mL Versus Insulin Glargine 100 U/mL in High-Risk and Low-Risk Patients with Type 2 Diabetes Stratified Using Common Clinical Performance Measures.

PubMed

Lingvay, Ildiko; Chao, Jason; Dalal, Mehul R; Meneghini, Luigi F

2017-05-01

To determine whether previously reported reductions in hypoglycemia associated with insulin glargine 300 U/mL (Gla-300) compared with insulin glargine 100 U/mL (Gla-100) are impacted by patient risk category in type 2 diabetes (T2D), clinical performance measures based on the Healthcare Effectiveness Data and Information Set (HEDIS) were applied to patient-level data from the EDITION 2 and EDITION 3 clinical trials that compared Gla-300 and Gla-100. In this post hoc analysis, patients were stratified as low risk (LR) if patients were <65 years old with no comorbidities derived from HEDIS (HbA1c target <7.0% [53 mmol/mol]), or as high risk (HR) if patients were either ≥65 years old or had one or more HEDIS-defined comorbidities (HbA1c target <8.0% [64 mmol/mol]). Primary endpoint was a composite of patients achieving HbA1c target without confirmed or severe hypoglycemia over 6 months in the different treatment groups in each of the EDITION trials. There was a statistically nonsignificant trend of more patients treated with Gla-300 achieving the composite endpoint compared with Gla-100 in both the LR and HR patient cohorts, regardless of prior insulin experience. A similar trend was observed for the composite endpoint of HbA1c target without nocturnal hypoglycemia. There is a consistent, nonsignificant trend suggesting that Gla-300 might reduce the burden of hypoglycemia compared with Gla-100 in patients with T2D irrespective of whether they are classed as LR or HR based on age- and National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set-derived comorbidities.

Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention.

PubMed

Roolvink, Vincent; Ibáñez, Borja; Ottervanger, Jan Paul; Pizarro, Gonzalo; van Royen, Niels; Mateos, Alonso; Dambrink, Jan-Henk E; Escalera, Noemi; Lipsic, Erik; Albarran, Agustín; Fernández-Ortiz, Antonio; Fernández-Avilés, Francisco; Goicolea, Javier; Botas, Javier; Remkes, Wouter; Hernandez-Jaras, Victoria; Kedhi, Elvin; Zamorano, José L; Navarro, Felipe; Alfonso, Fernando; García-Lledó, Alberto; Alonso, Joaquin; van Leeuwen, Maarten; Nijveldt, Robin; Postma, Sonja; Kolkman, Evelien; Gosselink, Marcel; de Smet, Bart; Rasoul, Saman; Piek, Jan J; Fuster, Valentin; van 't Hof, Arnoud W J

2016-06-14

The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI) on infarct size and clinical outcomes is not well established. This study sought to conduct the first double-blind, placebo-controlled international multicenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI) population. STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were randomized 1:1 to IV metoprolol (2 × 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock. A total of 683 patients (mean age 62 ± 12 years; 75% male) were randomized to metoprolol (n = 336) or placebo (n = 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not differ between the metoprolol (15.3 ± 11.0%) and placebo groups (14.9 ± 11.5%; p = 0.616). Peak and area under the creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 ± 10.9% in the metoprolol group and 51.6 ± 10.8% in the placebo group (p = 0.68). The incidence of malignant arrhythmias was 3.6% in the metoprolol group versus 6.9% in placebo (p = 0.050). The incidence of adverse events was not different between groups. In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. (Early-Beta blocker Administration before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI]; EudraCT no: 2010-023394-19). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults

PubMed Central

Mai, Nguyen TH; Dobbs, Nicholas; Phu, Nguyen Hoan; Colas, Romain A; Thao, Le TP; Thuong, Nguyen TT; Nghia, Ho DT; Hanh, Nguyen HH; Hang, Nguyen T; Heemskerk, A Dorothee; Day, Jeremy N; Ly, Lucy; Thu, Do DA; Merson, Laura; Kestelyn, Evelyne; Wolbers, Marcel; Geskus, Ronald; Summers, David; Chau, Nguyen VV; Dalli, Jesmond

2018-01-01

Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial. PMID:29482717

IDENTIFICATION AND PREDICTION OF FISH ASSEMBLAGES IN STREAMS OF THE MID-ATLANTIC HIGHLANDS, USA

EPA Science Inventory

Managing aquatic resources requires meaningful assessment endpoints on which to base decisions. In freshwater streams, assessment endpoints are often defined as fish communities. Given limited resources available for environmental monitoring, having a means of predicting fish a...

Nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS): first analysis on survival.

PubMed

Ito, Kazuto; Saito, Shiro; Yorozu, Atsunori; Kojima, Shinsuke; Kikuchi, Takashi; Higashide, Satoshi; Aoki, Manabu; Koga, Hirofumi; Satoh, Takefumi; Ohashi, Toshio; Nakamura, Katsumasa; Katayama, Norihisa; Tanaka, Nobumichi; Nakano, Masahiro; Shigematsu, Naoyuki; Dokiya, Takushi; Fukushima, Masanori

2018-06-22

Investigating oncological outcomes in patients registered in the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) in terms of biochemical relapse-free survival (bRFS) by the Phoenix and the newly developed J-POPS definitions, exploration of predictive factors for bRFS, and preliminary verification of pitfalls of prostate-specific antigen (PSA) failure definitions. Between July 2005 and June 2007, 2316 clinically localized patients underwent permanent seed implantation. The primary endpoint was bRFS. One of the secondary endpoints was overall survival (OS). The median age was 69 and performance status was 0 in 99.1% of participants. The median biologically effective dose (BED) was about 180 Gy 2 . During a median follow-up of 60.0 months, 8.4 and 5.9% had PSA failure by the Phoenix and the J-POPS definitions, respectively. The 5-year bRFSs based on the Phoenix and the J-POPS definitions were 89.1 and 91.6%, respectively. The 5-year OS was 97.3%. According to multivariate analyses, only age affected bRFS based on the Phoenix definition, whereas the risk group and BED independently affected bRFS based on the J-POPS definition. A spontaneous PSA decrease was seen in 91.1% of participants after PSA failure based on the Phoenix definition alone, but in only 22.2% after PSA failure based on the J-POPS definition alone. The world's largest registration study, J-POPS, consisted of patients with longevity, and a highly quality-controlled BED resulted in excellent bRFS and OS. The high likelihood of PSA bounce by the Phoenix definition should be taken into account, especially in younger patients. NCT00534196.

Earlier response assessment in invasive aspergillosis based on the kinetics of serum Aspergillus galactomannan: proposal for a new definition.

PubMed

Nouér, Simone A; Nucci, Marcio; Kumar, Naveen Sanath; Grazziutti, Monica; Barlogie, Bart; Anaissie, Elias

2011-10-01

Current criteria for assessing treatment response of invasive aspergillosis (IA) rely on nonspecific subjective parameters. We hypothesized that an Aspergillus-specific response definition based on the kinetics of serum Aspergillus galactomannan index (GMI) would provide earlier and more objective response assessment. We compared the 6-week European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) response criteria with GMI-based response among 115 cancer patients with IA. Success according to GMI required survival with repeatedly negative GMI for ≥2 weeks. Time to response and agreement between the 2 definitions were the study endpoints. Success according to EORTC/MSG and GMI criteria was observed in 73 patients (63%) and 83 patients (72%), respectively. The GMI-based response was determined at a median of 21 days after treatment initiation (range, 15-41 days), 3 weeks before the EORTC/MSG time point, in 72 (87%) of 83 responders. Agreement between definitions was shown in all 32 nonresponders and in 73 of the 83 responders (91% overall), with an excellent κ correlation coefficient of 0.819. Among 10 patients with discordant response (EORTC/MSG failure, GMI success), 1 is alive without IA 3 years after diagnosis; for the other, aspergillosis could not be detected at autopsy. The presence of other life-threatening complications in the remaining 8 patients indicates that IA had resolved. The Aspergillus-specific GMI-based criteria compare favorably to current response definitions for IA and significantly shorten time to response assessment. These criteria rely on a simple, reproducible, objective, and Aspergillus-specific test and should serve as the primary endpoint in trials of IA.

The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in chronic obstructive pulmonary disease.

PubMed

Bakerly, Nawar Diar; Woodcock, Ashley; New, John P; Gibson, J Martin; Wu, Wei; Leather, David; Vestbo, Jørgen

2015-09-04

New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy. Patients with chronic obstructive pulmonary disease (COPD), ≥ 40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data. The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in COPD. Clinicaltrials.gov identifier NCT01551758.

Further analysis of PREVAIL: enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer

PubMed Central

Aragon-Ching, Jeanny B

2014-01-01

PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC), which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA) progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy. PMID:25080931

Further analysis of PREVAIL: enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

PubMed

Aragon-Ching, Jeanny B

2014-01-01

PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC), which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA) progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy.

A multicentre, randomized, single-blind, parallel-group study comparing the efficacy and tolerability of benzoyl peroxide 3%/clindamycin 1% with azelaic acid 20% in the topical treatment of mild-to-moderate acne vulgaris.

PubMed

Schaller, M; Sebastian, M; Ress, C; Seidel, D; Hennig, M

2016-06-01

Mild-to-moderate acne vulgaris is treated with a range of mono- and combination therapies; however, clinical evidence is still required to optimize treatment recommendations. To compare the efficacy, tolerability and safety of a combination of benzoyl peroxide 3% and clindamycin 1% (BPO + CLN) with azelaic acid 20% (AzA) for the topical treatment of mild-to-moderate acne vulgaris. This was a randomized, assessor-blinded, parallel-group, multicentre study conducted in Germany. Patients with a confirmed diagnosis of acne vulgaris, aged 12-45 years, were randomized 1 : 1 to once-daily BPO + CLN gel or twice-daily AzA cream for up to 12 weeks. The primary endpoint was the percentage change in inflammatory lesions from baseline at Week 4. Secondary endpoints included total and inflammatory lesion counts and tolerability assessments. For selected secondary endpoints, inductive statistical analysis was performed post hoc. Patient safety was assessed by adverse event (AE) monitoring. Efficacy was assessed in the modified intent-to-treat (mITT) population [patients using ≥1 dose of study medication (ITT), plus baseline and ≥1 post-baseline lesion count (n = 215)]. There was a statistically significant difference in the primary endpoint, with a median decrease of -52.6% for BPO + CLN (n = 107) vs.-38.8% for AzA (n = 108; P = 0.0004). There was also a greater difference in secondary lesion endpoints at Week 12, with a median decrease in inflammatory lesions of -78.8% and -65.3% and total lesions of -69.0% and -53.9% with BPO + CLN and AzA, respectively (both P < 0.0001). Tolerability was acceptable for both treatments. Overall, 55.6% (BPO + CLN) and 69.7% (AzA) of patients reported treatment-emergent AEs, and 15.7% and 35.8% of patients experienced application site reactions with BPO + CLN (24 events; 17 patients) and AzA (60 events; 39 patients) treatment, respectively (ITT population). BPO + CLN demonstrated greater efficacy than AzA in the treatment of mild-to-moderate acne vulgaris and has a positive tolerability and safety profile. © 2016 European Academy of Dermatology and Venereology.

Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.

PubMed

Hendriksz, Christian J; Giugliani, Roberto; Harmatz, Paul; Mengel, Eugen; Guffon, Nathalie; Valayannopoulos, Vassili; Parini, Rossella; Hughes, Derralynn; Pastores, Gregory M; Lau, Heather A; Al-Sayed, Moeenaldeen D; Raiman, Julian; Yang, Ke; Mealiffe, Matthew; Haller, Christine

2015-02-01

To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population. Copyright © 2014. Published by Elsevier Inc.

Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial

PubMed Central

Aga, Anna-Birgitte; Olsen, Inge Christoffer; Lillegraven, Siri; Hammer, Hilde B; Uhlig, Till; Fremstad, Hallvard; Madland, Tor Magne; Lexberg, Åse Stavland; Haukeland, Hilde; Rødevand, Erik; Høili, Christian; Stray, Hilde; Noraas, Anne; Hansen, Inger Johanne Widding; Bakland, Gunnstein; Nordberg, Lena Bugge; van der Heijde, Désirée; Kvien, Tore K

2016-01-01

Objective To determine whether a treatment strategy based on structured ultrasound assessment would lead to improved outcomes in rheumatoid arthritis, compared with a conventional strategy. Design Multicentre, open label, two arm, parallel group, randomised controlled strategy trial. Setting Ten rheumatology departments and one specialist centre in Norway, from September 2010 to September 2015. Participants 238 patients were recruited between September 2010 and April 2013, of which 230 (141 (61%) female) received the allocated intervention and were analysed for the primary outcome. The main inclusion criteria were age 18-75 years, fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis, disease modifying anti-rheumatic drug naivety with indication for disease modifying drug therapy, and time from first patient reported swollen joint less than two years. Patients with abnormal kidney or liver function or major comorbidities were excluded. Interventions 122 patients were randomised to an ultrasound tight control strategy targeting clinical and imaging remission, and 116 patients were randomised to a conventional tight control strategy targeting clinical remission. Patients in both arms were treated according to the same disease modifying anti-rheumatic drug escalation strategy, with 13 visits over two years. Main outcome measures The primary endpoint was the proportion of patients with a combination between 16 and 24 months of clinical remission, no swollen joints, and non-progression of radiographic joint damage. Secondary outcomes included measures of disease activity, radiographic progression, functioning, quality of life, and adverse events. All participants who attended at least one follow-up visit were included in the full analysis set. Results 26 (22%) of the 118 analysed patients in the ultrasound tight control arm and 21 (19%) of the 112 analysed patients in the clinical tight control arm reached the primary endpoint (mean difference 3.3%, 95% confidence interval −7.1% to 13.7%). Secondary endpoints (disease activity, physical function, and joint damage) were similar between the two groups. Six (5%) patients in the ultrasound tight control arm and seven (6%) patients in the conventional arm had serious adverse events. Conclusions The systematic use of ultrasound in the follow-up of patients with early rheumatoid arthritis treated according to current recommendations is not justified on the basis of the ARCTIC results. The findings highlight the need for randomised trials assessing the clinical application of medical technology. Trial registration Clinical trials NCT01205854. PMID:27530741

Efficacy of early administration of escitalopram on depressive and emotional symptoms and neurological dysfunction after stroke: a multicentre, double-blind, randomised, placebo-controlled study.

PubMed

Kim, Jong S; Lee, Eun-Jae; Chang, Dae-Il; Park, Jong-Ho; Ahn, Seong Hwan; Cha, Jae-Kwan; Heo, Ji Hoe; Sohn, Sung-Il; Lee, Byung-Chul; Kim, Dong-Eog; Kim, Hahn Young; Kim, Seongheon; Kwon, Do-Young; Kim, Jei; Seo, Woo-Keun; Lee, Jun; Park, Sang-Won; Koh, Seong-Ho; Kim, Jin Young; Choi-Kwon, Smi

2017-01-01

Mood and emotional disturbances are common in patients with stroke, and adversely affect the clinical outcome. We aimed to evaluate the efficacy of early administration of escitalopram to reduce moderate or severe depressive symptoms and improve emotional and neurological dysfunction in patients with stroke. This was a placebo controlled, double-blind trial done at 17 centres in South Korea. Patients who had had an acute stroke within the past 21 days were randomly assigned in a 1:1 ratio to receive oral escitalopram (10 mg/day) or placebo for 3 months. Randomisation was done with permuted blocks stratified by centre, via a web-based system. The primary endpoint was the frequency of moderate or severe depressive symptoms (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥16). Endpoints were assessed at 3 months after randomisation in the full analysis set (patients who took study medication and underwent assessment of primary endpoint after randomisation), in all patients who were enrolled and randomly assigned (intention to treat), and in all patients who completed the trial (per-protocol analysis). This trial is registered with ClinicalTrials.gov, number NCT01278498. Between Jan 27, 2011, and June 30, 2014, 478 patients were assigned to placebo (n=237) or escitalopram (n=241); 405 were included in the full analysis set (195 in the placebo group, 210 in the escitalopram group). The primary outcome did not differ by study group in the full analysis set (25 [13%] patients in the placebo group vs 27 [13%] in the escitalopram group; odds ratio [OR] 1·00, 95% CI 0·56-1·80; p>0·99) or in the intention-to-treat analysis (34 [14%] vs 35 [15%]; OR 1·01, 95% CI 0·61-1·69, p=0·96). The study medication was generally well tolerated; the most common adverse events were constipation (14 [6%] patients who received placebo vs 14 [6%] who received escitalopram), muscle pain (16 [7%] vs ten [4%]), and insomnia (12 [5%] vs 12 [5%]). Diarrhoea was more common in the escitalopram group (nine [4%] patients) than in the placebo group (two [1%] patients). Escitalopram did not significantly reduce moderate or severe depressive symptoms in patients with acute stroke. Dong-A Pharmaceutical and Ministry for Health, Welfare, and Family Affairs, South Korea. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pure transumbilical SILS gastric bypass with mechanical circular gastrojejunal anastomosis feasibility.

PubMed

Pitot, Denis; Takieddine, Mazen; Abbassi, Ziad; Agrafiotis, Apostolos; Bruyns, Laurence; Ceuterick, Michel; Daoudi, Nabil; Dolimont, Amaury; Soulimani, Abdelak; Vaneukem, Pol

2014-10-01

Since Wittgrove introduced the laparoscopic version of the gastric bypass in 1994, the interest still remains in the decrease of the abdominal wall trauma in order to optimize the benefits of laparoscopy on postoperative pain, cosmesis, hospital stay, and convalescence in bariatric patients. This work is to report the feasibility of gastric bypass surgery by a pure transumbilical single-incision laparoscopic surgery (SILS) with a mechanical circular gastrojejunal anastomosis. Thirty-four patients (10 males and 24 females) were offered to receive gastric bypass with circular mechanical gastrojejunal anastomosis by Single Incision Laparoscopic Surgery (SILS) using pure transumbilical access. Anastomotic leak occurrence was the primary end-point. Patients demographics, operative time, additional trocarts, hemorrhage, intra abdominal abscess, length of post-operative stay, readmission, 30 days death, gastrojejunal anastomosis stricture, marginal ulcers, reflux complains, seromas, incisional hernias, and % excess BMI loss were also recorded in a prospective database. Primary end-point showed no anastomotic leak occurrence during the hospital stay or during the first 30 post-operative days. SILS gastric bypass with a circular mechanical gastrojejunal anastomosis is feasible and seems to be safe.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.

Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment thatmore » integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches.« less

Inclusion and definition of acute renal dysfunction in critically ill patients in randomized controlled trials: a systematic review.

PubMed

da Hora Passos, Rogerio; Ramos, Joao Gabriel Rosa; Gobatto, André; Caldas, Juliana; Macedo, Etienne; Batista, Paulo Benigno

2018-04-24

In evidence-based medicine, multicenter, prospective, randomized controlled trials (RCTs) are the gold standard for evaluating treatment benefits and ensuring the effectiveness of interventions. Patient-centered outcomes, such as mortality, are most often the preferred evaluated outcomes. While there is currently agreement on how to classify renal dysfunction in critically ill patients , the application frequency of this new classification system in RCTs has not previously been evaluated. In this study, we aim to assess the definition of renal dysfunction in multicenter RCTs involving critically ill patients that included mortality as a primary endpoint. A comprehensive search was conducted for publications reporting multicenter randomized controlled trials (RCTs) involving adult patients in intensive care units (ICUs) that included mortality as a primary outcome. MEDLINE and PUBMED were queried for relevant articles in core clinical journals published between May 2004 and December 2017. Of 418 articles reviewed, 46 multicenter RCTs with a primary endpoint related to mortality were included. Thirty-six (78.3%) of the trial reports provided information on renal function in the participants. Only seven articles (15.2%) included mean or median serum creatinine levels, mean creatinine clearance or estimated glomerular filtration rates. Sequential organ failure assessment (SOFA) score was the most commonly used definition of renal dysfunction (20 studies; 43.5%). Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria were used in five (10.9%) trials. In thirteen trials (28.3%), no renal dysfunction criteria were reported. Only one trial excluded patients with renal dysfunction, and it used urinary output or need for renal replacement therapy (RRT) as criteria for this diagnosis. The presence of renal dysfunction was included as a baseline patient characteristic in most RCTs. The RIFLE, AKIN and KDIGO classification systems were infrequently used; renal dysfunction was generally defined using the SOFA score.

Efficacy and safety of renal denervation for Chinese patients with resistant hypertension using a microirrigated catheter: study design and protocol for a prospective multicentre randomised controlled trial.

PubMed

Liu, Zongjun; Shen, Li; Huang, Weijian; Zhao, Xianxian; Fang, Weiyi; Wang, Changqian; Yin, Zhaofang; Wang, Jianan; Fu, Guosheng; Liu, Xuebo; Jiang, Jianjun; Zhang, Zhihui; Li, Jingbo; Lu, Yingmin; Ge, Junbo

2017-09-01

Available data show that approximately 8%-18% of patients with primary hypertension will develop resistant hypertension. In recent years, catheter-based renal denervation (RDN) has emerged as a potential treatment option for resistant hypertension. A number of observational studies and randomised controlled trials among non-Chinese patients have demonstrated its potential safety and efficacy. This is a multicentre, randomised, open-label, parallel-group, active controlled trial that will investigate the efficacy and safety of a 5F saline-irrigated radiofrequency ablation (RFA) used for RDN in the treatment of Chinese patients with resistant hypertension. A total of 254 patients who have failed pharmacological therapy will be enrolled. Eligible subjects will be randomised in a 1:1 ratio to undergo RDN using the RFA plus antihypertensive medication or to receive treatment with antihypertensive medication alone. The primary outcome measure is the change in 24 hours average ambulatory systolic blood pressure from baseline to 3 months, comparing the RDN-plus-medication group with the medication-alone group. Important secondary endpoints include the change in office blood pressure from baseline to 6 months after randomisation. Safety endpoints such as changes in renal function will also be evaluated. The full analysis set, according to the intent-to-treat principle, will be established as the primary analysis population. All participants will provide informed consent; the study protocol has been approved by the Independent Ethics Committee for each site. This study is designed to investigate the efficacy and safety of RDN using a 5F saline microirrigated RFA. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of resistant hypertension in China. ClinicalTrials.gov ID: NCT02900729; pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chera, Bhishamjit S., E-mail: bchera@med.unc.edu; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Amdur, Robert J.

Purpose: To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus–associated oropharyngeal squamous cell carcinoma. Methods and Materials: The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m{sup 2}). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless ofmore » radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. Results: The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. Conclusions: The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. (ClinicalTrials.gov) ID: (NCT01530997).« less

EFFECT of daily antiseptic body wash with octenidine on nosocomial primary bacteraemia and nosocomial multidrug-resistant organisms in intensive care units: design of a multicentre, cluster-randomised, double-blind, cross-over study

PubMed Central

Meißner, Anne; Hasenclever, Dirk; Brosteanu, Oana; Chaberny, Iris Freya

2017-01-01

Introduction Nosocomial infections are serious complications that increase morbidity, mortality and costs and could potentially be avoidable. Antiseptic body wash is an approach to reduce dermal micro-organisms as potential pathogens on the skin. Large-scale trials with chlorhexidine as the antiseptic agent suggest a reduction of nosocomial infection rates. Octenidine is a promising alternative agent which could be more effective against Gram-negative organisms. We hypothesise that daily antiseptic body wash with octenidine reduces the risk of intensive care unit (ICU)-acquired primary bacteraemia and ICU-acquired multidrug-resistant organisms (MDRO) in a standard care setting. Methods and analysis EFFECT is a controlled, cluster-randomised, double-blind study. The experimental intervention consists in using octenidine-impregnated wash mitts for the daily routine washing procedure of the patients. This will be compared with using placebo wash mitts. Replacing existing washing methods is the only interference into clinical routine. Participating ICUs are randomised in an AB/BA cross-over design. There are two 15-month periods, each consisting of a 3-month wash-out period followed by a 12-month intervention and observation period. Randomisation determines only the sequence in which octenidine-impregnated or placebo wash mitts are used. ICUs are left unaware of what mitts packages they are using. The two coprimary endpoints are ICU-acquired primary bacteraemia and ICU-acquired MDRO. Endpoints are defined based on individual ward-movement history and microbiological test results taken from the hospital information systems without need for extra documentation. Data on clinical symptoms of infection are not collected. EFFECT aims at recruiting about 45 ICUs with about 225 000 patient-days per year. Ethics and dissemination The study was approved by the ethics committee of the University of Leipzig (number 340/16-ek) in November 2016. Findings will be published in peer-reviewed journals. Trial registration number DRKS-ID: DRKS00011282. PMID:29122787

Stent placement vs. balloon angioplasty for popliteal artery treatment: two-year results of a prospective, multicenter, randomized trial.

PubMed

Rastan, Aljoscha; Krankenberg, Hans; Baumgartner, Iris; Blessing, Erwin; Müller-Hülsbeck, Stefan; Pilger, Ernst; Scheinert, Dierk; Lammer, Johannes; Beschorner, Ulrich; Noory, Elias; Neumann, Franz-Josef; Zeller, Thomas

2015-02-01

To investigate the 2-year technical and clinical results of primary nitinol stent placement in comparison with percutaneous transluminal angioplasty (PTA) in the treatment of de novo lesions of the popliteal artery. The ETAP study (Endovascular Treatment of Atherosclerotic Popliteal Artery Lesions: balloon angioplasty vs. primary stenting; www.ClinicalTrials.gov identifier NCT00712309) is a prospective, randomized trial that enrolled 246 patients (158 men; mean age 72 years) who were randomly assigned to receive a nitinol stent (n=119) or PTA (n=127) for lesions averaging 42.3 mm in length. The results of the primary study endpoint were published. Secondary outcome measures and endpoints included primary patency (freedom from duplex-detected target lesion restenosis), target lesion revascularization (TLR), secondary patency, changes in ankle-brachial index and Rutherford class, and event-free survival (freedom from target limb amputation, TLR, myocardial infarction, and death). In total, 183 patients (89 stent and 94 PTA) were available for the 2-year analysis. The primary patency rate was significantly higher in the stent group (64.2%) than in the PTA group (31.3%, p=0.0001). TLR rates were 22.4% and 59.5%, respectively (p=0.0001). When provisional stent placement in the PTA arm was not considered as TLR and loss in patency, the differences prevailed between the study groups but were not significant (64.2% vs. 56.1% for primary patency, respectively; p=0.44). A significant improvement in ABI and Rutherford category was observed at 2 years in both groups. In treatment of obstructive popliteal artery lesions, provisional stenting reveals equivalent patency in comparison to primary stenting. However, the 2-year results of this trial suggest the possibility of a shift toward higher patency rates in favor of primary stenting. © The Author(s) 2015.

Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review.

PubMed

Savina, Marion; Gourgou, Sophie; Italiano, Antoine; Dinart, Derek; Rondeau, Virginie; Penel, Nicolas; Mathoulin-Pelissier, Simone; Bellera, Carine

2018-03-01

In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA). We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of Gene Expression Endpoints in the Context of a Xenopus laevis Metamorphosis-based Bioassay to Detect Thyroid Hormone Disruptors

EPA Science Inventory

This study accentuates the need to examine multiple tissues and provides critical information required for optimization of exposure regimens and endpoint assessments that focus on the detection of disruption in TH-regulatory systems.

Comparative toxicity of copper nanoparticles across three Lemnaceae species.

PubMed

Song, Lan; Vijver, Martina G; Peijnenburg, Willie J G M

2015-06-15

Metallic nanoparticles can end up in aquatic ecosystems due to their widespread application. Even though the toxicological effects of metallic nanoparticles to a diversity of species have been reported extensively, the toxicological data achieved in different studies are not always comparable and little is known regarding the comparative toxicity of nanoparticles across species, as different test strategies and endpoints were applied. To attempt to fill this knowledge gap, Spirodela polyrhiza, Lemna minor and Wolffia arrhiza were exposed to 25 nm spherical copper nanoparticles to investigate the inhibiting effect of copper nanoparticle suspensions across species at three endpoints: total frond area, frond number and dry weight based relative growth rate. The total frond area based relative growth rate was found to be the most sensitive endpoint, with an EC50 of 1.15±0.09 mg/L for S. polyrhiza, 0.84±0.12 mg/L for L. minor and 0.64±0.05 mg/L for W. arrhiza. Both the particles and the copper ions contributed to the inhibiting effects of copper nanoparticle suspensions at all endpoints studied. Dose-response related inhibiting effects caused by the copper ions were found at all endpoints studied, whereas the particles only showed dose-response related inhibiting effects on the total frond area based relative growth rate. This suggests that different physiological processes are involved in case of exposure to particles and copper ions. W. arrhiza was found to be the most sensitive species tested and S. polyrhiza was the least sensitive species tested, when the inhibiting effect was evaluated based on the relative growth rate calculated from total frond area. These findings exemplify the importance of identifying the suitable endpoints of toxicity assessment and considering the intrinsic differences between species when evaluating the toxicological profile of metallic nanoparticles across species. Copyright © 2015 Elsevier B.V. All rights reserved.