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...

Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials.

PubMed

Patel, Ravi B; Vaduganathan, Muthiah; Samman-Tahhan, Ayman; Kalogeropoulos, Andreas P; Georgiopoulou, Vasiliki V; Fonarow, Gregg C; Gheorghiade, Mihai; Butler, Javed

2016-06-01

Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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.

Biomarkers and surrogate endpoints in glaucoma clinical trials.

PubMed

Medeiros, Felipe A

2015-05-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. 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.

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.

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

Surrogate clinical endpoints to predict overall survival in non-small cell lung cancer trials-are we in a new era?

PubMed

Clarke, Jeffrey M; Wang, Xiaofei; Ready, Neal E

2015-12-01

Surrogate endpoints for clinical trials in oncology offer an alternative metric for measuring clinical benefit, allowing for shorter trial duration, smaller patient cohorts, and single arm design. The correlation of surrogate endpoints with overall survival (OS) in therapeutic studies is a central consideration to their validity. The Food and Drug Administration (FDA) recently published an analysis of fourteen clinical trials in advanced non-small cell lung cancer (NSCLC), and discovered a strong association between response rate and progression free survival. Furthermore, a correlation between response rate and OS is demonstrated when analyzing the experimental treatment arm separately, minimizing bias from patient crossover. We also highlight multiple, important considerations when using response as an endpoint in clinical trials involving NSCLC patients.

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps

PubMed Central

Kelly, Lauren E; Sinha, Yashwant; Barker, Charlotte I S; Standing, Joseph F; Offringa, Martin

2018-01-01

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families. PMID:29667952

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

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.

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.

Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

DTIC Science & Technology

2016-10-01

consensus meeting, with input from investigators in the Prostate Cancer Clinical Trials Consortium, FDA Office of Oncology Drug Products, FDA Study...Cancer Clinical Trials Consortium, FDA Office of Oncology Drug Products, FDA Study Endpoint and Label Development Team, and FDA Division of...Abstract. American Society of Clinical Oncology . Chicago IL, June 1-5, 2013. INVENTIONS, PATENTS AND LICENSES None 11 REPORTABLE OUTCOMES

Biomarkers and surrogate endpoints in clinical trials.

PubMed

Fleming, Thomas R; Powers, John H

2012-11-10

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.

Biomarkers and Surrogate Endpoints In Clinical Trials

PubMed Central

Fleming, Thomas R.; Powers, John H

2012-01-01

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures and radiological tests, often are considered as replacement endpoints or “surrogates” for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. . PMID:22711298

Remune trial will stop; new trials planned.

PubMed

James, J S

1999-05-21

A clinical trial using remune, the anti-HIV vaccine developed by the late Dr. Jonas Salk, has been ended. The study is a clinical-endpoint trial which looks for statistically significant differences in AIDS sickness or death between patients who add remune to their treatment regimens versus those who use a placebo. Agouron Pharmaceuticals and the Immune Response Corporation who were conducting the trial announced their decision to stop it after an analysis by the Data Safety Monitoring Board. No differences in clinical endpoints were found and it was projected that continuing the trial would likely not find any. The companies are now planning two new Phase III trials using viral load testing rather than clinical endpoints as study criteria.

Modeling hard clinical end-point data in economic analyses.

PubMed

Kansal, Anuraag R; Zheng, Ying; Palencia, Roberto; Ruffolo, Antonio; Hass, Bastian; Sorensen, Sonja V

2013-11-01

The availability of hard clinical end-point data, such as that on cardiovascular (CV) events among patients with type 2 diabetes mellitus, is increasing, and as a result there is growing interest in using hard end-point data of this type in economic analyses. This study investigated published approaches for modeling hard end-points from clinical trials and evaluated their applicability in health economic models with different disease features. A review of cost-effectiveness models of interventions in clinically significant therapeutic areas (CV diseases, cancer, and chronic lower respiratory diseases) was conducted in PubMed and Embase using a defined search strategy. Only studies integrating hard end-point data from randomized clinical trials were considered. For each study included, clinical input characteristics and modeling approach were summarized and evaluated. A total of 33 articles (23 CV, eight cancer, two respiratory) were accepted for detailed analysis. Decision trees, Markov models, discrete event simulations, and hybrids were used. Event rates were incorporated either as constant rates, time-dependent risks, or risk equations based on patient characteristics. Risks dependent on time and/or patient characteristics were used where major event rates were >1%/year in models with fewer health states (<7). Models of infrequent events or with numerous health states generally preferred constant event rates. The detailed modeling information and terminology varied, sometimes requiring interpretation. Key considerations for cost-effectiveness models incorporating hard end-point data include the frequency and characteristics of the relevant clinical events and how the trial data is reported. When event risk is low, simplification of both the model structure and event rate modeling is recommended. When event risk is common, such as in high risk populations, more detailed modeling approaches, including individual simulations or explicitly time-dependent event rates, are more appropriate to accurately reflect the trial data.

Ultrasound and radiology surrogate endpoints in pharmacological studies.

PubMed

Agewall, S; DeGroot, E; Marcos-Alberca, P; Zamorano, J L; Barrero, A A; Badano, L P; Perrone-Filardi, P

2012-09-01

Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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.

76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-17

...] Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer... entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics... draft guidance for industry entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

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.

Common Filing Deficiencies in Abbreviated New Drug Applications Containing Clinical Endpoint Studies.

PubMed

Fermaglich, Lewis J; Chen, Ru; Kim, Carol Y; Chuh, Eunjung Esther; Thomas, Teena; Shetty, Daiva; Lee, Julia; Young, Johnny; Fan, Ying

2018-01-01

The objective of this report is to summarize common deficiencies identified in the filing reviews of abbreviated new drug applications (ANDAs) with clinical endpoint bioequivalence studies and skin irritation, sensitization, and adhesion (I/S/A) studies received by the US Food and Drug Administration (FDA) between 2007 and 2017, to help applicants avoid common deficiencies, minimize "refuse-to-receive" (RTR) actions, "information requests," and ANDA approval delays. Multiple internal FDA databases were searched to evaluate and summarize common deficiencies identified in ANDA submissions containing clinical endpoint studies and skin I/S/A studies that required review by the Division of Clinical Review. A total of 275 ANDA submissions with filing reviews from January 2007 to June 2017 were analyzed in this report. Two hundred eighteen (79.3%) filing reviews contained one or more deficiencies. Seventy-nine (28.7%) ANDAs were issued RTR letters because of major clinical deficiencies, specifically bioequivalence and clinical deficiencies, accounting for 9% of overall identified deficiencies. Twenty-two other categories of deficiencies are summarized into 4 main categories: missing information related to the clinical studies other than data sets (38%), missing data sets (35%), formulation issues (12%), and organization/format issues (6%). The most common deficiency in the "missing information related to the clinical studies other than data sets" category was "missing clarification of information" (22%). We also noted that the Division of Filing Review has identified these same types of deficiencies since assuming responsibility of the filing assessment for ANDAs with clinical endpoint BE studies and skin I/S/A studies. In conclusion, to minimize "refuse-to-receive" actions, "information requests," and approval of ANDA delays for generic drug products, applicants should submit full clinical study reports, including all data sets for drug products recommending clinical studies.

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.

Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.

PubMed

Buyse, Marc; Molenberghs, Geert; Paoletti, Xavier; Oba, Koji; Alonso, Ariel; Van der Elst, Wim; Burzykowski, Tomasz

2016-01-01

A surrogate endpoint is intended to replace a clinical endpoint for the evaluation of new treatments when it can be measured more cheaply, more conveniently, more frequently, or earlier than that clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these. Besides the biological plausibility of a surrogate, a quantitative assessment of the strength of evidence for surrogacy requires the demonstration of the prognostic value of the surrogate for the clinical outcome, and evidence that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome. We focus on these two conditions, and outline the statistical approaches that have been proposed to assess the extent to which these conditions are fulfilled. When data are available from a single trial, one can assess the "individual level association" between the surrogate and the true endpoint. When data are available from several trials, one can additionally assess the "trial level association" between the treatment effect on the surrogate and the treatment effect on the true endpoint. In the latter case, the "surrogate threshold effect" can be estimated as the minimum effect on the surrogate endpoint that predicts a statistically significant effect on the clinical endpoint. All these concepts are discussed in the context of randomized clinical trials in oncology, and illustrated with two meta-analyses in gastric cancer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[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.

A modified varying-stage adaptive phase II/III clinical trial design.

PubMed

Dong, Gaohong; Vandemeulebroecke, Marc

2016-07-01

Conventionally, adaptive phase II/III clinical trials are carried out with a strict two-stage design. Recently, a varying-stage adaptive phase II/III clinical trial design has been developed. In this design, following the first stage, an intermediate stage can be adaptively added to obtain more data, so that a more informative decision can be made. Therefore, the number of further investigational stages is determined based upon data accumulated to the interim analysis. This design considers two plausible study endpoints, with one of them initially designated as the primary endpoint. Based on interim results, another endpoint can be switched as the primary endpoint. However, in many therapeutic areas, the primary study endpoint is well established. Therefore, we modify this design to consider one study endpoint only so that it may be more readily applicable in real clinical trial designs. Our simulations show that, the same as the original design, this modified design controls the Type I error rate, and the design parameters such as the threshold probability for the two-stage setting and the alpha allocation ratio in the two-stage setting versus the three-stage setting have a great impact on the design characteristics. However, this modified design requires a larger sample size for the initial stage, and the probability of futility becomes much higher when the threshold probability for the two-stage setting gets smaller. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical Trial Principles and Endpoint Definitions for Paravalvular Leaks in Surgical Prosthesis: An Expert Statement.

PubMed

Ruiz, Carlos E; Hahn, Rebecca T; Berrebi, Alain; Borer, Jeffrey S; Cutlip, Donald E; Fontana, Greg; Gerosa, Gino; Ibrahim, Reda; Jelnin, Vladimir; Jilaihawi, Hasan; Jolicoeur, E Marc; Kliger, Chad; Kronzon, Itzhak; Leipsic, Jonathon; Maisano, Francesco; Millan, Xavier; Nataf, Patrick; O'Gara, Patrick T; Pibarot, Philippe; Ramee, Stephen R; Rihal, Charanjit S; Rodes-Cabau, Josep; Sorajja, Paul; Suri, Rakesh; Swain, Julie A; Turi, Zoltan G; Tuzcu, E Murat; Weissman, Neil J; Zamorano, Jose L; Serruys, Patrick W; Leon, Martin B

2017-04-25

The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted. Copyright © 2017 American College of Cardiology Foundation and European Society of Cardiology. Published by Elsevier Inc. All rights reserved.

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

PubMed Central

Plewes, Katherine; Maude, Richard J.; Hanson, Josh; Herdman, M. Trent; Leopold, Stije J.; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M. Mahtab Uddin; Fanello, Caterina I.; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

2017-01-01

Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality. PMID:28052109

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

PubMed

Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

2017-01-01

Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study

PubMed Central

Erdman, Laura K.; D’Acremont, Valérie; Hayford, Kyla; Kilowoko, Mary; Kyungu, Esther; Hongoa, Philipina; Alamo, Leonor; Streiner, David L.; Genton, Blaise; Kain, Kevin C.

2015-01-01

Background Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance. Methods We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis. Results Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5–98.8), 80.8% specificity (72.6–87.1), positive likelihood ratio 4.9 (3.4–7.1), negative likelihood ratio 0.083 (0.022–0.32), and misclassification rate 0.20 (standard error 0.038). Conclusions In Tanzanian children with WHO-defined clinical pneumonia, combinations of host biomarkers distinguished between end-point pneumonia, other infiltrates, and normal chest x-ray, whereas clinical variables did not. These findings generate pathophysiological hypotheses and may have potential research and clinical utility. PMID:26366571

Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint.

PubMed

Lacy, Brian E; Nicandro, Jean Paul; Chuang, Emil; Earnest, David L

2018-01-01

Alosetron is approved to treat women with severe IBS and diarrhea (IBS-D) who have failed standard therapy. In our study, we aimed to evaluate alosetron efficacy using new US Food and Drug Administration (FDA) endpoints and utilization in clinical practice. This prospective, open-label, multicenter, observational 12-week study evaluated women with severe IBS-D enrolled in the alosetron prescribing program. The coprimary FDA endpoints were changes from baseline in stool consistency and abdominal pain severity. Responders achieved a 30% decrease compared with baseline in weekly average of the worst abdominal pain in the past 24 h, and a 50% or greater reduction from baseline in the number of days/week with at least one stool of type 6 (mushy) or type 7 (watery) consistency. Secondary endpoints included changes from baseline in stool frequency, fecal urgency and fecal incontinence. Enrolled patients ( n = 192) were primarily White (90.6%), with a mean age of 44.5 years. Patient and physician rating of IBS severity was between moderate and severe (85.9% concordance, Spearman coefficient 0.429, p < 0.0001). Alosetron 0.5 mg twice daily (82.8%) was the most common dosing regimen. A total of 152 alosetron-treated patients completed the study. Of 105 fully evaluable patients, 45% met the FDA composite endpoint responder criteria for ⩾50% of the study period. Improvements in all individual symptoms were statistically significant compared with baseline. There were no serious adverse events, cases of colonic ischemia, or complications of constipation. In a clinical practice setting study, alosetron demonstrated treatment success using a rigorous FDA composite endpoint and also improved multiple other IBS symptoms, including fecal urgency and incontinence in women with severe IBS-D [ClinicalTrials.gov identifier: NCT01257477].

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

The Role of Surrogate Endpoints in the Evaluation of Efficacy and Safety of Therapeutic Interventions in Diabetes Mellitus

PubMed Central

Wieczorek, Aleksandra; Rys, Przemyslaw; Skrzekowska-Baran, Iwona; Malecki, Maciej

2008-01-01

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology. PMID:19099084

The role of surrogate endpoints in the evaluation of efficacy and safety of therapeutic interventions in diabetes mellitus.

PubMed

Wieczorek, Aleksandra; Rys, Przemyslaw; Skrzekowska-Baran, Iwona; Malecki, Maciej

2008-01-01

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology.

Determining the Primary Endpoint for a Stimulant Abuse Trial: Lessons Learned from STRIDE (CTN 0037)

PubMed Central

Trivedi, Madhukar H.; Greer, Tracy L.; Potter, Jennifer Sharpe; Grannemann, Bruce D.; Nunes, Edward V.; Rethorst, Chad; Warden, Diane; Ring, Kolette M.; Somoza, Eugene

2012-01-01

Background No consensus is available for identifying the best primary outcome for substance abuse trials. While abstinence is the most desirable outcome for substance use interventions, a wide variety of other endpoints have been used to evaluate efficacy trials. Objectives This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common primary endpoint across trials will facilitate comparisons of treatment efficacy. Methods Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity and tests of clinical meaningfulness. Conclusion We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back (TLFB) interview conducted three times a week with recall aided by a take-home Substance Use Diary. To further improve the accuracy of the self-reported drug use, an algorithm will be applied to reconcile the results from the TLFB with the results of qualitative urine drug screens. Scientific Significance There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended endpoint be considered for use in this field. PMID:21854276

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.

Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium†

PubMed Central

Leon, Martin B.; Piazza, Nicolo; Nikolsky, Eugenia; Blackstone, Eugene H.; Cutlip, Donald E.; Kappetein, Arie Pieter; Krucoff, Mitchell W.; Mack, Michael; Mehran, Roxana; Miller, Craig; Morel, Marie-angèle; Petersen, John; Popma, Jeffrey J.; Takkenberg, Johanna J.M.; Vahanian, Alec; van Es, Gerrit-Anne; Vranckx, Pascal; Webb, John G.; Windecker, Stephan; Serruys, Patrick W.

2011-01-01

Objectives To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health. Background Transcatheter aortic valve implantation may provide a worthwhile less invasive treatment in many patients with severe aortic stenosis and since its introduction to the medical community in 2002, there has been an explosive growth in procedures. The integration of TAVI into daily clinical practice should be guided by academic activities, which requires a harmonized and structured process for data collection, interpretation, and reporting during well-conducted clinical trials. Methods and results The Valve Academic Research Consortium established an independent collaboration between Academic Research organizations and specialty societies (cardiology and cardiac surgery) in the USA and Europe. Two meetings, in San Francisco, California (September 2009) and in Amsterdam, the Netherlands (December 2009), including key physician experts, and representatives from the US Food and Drug Administration (FDA) and device manufacturers, were focused on creating consistent endpoint definitions and consensus recommendations for implementation in TAVI clinical research programs. Important considerations in developing endpoint definitions included (i) respect for the historical legacy of surgical valve guidelines; (ii) identification of pathophysiological mechanisms associated with clinical events; (iii) emphasis on clinical relevance. Consensus criteria were developed for the following endpoints: mortality, myocardial infarction, stroke, bleeding, acute kidney injury, vascular complications, and prosthetic valve performance. Composite endpoints for TAVI safety and effectiveness were also recommended. Conclusion Although consensus criteria will invariably include certain arbitrary features, an organized multidisciplinary process to develop specific definitions for TAVI clinical research should provide consistency across studies that can facilitate the evaluation of this new important catheter-based therapy. The broadly based consensus endpoint definitions described in this document may be useful for regulatory and clinical trial purposes. PMID:21216739

Surrogate endpoints and competing risk of death in cardiac arrest research.

PubMed

McCredie, Victoria A; Scales, Damon C

2016-06-29

We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest.

Clinical features and prognosis of patients with acute non-specific chest pain in emergency and cardiology departments after the introduction of high-sensitivity troponins: a prospective cohort study.

PubMed

Ilangkovan, Nivethitha; Mickley, Hans; Diederichsen, Axel; Lassen, Annmarie; Sørensen, Thomas L; Sheta, Hussam Mahmoud; Stæhr, Peter B; Mogensen, Christian Backer

2017-12-22

To determine the incidence of clinical, cardiac-related endpoints and mortality among patients presenting to an emergency or cardiology department with non-specific chest pain (NSCP), and who receive testing with a high-sensitivity troponin. A second objective was to identify risk factors for the above-noted endpoints during 12 months of follow-up. A prospective multicentre study. Emergency and cardiology departments in Southern Denmark. The study enrolled 1027 patients who were assessed for acute chest pain in an emergency or cardiology department, and in whom a myocardial infarction or another obvious reason for chest pain had been ruled out. Patients were enrolled from September 2014 to June 2015 and followed for 1 year. Clinical, cardiac-related endpoints (cardiac-related death, acute myocardial infarction, unstable angina and coronary revascularisation) and all-cause mortality. Over a period of 1 year, cardiac-related endpoints were found in 19 patients (1.9%): 0 patients experienced cardiac-related death, 2 (0.2%) had myocardial infarction, 4 (0.4%) had unstable angina pectoris and 17 (1.7%) underwent coronary revascularisation. All-cause mortality was observed in seven patients (0.7%). When compared with the general population, the standardised mortality ratio did not differ. The risk factors associated with the study endpoints included male gender, body mass index >25 kg/m 2 , previous known coronary artery disease, hypertension, hypercholesterolaemia, diabetes mellitus and the use of statins. A total of 73% of the endpoints occurred in males. The prognosis for patients with NSCP is favourable, with a 1-year mortality after discharge that is comparable with the background population. Few clinical endpoints took place during follow-up, and those that did were predominantly in males. © 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.

Combining censored and uncensored data in a U-statistic: design and sample size implications for cell therapy research.

PubMed

Moyé, Lemuel A; Lai, Dejian; Jing, Kaiyan; Baraniuk, Mary Sarah; Kwak, Minjung; Penn, Marc S; Wu, Colon O

2011-01-01

The assumptions that anchor large clinical trials are rooted in smaller, Phase II studies. In addition to specifying the target population, intervention delivery, and patient follow-up duration, physician-scientists who design these Phase II studies must select the appropriate response variables (endpoints). However, endpoint measures can be problematic. If the endpoint assesses the change in a continuous measure over time, then the occurrence of an intervening significant clinical event (SCE), such as death, can preclude the follow-up measurement. Finally, the ideal continuous endpoint measurement may be contraindicated in a fraction of the study patients, a change that requires a less precise substitution in this subset of participants.A score function that is based on the U-statistic can address these issues of 1) intercurrent SCE's and 2) response variable ascertainments that use different measurements of different precision. The scoring statistic is easy to apply, clinically relevant, and provides flexibility for the investigators' prospective design decisions. Sample size and power formulations for this statistic are provided as functions of clinical event rates and effect size estimates that are easy for investigators to identify and discuss. Examples are provided from current cardiovascular cell therapy research.

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

PubMed

Angel, Juana; Steele, A Duncan; Franco, Manuel A

2014-01-01

Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

[Immunological surrogate endpoints to evaluate vaccine efficacy].

PubMed

Jin, Pengfei; Li, Jingxin; Zhou, Yang; Zhu, Fengcai

2015-12-01

An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

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...

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

The Impact of Worsening Heart Failure in the United States

PubMed Central

Cooper, Lauren B.; DeVore, Adam D.; Felker, G. Michael

2015-01-01

Synopsis In-hospital worsening heart failure represents a clinical scenario in which a patient hospitalized for treatment of acute heart failure experiences a worsening of their condition while in the hospital, requiring escalation of therapy. In-hospital worsening heart failure is associated with worse in-hospital and post-discharge outcomes. In-hospital worsening heart failure is increasingly being used as an endpoint, or as part of a combined endpoint, in many clinical trials in acute heart failure. This endpoint has advantages over other endpoints commonly used in acute and chronic heart failure trials, such as dyspnea relief and mortality or rehospitalization. Despite the extensive study of this condition, no treatment strategies have been approved for the prevention of this condition. However, several prediction models have been developed to identify worsening heart failure. Continued study in this area is warranted. PMID:26462100

Detection of Bordetella pertussis from Clinical Samples by Culture and End-Point PCR in Malaysian Patients.

PubMed

Ting, Tan Xue; Hashim, Rohaidah; Ahmad, Norazah; Abdullah, Khairul Hafizi

2013-01-01

Pertussis or whooping cough is a highly infectious respiratory disease caused by Bordetella pertussis. In vaccinating countries, infants, adolescents, and adults are relevant patients groups. A total of 707 clinical specimens were received from major hospitals in Malaysia in year 2011. These specimens were cultured on Regan-Lowe charcoal agar and subjected to end-point PCR, which amplified the repetitive insertion sequence IS481 and pertussis toxin promoter gene. Out of these specimens, 275 were positive: 4 by culture only, 6 by both end-point PCR and culture, and 265 by end-point PCR only. The majority of the positive cases were from ≤3 months old patients (77.1%) (P < 0.001). There was no significant association between type of samples collected and end-point PCR results (P > 0.05). Our study showed that the end-point PCR technique was able to pick up more positive cases compared to culture method.

77 FR 49447 - Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-16

...] Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop AGENCY: Food and Drug... public workshop to discuss the endpoints for clinical trials of drugs and therapeutic biologics in kidney... trials of kidney transplantation. The meeting will include a discussion of measure of patient and graft...

Biomarkers and surrogate endpoints in kidney disease.

PubMed

Hartung, Erum A

2016-03-01

Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. "Hard" endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease.

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

Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper.

PubMed

Herzog, Thomas J; Armstrong, Deborah K; Brady, Mark F; Coleman, Robert L; Einstein, Mark H; Monk, Bradley J; Mannel, Robert S; Thigpen, J Tate; Umpierre, Sharee A; Villella, Jeannine A; Alvarez, Ronald D

2014-01-01

To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken. Copyright © 2013. Published by Elsevier Inc.

Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper

PubMed Central

Herzog, Thomas J.; Armstrong, Deborah K.; Brady, Mark F.; Coleman, Robert L.; Einstein, Mark H.; Monk, Bradley J.; Mannel, Robert S.; Thigpen, J. Tate; Umpierre, Sharee A.; Villella, Jeannine A.; Alvarez, Ronald D.

2015-01-01

Objective To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. Methods A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Results Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Conclusions Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken. PMID:24239753

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.

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.

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

Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis.

PubMed

Hu, Chuanpu; Zhou, Honghui

2016-02-01

Improving the quality of exposure-response modeling is important in clinical drug development. The general joint modeling of multiple endpoints is made possible in part by recent progress on the latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate, when modeling a continuous and a categorical clinical endpoint, the level of improvement achievable by joint modeling in the latent variable IDR modeling framework through the sharing of model parameters for the individual endpoints, guided by the appropriate representation of drug and placebo mechanism. This was illustrated with data from two phase III clinical trials of intravenously administered mAb X for the treatment of rheumatoid arthritis, with the 28-joint disease activity score (DAS28) and 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria were used as efficacy endpoints. The joint modeling framework led to a parsimonious final model with reasonable performance, evaluated by visual predictive check. The results showed that, compared with the more common approach of separately modeling the endpoints, it is possible for the joint model to be more parsimonious and yet better describe the individual endpoints. In particular, the joint model may better describe one endpoint through subject-specific random effects that would not have been estimable from data of this endpoint alone.

Health-related quality-of-life as co-primary endpoint in randomized clinical trials in oncology.

PubMed

Fiteni, Frédéric; Pam, Alhousseiny; Anota, Amélie; Vernerey, Dewi; Paget-Bailly, Sophie; Westeel, Virginie; Bonnetain, Franck

2015-01-01

Overall survival (OS) has been considered as the most relevant primary endpoint but trials using OS often require large numbers of patients and long-term follow-up. Therefore composite endpoints, which are assessed earlier, are frequently used as primary endpoint but suffer from important limitations specially a lack of validation as surrogate of OS. Therefore, Health-related quality of life (HRQoL) could be considered as an outcome to judge efficacy of a treatment. An alternative approach would be to combine HRQoL with composite endpoints as co-primary endpoint to ensure a clinical benefit for patients of a new therapy. The decision rules of such design, the procedure to control the Type I error and the determination of sample size remain questions to debate. Here, we discusses HRQoL as co-primary endpoints in randomized clinical trials in oncology and provide some solutions to promote such design.

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).

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

Post hoc analyses: after the facts.

PubMed

Srinivas, Titte R; Ho, Bing; Kang, Joseph; Kaplan, Bruce

2015-01-01

Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.

Does the decision in a validation process of a surrogate endpoint change with level of significance of treatment effect? A proposal on validation of surrogate endpoints.

PubMed

Sertdemir, Y; Burgut, R

2009-01-01

In recent years the use of surrogate end points (S) has become an interesting issue. In clinical trials, it is important to get treatment outcomes as early as possible. For this reason there is a need for surrogate endpoints (S) which are measured earlier than the true endpoint (T). However, before a surrogate endpoint can be used it must be validated. For a candidate surrogate endpoint, for example time to recurrence, the validation result may change dramatically between clinical trials. The aim of this study is to show how the validation criterion (R(2)(trial)) proposed by Buyse et al. are influenced by the magnitude of treatment effect with an application using real data. The criterion R(2)(trial) proposed by Buyse et al. (2000) is applied to the four data sets from colon cancer clinical trials (C-01, C-02, C-03 and C-04). Each clinical trial is analyzed separately for treatment effect on survival (true endpoint) and recurrence free survival (surrogate endpoint) and this analysis is done also for each center in each trial. Results are used for standard validation analysis. The centers were grouped by the Wald statistic in 3 equal groups. Validation criteria R(2)(trial) were 0.641 95% CI (0.432-0.782), 0.223 95% CI (0.008-0.503), 0.761 95% CI (0.550-0.872) and 0.560 95% CI (0.404-0.687) for C-01, C-02, C-03 and C-04 respectively. The R(2)(trial) criteria changed by the Wald statistics observed for the centers used in the validation process. Higher the Wald statistic groups are higher the R(2)(trial) values observed. The recurrence free survival is not a good surrogate for overall survival in clinical trials with non significant treatment effects and moderate for significant treatment effects. This shows that the level of significance of treatment effect should be taken into account in validation process of surrogate endpoints.

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.

Biomarkers and surrogate endpoints in kidney disease

PubMed Central

2015-01-01

Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. “Hard” endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease. PMID:25980469

The importance and pitfalls of correlational science in palliative care research.

PubMed

Klepstad, Pål; Kaasa, Stein

2012-12-01

Correlational science discovers associations between patient characteristics, symptoms and biomarkers. Correlational science using data from cross-sectional studies is the most frequently applied study design in palliative care research. The purpose of this review is to address the importance and potential pitfalls in correlational science. Associations observed in correlational science studies can be the basis for generating hypotheses that can be tested in experimental studies and are the basic data needed to develop classification systems that can predict patient outcomes. Major pitfalls in correlational science are that associations do not equate with causality and that statistical significance does not necessarily equal a correlation that is of clinical interest. Researchers should be aware of the end-points that are clinically relevant, that end-points should be defined before the start of the analyses, and that studies with several end-points should account for multiplicity. Correlational science in palliative care research can identify related clinical factors and biomarkers. Interpretation of identified associations should be done with careful consideration of the limitations underlying correlational analyses.

Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache.

PubMed

Aicher, Bernhard; Peil, Hubertus; Peil, Barbara; Diener, Hans-Christoph

2012-10-01

To quantify and compare the responsiveness within the meaning of clinical relevance of efficacy endpoints in a clinical trial with over the counter (OTC) analgesics for headache. Efficacy endpoints and observed differences in clinical trials need to be clinically meaningful and mirror the change in the clinical status of a patient. This must be demonstrated for the specific disease indication and the particular patient population based on the application of treatments with proven efficacy. Patient's global efficacy assessment during two study phases (pre-phase and treatment phase) was used to classify patients as satisfied or non-satisfied with the efficacy of their medication. The analysis is based on 1734 patients included in the efficacy analysis of a randomized, placebo-controlled, double-blind, multi-centre parallel group trial with six treatment arms. Based on this classification and the pain intensity recorded by the patients on a 100 mm visual analogue scale, group differences by assessment categories and receiver operating characteristic (ROC) curve methods were used to quantify responsiveness of the efficacy endpoints 'time to 50% pain relief', 'time until reduction of pain intensity to 10 mm', 'weighted sum of pain intensity difference' (%SPIDweighted), 'pain intensity difference (PID) relative to baseline at 2 hours', and 'pain-free at 2 hours'. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed for all efficacy endpoints. Patients with the highest rating of efficacy had the fastest and strongest pain relief. In comparison, patients assessing efficacy as 'less good' reached a 50% pain relief on average nearly an hour later than those scoring efficacy as at least 'good'. Simultaneously, their extent of pain relief was only half as great 2 hours after medication intake. Patients scoring efficacy as 'poor' experienced practically no pain relief within the 4 hour observation interval. ROC curve calculations confirmed an adequate responsiveness for all continuous endpoints. The following cut-off points for differentiating between satisfied and non-satisfied patients were deduced from the data in the pre- and treatment phase, respectively: 'time to 50% pain relief' 1:10 and 1:31 h:min, 'time until reduction of pain intensity to 10 mm' 2:40 and 3:00 h:min, '%SPIDweighted' 68 and 64%, 'PID at 2 hours' 35 and 35 mm. The sensitivity and specificity based on these cut-off points ranged from 70 to 79%. The binary endpoint 'pain-free at 2 hours' showed a clearly higher specificity (80 and 87%) than sensitivity (65 and 61%) in the pre- and treatment phase, respectively. When global assessment of efficacy by the patient was used as external criterion, ROC curve calculations confirmed a high responsiveness for all efficacy endpoints included in this study. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed. The endpoint '%SPIDweighted' proved slightly but consistently superior to the other endpoints. SPID and %SPIDweighted are not easy to interpret and the time course of pain reduction is of high importance for the patients in the treatment of acute pain, including headache. The endpoint 'pain-free at 2 hours' showed the expected high specificity, but at the cost of a concurrently low sensitivity and clearly makes less use of the available information than the endpoint 'time to 50% pain reduction', which combines the highly relevant aspects of time course and extent of pain reduction. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specific condition of a patient, should be added in future revisions of IHS guidelines for clinical trials in headache disorders.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective

PubMed Central

Oza, A.M.; Castonguay, V.; Tsoref, D.; Diaz–Padilla, I.; Karakasis, K.; Mackay, H.; Welch, S.; Weberpals, J.; Hoskins, P.; Plante, M.; Provencher, D.; Tonkin, K.; Covens, A.; Ghatage, P.; Gregoire, J.; Hirte, H.; Miller, D.; Rosen, B.; Maroun, J.; Buyse, M.; Coens, C.; Brady, M.F.; Stuart, G.C.E.

2011-01-01

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer. Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention. PMID:21969808

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.

On the relationship between the causal-inference and meta-analytic paradigms for the validation of surrogate endpoints.

PubMed

Alonso, Ariel; Van der Elst, Wim; Molenberghs, Geert; Buyse, Marc; Burzykowski, Tomasz

2015-03-01

The increasing cost of drug development has raised the demand for surrogate endpoints when evaluating new drugs in clinical trials. However, over the years, it has become clear that surrogate endpoints need to be statistically evaluated and deemed valid, before they can be used as substitutes of "true" endpoints in clinical studies. Nowadays, two paradigms, based on causal-inference and meta-analysis, dominate the scene. Nonetheless, although the literature emanating from these paradigms is wide, till now the relationship between them has largely been left unexplored. In the present work, we discuss the conceptual framework underlying both approaches and study the relationship between them using theoretical elements and the analysis of a real case study. Furthermore, we show that the meta-analytic approach can be embedded within a causal-inference framework on the one hand and that it can be heuristically justified why surrogate endpoints successfully evaluated using this approach will often be appealing from a causal-inference perspective as well, on the other. A newly developed and user friendly R package Surrogate is provided to carry out the evaluation exercise. © 2014, The International Biometric Society.

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

 Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

PubMed

Hilscher, Moira; Enders, Felicity B; Carey, Elizabeth J; Lindor, Keith D; Tabibian, James H

2016-01-01

 Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases

PubMed Central

2011-01-01

Background Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases. Methods To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments. Results We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment. Conclusion Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases. PMID:21733145

A Review of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient Outcomes in the United States.

PubMed

Divers, Christine; Platt, David; Wang, Edward; Lin, Jay; Lingohr-Smith, Melissa; Mathai, Stephen C

2017-01-01

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subgroups of pulmonary hypertension and are considered rare diseases. Understanding how endpoints of clinical trials (and patient registry studies) of patients with PAH and CTEPH are associated with patient outcomes is important in order to address the concerns of patients, health care providers, decision makers, and payers. The purpose of this review was to examine how endpoints used in clinical trials and patient registry studies are associated with outcomes of patients with PAH and CTEPH. A PubMed literature search was conducted to retrieve published studies, including randomized phase III clinical trials and observational studies, from years 2000 to May 2015 that evaluated the associations between change in 6-minute walking distance (6MWD), 6MWD thresholds, change in World Health Organization functional class (WHO-FC), and time to clinical worsening with outcomes of patients with PAH and CTEPH. Based on this review of published literature, a reduction in 6MWD as a criterion for PAH worsening, a deterioration in WHO-FC, and delay in the time to clinical worsening are clinically meaningful trial endpoints and are associated with outcomes of patients with PAH and CTEPH. Utilization and standardization of these endpoints will be useful for comparing interventions of clinical trials and therapies. Hospitalizations are frequent among patients with PAH and CTEPH, and total health care costs are high. From a U.S. payer perspective, clinical worsening is an important composite endpoint in that it includes hospitalization, which can be transformed into a preventative cost value associated with efficacious treatment of patients with PAH and CTEPH. In view of the greater number of medications available to treat PAH, the introduction of the first approved therapy to treat CTEPH, and the increasing use of combination pharmacotherapy, reliable prognostic markers of treatment responsiveness are important to help guide appropriate management. As new clinical trials and observational studies are conducted, it will be important to maintain universal endpoints so that health care providers, decision makers, and payers can better understand the value of targeted pharmacotherapies and combination therapies for the treatment of patients with PAH and CTEPH. Sponsorship for this review and article processing charges were funded by Bayer HealthCare Pharmaceuticals. Divers and Platt are employees of Bayer HealthCare Pharmaceuticals. Wang is an employee of Bayer HealthCare Pharmaceuticals and owns stock in the company. Lin and Lingohr-Smith are employees of Novosys Health, which received research funds from Bayer HealthCare Pharmaceuticals in connection with conducting this review and developing this manuscript. Mathai is a consultant to Bayer HealthCare Pharmaceuticals and also reports consulting fees from Actelion and Gilead. Study concept and design were contributed by Divers, Platt, Lin, and Mathai. Lin and Lingohr-Smith collected the data, and data interpretation was performed by Divers, Platt, Wang, and Matthai. The manuscript was written primarily by Lingohr-Smith, with assistance from the other authors, and revised by Divers, Platt, Wang, and Mathai.

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.

Improvement in latent variable indirect response modeling of multiple categorical clinical endpoints: application to modeling of guselkumab treatment effects in psoriatic patients.

PubMed

Hu, Chuanpu; Randazzo, Bruce; Sharma, Amarnath; Zhou, Honghui

2017-10-01

Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure-response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23. A Phase 2b study was conducted in 238 patients with psoriasis for which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores. A latent variable Type I IDR model was developed to evaluate the therapeutic effect of guselkumab dosing on 75, 90 and 100% improvement of PASI scores from baseline and PGA scores, with placebo effect empirically modeled. The results showed that the joint model is able to describe the observed data better with fewer parameters compared with the common approach of separately modeling the endpoints.

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.

On assessing surrogacy in a single trial setting using a semi-competing risks paradigm

PubMed Central

Ghosh, Debashis

2009-01-01

Summary There has been a recent emphasis on the identification of biomarkers and other biologic measures that may be potentially used as surrogate endpoints in clinical trials. We focus on the setting of data from a single clinical trial. In this paper, we consider a framework in which the surrogate must occur before the true endpoint. This suggests viewing the surrogate and true endpoints as semi-competing risks data; this approach is new to the literature on surrogate endpoints and leads to an asymmetrical treatment of the surrogate and true endpoints. However, such a data structure also conceptually complicates many of the previously considered measures of surrogacy in the literature. We propose novel estimation and inferential procedures for the relative effect and adjusted association quantities proposed by Buyse and Molenberghs (1998, Biometrics, 1014 – 1029). The proposed methodology is illustrated with application to simulated data, as well as to data from a leukemia study. PMID:18759839

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

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.

77 FR 51027 - Agency Information Collection Activities; Proposed Collection; Comment Request; Communicating...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-23

... one research project cannot test them all. In this study, we have chosen to examine three different...) Advertising.'' This study is designed to explore how consumers understand and interpret composite endpoint... clinical trials (Refs. 1 and 2). In some cases, drug efficacy can be measured by a single endpoint, such as...

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.

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

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.

Clinical evidence for orphan medicinal products-a cause for concern?

PubMed

Picavet, Eline; Cassiman, David; Hollak, Carla E; Maertens, Johan A; Simoens, Steven

2013-10-16

The difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool. We quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA. The 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal' or 'main' studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies. In conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-making.

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.

Ideal discrimination of discrete clinical endpoints using multilocus genotypes.

PubMed

Hahn, Lance W; Moore, Jason H

2004-01-01

Multifactor Dimensionality Reduction (MDR) is a method for the classification and prediction of discrete clinical endpoints using attributes constructed from multilocus genotype data. Empirical studies with both real and simulated data suggest that MDR has good power for detecting gene-gene interactions in the absence of independent main effects. The purpose of this study is to develop an objective, theory-driven approach to evaluate the strengths and limitations of MDR. To accomplish this goal, we borrow concepts from ideal observer analysis used in visual perception to evaluate the theoretical limits of classifying and predicting discrete clinical endpoints using multilocus genotype data. We conclude that MDR ideally discriminates between low risk and high risk subjects using attributes constructed from multilocus genotype data. We also how that the classification approach used once a multilocus attribute is constructed is similar to that of a naive Bayes classifier. This study provides a theoretical foundation for the continued development, evaluation, and application of the MDR as a data mining tool in the domain of statistical genetics and genetic epidemiology.

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.

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.

Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials

PubMed Central

Crane, Paul K.; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J.; Lange, Rael T.; Manley, Geoffrey T.; McCrea, Michael; Iverson, Grant L.

2017-01-01

Abstract Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint. PMID:27188248

Evaluating principal surrogate endpoints with time-to-event data accounting for time-varying treatment efficacy.

PubMed

Gabriel, Erin E; Gilbert, Peter B

2014-04-01

Principal surrogate (PS) endpoints are relatively inexpensive and easy to measure study outcomes that can be used to reliably predict treatment effects on clinical endpoints of interest. Few statistical methods for assessing the validity of potential PSs utilize time-to-event clinical endpoint information and to our knowledge none allow for the characterization of time-varying treatment effects. We introduce the time-dependent and surrogate-dependent treatment efficacy curve, ${\\mathrm {TE}}(t|s)$, and a new augmented trial design for assessing the quality of a biomarker as a PS. We propose a novel Weibull model and an estimated maximum likelihood method for estimation of the ${\\mathrm {TE}}(t|s)$ curve. We describe the operating characteristics of our methods via simulations. We analyze data from the Diabetes Control and Complications Trial, in which we find evidence of a biomarker with value as a PS.

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.

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.

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.

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

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.

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 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...

Is Suicide Ideation a Surrogate Endpoint for Geriatric Suicide?

ERIC Educational Resources Information Center

Links, Paul S.; Heisel, Marnin J.; Quastel, Adam

2005-01-01

The present study explored the validity of treating suicide ideation as a surrogate endpoint that can serve as a proxy for suicide in clinical intervention research with suicidal seniors. Two criteria; that suicide ideation is modulated by the proposed intervention and that modulation of suicide ideation leads to a quantitative reduction in…

Marital quality and health: A meta-analytic review

PubMed Central

Robles, Theodore F.; Slatcher, Richard B.; Trombello, Joseph M.; McGinn, Meghan M.

2013-01-01

This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in over 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality, r = .11, and lower cardiovascular reactivity during marital conflict, r = −.13, but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health. PMID:23527470

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.

The AIMS65 score compared with the Glasgow-Blatchford score in predicting outcomes in upper GI bleeding.

PubMed

Hyett, Brian H; Abougergi, Marwan S; Charpentier, Joseph P; Kumar, Navin L; Brozovic, Suzana; Claggett, Brian L; Travis, Anne C; Saltzman, John R

2013-04-01

We previously derived and validated the AIMS65 score, a mortality prognostic scale for upper GI bleeding (UGIB). To validate the AIMS65 score in a different patient population and compare it with the Glasgow-Blatchford risk score (GBRS). Retrospective cohort study. Adults with a primary diagnosis of UGIB. inpatient mortality. composite clinical endpoint of inpatient mortality, rebleeding, and endoscopic, radiologic or surgical intervention; blood transfusion; intensive care unit admission; rebleeding; length of stay; timing of endoscopy. The area under the receiver-operating characteristic curve (AUROC) was calculated for each score. Of the 278 study patients, 6.5% died and 35% experienced the composite clinical endpoint. The AIMS65 score was superior in predicting inpatient mortality (AUROC, 0.93 vs 0.68; P < .001), whereas the GBRS was superior in predicting blood transfusions (AUROC, 0.85 vs 0.65; P < .01) The 2 scores were similar in predicting the composite clinical endpoint (AUROC, 0.62 vs 0.68; P = .13) as well as the secondary outcomes. A GBRS of 10 and 12 or more maximized the sum of the sensitivity and specificity for inpatient mortality and rebleeding, respectively. The cutoff was 2 or more for the AIMS65 score for both outcomes. Retrospective, single-center study. The AIMS65 score is superior to the GBRS in predicting inpatient mortality from UGIB, whereas the GBRS is superior for predicting blood transfusion. Both scores are similar in predicting the composite clinical endpoint and other outcomes in clinical care and resource use. Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

Carotid Plaque Lipid Content and Fibrous Cap Status Predict Systemic CV Outcomes: The MRI Substudy in AIM-HIGH.

PubMed

Sun, Jie; Zhao, Xue-Qiao; Balu, Niranjan; Neradilek, Moni B; Isquith, Daniel A; Yamada, Kiyofumi; Cantón, Gádor; Crouse, John R; Anderson, Todd J; Huston, John; O'Brien, Kevin; Hippe, Daniel S; Polissar, Nayak L; Yuan, Chun; Hatsukami, Thomas S

2017-03-01

The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease. Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden. As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models. Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment. Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Evidence for the use of parenteral nutrition in the pediatric intensive care unit.

PubMed

Fivez, Tom; Kerklaan, Dorian; Mesotten, Dieter; Verbruggen, Sascha; Joosten, Koen; Van den Berghe, Greet

2017-02-01

During hospitalization in a pediatric intensive care unit (PICU), critically ill children are fed artificially. Administered via the preferred enteral route, caloric targets are often not reached. Hence, parenteral nutrition is given to this patient population. In this review we analyzed the available evidence from randomized controlled trials (RCTs) that supports the use of parenteral nutrition in children during critical illness. A search strategy in Ovid MEDLINE and Ovid EMBASE was created and trial registries were screened to identify the relevant RCTs. Studies were included if they were randomized controlled trials, involved pediatric patients admitted to PICU, and compared different dosing/compositions of parenteral nutrition. Descriptive studies and reviews were excluded. Of the 584 articles identified by the search strategy, only 114 articles were retained after title screening. Further abstract and full text screening identified 6 small RCTs that compared two dosing/composition strategies of parenteral nutrition. These trials reported differences in surrogate endpoints without an effect on hard clinical endpoints. The RCTs observed improvements in these surrogate endpoints with the use of more calories or when parenteral glutamine or fish oil was added. The few RCTs suggest that surrogate endpoints can be affected by providing parenteral nutrition to critically ill children, but the studies were not statistically powered to draw meaningful clinical conclusions. Large RCTs with clinically relevant outcome measures are urgently needed to support the current nutritional guidelines that advise the use of parenteral nutrition in the PICU. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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.

Upper Limb Coordination in Individuals With Stroke: Poorly Defined and Poorly Quantified.

PubMed

Tomita, Yosuke; Rodrigues, Marcos R M; Levin, Mindy F

2017-01-01

The identification of deficits in interjoint coordination is important in order to better focus upper limb rehabilitative treatment after stroke. The majority of standardized clinical measures characterize endpoint performance, such as accuracy, speed, and smoothness, based on the assumption that endpoint performance reflects interjoint coordination, without measuring the underlying temporal and spatial sequences of joint recruitment directly. However, this assumption is questioned since improvements of endpoint performance can be achieved through different degrees of restitution or compensation of upper limb motor impairments based on the available kinematic redundancy of the system. Confusion about adequate measurement may stem from a lack a definition of interjoint coordination during reaching. We suggest an operational definition of interjoint coordination during reaching as a goal-oriented process in which joint degrees of freedom are organized in both spatial and temporal domains such that the endpoint reaches a desired location in a context-dependent manner. In this point-of-view article, we consider how current approaches to laboratory and clinical measures of coordination comply with our definition. We propose future study directions and specific research strategies to develop clinical measures of interjoint coordination with better construct and content validity than those currently in use.

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...

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.

A Review of Clinical Trials Conducted With Oral, Multicomponent Dietary Supplements for Improving Photoaged Skin.

PubMed

Birnbaum, Jay; Le Moigne, Anne; Dispensa, Lisa; Buchner, Larry

2015-12-01

Although the FDA does not require documentation of efficacy of dietary supplements, prospective clinical studies, including randomized controlled trials, have been conducted with individual micronutrients alone and in combination with other ingredients for promoting skin health. Proposed mechanisms include antioxidation, anti-inflammation, photoprotection, collagen formation, reductions in matrix metalloproteinases, and other effects on photoaging. Literature searches were conducted to identify clinical trials assessing multicomponent dietary supplement formulations on photoaging outcomes. Sixteen studies of various nutrient and non-nutrient ingredients, including essential micronutrients (vitamins, minerals), plant extracts (polyphenols, carotenoids), and marine- or animal-derived ingredients, were identified. Studies were single center, 2-12 months in duration, primarily enrolled women, and evaluated numerous outcomes, including investigator/subject assessments and instrumental/objective measures. Methods to control for potential confounders were implemented in some studies, including limiting sun exposure, cosmetic procedures, and changes in dietary habits/body weight. Given the range of different products, clinical/methodologic heterogeneity, insufficient detail in reporting, and lack of comparable outcome measures, quantitative analysis of results was not possible. Results of individual studies revealed significant improvements from baseline for the dietary supplement group(s) on ≥ 1 endpoint across all studies; significant differences from placebo were observed in 7 of 12 controlled studies (although only 1 study designated a prospectively defined primary endpoint). Most products had only been tested in 1 study; confirmatory studies were rarely conducted per the publicly available literature. Meaningful assessment of dietary supplements, which typically contain nutrients found in the diet, requires unique methodologic considerations and endpoints appropriate for measuring changes that are more subtle and gradual than those observed with topical/injectable products. Although definitive conclusions could not be drawn from the existing evidence, available data are supportive of beneficial effects of oral multicomponent supplements on skin health. Confirmation of positive effects with the same formulation/endpoint from more than a single study/investigator is needed.

Potential surrogate endpoints for prostate cancer survival: analysis of a phase III randomized trial.

PubMed

Ray, Michael E; Bae, Kyounghwa; Hussain, Maha H A; Hanks, Gerald E; Shipley, William U; Sandler, Howard M

2009-02-18

The identification of surrogate endpoints for prostate cancer-specific survival may shorten the length of clinical trials for prostate cancer. We evaluated distant metastasis and general clinical treatment failure as potential surrogates for prostate cancer-specific survival by use of data from the Radiation Therapy and Oncology Group 92-02 randomized trial. Patients (n = 1554 randomly assigned and 1521 evaluable for this analysis) with locally advanced prostate cancer had been treated with 4 months of neoadjuvant and concurrent androgen deprivation therapy with external beam radiation therapy and then randomly assigned to no additional therapy (control arm) or 24 additional months of androgen deprivation therapy (experimental arm). Data from landmark analyses at 3 and 5 years for general clinical treatment failure (defined as documented local disease progression, regional or distant metastasis, initiation of androgen deprivation therapy, or a prostate-specific antigen level of 25 ng/mL or higher after radiation therapy) and/or distant metastasis were tested as surrogate endpoints for prostate cancer-specific survival at 10 years by use of Prentice's four criteria. All statistical tests were two-sided. At 3 years, 1364 patients were alive and contributed data for analysis. Both distant metastasis and general clinical treatment failure at 3 years were consistent with all four of Prentice's criteria for being surrogate endpoints for prostate cancer-specific survival at 10 years. At 5 years, 1178 patients were alive and contributed data for analysis. Although prostate cancer-specific survival was not statistically significantly different between treatment arms at 5 years (P = .08), both endpoints were consistent with Prentice's remaining criteria. Distant metastasis and general clinical treatment failure at 3 years may be candidate surrogate endpoints for prostate cancer-specific survival at 10 years. These endpoints, however, must be validated in other datasets.

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

PubMed

Johannsson, Gudmundur; Bidlingmaier, Martin; Biller, Beverly M K; Boguszewski, Margaret; Casanueva, Felipe F; Chanson, Philippe; Clayton, Peter E; Choong, Catherine S; Clemmons, David; Dattani, Mehul; Frystyk, Jan; Ho, Ken; Hoffman, Andrew R; Horikawa, Reiko; Juul, Anders; Kopchick, John J; Luo, Xiaoping; Neggers, Sebastian; Netchine, Irene; Olsson, Daniel S; Radovick, Sally; Rosenfeld, Ron; Ross, Richard J; Schilbach, Katharina; Solberg, Paulo; Strasburger, Christian; Trainer, Peter; Yuen, Kevin C J; Wickstrom, Kerstin; Jorgensen, Jens O L

2018-03-01

The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly. © 2018 Growth Hormone Research Society.

Percutaneous left atrial appendage occlusion: the Munich consensus document on definitions, endpoints, and data collection requirements for clinical studies.

PubMed

Tzikas, Apostolos; Holmes, David R; Gafoor, Sameer; Ruiz, Carlos E; Blomström-Lundqvist, Carina; Diener, Hans-Christoph; Cappato, Riccardo; Kar, Saibal; Lee, Randal J; Byrne, Robert A; Ibrahim, Reda; Lakkireddy, Dhanunjaya; Soliman, Osama I; Nabauer, Michael; Schneider, Steffen; Brachmann, Johannes; Saver, Jeffrey L; Tiemann, Klaus; Sievert, Horst; Camm, A John; Lewalter, Thorsten

2017-01-01

The increasing interest in left atrial appendage occlusion (LAAO) for ischaemic stroke prevention in atrial fibrillation (AF) fuels the need for more clinical data on the safety and effectiveness of this therapy. Besides an assessment of the effectiveness of the therapy in specific patients groups, comparisons with pharmacological stroke prophylaxis, surgical approaches, and other device-based therapies are warranted. This paper documents the consensus reached among clinical experts in relevant disciplines from Europe and North America, European cardiology professional societies, and representatives from the medical device industry regarding definitions for parameters and endpoints to be assessed in clinical studies. Adherence to these definitions is proposed in order to achieve a consistent approach across clinical studies on LAAO among the involved stakeholders and various clinical disciplines and thereby facilitate continued evaluation of therapeutic strategies available. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Endpoints and surrogate endpoints in colorectal cancer: a review of recent developments.

PubMed

Piedbois, Pascal; Buyse, Marc

2008-07-01

The purpose of this review is to discuss recently published work on endpoints for early and advanced colorectal cancer, as well as the statistical approaches used to validate surrogate endpoints. Most attempts to validate surrogate endpoints have estimated the correlation between the surrogate and the true endpoint, and between the treatment effects on these endpoints. The correlation approach has made it possible to validate disease-free survival and progression-free survival as acceptable surrogates for overall survival in early and advanced disease, respectively. The search for surrogate endpoints will intensify over the coming years. In parallel, efforts to either standardize or extend the endpoints or both will improve the reliability and relevance of clinical trial results.

Mixed response and time-to-event endpoints for multistage single-arm phase II design.

PubMed

Lai, Xin; Zee, Benny Chung-Ying

2015-06-04

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

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.

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

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.

What makes patients with fibromyalgia feel better? Correlations between Patient Global Impression of Improvement and changes in clinical symptoms and function: a pooled analysis of 4 randomized placebo-controlled trials of duloxetine.

PubMed

Hudson, James I; Arnold, Lesley M; Bradley, Laurence A; Choy, Ernest H S; Mease, Philip J; Wang, Fujun; Ahl, Jonna; Wohlreich, Madelaine M

2009-11-01

To investigate the relationship between changes in clinical rating scale items and endpoint Patient Global Impression of Improvement (PGI-I). Data were pooled from 4 randomized, double-blind, placebo-controlled studies of duloxetine in patients with fibromyalgia (FM). Variables included in the analyses were those that assessed symptoms in FM domains of pain, fatigue, sleep, cognitive difficulties, emotional well-being, physical function, and impact on daily living. The association of endpoint PGI-I with changes from baseline in individual variables was assessed using Pearson product-moment correlations (r). Stepwise linear regression was used to identify those variables for which changes from baseline were statistically significant independent predictors of the endpoint PGI-I ratings. Changes in pain variables and interference of symptoms with the ability to work were highly correlated (r >or= 0.5 or r

The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification.

PubMed

Harris, Hannah M; Carpenter, Jessica M; Black, Jonathan R; Smitherman, Todd A; Sufka, Kenneth J

2017-06-01

Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance. Rats received 5 nitroglycerin (10mg/kg/2ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15days. Behavioral endpoints were assessed 110min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia. Animals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode. Most NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia. This repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints. Copyright © 2017 Elsevier B.V. All rights reserved.

Validation of surrogate endpoints in cancer clinical trials via principal stratification with an application to a prostate cancer trial.

PubMed

Tanaka, Shiro; Matsuyama, Yutaka; Ohashi, Yasuo

2017-08-30

Increasing attention has been focused on the use and validation of surrogate endpoints in cancer clinical trials. Previous literature on validation of surrogate endpoints are classified into four approaches: the proportion explained approach; the indirect effects approach; the meta-analytic approach; and the principal stratification approach. The mainstream in cancer research has seen the application of a meta-analytic approach. However, VanderWeele (2013) showed that all four of these approaches potentially suffer from the surrogate paradox. It was also shown that, if a principal surrogate satisfies additional criteria called one-sided average causal sufficiency, the surrogate cannot exhibit a surrogate paradox. Here, we propose a method for estimating principal effects under a monotonicity assumption. Specifically, we consider cancer clinical trials which compare a binary surrogate endpoint and a time-to-event clinical endpoint under two naturally ordered treatments (e.g. combined therapy vs. monotherapy). Estimation based on a mean score estimating equation will be implemented by the expectation-maximization algorithm. We will also apply the proposed method as well as other surrogacy criteria to evaluate the surrogacy of prostate-specific antigen using data from a phase III advanced prostate cancer trial, clarifying the complementary roles of both the principal stratification and meta-analytic approaches in the evaluation of surrogate endpoints in cancer. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Electroencephalogram-based indices applied to dogs' depth of anaesthesia monitoring.

PubMed

Brás, S; Georgakis, A; Ribeiro, L; Ferreira, D A; Silva, A; Antunes, L; Nunes, C S

2014-12-01

Hypnotic drug administration causes alterations in the electroencephalogram (EEG) in a dose-dependent manner. These changes cannot be identified easily in the raw EEG, therefore EEG based indices were adopted for assessing depth of anaesthesia (DoA). This study examines several indices for estimating dogs' DoA. Data (EEG, clinical end-points) were collected from 8 dogs anaesthetized with propofol. EEG was initially collected without propofol. Then, 100 ml h⁻¹ (1000 mg h⁻¹) of propofol 1% infusion rate was administered until a deep anaesthetic stage was reached. The infusion rate was temporarily increased to 200 ml h⁻¹ (2000 mg h⁻¹) to achieve 80% of burst suppression. The index performance was accessed by correlation coefficient with the propofol concentrations, and prediction probability with the anaesthetic clinical end-points. The temporal entropy and the averaged instantaneous frequency were the best indices because they exhibit: (a) strong correlations with propofol concentrations, (b) high probabilities of predicting anaesthesia clinical end-points. Copyright © 2014 Elsevier Ltd. All rights reserved.

Time-dependent efficacy of longitudinal biomarker for clinical endpoint.

PubMed

Kolamunnage-Dona, Ruwanthi; Williamson, Paula R

2018-06-01

Joint modelling of longitudinal biomarker and event-time processes has gained its popularity in recent years as they yield more accurate and precise estimates. Considering this modelling framework, a new methodology for evaluating the time-dependent efficacy of a longitudinal biomarker for clinical endpoint is proposed in this article. In particular, the proposed model assesses how well longitudinally repeated measurements of a biomarker over various time periods (0,t) distinguish between individuals who developed the disease by time t and individuals who remain disease-free beyond time t. The receiver operating characteristic curve is used to provide the corresponding efficacy summaries at various t based on the association between longitudinal biomarker trajectory and risk of clinical endpoint prior to each time point. The model also allows detecting the time period over which a biomarker should be monitored for its best discriminatory value. The proposed approach is evaluated through simulation and illustrated on the motivating dataset from a prospective observational study of biomarkers to diagnose the onset of sepsis.

[Clinical research=design*measurements*statistical analyses].

PubMed

Furukawa, Toshiaki

2012-06-01

A clinical study must address true endpoints that matter for the patients and the doctors. A good clinical study starts with a good clinical question. Formulating a clinical question in the form of PECO can sharpen one's original question. In order to perform a good clinical study one must have a knowledge of study design, measurements and statistical analyses: The first is taught by epidemiology, the second by psychometrics and the third by biostatistics.

Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease.

PubMed

Satlin, Andrew; Wang, Jinping; Logovinsky, Veronika; Berry, Scott; Swanson, Chad; Dhadda, Shobha; Berry, Donald A

2016-01-01

Recent failures in phase 3 clinical trials in Alzheimer's disease (AD) suggest that novel approaches to drug development are urgently needed. Phase 3 risk can be mitigated by ensuring that clinical efficacy is established before initiating confirmatory trials, but traditional phase 2 trials in AD can be lengthy and costly. We designed a Bayesian adaptive phase 2, proof-of-concept trial with a clinical endpoint to evaluate BAN2401, a monoclonal antibody targeting amyloid protofibrils. The study design used dose response and longitudinal modeling. Simulations were used to refine study design features to achieve optimal operating characteristics. The study design includes five active treatment arms plus placebo, a clinical outcome, 12-month primary endpoint, and a maximum sample size of 800. The average overall probability of success is ≥80% when at least one dose shows a treatment effect that would be considered clinically meaningful. Using frequent interim analyses, the randomization ratios are adapted based on the clinical endpoint, and the trial can be stopped for success or futility before full enrollment. Bayesian statistics can enhance the efficiency of analyzing the study data. The adaptive randomization generates more data on doses that appear to be more efficacious, which can improve dose selection for phase 3. The interim analyses permit stopping as soon as a predefined signal is detected, which can accelerate decision making. Both features can reduce the size and duration of the trial. This study design can mitigate some of the risks associated with advancing to phase 3 in the absence of data demonstrating clinical efficacy. Limitations to the approach are discussed.

Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema.

PubMed

Lassere, Marissa N; Johnson, Kent R; Boers, Maarten; Tugwell, Peter; Brooks, Peter; Simon, Lee; Strand, Vibeke; Conaghan, Philip G; Ostergaard, Mikkel; Maksymowych, Walter P; Landewe, Robert; Bresnihan, Barry; Tak, Paul-Peter; Wakefield, Richard; Mease, Philip; Bingham, Clifton O; Hughes, Michael; Altman, Doug; Buyse, Marc; Galbraith, Sally; Wells, George

2007-03-01

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. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.

Clinical endpoints in allogeneic hematopoietic stem cell transplantation studies: the cost of freedom.

PubMed

Kim, Haesook T; Armand, Philippe

2013-06-01

When designing a study for allogeneic hematopoietic stem cell transplantation (HSCT), many choices must be made, including conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prevention method. For each of these, there are a growing number of options, which can be combined into a bewildering number of possible HSCT protocols. To properly interpret the results of a given strategy and compare them with others, it is essential that there be agreement on the definitions and estimation methods of HSCT endpoints. We report a survey of the recent HSCT literature that confirms the heterogeneity of endpoint definitions and estimation methods used. Unfortunately, this heterogeneity may lead to significant biases in the estimates of key endpoints, including nonrelapse mortality, relapse, GVHD, or engraftment. This can preclude adequate comparisons among studies, even though such comparisons are the major tool with which to improve HSCT outcome. In the context of our survey, we discuss some of the statistical issues that arise when dealing with HSCT endpoints and the ramifications of the choice of endpoint definition, when the endpoint occurs in the context of competing risks. Our hope is to generate discussion and motivate a search for consensus among those who perform transplantations and statisticians. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.

PubMed

Wagner, J A; Ball, J R

2015-07-01

The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use? © 2015 American Society for Clinical Pharmacology and Therapeutics.

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics.

PubMed

Liu, Jianfang; Lichtenberg, Tara; Hoadley, Katherine A; Poisson, Laila M; Lazar, Alexander J; Cherniack, Andrew D; Kovatich, Albert J; Benz, Christopher C; Levine, Douglas A; Lee, Adrian V; Omberg, Larsson; Wolf, Denise M; Shriver, Craig D; Thorsson, Vesteinn; Hu, Hai

2018-04-05

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Copyright © 2018 Elsevier Inc. All rights reserved.

Hard, harder, hardest: principal stratification, statistical identifiability, and the inherent difficulty of finding surrogate endpoints.

PubMed

Wolfson, Julian; Henn, Lisa

2014-01-01

In many areas of clinical investigation there is great interest in identifying and validating surrogate endpoints, biomarkers that can be measured a relatively short time after a treatment has been administered and that can reliably predict the effect of treatment on the clinical outcome of interest. However, despite dramatic advances in the ability to measure biomarkers, the recent history of clinical research is littered with failed surrogates. In this paper, we present a statistical perspective on why identifying surrogate endpoints is so difficult. We view the problem from the framework of causal inference, with a particular focus on the technique of principal stratification (PS), an approach which is appealing because the resulting estimands are not biased by unmeasured confounding. In many settings, PS estimands are not statistically identifiable and their degree of non-identifiability can be thought of as representing the statistical difficulty of assessing the surrogate value of a biomarker. In this work, we examine the identifiability issue and present key simplifying assumptions and enhanced study designs that enable the partial or full identification of PS estimands. We also present example situations where these assumptions and designs may or may not be feasible, providing insight into the problem characteristics which make the statistical evaluation of surrogate endpoints so challenging.

Hard, harder, hardest: principal stratification, statistical identifiability, and the inherent difficulty of finding surrogate endpoints

PubMed Central

2014-01-01

In many areas of clinical investigation there is great interest in identifying and validating surrogate endpoints, biomarkers that can be measured a relatively short time after a treatment has been administered and that can reliably predict the effect of treatment on the clinical outcome of interest. However, despite dramatic advances in the ability to measure biomarkers, the recent history of clinical research is littered with failed surrogates. In this paper, we present a statistical perspective on why identifying surrogate endpoints is so difficult. We view the problem from the framework of causal inference, with a particular focus on the technique of principal stratification (PS), an approach which is appealing because the resulting estimands are not biased by unmeasured confounding. In many settings, PS estimands are not statistically identifiable and their degree of non-identifiability can be thought of as representing the statistical difficulty of assessing the surrogate value of a biomarker. In this work, we examine the identifiability issue and present key simplifying assumptions and enhanced study designs that enable the partial or full identification of PS estimands. We also present example situations where these assumptions and designs may or may not be feasible, providing insight into the problem characteristics which make the statistical evaluation of surrogate endpoints so challenging. PMID:25342953

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.

Study design of J-ELD AF: A multicenter prospective cohort study to investigate the efficacy and safety of apixaban in Japanese elderly patients.

PubMed

Akao, Masaharu; Yamashita, Takeshi; Okumura, Ken

2016-12-01

Apixaban, one of the non-vitamin K antagonist oral anticoagulants, was reported to be effective and safe in stroke prevention in patients with atrial fibrillation (AF) based on the global randomized clinical trial, but data are limited on the efficacy and safety of apixaban in Japanese elderly patients. The J-ELD AF Registry is a large-scale, contemporary observational study, continuously and prospectively registering elderly Japanese patients with AF aged 75 years or older who are currently taking apixaban or the elderly who are to receive apixaban in daily clinical practice, and accumulating the outcomes during one-year follow-up period. In addition to standard baseline characteristics, prothrombin time and anti-Xa activity will be measured to investigate the biomarker characteristics. The primary efficacy endpoints will be stroke and systemic embolism, and the primary safety endpoint will be major bleeding requiring hospitalization. The secondary endpoints in this study will be all-cause death, cardiovascular death, acute myocardial infarction, and the composite of stroke/systemic embolism, cardiovascular death, and acute myocardial infarction. As a primary analysis, the primary/secondary endpoints in the enrolled patients will be totalized for the entire group, and the incidence of events will be described by age, CHADS 2 score, HAS-BLED score, and apixaban dose (5 or 2.5mg bid). The factors that independently predict the incidence of the primary/secondary endpoints will be searched for by Cox regression. The relationship between the biomarkers and the primary/secondary endpoints will also be examined in an explorative manner. This study will provide important information on the efficacy and safety of apixaban in elderly Japanese patients aged 75 years or older, and those of low-dose administration of apixaban (2.5mg bid) for which many of the Japanese elderly are indicated. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective.

PubMed

Bouxsein, Mary L; Delmas, Pierre D

2008-08-01

Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.

The concept of equivalence and its application to the assessment of thrombolytic effects.

PubMed

Hampton, J R

1997-12-01

Very large clinical trials have become the norm in the evaluation of thrombolytic agents, and these 'megatrials' are administratively complex and expensive. It remains to be seen whether new thrombolytics will lead to further large reductions in fatality from an acute myocardial infarction, but new agents may well have advantages in areas such as safety and ease of administration, in addition to other clinical benefits (i.e. fewer cases of cardiac shock, heart failure and atrial fibrillation). The problem is how to introduce such new agents without a megatrial for each one. Endpoints other than fatality have some advantages and, in thrombolysis, angiographic studies are a necessary step in the development of new agents. However, such studies may not always correlate precisely with the results of mortality endpoint studies. Measurements of the resolution of ST segment elevation in myocardial infarction seem to provide a very useful method of assessing thrombolysis, but although such a technique can be applied to large numbers of patients, it cannot totally replace mortality endpoint trials. The 'equivalence' of two treatments is a clinical, not a statistical, concept, although statistical principles that allow equivalence to be investigated with medium-sized trials should be applied. Demonstrating equivalence in outcome between the new thrombolytic reteplase and streptokinase was the aim of the INJECT study.

Trial endpoints for drug approval in oncology: Chemoprevention.

PubMed

Beitz, J

2001-04-01

As with other drugs, new drug applications for marketing approval of chemopreventive drugs must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. This article summarizes the regulatory requirements for traditional marketing approval, as well as for approval under the accelerated approval regulations. Unlike traditional approval, accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Discussions with the Food and Drug Administration (FDA) regarding the validity of trial endpoints that may serve as surrogates for clinical benefit for accelerated approval should take place as early as possible in drug development. Meetings with the FDA to discuss these issues may be requested throughout the clinical development of a new drug.

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.

The data management of a phase III efficacy trial of an 11-valent pneumococcal conjugate vaccine and related satellite studies conducted in the Philippines

PubMed Central

2012-01-01

Background A large phase III placebo-controlled, randomized efficacy trial of an investigational 11-valent pneumococcal conjugate vaccine against pneumonia in children less than 2 years of age was conducted in the Philippines from July 2000 to December 2004. Clinical data from 12,194 children who were given either study vaccine or placebo was collected from birth up to two years of age for the occurrence of radiologically proven pneumonia as the primary endpoint, and for clinical pneumonia and invasive pneumococcal disease as the secondary endpoints. Several tertiary endpoints were also explored. Along the core trial, several satellite studies on herd immunity, cost-effectiveness of the study vaccine, acute otitis media, and wheezing were conducted. Results We describe here in detail how the relevant clinical records were managed and how quality control procedures were implemented to ensure that valid data were obtained respectively for the core trial and for the satellite studies. We discuss how the task was achieved, what the challenges were and what might have been done differently. Conclusions There were several factors that made the task of data management doable and efficient. First, a pre-trial data management system was available. Secondly, local committed statisticians, programmers and support staff were available and partly familiar to clinical trials. Thirdly, the personnel had undergone training during trial and grew with the task they were supposed to do. Thus the knowledge needed to develop and operate clinical data system was fully transferred to local staff. Trial registration Current Controlled Trials ISRCTN62323832 PMID:22676626

The data management of a phase III efficacy trial of an 11-valent pneumococcal conjugate vaccine and related satellite studies conducted in the Philippines.

PubMed

Sanvictores, Diozele Hazel M; Lucero, Marilla G; Nohynek, Hanna; Tallo, Veronica L; Tanskanen, Antti; Nillos, Leilani T; Williams, Gail

2012-06-07

A large phase III placebo-controlled, randomized efficacy trial of an investigational 11-valent pneumococcal conjugate vaccine against pneumonia in children less than 2 years of age was conducted in the Philippines from July 2000 to December 2004. Clinical data from 12,194 children who were given either study vaccine or placebo was collected from birth up to two years of age for the occurrence of radiologically proven pneumonia as the primary endpoint, and for clinical pneumonia and invasive pneumococcal disease as the secondary endpoints. Several tertiary endpoints were also explored. Along the core trial, several satellite studies on herd immunity, cost-effectiveness of the study vaccine, acute otitis media, and wheezing were conducted. We describe here in detail how the relevant clinical records were managed and how quality control procedures were implemented to ensure that valid data were obtained respectively for the core trial and for the satellite studies. We discuss how the task was achieved, what the challenges were and what might have been done differently. There were several factors that made the task of data management doable and efficient. First, a pre-trial data management system was available. Secondly, local committed statisticians, programmers and support staff were available and partly familiar to clinical trials. Thirdly, the personnel had undergone training during trial and grew with the task they were supposed to do. Thus the knowledge needed to develop and operate clinical data system was fully transferred to local staff. Current Controlled Trials ISRCTN62323832.

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.

Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium.

PubMed

Seltzer, Jonathan H; Heise, Ted; Carson, Peter; Canos, Daniel; Hiatt, Jo Carol; Vranckx, Pascal; Christen, Thomas; Cutlip, Donald E

2017-08-01

This white paper provides a summary of presentations, discussions and conclusions of a Thinktank entitled "The Role of Endpoint Adjudication in Medical Device Clinical Trials". The think tank was cosponsored by the Cardiac Safety Research Committee, MDEpiNet and the US Food and Drug Administration (FDA) and was convened at the FDA's White Oak headquarters on March 11, 2016. Attention was focused on tailoring best practices for evaluation of endpoints in medical device clinical trials, practical issues in endpoint adjudication of therapeutic, diagnostic, biomarker and drug-device combinations, and the role of adjudication in regulatory and reimbursement issues throughout the device lifecycle. Attendees included representatives from medical device companies, the FDA, Centers for Medicare and Medicaid Services (CMS), end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding (1) rationale for when adjudication is appropriate, (2) best practices establishment and operation of a medical device adjudication committee and (3) the role of endpoint adjudication for post market evaluation in the emerging era of real world evidence. Copyright © 2017. Published by Elsevier Inc.

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.

Role of multidetector computed tomography in the diagnosis and management of patients attending the rapid access chest pain clinic, The Scottish computed tomography of the heart (SCOT-HEART) trial: study protocol for randomized controlled trial

PubMed Central

2012-01-01

Background Rapid access chest pain clinics have facilitated the early diagnosis and treatment of patients with coronary heart disease and angina. Despite this important service provision, coronary heart disease continues to be under-diagnosed and many patients are left untreated and at risk. Recent advances in imaging technology have now led to the widespread use of noninvasive computed tomography, which can be used to measure coronary artery calcium scores and perform coronary angiography in one examination. However, this technology has not been robustly evaluated in its application to the clinic. Methods/design The SCOT-HEART study is an open parallel group prospective multicentre randomized controlled trial of 4,138 patients attending the rapid access chest pain clinic for evaluation of suspected cardiac chest pain. Following clinical consultation, participants will be approached and randomized 1:1 to receive standard care or standard care plus ≥64-multidetector computed tomography coronary angiography and coronary calcium score. Randomization will be conducted using a web-based system to ensure allocation concealment and will incorporate minimization. The primary endpoint of the study will be the proportion of patients diagnosed with angina pectoris secondary to coronary heart disease at 6 weeks. Secondary endpoints will include the assessment of subsequent symptoms, diagnosis, investigation and treatment. In addition, long-term health outcomes, safety endpoints, such as radiation dose, and health economic endpoints will be assessed. Assuming a clinic rate of 27.0% for the diagnosis of angina pectoris due to coronary heart disease, we will need to recruit 2,069 patients per group to detect an absolute increase of 4.0% in the rate of diagnosis at 80% power and a two-sided P value of 0.05. The SCOT-HEART study is currently recruiting participants and expects to report in 2014. Discussion This is the first study to look at the implementation of computed tomography in the patient care pathway that is outcome focused. This study will have major implications for the management of patients with cardiovascular disease. Trial registration ClinicalTrials.gov Identifier: NCT01149590 PMID:23036114

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.

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.

Application of the Stable Isotope Label Approach in Clinical Development-Supporting Dissolution Specifications for a Commercial Tablet Product with Tafenoquine, a Long Half-life Compound.

PubMed

Goyal, Navin; Mohamed, Khadeeja; Rolfe, Katie; Sahota, Satty; Ernest, Terry; Duparc, Stephan; Taylor, Maxine; Casillas, Linda; Koh, Gavin C K W

2018-06-04

Bioavailability/bioequivalence studies supporting clinical drug development or commercial supply of drug formulations are often time, cost, and resource intensive. The drug's pharmacokinetic (PK) variability, systemic half-life, and safety issues may pose additional challenges. The stable isotope label (SIL) approach provides a useful tool to significantly reduce the study size in clinical PK studies. Tafenoquine (TQ) is an 8-aminoquinoline under development for preventing Plasmodium vivax malaria relapse. This SIL study assessed the impact of differences in the in vitro dissolution profiles on in vivo exposure of TQ tablets. Fourteen healthy volunteers received a single dose of 300 mg TQ Intermediate Aged or 300 mg TQ Control formulations in this single-center, two-arm, randomized, open-label, parallel-group study. Endpoints included the geometric means ratio of the area under the concentration-time curve (AUC (0-t) and AUC (0-∞) ; primary endpoint) and maximum plasma concentration (C max ) for Intermediate Aged versus Control TQ; correlation of PK parameters for venous versus peripheral (via microsample) blood samples; and safety and tolerability endpoints. Geometric mean ratios for PK parameters (AUC and C max ) and their 90% confidence intervals fell well within standard bioequivalence limits (0.80-1.25). Only one mild adverse event (skin abrasion) was reported. In summary, this SIL methodology-based study demonstrates that the observed differences in the in vitro dissolution profiles between the Control and Intermediate Aged TQ tablets have no clinically relevant effect on systemic TQ exposure. The SIL approach was successfully implemented to enable the setting of a clinically relevant dissolution specification. This study (GSK study number 201780) is registered at clinicaltrials.gov with identifier NCT02751294.

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.

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

PubMed Central

Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

2014-01-01

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330 PMID:24841795

Pneumococcal Conjugate Vaccines and Otitis Media: An Appraisal of the Clinical Trials

PubMed Central

Fletcher, Mark A.; Fritzell, Bernard

2012-01-01

Streptococcus pneumoniae is the predominant otitis media pathogen and its prevention through effective vaccination could diminish childhood illness and antibiotic use. This paper reviews 5 pneumococcal conjugate vaccine (PCV) trials that used otitis media as an endpoint: Northern California Kaiser Permanente (NCKP; vaccine, 7-valent PCV [PCV7]-CRM); Finnish Otitis Media (FinOM; vaccines, PCV7-CRM or PCV7-OMPC); Native American Trial (vaccine, PCV7-CRM); Pneumococcal Otitis Efficacy Trial (POET; vaccine, 11-valent PCV [PCV11]-PD). For the microbiological endpoint, vaccine efficacy against vaccine-serotype pneumococcal otitis media was about 60% across trials. Against the clinical endpoint of all episodes, vaccine efficacy was 7% (PCV7-CRM/NCKP), 6% (PCV7-CRM/FinOM), −1% (PCV7-OMPC/FinOM), and −0.4% (PCV7-CRM/Native American Trial); 34% against first episodes of ear, nose, and throat specialist-referral cases (PCV11-PD/POET). Both follow-up through 2 years of age, for the 5 trials, and long-term follow-up, for PCV7-CRM/NCKP and PCV7-CRM/FinOM, demonstrated greater vaccine efficacy against recurrent AOM and tympanostomy-tube placement, suggesting that vaccination against early episodes of AOM may prevent subsequent episodes of complicated otitis media. Although study designs varied by primary endpoint measured, age at follow-up, source of middle-ear fluid for culture, case ascertainment, and type of randomization, each clinical trial demonstrated vaccine efficacy against microbiological and/or clinical otitis media. PMID:22701486

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.

Power/Sample Size Calculations for Assessing Correlates of Risk in Clinical Efficacy Trials

PubMed Central

Gilbert, Peter B.; Janes, Holly E.; Huang, Yunda

2016-01-01

In a randomized controlled clinical trial that assesses treatment efficacy, a common objective is to assess the association of a measured biomarker response endpoint with the primary study endpoint in the active treatment group, using a case-cohort, case-control, or two-phase sampling design. Methods for power and sample size calculations for such biomarker association analyses typically do not account for the level of treatment efficacy, precluding interpretation of the biomarker association results in terms of biomarker effect modification of treatment efficacy, with detriment that the power calculations may tacitly and inadvertently assume that the treatment harms some study participants. We develop power and sample size methods accounting for this issue, and the methods also account for inter-individual variability of the biomarker that is not biologically relevant (e.g., due to technical measurement error). We focus on a binary study endpoint and on a biomarker subject to measurement error that is normally distributed or categorical with two or three levels. We illustrate the methods with preventive HIV vaccine efficacy trials, and include an R package implementing the methods. PMID:27037797

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

Trials with patient-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR).

PubMed

Mercieca-Bebber, Rebecca; Williams, Douglas; Tait, Margaret-Ann; Roydhouse, Jessica; Busija, Lucy; Sundaram, Chindhu Shunmuga; Wilson, Michelle; Langford, Ailsa; Rutherford, Claudia; Roberts, Natasha; King, Madeleine; Vodicka, Elisabeth; Devine, Beth

2018-06-18

It is important to understand the number, types and regions of trials that include patient-reported outcomes (PROs) to appreciate how patient experiences have been considered in studies of health and interventions. Twenty-seven percent of trials registered with ClinicalTrials.gov (2007-2013) included PROs; however, a regional breakdown was not provided and no reviews have been conducted of the Australia New Zealand Clinical Trials Registry (ANZCTR). We aimed to identify trials registered with ANZCTR with PRO endpoints and describe their characteristics. ANZCTR was systematically searched from inception (2005) to 31 March 2017 for trials with PRO endpoints. Search terms included PRO measures listed in Patient-Reported Outcomes Quality of Life Instrument Database and Grid-Enabled Measures, as well as generic PRO terms (e.g. "quality of life" (QOL)). Trial endpoints were individually coded using an established framework to identify trials with PROs for the analysis. Of 13,666 registered trials, 6168 (45.1%) included a PRO. The proportion of studies including PROs increased between 2006 and 2016 (r = 0.74, p = 0.009). Among the 6168 trials, there were 17,961 individual PRO endpoints, including symptoms/functional outcomes/condition-specific QOL (65.6%), generic QOL (13.2%), patient-reported experiences (9.9%), patient-reported behaviours (7.9%). Mental health was the most common category (99.8% included PROs), followed by physical medicine/rehabilitation (65.6%), musculoskeletal (63.5%), public health (63.1%), and cancer (54.2%). Our findings suggest growing use of PROs in the assessment of health and interventions in ANZ. Our review identifies trial categories with limited patient-reported information and provides a basis for future work on the impact of PRO findings in clinical care.

Defining clinically important perioperative blood loss and transfusion for the Standardised Endpoints for Perioperative Medicine (StEP) collaborative: a protocol for a scoping review.

PubMed

Bartoszko, Justyna; Vorobeichik, Leon; Jayarajah, Mohandas; Karkouti, Keyvan; Klein, Andrew A; Lamy, Andre; Mazer, C David; Murphy, Mike; Richards, Toby; Englesakis, Marina; Myles, Paul S; Wijeysundera, Duminda N

2017-06-30

'Standardised Endpoints for Perioperative Medicine' (StEP) is an international collaboration undertaking development of consensus-based consistent definitions for endpoints in perioperative clinical trials. Inconsistency in endpoint definitions can make interpretation of trial results more difficult, especially if conflicting evidence is present. Furthermore, this inconsistency impedes evidence synthesis and meta-analyses. The goals of StEP are to harmonise definitions for clinically meaningful endpoints and specify standards for endpoint reporting in clinical trials. To help inform this endeavour, we aim to conduct a scoping review to systematically characterise the definitions of clinically important endpoints in the existing published literature on perioperative blood loss and transfusion. The scoping review will be conducted using the widely adopted framework developed by Arksey and O'Malley, with modifications from Levac. We refined our methods with guidance from research librarians as well as researchers and clinicians with content expertise. The electronic literature search will involve several databases including Medline, PubMed-not-Medline and Embase. Our review has three objectives, namely to (1) identify definitions of significant blood loss and transfusion used in previously published large perioperative randomised trials; (2) identify previously developed consensus-based definitions for significant blood loss and transfusion in perioperative medicine and related fields; and (3) describe the association between different magnitudes of blood loss and transfusion with postoperative outcomes. The multistage review process for each question will involve two reviewers screening abstracts, reading full-text articles and performing data extraction. The abstracted data will be organised and subsequently analysed in an iterative process. This scoping review of the previously published literature does not require research ethics approval. The results will be used to inform a consensus-based process to develop definitions of clinically important perioperative blood loss and transfusion. The results of the scoping review will be published in a peer-reviewed scientific journal. © 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.

Improved participants' understanding of research information in real settings using the SIDCER informed consent form: a randomized-controlled informed consent study nested with eight clinical trials.

PubMed

Koonrungsesomboon, Nut; Tharavanij, Thipaporn; Phiphatpatthamaamphan, Kittichet; Vilaichone, Ratha-Korn; Manuwong, Sudsayam; Curry, Parichat; Siramolpiwat, Sith; Punchaipornpon, Thanachai; Kanitnate, Supakit; Tammachote, Nattapol; Yamprasert, Rodsarin; Chanvimalueng, Waipoj; Kaewkumpai, Ruchirat; Netanong, Soiphet; Kitipawong, Peerapong; Sritipsukho, Paskorn; Karbwang, Juntra

2017-02-01

This study aimed to test the applicability and effectiveness of the principles and informed consent form (ICF) template proposed by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER) across multiple clinical trials involving Thai research participants with various conditions. A single-center, randomized-controlled study nested with eight clinical trials was conducted at Thammasat University Hospital, Thailand. A total of 258 participants from any of the eight clinical trials were enrolled and randomly assigned to read either the SIDCER ICF (n = 130) or the conventional ICF (n = 128) of the respective trial. Their understanding of necessary information was assessed using the post-test questionnaire; they were allowed to consult a given ICF while completing the questionnaire. The primary endpoint was the proportion of the participants who had the post-test score of ≥80%, and the secondary endpoint was the total score of the post-test. The proportion of the participants in the SIDCER ICF group who achieved the primary endpoint was significantly higher than that of the conventional ICF group (60.8 vs. 41.4%, p = 0.002). The total score of the post-test was also significantly higher among the participants who read the SIDCER ICF than those who read the conventional ICF (83.3 vs. 76.0%, p < 0.001). The present study demonstrated that the SIDCER ICF was applicable and effective to improve Thai research participants' understanding of research information in diverse clinical trials. Using the SIDCER ICF methodology, clinical researchers can improve the quality of ICFs for their trials.

The Sleep Apnea cardioVascular Endpoints (SAVE) Trial: Rationale, Ethics, Design, and Progress

PubMed Central

Antic, Nick A.; Heeley, Emma; Anderson, Craig S.; Luo, Yuanming; Wang, Jiguang; Neal, Bruce; Grunstein, Ron; Barbe, Ferran; Lorenzi-Filho, Geraldo; Huang, Shaoguang; Redline, Susan; Zhong, Nanshan; McEvoy, R. Doug

2015-01-01

The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed. Clinical Trials Registration Number: NCT00738179. Australia New Zealand Clinical Trials Registry Number: ACTRN12608000409370. Citation: Antic NA, Heeley E, Anderson CS, Luo Y, Wang J, Neal B, Grunstein R, Barbe F, Lorenzi-Filho G, Huang S, Redline S, Zhong N, McEvoy RD. The sleep apnea cardiovascular endpoints (SAVE) trial: rationale, ethics, design, and progress. SLEEP 2015;38(8):1247–1257. PMID:25669180

Improvement in surrogate endpoints by a multidisciplinary team in a mobile clinic serving a low-income, immigrant minority population in South Florida.

PubMed

Singh-Franco, Devada; Perez, Alexandra; Wolowich, William R

2013-02-01

To determine effect on surrogate endpoints for cardiovascular disease (CVD), we performed a retrospective chart review of 114 patients seen by a multidisciplinary team that provided primary care services in a mobile clinic over 12 months. Eligible patients had outcomes available for at least six months. Mixed effect modeling examined variation in surrogate markers for CVD: blood pressure (BP), heart rate, and body mass index. Repeated measures ANOVA compared lipids, hemoglobin A1c, and medication use from baseline and throughout study. Most patients were female (75%), Haitian (76%), and low-income ($747/month) with average age 63 years. Common diagnoses were hypertension (82%) and hyperlipidemia (63%). Significant reduction in systolic BP, total- and LDL-cholesterol, and hemoglobin A1c were found (p<.05). Use of ACE-inhibitors, beta-blockers, diuretics, aspirin, metformin, and statins increased significantly (p<.05). Mobile clinic with a multidisciplinary team improved surrogate endpoints over 12 months in underserved, low-income, mostly foreign-born, Haitian population in U.S.

Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials.

PubMed

Pasquini, Marcelo C; Logan, Brent; Jones, Richard J; Alousi, Amin M; Appelbaum, Frederick R; Bolaños-Meade, Javier; Flowers, Mary E D; Giralt, Sergio; Horowitz, Mary M; Jacobsohn, David; Koreth, John; Levine, John E; Luznik, Leo; Maziarz, Richard; Mendizabal, Adam; Pavletic, Steven; Perales, Miguel-Angel; Porter, David; Reshef, Ran; Weisdorf, Daniel; Antin, Joseph H

2018-06-01

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. 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.

Bayesian Adaptive Trial Design for a Newly Validated Surrogate Endpoint

PubMed Central

Renfro, Lindsay A.; Carlin, Bradley P.; Sargent, Daniel J.

2011-01-01

Summary The evaluation of surrogate endpoints for primary use in future clinical trials is an increasingly important research area, due to demands for more efficient trials coupled with recent regulatory acceptance of some surrogates as ‘valid.’ However, little consideration has been given to how a trial which utilizes a newly-validated surrogate endpoint as its primary endpoint might be appropriately designed. We propose a novel Bayesian adaptive trial design that allows the new surrogate endpoint to play a dominant role in assessing the effect of an intervention, while remaining realistically cautious about its use. By incorporating multi-trial historical information on the validated relationship between the surrogate and clinical endpoints, then subsequently evaluating accumulating data against this relationship as the new trial progresses, we adaptively guard against an erroneous assessment of treatment based upon a truly invalid surrogate. When the joint outcomes in the new trial seem plausible given similar historical trials, we proceed with the surrogate endpoint as the primary endpoint, and do so adaptively–perhaps stopping the trial for early success or inferiority of the experimental treatment, or for futility. Otherwise, we discard the surrogate and switch adaptive determinations to the original primary endpoint. We use simulation to test the operating characteristics of this new design compared to a standard O’Brien-Fleming approach, as well as the ability of our design to discriminate trustworthy from untrustworthy surrogates in hypothetical future trials. Furthermore, we investigate possible benefits using patient-level data from 18 adjuvant therapy trials in colon cancer, where disease-free survival is considered a newly-validated surrogate endpoint for overall survival. PMID:21838811

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.

Warfarin Pharmacogenetics

PubMed Central

Johnson, Julie A.; Cavallari, Larisa H.

2014-01-01

The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID:25282448

Translational research in addiction: toward a framework for the development of novel therapeutics.

PubMed

Paterson, Neil E

2011-06-15

The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation. 2011 Elsevier Inc. All rights reserved.

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.

Comparison of intradermal dilutional testing, skin prick testing, and modified quantitative testing for common allergens.

PubMed

Peltier, Jacques; Ryan, Matthew W

2007-08-01

To compare and correlate wheal size using the Multi-Test II applicator with the endpoint obtained by intradermal dilutional testing (IDT) for 5 common allergens. To examine the safety of modified quantitative testing (MQT) for determining immunotherapy starting doses. Prospective comparative clinical study. A total of 134 subjects were simultaneously skin tested for immediate hypersensitivity using the Multi-Test II device and IDT. There was a 77% concordance between results from IDT and results from MQT. When there was a difference, MQT predicted a safer endpoint for starting immunotherapy in all but 2 cases. Wheal size by SPT is predictive of endpoint by IDT. MQT is nearly as effective as formal IDT in determining endpoint. Modified quantitative testing appears to be a safe alternative to IDT for determining starting doses for immunotherapy.

Clinical Observed Performance Evaluation: A Prospective Study in Final Year Students of Surgery

ERIC Educational Resources Information Center

Markey, G. C.; Browne, K.; Hunter, K.; Hill, A. D.

2011-01-01

We report a prospective study of clinical observed performance evaluation (COPE) for 197 medical students in the pre-qualification year of clinical education. Psychometric quality was the main endpoint. Students were assessed in groups of 5 in 40-min patient encounters, with each student the focus of evaluation for 8 min. Each student had a series…

Evaluating principal surrogate endpoints with time-to-event data accounting for time-varying treatment efficacy

PubMed Central

Gabriel, Erin E.; Gilbert, Peter B.

2014-01-01

Principal surrogate (PS) endpoints are relatively inexpensive and easy to measure study outcomes that can be used to reliably predict treatment effects on clinical endpoints of interest. Few statistical methods for assessing the validity of potential PSs utilize time-to-event clinical endpoint information and to our knowledge none allow for the characterization of time-varying treatment effects. We introduce the time-dependent and surrogate-dependent treatment efficacy curve, \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${\\mathrm {TE}}(t|s)$\\end{document}, and a new augmented trial design for assessing the quality of a biomarker as a PS. We propose a novel Weibull model and an estimated maximum likelihood method for estimation of the \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${\\mathrm {TE}}(t|s)$\\end{document} curve. We describe the operating characteristics of our methods via simulations. We analyze data from the Diabetes Control and Complications Trial, in which we find evidence of a biomarker with value as a PS. PMID:24337534

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.

Priorities for CMV vaccine development

PubMed Central

Krause, Philip R.; Bialek, Stephanie R.; Boppana, Suresh B.; Griffiths, Paul D.; Laughlin, Catherine A.; Ljungman, Per; Mocarski, Edward S.; Pass, Robert F.; Read, Jennifer S.; Schleiss, Mark R.; Plotkin, Stanley A.

2015-01-01

A multidisciplinary meeting addressed priorities related to development of vaccines against cytomegalovirus (CMV), the cause of congenital CMV (cCMV) disease and of serious disease in the immunocompromised. Participants discussed optimal uses of a CMV vaccine, aspects of clinical study design, and the value of additional research. A universal childhood CMV vaccine could potentially rapidly reduce cCMV disease, as infected children are sources of viral transmission to seronegative and seropositive mothers. A vaccine administered to adolescents or adult women could also reduce cCMV disease by making them immune prior to pregnancy. Clinical trials of CMV vaccines in women should evaluate protection against cCMV infection, an essential precursor of cCMV disease, which is a more practical and acceptable endpoint for assessing vaccine effects on maternal-fetal transmission. Clinical trials of vaccines to evaluate prevention of CMV disease in stem cell transplant recipients could use CMV viremia at a level triggering preemptive antiviral therapy as an endpoint, because widespread use of preemptive and prophylactic antivirals has rendered CMV-induced disease too rare to be a practical endpoint for clinical trials. In solid organ transplant patients, CMV-associated disease is sufficiently common for use as a primary endpoint. Additional research to advance CMV vaccine development should include identifying factors that predict fetal loss due to CMV, determining age-specific incidence and transmission rates, defining the mechanism and relative contributions of maternal reactivation and re-infection to cCMV disease, developing assays that can distinguish between reactivation and re-infection in seropositive vaccinees, further defining predictors of sequelae from cCMV infection, and identifying clinically relevant immune response parameters to CMV (including developing validated assays that could assess CMV antibody avidity) that could lead to the establishment of immune correlates of protection. PMID:24129123

To what extent have functional studies of ischaemia in animals been useful in the assessment of potential neuroprotective agents?

PubMed

Hunter, A J; Mackay, K B; Rogers, D C

1998-02-01

A general consensus is being reached on the use of a combination of mortality and functional end-points in clinical trials of neuroprotective agents. However, to date, few preclinical studies have examined the effects of putative neuroprotective agents on functional outcome after ischaemia. The data described in this review show the importance of combining both histopathological and neurobehavioural studies when evaluating the neuroprotective efficacy of anti-ischaemic agents in animal models of cerebral ischaemia. Here, Jackie Hunter, Ken Mackay and Derek Rogers argue that measures of functional improvement in models of ischaemia should be incorporated to characterize further the neuroprotection afforded by a compound that could aid the selection of doses and end-point measures in early clinical trials.

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

Successful Repeat Catheter Ablation of Recurrent Longstanding Persistent Atrial Fibrillation With Rotor Elimination as the Procedural Endpoint: A Case Series.

PubMed

Sommer, Philipp; Kircher, Simon; Rolf, Sascha; John, Silke; Arya, Arash; Dinov, Borislav; Richter, Sergio; Bollmann, Andreas; Hindricks, Gerhard

2016-03-01

There remains a lack of consensus regarding the ideal ablation strategy for atrial fibrillation (AF), particularly in patients with persistent or longstanding persistent AF. Given increasing evidence from clinical imaging studies that rotors sustain AF, rotor elimination may be a desirable procedural endpoint. However, there is no description to date of the clinical outcomes using rotor elimination during ablation as the procedural endpoint. Moreover, a series of studies question whether procedural AF termination is a desirable endpoint for ablation after many forms of AF ablation. We report a single-center experience of rotor elimination during AF ablation using Focal Impulse and Rotor Mapping (FIRM), describing 20 consecutive patients with case descriptions of 3 patients with recurrent longstanding persistent AF after prior ablation. In all cases, endocardial mapping using a 64-electrode basket catheter was performed to identify rotors, which were eliminated using radiofrequency catheter ablation. After it was verified that all identified rotors were eliminated, standard ablation consisting of PV isolation was performed. Notably, persistent AF terminated in only 1/20 (5%) patients. However, after a follow-up of 6 months, single-procedure freedom from AF was 80% (16/20 patients) with only 1 patient on antiarrhythmic drugs. All three patients in the highlighted series are AF free despite the lack of acute procedural AF termination. Patients with persistent AF including those with unsuccessful prior ablation can be treated successfully by rotor targeted ablation, using the elimination of all rotors rather than acute AF termination as the procedural endpoint. © 2015 Wiley Periodicals, Inc.

Evaluating Candidate Principal Surrogate Endpoints

PubMed Central

Gilbert, Peter B.; Hudgens, Michael G.

2009-01-01

Summary Frangakis and Rubin (2002, Biometrics 58, 21–29) proposed a new definition of a surrogate endpoint (a “principal” surrogate) based on causal effects. We introduce an estimand for evaluating a principal surrogate, the causal effect predictiveness (CEP) surface, which quantifies how well causal treatment effects on the biomarker predict causal treatment effects on the clinical endpoint. Although the CEP surface is not identifiable due to missing potential outcomes, it can be identified by incorporating a baseline covariate(s) that predicts the biomarker. Given case–cohort sampling of such a baseline predictor and the biomarker in a large blinded randomized clinical trial, we develop an estimated likelihood method for estimating the CEP surface. This estimation assesses the “surrogate value” of the biomarker for reliably predicting clinical treatment effects for the same or similar setting as the trial. A CEP surface plot provides a way to compare the surrogate value of multiple biomarkers. The approach is illustrated by the problem of assessing an immune response to a vaccine as a surrogate endpoint for infection. PMID:18363776

A novel integrated care concept (NICC) versus standard care in the treatment of chronic cardiovascular diseases: protocol for the randomized controlled trial CardioCare MV.

PubMed

Schmidt, Christian; Öner, Alper; Mann, Miriam; Krockenberger, Katja; Abbondanzieri, Melanie; Brandewiede, Bernard; Brüge, Armin; Hostenkamp, Gisela; Kaiser, Axel; Neumeyer, Henriette; Ziegler, Andreas

2018-02-20

Cardiovascular diseases are the major cause of death globally and represent a major economic burden on health care systems. Positive effects of disease management programs have been shown for patients with heart failure (HF). Remote monitoring and telemonitoring with active intervention are beneficial in atrial fibrillation (AF) and therapy-resistant hypertension (TRH), respectively. For these patients, we have developed a novel integrated care concept (NICC) which combines telemedicine with intensive support by a care center, including a call center, an integrated care network including inpatient and outpatient care providers and guideline therapy for patients. The aim of the study is to demonstrate the superiority of NICC over guideline therapy alone. The trial is designed as open-label, bi-center, parallel-group design with two groups and a blinded observer. Patients will be included if they are either inpatients or if they are referred to the outpatient clinic of the hospitals by their treating physician. Randomization will be done individually with stratification by cardiovascular disease (AF, HF, TRH), center and admission type. Primary endpoints are based on the 1-year observation period after randomization. The first primary endpoint is the composite endpoint consisting of mortality, stroke and myocardial infarction. The number of hospitalizations form the second primary endpoint. The third primary endpoint is identical to the first primary endpoint plus cardiac decompensation. Adjustments for multiple testing are done using a fall-back strategy. Secondary endpoints include patient adherence, health care costs, quality of life, and safety. A sample size of 2930 gives 80% power at the two-sided 2.5% test level for the first primary endpoint. The power for the second primary endpoint is 99.8% at this sample size, and it is 80% with 1086 patients. This study will inform care providers whether quality of care can be improved by an integrated care concept providing telemedicine through a round-the-clock call center approach. We expect that cost of the NICC will be lower than standard care because of reduced hospitalizations. If the study has a positive result, NICC is planned to be immediately rolled out in the federal state of Mecklenburg-West Pomerania and other federal states in Germany. The trial will also guide additional research to disentangle the effects of this complex intervention. DRKS, ID: DRKS00013124 . Registered on 5 October 2017; ClinicalTrials.gov , ID: NCT03317951. Registered on 17 October 2017.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

PubMed

Calderón, M A; Larenas, D; Kleine-Tebbe, J; Jacobsen, L; Passalacqua, G; Eng, P A; Varga, E M; Valovirta, E; Moreno, C; Malling, H J; Alvarez-Cuesta, E; Durham, S; Demoly, P

2011-10-01

For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. © 2011 John Wiley & Sons A/S.

A back translation of pregabalin and carbamazepine against evoked and non-evoked endpoints in the rat spared nerve injury model of neuropathic pain.

PubMed

Lau, W; Dykstra, C; Thevarkunnel, S; Silenieks, L B; de Lannoy, I A M; Lee, D K H; Higgins, G A

2013-10-01

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 μg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition. Copyright © 2013 Elsevier Ltd. All rights reserved.

Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials.

PubMed

Mayer-Hamblett, Nicole; Saiman, Lisa; Lands, Larry C; Anstead, Michael; Rosenfeld, Margaret; Kloster, Margaret; Fisher, Leigh; Ratjen, Felix

2013-09-01

In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use. A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed. 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]). PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

Patient-reported urinary incontinence after radiotherapy for prostate cancer: Quantifying the dose-effect.

PubMed

Cozzarini, Cesare; Rancati, Tiziana; Palorini, Federica; Avuzzi, Barbara; Garibaldi, Elisabetta; Balestrini, Damiano; Cante, Domenico; Munoz, Fernando; Franco, Pierfrancesco; Girelli, Giuseppe; Sini, Carla; Vavassori, Vittorio; Valdagni, Riccardo; Fiorino, Claudio

2017-10-01

Urinary incontinence following radiotherapy (RT) for prostate cancer (PCa) has a relevant impact on patient's quality of life. The aim of the study was to assess the unknown dose-effect relationship for late patient-reported urinary incontinence (LPRUI). Patients were enrolled within the multi-centric study DUE01. Clinical and dosimetry data including the prescribed 2Gy equivalent dose (EQD2) were prospectively collected. LPRUI was evaluated through the ICIQ-SF questionnaire filled in by the patients at RT start/end and therefore every 6months. Patients were treated with conventional (74-80Gy, 1.8-2Gy/fr) or moderately hypo-fractionated RT (65-75.2Gy, 2.2-2.7Gy/fr) in 5 fractions/week with intensity-modulated radiotherapy. Six different end-points of 3-year LPRUI, including or not patient's perception (respectively, subjective and objective end-points), were considered. Multivariable logistic models were developed for each end-point. Data of 298 patients were analyzed. The incidence of the most severe end-point (ICIQ-SF>12) was 5.1%. EQD2 calculated with alpha-beta=0.8Gy showed the best performance in fitting data: the risk of LPRUI markedly increased for EQD2>80Gy. Previous abdominal/pelvic surgery and previous TURP were the clinical factors more significantly predictive of LPRUI. Models showed excellent performances in terms of goodness-of-fit and calibration, confirmed by bootstrap-based internal validation. When included in the analyses, baseline symptoms were a major predictor for 5 out of six end-points. LPRUI after RT for PCa dramatically depends on EQD2 and few clinical factors. Results are consistent with a larger than expected impact of moderate hypo-fractionation on the risk of LPRUI. As expected, baseline symptoms, as captured by ICIQ-SF, are associated to an increased risk of LPRUI. Copyright © 2017 Elsevier B.V. All rights reserved.

Prediction of clinical outcome in patients treated with cardiac resynchronization therapy - the role of NT-ProBNP and a combined response score.

PubMed

Bakos, Z; Chatterjee, N C; Reitan, C; Singh, J P; Borgquist, R

2018-04-24

Cardiac resynchronization therapy (CRT) is an established therapy for appropriately selected patients with heart failure. Response to CRT has been heterogeneously defined using both clinical and echocardiographic measures, with poor correlation between the two. The study cohort was comprised of 202 CRT-treated patients and CRT response was defined at 6 months post-implant. Echocardiographic response (E+) was defined as a reduction in LVESV ≥ 15%, clinical response as an improvement of ≥ 1 NYHA class (C+), and biomarker response as a ≥ 25% reduction in NT-proBNP(B+). The association of response measures (E+, B+, C+; response score range 0-3) and clinical endpoints at 3 years was assessed in landmarked Cox models. Echo and clinical responders demonstrated greater declines in NT-proBNP than non-responders (median [E+/B+]: -52%, [E+]: -27%, [C+]: -39% and [E-/C-]: -13%; p = 0.01 for trend). Biomarker (HR 0.43 [95% CI: 0.22-0.86], p = 0.02) and clinical (HR 0.40 [0.23-0.70] p = 0.001) response were associated with a significantly reduced risk of the primary endpoint. When integrating each response measure into a composite score, each 1 point increase was associated with a 31% decreased risk for a composite endpoint of mortality, LVAD, transplant and HF hospitalization (HR 0.69 [95% CI: 0.50-0.96], p = 0.03), and a 52% decreased risk of all-cause mortality (HR 0.48 [95% CI: 0.26-0.89], p = 0.02). Serial changes in NT-proBNP are associated with clinical outcomes following CRT implant. Integration of biomarker, clinical, and echocardiographic response may discriminate CRT responders versus non-responders in a clinically meaningful way, and with higher accuracy. The cohort was combined from study NCT01949246 and the study based on local review board approval 2011/550 in Lund, Sweden.

A Bayesian prediction model between a biomarker and the clinical endpoint for dichotomous variables.

PubMed

Jiang, Zhiwei; Song, Yang; Shou, Qiong; Xia, Jielai; Wang, William

2014-12-20

Early biomarkers are helpful for predicting clinical endpoints and for evaluating efficacy in clinical trials even if the biomarker cannot replace clinical outcome as a surrogate. The building and evaluation of an association model between biomarkers and clinical outcomes are two equally important concerns regarding the prediction of clinical outcome. This paper is to address both issues in a Bayesian framework. A Bayesian meta-analytic approach is proposed to build a prediction model between the biomarker and clinical endpoint for dichotomous variables. Compared with other Bayesian methods, the proposed model only requires trial-level summary data of historical trials in model building. By using extensive simulations, we evaluate the link function and the application condition of the proposed Bayesian model under scenario (i) equal positive predictive value (PPV) and negative predictive value (NPV) and (ii) higher NPV and lower PPV. In the simulations, the patient-level data is generated to evaluate the meta-analytic model. PPV and NPV are employed to describe the patient-level relationship between the biomarker and the clinical outcome. The minimum number of historical trials to be included in building the model is also considered. It is seen from the simulations that the logit link function performs better than the odds and cloglog functions under both scenarios. PPV/NPV ≥0.5 for equal PPV and NPV, and PPV + NPV ≥1 for higher NPV and lower PPV are proposed in order to predict clinical outcome accurately and precisely when the proposed model is considered. Twenty historical trials are required to be included in model building when PPV and NPV are equal. For unequal PPV and NPV, the minimum number of historical trials for model building is proposed to be five. A hypothetical example shows an application of the proposed model in global drug development. The proposed Bayesian model is able to predict well the clinical endpoint from the observed biomarker data for dichotomous variables as long as the conditions are satisfied. It could be applied in drug development. But the practical problems in applications have to be studied in further research.

Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments.

PubMed

Gropp, Kathryn E; Carlson, Cathy S; Evans, Mark G; Bagi, Cedo M; Reagan, William J; Hurst, Susan I; Shelton, David L; Zorbas, Mark A

2018-01-01

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article-related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review.

PubMed

Wang, Bo; Kesselheim, Aaron S

2015-09-23

To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs' originally approved indications. Systematic review. Publicly accessible data on supplemental indications approved by the US Food and Drug Administration from 2005 to 2014. Types of comparators (active, placebo, historical, none) and endpoints (clinical outcomes, clinical scales, surrogate) in the efficacy trials for these drugs' supplemental and original indication approvals. The cohort included 295 supplemental indications. Thirty per cent (41/136) of supplemental approvals for new indications were supported by efficacy trials with active comparators, compared with 51% (47/93) of modified use approvals and 11% (7/65) of approvals expanding the patient population (P<0.001), almost all of which related to pediatric patients (61/65; 94%). Trials using clinical outcome endpoints led to approval for 32% (44/137) of supplemental approvals for new indications, 30% (28/93) of modified indication approvals, and 22% (14/65) of expanded population approvals (P=0.29). Orphan drugs had supplemental approvals for 40 non-orphan indications, which were supported by similar proportions of trials using active comparators (28% (11/40) for non-orphan supplemental indications versus 24% (10/42) for original orphan indications; P=0.70) and clinical outcome endpoints (25% (10/40) versus 31% (13/42); P=0.55). Wide variations were seen in the evidence supporting approval of supplemental indications, with the fewest active comparators and clinical outcome endpoints used in trials leading to supplemental approvals that expanded the patient population. © Wang et al 2015.

A Poisson approach to the validation of failure time surrogate endpoints in individual patient data meta-analyses.

PubMed

Rotolo, Federico; Paoletti, Xavier; Burzykowski, Tomasz; Buyse, Marc; Michiels, Stefan

2017-01-01

Surrogate endpoints are often used in clinical trials instead of well-established hard endpoints for practical convenience. The meta-analytic approach relies on two measures of surrogacy: one at the individual level and one at the trial level. In the survival data setting, a two-step model based on copulas is commonly used. We present a new approach which employs a bivariate survival model with an individual random effect shared between the two endpoints and correlated treatment-by-trial interactions. We fit this model using auxiliary mixed Poisson models. We study via simulations the operating characteristics of this mixed Poisson approach as compared to the two-step copula approach. We illustrate the application of the methods on two individual patient data meta-analyses in gastric cancer, in the advanced setting (4069 patients from 20 randomized trials) and in the adjuvant setting (3288 patients from 14 randomized trials).

Micropulsed diode laser therapy: evolution and clinical applications.

PubMed

Sivaprasad, Sobha; Elagouz, Mohammed; McHugh, Dominic; Shona, Olajumoke; Dorin, Giorgio

2010-01-01

Many clinical trials have demonstrated the clinical efficacy of laser photocoagulation in the treatment of retinal vascular diseases, including diabetic retinopathy. There is, however, collateral iatrogenic retinal damage and functional loss after conventional laser treatment. Such side effects may occur even when the treatment is appropriately performed because of morphological damage caused by the visible endpoint, typically a whitening burn. The development of the diode laser with micropulsed emission has allowed subthreshold therapy without a visible burn endpoint. This greatly reduces the risk of structural and functional retinal damage, while retaining the therapeutic efficacy of conventional laser treatment. Studies using subthreshold micropulse laser protocols have reported successful outcomes for diabetic macular edema, central serous chorioretinopathy, macular edema secondary to retinal vein occlusion, and primary open angle glaucoma. The report includes the rationale and basic principles underlying micropulse diode laser therapy, together with a review of its current clinical applications. Copyright © 2010 Elsevier Inc. All rights reserved.

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

PubMed

Lansky, Alexandra J; Messé, Steven R; Brickman, Adam M; Dwyer, Michael; Bart van der Worp, H; Lazar, Ronald M; Pietras, Cody G; Abrams, Kevin J; McFadden, Eugene; Petersen, Nils H; Browndyke, Jeffrey; Prendergast, Bernard; Ng, Vivian G; Cutlip, Donald E; Kapadia, Samir; Krucoff, Mitchell W; Linke, Axel; Scala Moy, Claudia; Schofer, Joachim; van Es, Gerrit-Anne; Virmani, Renu; Popma, Jeffrey; Parides, Michael K; Kodali, Susheel; Bilello, Michel; Zivadinov, Robert; Akar, Joseph; Furie, Karen L; Gress, Daryl; Voros, Szilard; Moses, Jeffrey; Greer, David; Forrest, John K; Holmes, David; Kappetein, Arie P; Mack, Michael; Baumbach, Andreas

2018-05-14

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.

Generalized optimal design for two-arm, randomized phase II clinical trials with endpoints from the exponential dispersion family.

PubMed

Jiang, Wei; Mahnken, Jonathan D; He, Jianghua; Mayo, Matthew S

2016-11-01

For two-arm randomized phase II clinical trials, previous literature proposed an optimal design that minimizes the total sample sizes subject to multiple constraints on the standard errors of the estimated event rates and their difference. The original design is limited to trials with dichotomous endpoints. This paper extends the original approach to be applicable to phase II clinical trials with endpoints from the exponential dispersion family distributions. The proposed optimal design minimizes the total sample sizes needed to provide estimates of population means of both arms and their difference with pre-specified precision. Its applications on data from specific distribution families are discussed under multiple design considerations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Treatment of Men for “Low Testosterone”: A Systematic Review

PubMed Central

Huo, Samantha; Scialli, Anthony R.; McGarvey, Sean; Hill, Elizabeth; Tügertimur, Buğra; Hogenmiller, Alycia; Hirsch, Alessandra I.; Fugh-Berman, Adriane

2016-01-01

Testosterone products are recommended by some prescribers in response to a diagnosis or presumption of “low testosterone” (low-T) for cardiovascular health, sexual function, muscle weakness or wasting, mood and behavior, and cognition. We performed a systematic review of 156 eligible randomized controlled trials in which testosterone was compared to placebo for one or more of these conditions. We included studies in bibliographic databases between January 1, 1950 and April 9, 2016, and excluded studies involving bodybuilding, contraceptive effectiveness, or treatment of any condition in women or children. Studies with multiple relevant endpoints were included in all relevant tables. Testosterone supplementation did not show consistent benefit for cardiovascular risk, sexual function, mood and behavior, or cognition. Studies that examined clinical cardiovascular endpoints have not favored testosterone therapy over placebo. Testosterone is ineffective in treating erectile dysfunction and controlled trials did not show a consistent effect on libido. Testosterone supplementation consistently increased muscle strength but did not have beneficial effects on physical function. Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. The prescription of testosterone supplementation for low-T for cardiovascular health, sexual function, physical function, mood, or cognitive function is without support from randomized clinical trials. PMID:27655114

Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa

PubMed Central

Ramachandran, Rithambara; Cai, Cindy X.; Lee, Dongwon; Epstein, Benjamin C.; Locke, Kirsten G.; Birch, David G.; Hood, Donald C.

2016-01-01

Purpose We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). Methods A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. Results Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 μm) was close to 0 μm, and the 95% limits were between −284 and 323 μm, approximately ±1.1°. Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 μm, approximately 1.2°, for both test times. Conclusions While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. Translational Relevance For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under ±2.0°, are considerably smaller than the 6° spacing for the typically used static visual field. PMID:27226930

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.

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.

Establishing Good Practices for Exposure–Response Analysis of Clinical Endpoints in Drug Development

PubMed Central

Overgaard, RV; Ingwersen, SH; Tornøe, CW

2015-01-01

This tutorial aims at promoting good practices for exposure–response (E-R) analyses of clinical endpoints in drug development. The focus is on practical aspects of E-R analyses to assist modeling scientists with a process of performing such analyses in a consistent manner across individuals and projects and tailored to typical clinical drug development decisions. This includes general considerations for planning, conducting, and visualizing E-R analyses, and how these are linked to key questions. PMID:26535157

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine

PubMed Central

KOTLER, MOSHE; DILBAZ, NESRIN; ROSA, FERNANDA; PATERAKIS, PERIKLIS; MILANOVA, VIHRA; SMULEVICH, ANATOLY B.; LAHAYE, MARJOLEIN

2016-01-01

Objective: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Methods: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Results: Of 396 patients, 65.2% were men, mean age was 40.0±12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8±5.2 kg at endpoint, and a clinically relevant weight gain of ≥7% occurred in 8.0% of patients. Conclusion: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine. PMID:26813484

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine.

PubMed

Kotler, Moshe; Dilbaz, Nesrin; Rosa, Fernanda; Paterakis, Periklis; Milanova, Vihra; Smulevich, Anatoly B; Lahaye, Marjolein; Schreiner, Andreas

2016-01-01

The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤ 5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Of 396 patients, 65.2% were men, mean age was 40.0 ± 12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥ 20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8 ± 5.2 kg at endpoint, and a clinically relevant weight gain of ≥ 7% occurred in 8.0% of patients. Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

Time-to-first-event versus recurrent-event analysis: points to consider for selecting a meaningful analysis strategy in clinical trials with composite endpoints.

PubMed

Rauch, Geraldine; Kieser, Meinhard; Binder, Harald; Bayes-Genis, Antoni; Jahn-Eimermacher, Antje

2018-05-01

Composite endpoints combining several event types of clinical interest often define the primary efficacy outcome in cardiologic trials. They are commonly evaluated as time-to-first-event, thereby following the recommendations of regulatory agencies. However, to assess the patient's full disease burden and to identify preventive factors or interventions, subsequent events following the first one should be considered as well. This is especially important in cohort studies and RCTs with a long follow-up leading to a higher number of observed events per patients. So far, there exist no recommendations which approach should be preferred. Recently, the Cardiovascular Round Table of the European Society of Cardiology indicated the need to investigate "how to interpret results if recurrent-event analysis results differ […] from time-to-first-event analysis" (Anker et al., Eur J Heart Fail 18:482-489, 2016). This work addresses this topic by means of a systematic simulation study. This paper compares two common analysis strategies for composite endpoints differing with respect to the incorporation of recurrent events for typical data scenarios motivated by a clinical trial. We show that the treatment effects estimated from a time-to-first-event analysis (Cox model) and a recurrent-event analysis (Andersen-Gill model) can systematically differ, particularly in cardiovascular trials. Moreover, we provide guidance on how to interpret these results and recommend points to consider for the choice of a meaningful analysis strategy. When planning trials with a composite endpoint, researchers, and regulatory agencies should be aware that the model choice affects the estimated treatment effect and its interpretation.

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

Alzheimer’s Prevention Initiative: A Plan to Accelerate the Evaluation of Presymptomatic Treatments

PubMed Central

Reiman, Eric M.; Langbaum, Jessica B.S.; Fleisher, Adam S.; Caselli, Richard J.; Chen, Kewei; Ayutyanont, Napatkamon; Quiroz, Yakeel T.; Kosik, Kenneth S.; Lopera, Francisco; Tariot, Pierre N.

2012-01-01

There is an urgent need to find effective presymptomatic Alzheimer’s disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer’s Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world’s largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE)ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment’s brain imaging and other biomarker effects predict a clinical benefit—information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials. PMID:21971471

Use of Intermediate Endpoints in the Economic Evaluation of New Treatments for Advanced Cancer and Methods Adopted When Suitable Overall Survival Data are Not Available.

PubMed

Beauchemin, Catherine; Lapierre, Marie-Ève; Letarte, Nathalie; Yelle, Louise; Lachaine, Jean

2016-09-01

This study assessed the use of intermediate endpoints in the economic evaluation of new treatments for advanced cancer and the methodological approaches adopted when overall survival (OS) data are unavailable or of limited use. A systematic literature review was conducted to identify economic evaluations of treatments for advanced cancer published between 2003 and 2013. Cost-effectiveness and cost-utility analyses expressed in cost per life-year gained and cost per quality-adjusted life-year using an intermediate endpoint as an outcome measure were eligible. Characteristics of selected studies were extracted and comprised population, treatment of interest, comparator, line of treatment, study perspective, and time horizon. Use of intermediate endpoints and methods adopted when OS data were lacking were analyzed. In total, 7219 studies were identified and 100 fulfilled the eligibility criteria. Intermediate endpoints mostly used were progression-free survival and time to progression, accounting for 92 % of included studies. OS data were unavailable for analysis in nearly 25 % of economic evaluations. In the absence of OS data, studies most commonly assumed an equal risk of death for all treatment groups. Other methods included use of indirect comparison based on numerous assumptions, use of a proxy for OS, consultation with clinical experts, and use of published external information from different treatment settings. Intermediate endpoints are widely used in the economic evaluation of new treatments for advanced cancer in order to estimate OS. Currently, different methods are used in the absence of suitable OS data and the choice of an appropriate method depends on many factors including the data availability.

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.

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.

Characteristics of efficacy evidence supporting approval of supplemental indications for prescription drugs in United States, 2005-14: systematic review

PubMed Central

Wang, Bo

2015-01-01

Objective To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs’ originally approved indications. Design Systematic review. Setting Publicly accessible data on supplemental indications approved by the US Food and Drug Administration from 2005 to 2014. Main outcome measures Types of comparators (active, placebo, historical, none) and endpoints (clinical outcomes, clinical scales, surrogate) in the efficacy trials for these drugs’ supplemental and original indication approvals. Results The cohort included 295 supplemental indications. Thirty per cent (41/136) of supplemental approvals for new indications were supported by efficacy trials with active comparators, compared with 51% (47/93) of modified use approvals and 11% (7/65) of approvals expanding the patient population (P<0.001), almost all of which related to pediatric patients (61/65; 94%). Trials using clinical outcome endpoints led to approval for 32% (44/137) of supplemental approvals for new indications, 30% (28/93) of modified indication approvals, and 22% (14/65) of expanded population approvals (P=0.29). Orphan drugs had supplemental approvals for 40 non-orphan indications, which were supported by similar proportions of trials using active comparators (28% (11/40) for non-orphan supplemental indications versus 24% (10/42) for original orphan indications; P=0.70) and clinical outcome endpoints (25% (10/40) versus 31% (13/42); P=0.55). Conclusions Wide variations were seen in the evidence supporting approval of supplemental indications, with the fewest active comparators and clinical outcome endpoints used in trials leading to supplemental approvals that expanded the patient population. PMID:26400844

Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08).

PubMed

van Roozendaal, L M; Vane, M L G; van Dalen, T; van der Hage, J A; Strobbe, L J A; Boersma, L J; Linn, S C; Lobbes, M B I; Poortmans, P M P; Tjan-Heijnen, V C G; Van de Vijver, K K B T; de Vries, J; Westenberg, A H; Kessels, A G H; de Wilt, J H W; Smidt, M L

2017-07-01

Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013-08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. The BOOG 2013-08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1-2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. The BOOG 2013-08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828.

The SABRE Trial (Sirolimus Angioplasty Balloon for Coronary In-Stent Restenosis): Angiographic Results and 1-Year Clinical Outcomes.

PubMed

Verheye, Stefan; Vrolix, Mathias; Kumsars, Indulis; Erglis, Andrejs; Sondore, Dace; Agostoni, Pierfrancesco; Cornelis, Kristoff; Janssens, Luc; Maeng, Michael; Slagboom, Ton; Amoroso, Giovanni; Jensen, Lisette Okkels; Granada, Juan F; Stella, Pieter

2017-10-23

The aim of this first-in-human study was to assess the safety and effectiveness of the Virtue sirolimus-eluting balloon in a cohort of patients with in-stent restenosis (ISR). Angioplasty balloons coated with the cytotoxic drug paclitaxel have been widely used for ISR treatment. The Virtue angioplasty balloon (Caliber Therapeutics, New Hope, Pennsylvania) delivers sirolimus in a nanoencapsulated liquid formulation. This clinical trial is the first to examine a sirolimus-eluting balloon for ISR. In this prospective, single-arm feasibility study at 9 European centers, 50 ISR patients were treated with the Virtue balloon. Angiographic measurements at 6 months are reported, along with 12-month clinical follow-up. Procedural success in the intention-to-treat population was 100%. The primary safety endpoint was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) assessed at 30 days (0%, n = 50). The primary performance endpoint was in-segment late lumen loss (LLL) at 6 months (0.31 ± 0.52 mm; n = 47). Secondary 6-month endpoints include binary restenosis (19.1%), diameter stenosis (30.3 ± 19.9%), and major adverse cardiac events (MACE) (10.2%, n = 49). In the 36-patient per-protocol population (excluding major protocol violations and previously stented ISR), LLL was 0.12 ± 0.33 mm at 6 months. Clinical outcomes at 1 year for the intention-to-treat group were 12.2% TLF and 14.3% MACE and for the per-protocol population were 2.8% TLF and 2.8% MACE. This first-in-human study showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon, 6-month LLL rates in line with current stent-free ISR treatment options, and clinical outcomes that warrant further evaluation in dedicated randomized studies. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Risk estimates for persistent high-risk human papillomavirus infections as surrogate endpoints of progressive cervical disease critically depend on reference category: analysis of the combined prospective cohort of the New Independent States of the Former Soviet Union and Latin American Screening studies.

PubMed

Syrjänen, K; Shabalova, I; Naud, P; Kozachenko, V; Derchain, S; Zakharchenko, S; Roteli-Martins, C; Nerovjna, R; Longatto-Filho, A; Kljukina, L; Tatti, S; Branovskaja, M; Hammes, L S; Branca, M; Grunjberga, V; Eržen, M; Juschenko, A; Costa, S; Sarian, L; Podistov, J; Syrjänen, S

2011-06-01

To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease.

A critical evaluation of the clinical evidence for pomegranate preparations in the prevention and treatment of cardiovascular diseases.

PubMed

Vlachojannis, Christian; Erne, Paul; Schoenenberger, Andreas W; Chrubasik-Hausmann, Sigrun

2015-04-01

This study attempts a critical evaluation of the clinical evidence behind the use of dietary pomegranate preparations in the prevention and treatment of cardiovascular diseases. A search of PubMed on August 10, 2014 identified 228 references, which yielded extractable data from 24 clinical studies of pomegranate preparations. Hand searching identified two further studies. The quality of the studies and evidence of effectiveness of pomegranate were assessed by an established set of conventional criteria. Overall, the study quality was poor. Even in the best studies, indications of benefit did not reach the conventional levels of statistical significance. The only study with a definitive design had a biochemical rather than a clinical endpoint: it showed the expected difference in blood concentrations of myeloperoxidase after a single dose of either pomegranate or placebo. Only 10 of the 26 studies provided HPLC data on the amounts of co-active ingredients in the preparations that were consumed by the subjects. If pomegranate has a role in the prevention and treatment of cardiovascular diseases, there is a pressing need for dose-finding and long-term confirmatory studies. The ultimate endpoint for definitive studies would be mortality, but reductions in blood pressure or demonstrable decreases in atherosclerotic plaques would be useful surrogates. Sample sizes for various assumptions are provided. Future studies need to prove the clinical benefit. Copyright © 2015 John Wiley & Sons, Ltd.

Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients.

PubMed

Bank, J R; Rabelink, T J; de Fijter, J W; Reinders, M E J

2015-01-01

Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.

Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials.

PubMed

Hung, H M James; Wang, Sue-Jane; Yang, Peiling; Jin, Kun; Lawrence, John; Kordzakhia, George; Massie, Tristan

2016-01-01

There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

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

State Variability and Psychopathological Attractors: the Behavioural Complexity as Discriminating Factor Between the Pathology and Normality Profiles

NASA Astrophysics Data System (ADS)

Marconi, Pier Luigi

369 patients, selected within a set of 1215 outpatients, were studied. The data were clustered into two set: the baseline set and the endpoint set. The clinical parameters had a higher variability at the baseline than at the endpoint. 4 to 5 factors were extracted in total group and 3 subgroups (190 "affective", 34 type-B personality, 166 without any of both disorders). In all subgroups there was a background pattern of 6 components: 3 components confirming the trifactorial temperamental model of Cloninger; 1 component related to the quality of social relationships; 2 components (that are the main components of factorial model about in all groups) relating to quality of life and adjustment self perceived by patients, and to pattern of dysfunctional behavior, inner feelings, and thought processes externally evaluated. These background components seem to aggregate differently in the subgroups in accordance to the clinical diagnosis. These patterns may be interpreted as expression of an increased "coherence" among parameters due to a lack of flexibility caused by the illness. The different class of illness can be further distinguished by intensity of maladjustment, that is related to the intensity of clinical signs just only at the baseline. These data suggest that the main interfering factors are clinical psychopathology at baseline and stable personality traits at endpoint. This persistent chronic maladjustment personality-driven is evidenced after the clinical disorder was cured by treatment. An interpretative model is presented by the author.

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.

A Prospective, Cross-Sectional Survey Study of the Natural History of Niemann-Pick B Disease

PubMed Central

McGovern, Margaret M.; Wasserstein, Melissa P.; Giugliani, Roberto; Bembi, Bruno; Vanier, Marie; Mengel, Eugen; Brodie, Scott E.; Mendelson, David; Skloot, Gwen; Desnick, Robert J.; Kuriyama, Noriko; Cox, Gerald F.

2009-01-01

Objective The objective of this study was to characterize the clinical features of patients with Niemann-Pick disease Type B and to identify efficacy endpoints for future clinical trials of enzyme replacement therapy. Patients and Methods Fifty-nine patients who had Niemann-Pick disease Type B, were at least 6 years of age, and manifested at least 2 disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; and assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life were obtained during a 2 to 3 day period. Results Fifty-three percent of the patients were male, 92% white, and the median age was 17.6 years. The R508del mutation accounted for 25% of all disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of LDL, VLDL, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function tests. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung disease. Patients commonly showed restrictive lung disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. Conclusions This study documents the multisystem involvement and clinical variability of Niemann-Pick B disease. Several efficacy endpoints were identified for future clinical treatment studies. Because of its correlation with disease severity, spleen volume may be a useful surrogate endpoint in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring treatment responses. PMID:18625664

Drugs' development in acute heart failure: what went wrong?

PubMed

Teneggi, Vincenzo; Sivakumar, Nithy; Chen, Deborah; Matter, Alex

2018-05-08

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

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.

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

PubMed

Lansky, Alexandra J; Messé, Steven R; Brickman, Adam M; Dwyer, Michael; van der Worp, H Bart; Lazar, Ronald M; Pietras, Cody G; Abrams, Kevin J; McFadden, Eugene; Petersen, Nils H; Browndyke, Jeffrey; Prendergast, Bernard; Ng, Vivian G; Cutlip, Donald E; Kapadia, Samir; Krucoff, Mitchell W; Linke, Axel; Moy, Claudia Scala; Schofer, Joachim; van Es, Gerrit-Anne; Virmani, Renu; Popma, Jeffrey; Parides, Michael K; Kodali, Susheel; Bilello, Michel; Zivadinov, Robert; Akar, Joseph; Furie, Karen L; Gress, Daryl; Voros, Szilard; Moses, Jeffrey; Greer, David; Forrest, John K; Holmes, David; Kappetein, Arie P; Mack, Michael; Baumbach, Andreas

2017-02-14

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Integrated Analysis of Pharmacologic, Clinical, and SNP Microarray Data using Projection onto the Most Interesting Statistical Evidence with Adaptive Permutation Testing

PubMed Central

Pounds, Stan; Cao, Xueyuan; Cheng, Cheng; Yang, Jun; Campana, Dario; Evans, William E.; Pui, Ching-Hon; Relling, Mary V.

2010-01-01

Powerful methods for integrated analysis of multiple biological data sets are needed to maximize interpretation capacity and acquire meaningful knowledge. We recently developed Projection Onto the Most Interesting Statistical Evidence (PROMISE). PROMISE is a statistical procedure that incorporates prior knowledge about the biological relationships among endpoint variables into an integrated analysis of microarray gene expression data with multiple biological and clinical endpoints. Here, PROMISE is adapted to the integrated analysis of pharmacologic, clinical, and genome-wide genotype data that incorporating knowledge about the biological relationships among pharmacologic and clinical response data. An efficient permutation-testing algorithm is introduced so that statistical calculations are computationally feasible in this higher-dimension setting. The new method is applied to a pediatric leukemia data set. The results clearly indicate that PROMISE is a powerful statistical tool for identifying genomic features that exhibit a biologically meaningful pattern of association with multiple endpoint variables. PMID:21516175

Bayesian adaptive bandit-based designs using the Gittins index for multi-armed trials with normally distributed endpoints.

PubMed

Smith, Adam L; Villar, Sofía S

2018-01-01

Adaptive designs for multi-armed clinical trials have become increasingly popular recently because of their potential to shorten development times and to increase patient response. However, developing response-adaptive designs that offer patient-benefit while ensuring the resulting trial provides a statistically rigorous and unbiased comparison of the different treatments included is highly challenging. In this paper, the theory of Multi-Armed Bandit Problems is used to define near optimal adaptive designs in the context of a clinical trial with a normally distributed endpoint with known variance. We report the operating characteristics (type I error, power, bias) and patient-benefit of these approaches and alternative designs using simulation studies based on an ongoing trial. These results are then compared to those recently published in the context of Bernoulli endpoints. Many limitations and advantages are similar in both cases but there are also important differences, specially with respect to type I error control. This paper proposes a simulation-based testing procedure to correct for the observed type I error inflation that bandit-based and adaptive rules can induce.

Sensitivity analysis for missing dichotomous outcome data in multi-visit randomized clinical trial with randomization-based covariance adjustment.

PubMed

Li, Siying; Koch, Gary G; Preisser, John S; Lam, Diana; Sanchez-Kam, Matilde

2017-01-01

Dichotomous endpoints in clinical trials have only two possible outcomes, either directly or via categorization of an ordinal or continuous observation. It is common to have missing data for one or more visits during a multi-visit study. This paper presents a closed form method for sensitivity analysis of a randomized multi-visit clinical trial that possibly has missing not at random (MNAR) dichotomous data. Counts of missing data are redistributed to the favorable and unfavorable outcomes mathematically to address possibly informative missing data. Adjusted proportion estimates and their closed form covariance matrix estimates are provided. Treatment comparisons over time are addressed with Mantel-Haenszel adjustment for a stratification factor and/or randomization-based adjustment for baseline covariables. The application of such sensitivity analyses is illustrated with an example. An appendix outlines an extension of the methodology to ordinal endpoints.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

PubMed Central

BRISCO, MEREDITH A.; ZILE, MICHAEL R.; HANBERG, JENNIFER S.; WILSON, F. PERRY; PARIKH, CHIRAG R.; COCA, STEVEN G.; TANG, W.H. WILSON; TESTANI, JEFFREY M.

2017-01-01

Background Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. Methods and Results We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67–0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77–1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57–4.03, P <.001). Conclusion The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. PMID:27374839

Daily remote monitoring of implantable cardioverter-defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST).

PubMed

Hindricks, Gerhard; Varma, Niraj; Kacet, Salem; Lewalter, Thorsten; Søgaard, Peter; Guédon-Moreau, Laurence; Proff, Jochen; Gerds, Thomas A; Anker, Stefan D; Torp-Pedersen, Christian

2017-06-07

Remote monitoring of implantable cardioverter-defibrillators may improve clinical outcome. A recent meta-analysis of three randomized controlled trials (TRUST, ECOST, IN-TIME) using a specific remote monitoring system with daily transmissions [Biotronik Home Monitoring (HM)] demonstrated improved survival. We performed a patient-level analysis to verify this result with appropriate time-to-event statistics and to investigate further clinical endpoints. Individual data of the TRUST, ECOST, and IN-TIME patients were pooled to calculate absolute risks of endpoints at 1-year follow-up for HM vs. conventional follow-up. All-cause mortality analysis involved all three trials (2405 patients). Other endpoints involved two trials, ECOST and IN-TIME (1078 patients), in which an independent blinded endpoint committee adjudicated the underlying causes of hospitalizations and deaths. The absolute risk of death at 1 year was reduced by 1.9% in the HM group (95% CI: 0.1-3.8%; P = 0.037), equivalent to a risk ratio of 0.62. Also the combined endpoint of all-cause mortality or hospitalization for worsening heart failure (WHF) was significantly reduced (by 5.6%; P = 0.007; risk ratio 0.64). The composite endpoint of all-cause mortality or cardiovascular (CV) hospitalization tended to be reduced by a similar degree (4.1%; P = 0.13; risk ratio 0.85) but without statistical significance. In a pooled analysis of the three trials, HM reduced all-cause mortality and the composite endpoint of all-cause mortality or WHF hospitalization. The similar magnitudes of absolute risk reductions for WHF and CV endpoints suggest that the benefit of HM is driven by the prevention of heart failure exacerbation.

A multicenter randomized double-blind study on the efficacy and safety of nicergoline in patients with multi-infarct dementia.

PubMed

Herrmann, W M; Stephan, K; Gaede, K; Apeceche, M

1997-01-01

A 6-month double-blind, randomized, placebo-controlled clinical trial preceded by a 3-week single-blind, washout/run-in placebo phase was performed in male and female patients, 55-85 years of age with a clinical diagnosis of mild to moderate multi-infarct dementia according to DSM-III to evaluate the therapeutic efficacy and safety of nicergoline 30 mg b.i.d. Primary endpoints for efficacy were the changes in the Sandoz Clinical Assessment Geriatric Scale (SCAG) and Mini-Mental State Examination (MMSE) scores at the end of the treatment with respect to baseline. Secondary endpoints were Clinical Global Impression, 3 subtests of the Weschsler Adult Intelligence Scale and Blessed A scale for activities of daily living, and all endpoints in 2-month intervals. A total of 252 patients were screened, 136 patients entered the double-blind phase and were evaluated as intent-to-treat (ITT) patients. Fifteen patients were excluded from the efficacy analyses of valid cases (VC) due to protocol violations or because they dropped out of the study prematurely. Confirmatory efficacy analysis after 6 months of treatment revealed superiority of nicergoline treatment with p < 0.01 for both SCAG and MMSE scores (ITT and VC). Subsequent descriptive efficacy analysis resulted in significant differences in favor of nicergoline, in the majority of cases as early as 2 months after start of treatment. Nicergoline was well tolerated and a similar number of adverse events were observed in both the placebo and the nicergoline group.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

PubMed

Krischer, Jeffrey P

2013-09-01

This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials

PubMed Central

Krischer, Jeffrey P.

2013-01-01

Aims/hypothesis This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Methods Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Results Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. Conclusions/interpretation The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials. PMID:23744306

Outcomes research in cancer clinical trial cooperative groups: the RTOG model.

PubMed

Bruner, D W; Movsas, B; Konski, A; Roach, M; Bondy, M; Scarintino, C; Scott, C; Curran, W

2004-08-01

The Radiation Therapy Oncology Group (RTOG), a National Cancer Institute sponsored cancer clinical trials research cooperative, has recently formed an Outcomes Committee to assess a comprehensive array of clinical trial endpoints and factors impacting the net effect of therapy. To study outcomes in a consistent, comprehensive and coordinated manner, the RTOG Outcomes Committee developed a model to assess clinical, humanistic, and economic outcomes important in clinical trials. This paper reviews how the RTOG incorporates outcomes research into cancer clinical trials, and demonstrates utilization of the RTOG Outcomes Model to test hypotheses related to non-small-cell lung cancer (NSCLC). In this example, the clinical component of the model indicates that the addition of chemotherapy to radiotherapy (RT) improves survival but increases the risk of toxicity. The humanistic component indicates that esophagitis is the symptom impacting quality of life the greatest and may outweigh the benefits in elderly (> or =70 years) patients. The economic component of the model indicates that accounting for quality-adjusted survival, concurrent chemoRT for the treatment of NSCLC is within the range of economically acceptable recommendations. The RTOG Outcomes Model guides a comprehensive program of research that systematically measures a triad of endpoints considered important to clinical trials research.

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.

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.

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.

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

Mittal, Bharat B., E-mail: bmittal@nmh.org; Wang, Edward; Sejpal, Samir

Purpose: The current study examined the effect of recombinant human deoxyribonuclease (rhDNase) on quality of life (QOL) measures, clinical improvement, and DNA content of thick oropharyngeal secretions (OPS) in patients with head-and-neck (H and N) cancers. Methods and Materials: Thirty-six patients with local-regional advanced H and N cancer receiving chemoradiationtherapy (CRT) were randomized to receive either placebo or rhDNase. Endpoints included MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) and Functional Assessment of Cancer Therapy–Head and Neck (FACT-NH) scores, along with clinical assessment and DNA concentration of OPS. Results: There were no statistically significant differences in patients' QOL outcomes over themore » study period. Both groups showed an increase in symptom and interference scores, although patients in the rhDNase group showed a greater decline in both scores during the 3 months posttreatment. Similarly, both groups showed a decline in physical and functional well being but recovered in the 3 months posttreatment follow-up, with the rhDNase group exhibiting speedier recovery. Patients in the rhDNase group exhibited significant clinical improvement in OPS, blindly assessed by a physician, compared with the placebo group (67% vs 27%, respectively; P=.046). The rhDNase group showed no change in OPS-DNA concentration, although the placebo group showed a significant increase in DNA concentration during the drug trial (P=.045). There was no differences in acute toxicities between the 2 groups. Conclusions: Our preliminary data suggest that rhDNase did not significantly improve study primary endpoints of QOL measures compared with the placebo group. However, there was a significant improvement in secondary endpoints of clinically assessed OPS and DNA concentration compared with placebo in H and N cancer patients treated with CRT. Further investigation in larger numbers of patients is warranted.« less

The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in asthma.

PubMed

Woodcock, Ashley; Bakerly, Nawar Diar; New, John P; Gibson, J Martin; Wu, Wei; Vestbo, Jørgen; Leather, David

2015-12-10

Novel therapies need to be evaluated in normal clinical practice to allow a true representation of the treatment effectiveness in real-world settings. The Salford Lung Study is a pragmatic randomised controlled trial in adult asthma, evaluating the clinical effectiveness and safety of once-daily fluticasone furoate (100 μg or 200 μg)/vilanterol 25 μg in a novel dry-powder inhaler, versus existing asthma maintenance therapy. The study was initiated before this investigational treatment was licensed and conducted in real-world clinical practice to consider adherence, co-morbidities, polypharmacy, and real-world factors. Asthma Control Test at week 24; safety endpoints include the incidence of serious pneumonias. The study utilises the Salford electronic medical record, which allows near to real-time collection and monitoring of safety data. The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in asthma. Use of patients' linked electronic health records to collect clinical endpoints offers minimal disruption to patients and investigators, and also ensures patient safety. This highly innovative study will complement standard double-blind randomised controlled trials in order to improve our understanding of the risk/benefit profile of fluticasone furoate/vilanterol in patients with asthma in real-world settings. Clinicaltrials.gov, NCT01706198; 04 October 2012.

ALLHAT in perspective: implications to clinical practice and clinical trials.

PubMed

Yusoff, K

2005-06-01

ALLHAT study is the biggest randomized clinical trial in hypertension ever conducted. Its objective was to ompare the efficacy of newer (calcium channel blocker amlodipine and angiotensin-converting enzyme inhibitor inopril) to the older (diuretic chlorthalidone) antihypertensive agents in the treatment of patients with hypertension. After enrolling 42,000 patients who were followed for an average of 4.9 years, ALLHAT did not find significant differences in the primary end-points between these antihypertenive agents. ALLHAT however found significant differences in the secondary end-points such as heart failure and strokes between chlorthalidone and amlodipine or lisinopril. Based on these and on economic reasons, the investigators unequivocally recommended diuretics as the first line therapy for hypertension. Since its publication, ALLHAT has been much discussed, debated A and opined. The choice of drugs for study, the study design, the conduct of the study and the conclusions drawn by the investigators had all been criticised or controversial. Yet ALLHAT has been widely quoted, commented upon or referred to and it has been instrumental in initiating the JNC VII Guidelines. Thus a thorough understanding of ALLHAT is necessary for clinical practice and in designing and evaluating clinical trials in the future. Moving Points: in Medicine will capture the essence of ALLHAT, discusses its implications to clinical trials and explores its possible impact on the practice of medicine in this country.

Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

DTIC Science & Technology

2017-10-01

publication delineating key methodological components of pain studies in prostate cancer. KEYWORDS Pain, metastatic castrate resistant prostate cancer...pain palliation and pain progression in prostate cancer clinical trials that are feasible, methodologically rigorous, and meet regulatory...requirements for drug approval and labeling. The primary aim of this award is to conduct an observational longitudinal study in men with castrate-resistant

Digital technologies for cognitive assessment to accelerate drug development in Alzheimer's disease.

PubMed

Leurent, C; Ehlers, M D

2015-11-01

For many neurological and psychiatric diseases, novel therapeutics have been elusive for decades. By focusing on attention interference in Alzheimer's disease (AD), we provide a future vision on how emerging mobile, computer, and device-based cognitive tools are converting classically noisy, subjective, data-poor clinical endpoints associated with neuropsychiatric disease assessment into a richer, scalable, and objective set of measurements. Incorporation of such endpoints into clinical drug trials holds promise for more quickly and efficiently developing new medicines. © 2015 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of The American Society for Clinical Pharmacology and Therapeutics.

Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis.

PubMed

Murphy, Sabina A; Gibson, Charles Michael; Morrow, David A; Van de Werf, Frans; Menown, Ian B; Goodman, Shaun G; Mahaffey, Kenneth W; Cohen, Marc; McCabe, Carolyn H; Antman, Elliott M; Braunwald, Eugene

2007-09-01

To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint. We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97). When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.

Improved Endpoints for Cancer Immunotherapy Trials

PubMed Central

Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

2010-01-01

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 2 Safety: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

PubMed

Ward, Denham S; Williams, Mark R; Berkenbosch, John W; Bhatt, Maala; Carlson, Douglas; Chappell, Phillip; Clark, Randall M; Constant, Isabelle; Conway, Aaron; Cravero, Joseph; Dahan, Albert; Dexter, Franklin; Dionne, Raymond; Dworkin, Robert H; Gan, Tong J; Gozal, David; Green, Steven; Irwin, Michael G; Karan, Suzanne; Kochman, Michael; Lerman, Jerrold; Lightdale, Jenifer R; Litman, Ronald S; Mason, Keira P; Miner, James; O'Connor, Robert E; Pandharipande, Pratik; Riker, Richard R; Roback, Mark G; Sessler, Daniel I; Sexton, Anne; Tobin, Joseph R; Turk, Dennis C; Twersky, Rebecca S; Urman, Richard D; Weiss, Mark; Wunsch, Hannah; Zhao-Wong, Anna

2018-05-17

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, a public-private partnership with the US Food and Drug Administration, convened a second meeting of sedation experts from a variety of clinical specialties and research backgrounds to develop recommendations for procedural sedation research. The previous meeting addressed efficacy and patient- and/or family-centered outcomes. This meeting addressed issues of safety, which was defined as "the avoidance of physical or psychological harm." A literature review identified 133 articles addressing safety measures in procedural sedation clinical trials. After basic reporting of vital signs, the most commonly measured safety parameter was oxygen saturation. Adverse events were inconsistently defined throughout the studies. Only 6 of the 133 studies used a previously validated measure of safety. The meeting identified methodological problems associated with measuring infrequent adverse events. With a consensus discussion, a set of core and supplemental measures were recommended to code for safety in future procedural clinical trials. When adopted, these measures should improve the integration of safety data across studies and facilitate comparisons in systematic reviews and meta-analyses.

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

Conclusions and future directions for the REiNS International Collaboration

PubMed Central

Blakeley, Jaishri O.; Dombi, Eva; Fisher, Michael J.; Hanemann, Clemens O.; Walsh, Karin S.; Wolters, Pamela L.; Plotkin, Scott R.

2013-01-01

The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for the use of endpoints in neurofibromatosis (NF) clinical trials. This supplement includes the first series of REiNS recommendations for the use of patient-reported, functional, and visual outcomes, and for the evaluation of imaging response in NF clinical trials. Recommendations for neurocognitive outcome measures, the use of whole-body MRI in NF, the evaluation of potential biomarkers of disease, and the comprehensive evaluation of functional and patient-reported outcomes in NF are in development. The REiNS recommendations are made based on current knowledge. Experience with the use of the recommended endpoints in clinical trials, development of new tools and technologies, new knowledge of the natural history of NF, and advances in the methods used to analyze endpoints will likely lead to modifications of the currently proposed guidelines, which will be shared with the NF research community through the REiNS Web site www.reinscollaboration.org. Due to the clinical complexity of NF, there is a need to seek expertise from multiple medical disciplines, regulatory agencies, and industry to develop trial endpoints and designs, which will lead to the identification and approval of effective treatments for NF tumor and nontumor manifestations. The REiNS Collaboration welcomes anyone interested in providing his or her expertise toward this effort. PMID:24249805

Recommendations for the clinical evaluation of agents for treatment of osteoporosis: consensus of an expert panel representing the American Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF).

PubMed

Silverman, Stuart L; Cummings, Steven R; Watts, Nelson B

2008-01-01

A panel of experts representing ASBMR, NOF, and ISCD reviewed evidence and reached consensus that regulatory approval of treatments for osteoporosis should be based on trials with fracture endpoints, lasting 18-24 mo, and extending treatment to 5 yr; other indications could be approved based on BMD and turnover markers. In response to an FDA request for clinical trial guidance in osteoporosis, an expert panel was convened with representatives from the American Society of Bone and Mineral Research, the International Society of Clinical Densitometry, and the National Osteoporosis Foundation. The panel used a validated evidence-based expert panel process (the Rand Appropriateness Method) to address issues of trial duration, trial design, use of intermediate endpoints as outcomes, and use of placebo-controlled trials in high-risk patients. The panel concluded that placebo-controlled trials with fracture endpoints are appropriate and, with informed consent, are ethical for registration of new compounds. Trials may be 18-24 mo in duration for efficacy, assuming longer duration to 5 yr for safety and demonstration of sustained fracture reduction. Once fracture efficacy has been established for a particular agent, intermediate endpoints (e.g., BMD and bone turnover markers) may be used as outcomes for new indications other than corticosteroid-induced osteoporosis.

Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data.

PubMed

Mauguen, Audrey; Pignon, Jean-Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J; Belani, Chandra P; Shepherd, Frances A; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T; Dahlberg, Suzanne E; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E; Parmar, Mahesh; Tierney, Jayne F; Le Pechoux, Cécile; Michiels, Stefan

2013-06-01

The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. We analysed individual patients' data from 15,071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ(2)=0.83, 95% CI 0.83-0.83 in trials without radiotherapy, and 0.87, 0.87-0.87 in trials with radiotherapy) and excellent at trial level (R(2)=0.92, 95% CI 0.88-0.95 in trials without radiotherapy and 0.99, 0.98-1.00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ(2) range 0.77-0.85, dependent on the regimen being assessed) and trial level (R(2) range 0.89-0.97). In studies with data on locoregional control, individual-level correlations were good (ρ(2)=0.71, 95% CI 0.71-0.71 for concurrent chemotherapy and ρ(2)=0.61, 0.61-0.61 for modified vs standard radiotherapy) and trial-level correlations very good (R(2)=0.85, 95% CI 0.77-0.92 for concurrent chemotherapy and R(2)=0.95, 0.91-0.98 for modified vs standard radiotherapy). We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis. Copyright © 2013 Elsevier Ltd. All rights reserved.

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.

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 .

Clinical trials for authorized biosimilars in the European Union: a systematic review

PubMed Central

Mielke, Johanna; Koenig, Franz; Jones, Byron

2016-01-01

Aim In 2006, Omnitrope (by Sandoz) was the first approved biosimilar in Europe. To date, 21 biosimilars for seven different biologics are on the market. The present study compared the clinical trials undertaken to obtain market authorization. Methods We summarized the findings of a comprehensive review of all clinical trials up to market authorization of approved biosimilars, using the European public assessment reports (EPARs) published by the European Medicines Agency (EMA). The features compared were, among others, the number of patients enrolled, the number of trials, the types of trial design, choice of endpoints and equivalence margins for pharmacokinetic (PK)/pharmacodynamic (PD) and phase III trials. Results The variability between the clinical development strategies is high. Some differences are explainable by the characteristics of the product; if, for example, the PD marker can be assumed to predict the clinical outcome, no efficacy trials might be necessary. However, even for products with the same reference product, the sample size, endpoints and statistical models are not always the same. Conclusions There seems to be flexibility for sponsors regarding the decision as to how best to prove biosimilarity. PMID:27580073

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

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study.

PubMed

Jin, Cai De; Kim, Moo Hyun; Bang, Junghee; Serebruany, Victor

The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017. © 2017 S. Karger AG, Basel.

On the use of published radiobiological parameters and the evaluation of NTCP models regarding lung pneumonitis in clinical breast radiotherapy.

PubMed

Svolos, Patricia; Tsougos, Ioannis; Kyrgias, Georgios; Kappas, Constantine; Theodorou, Kiki

2011-04-01

In this study we sought to evaluate and accent the importance of radiobiological parameter selection and implementation to the normal tissue complication probability (NTCP) models. The relative seriality (RS) and the Lyman-Kutcher-Burman (LKB) models were studied. For each model, a minimum and maximum set of radiobiological parameter sets was selected from the overall published sets applied in literature and a theoretical mean parameter set was computed. In order to investigate the potential model weaknesses in NTCP estimation and to point out the correct use of model parameters, these sets were used as input to the RS and the LKB model, estimating radiation induced complications for a group of 36 breast cancer patients treated with radiotherapy. The clinical endpoint examined was Radiation Pneumonitis. Each model was represented by a certain dose-response range when the selected parameter sets were applied. Comparing the models with their ranges, a large area of coincidence was revealed. If the parameter uncertainties (standard deviation) are included in the models, their area of coincidence might be enlarged, constraining even greater their predictive ability. The selection of the proper radiobiological parameter set for a given clinical endpoint is crucial. Published parameter values are not definite but should be accompanied by uncertainties, and one should be very careful when applying them to the NTCP models. Correct selection and proper implementation of published parameters provides a quite accurate fit of the NTCP models to the considered endpoint.

Bayesian enhancement two-stage design for single-arm phase II clinical trials with binary and time-to-event endpoints.

PubMed

Shi, Haolun; Yin, Guosheng

2018-02-21

Simon's two-stage design is one of the most commonly used methods in phase II clinical trials with binary endpoints. The design tests the null hypothesis that the response rate is less than an uninteresting level, versus the alternative hypothesis that the response rate is greater than a desirable target level. From a Bayesian perspective, we compute the posterior probabilities of the null and alternative hypotheses given that a promising result is declared in Simon's design. Our study reveals that because the frequentist hypothesis testing framework places its focus on the null hypothesis, a potentially efficacious treatment identified by rejecting the null under Simon's design could have only less than 10% posterior probability of attaining the desirable target level. Due to the indifference region between the null and alternative, rejecting the null does not necessarily mean that the drug achieves the desirable response level. To clarify such ambiguity, we propose a Bayesian enhancement two-stage (BET) design, which guarantees a high posterior probability of the response rate reaching the target level, while allowing for early termination and sample size saving in case that the drug's response rate is smaller than the clinically uninteresting level. Moreover, the BET design can be naturally adapted to accommodate survival endpoints. We conduct extensive simulation studies to examine the empirical performance of our design and present two trial examples as applications. © 2018, The International Biometric Society.

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.

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective.

PubMed

Piedbois, Pascal; Miller Croswell, Jennifer

2008-10-01

Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology).The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC).

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.

Percutaneous left atrial appendage occlusion: Effect of device positioning on outcome.

PubMed

Wolfrum, Mathias; Attinger-Toller, Adrian; Shakir, Samera; Gloekler, Steffen; Seifert, Burkhardt; Moschovitis, Aris; Khattab, Ahmed; Maisano, Francesco; Meier, Bernhard; Nietlispach, Fabian

2016-10-01

The study in patients with percutaneous left atrial appendage (LAA) occlusion investigates clinical outcomes according to the position of the Amplatzer Cardiac Plug (ACP) disc. The ACP consists of a disc and an anchoring lobe. The disc is meant to cover the ostium of the LAA, but frequently retracts partially or completely into the neck of the LAA. It is not known whether a retracted disc affects outcome. Outcomes of 169 consecutive patients (age 73.1 ± 10.4 years; 76% male) with successful LAA closure were analyzed according to the position of the ACP disc: group A had complete coverage of the LAA ostium; in group B the disc prolapsed partially or completely into the LAA-neck. Transesophageal echocardiography was performed 1-6 months after ACP implantation. The safety endpoint was the composite of clinically significant pericardial effusion, device embolization, procedure-related stroke/transient ischemic attack (TIA), major bleeding, or device thrombus. The efficacy endpoint was the composite of death, neurological events (ischemic and hemorrhagic stroke, TIA), or systemic embolism during follow-up. Group A comprised 76 patients (age 73.0 ± 9.9 years; 74% male) and group B 93 patients (age 73.3 ± 10.9 years; 79% male). Mean CHA 2 DS 2 -Vasc score and HASBLED score were 4.2 ± 1.7 (group A 4.3 ± 1.6; group B 4.2 ± 1.8) and 2.9 ± 1.1 (group A 2.9 ± 1.0; group B 3.0 ± 1.2), respectively. Mean follow-up of the study population was 13.0 ± 10.4 months. Overall, the composite safety and efficacy endpoints occurred in 20 (12%) and 6 patients (4%), respectively. There was no significant difference between groups A and B in the occurrence of the safety endpoint (13% vs. 11%, P = 0.64), or the efficacy endpoint (4% vs. 3%, P = 1.0). No evidence for a difference in the occurrence of the safety and efficacy endpoint was found between patients with complete vs. incomplete ACP disc coverage of the LAA ostium. The risk of repositioning attempts in case of incomplete coverage does not seem to be warranted. Current findings need further confirmation in a larger scale clinical trial. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Diagnostic yield of lumbosacral magnetic resonance imaging requested by paediatric urology consultations.

PubMed

Fernández-Ibieta, M; Rojas Ticona, J; Villamil, V; Guirao Piñera, M J; López García, A; Zambudio Carmona, G

2017-11-01

In the historical series, the diagnostic yield of lumbosacral magnetic resonance imaging to rule out occult spinal dysraphism (or occult myelodysplasia), requested by paediatric urology, ranged from 2% to 15%. The aim of this study was to define our cost-effectiveness in children with urinary symptoms and to define endpoints that increase the possibility of finding occult spinal dysraphism. A screening was conducted on patients with urinary dysfunction for whom an magnetic resonance imaging was requested by the paediatric urology clinic, for persistent symptoms after treatment, voiding dysfunction or other clinical or urodynamic findings. We analysed clinical (UTI, daytime leaks, enuresis, voiding dysfunction, urgency, renal ultrasonography, lumbosacral radiography, history of acute urine retention, skin stigma and myalgia) and urodynamic endpoints (hyperactivity or areflexia, voiding dysfunction, interrupted pattern, accommodation value and maximum flow). A univariate analysis was conducted with SPSS 20.0. We analysed 21 patients during the period 2011-2015. The median age was 6 years (3-10). Three patients (14.3%) had occult spinal dysraphism: one spinal lipoma, one filum lipomatosus and one caudal regression syndrome with channel stenosis. The endpoints with statistically significant differences were the myalgias and the history of acute urine retention (66.7% vs. 5.6%, P=.04; OR= 34; 95%CI: 1.5-781 for both endpoints). The diagnostic yield of magnetic resonance imaging requested for children with urinary dysfunctions without skin stigma or neuro-orthopaedic abnormalities is low, although nonnegligible. In this group, the patients with a history of acute urine retention and muscle pain (pain, «cramps») can experience a greater diagnostic yield or positive predictive value. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

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

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.

Challenges and opportunities in SLE clinical trials.

PubMed

van Vollenhoven, Ronald F

2013-09-01

To provide an update on the field of clinical trials in systemic lupus erythematosus (SLE). This review will examine failed and successful clinical trials in SLE in order to draw lessons and determine the optimal ways forward. Over the past decade, many clinical trials in SLE met with limited success, but in the past 2 years several SLE clinical trials have been successful. The two large phase III randomized controlled trials (RCTs) of belimumab achieved their primary endpoints and resulted in food and drug administration and European medicines agency approval of the drug. Characteristics of these trials were, among other things, a very large number of patients (>800 each), compound clinical endpoints, and a flexible design with regards to concomitant medication use. Likewise, large randomized controlled trials with mycophenolate mofetil, although nominally unsuccessful, clearly demonstrated the clinical benefit of this drug in lupus nephritis. Posthoc analyses of several failed trials involving abatacept and rituximab revealed design elements and/or outcomes that might have changed the outcomes of these studies. Many smaller trials have also been reported, in some instances with surprisingly positive results. An improved understanding of specific design features in SLE clinical trials combined with robust outcomes will make it possible more effectively to design and conduct clinical trials in SLE.

Single versus double-row repair of the rotator cuff: does double-row repair with improved anatomical and biomechanical characteristics lead to better clinical outcome?

PubMed

Pauly, Stephan; Gerhardt, Christian; Chen, Jianhai; Scheibel, Markus

2010-12-01

Several techniques for arthroscopic repair of rotator cuff defects have been introduced over the past years. Besides established techniques such as single-row repairs, new techniques such as double-row reconstructions have gained increasing interest. The present article therefore provides an overview of the currently available literature on both repair techniques with respect to several anatomical, biomechanical, clinical and structural endpoints. Systematic literature review of biomechanical, clinical and radiographic studies investigating or comparing single- and double-row techniques. These results were evaluated and compared to provide an overview on benefits and drawbacks of the respective repair type. Reconstructions of the tendon-to-bone unit for full-thickness tears in either single- or double-row technique differ with respect to several endpoints. Double-row repair techniques provide more anatomical reconstructions of the footprint and superior initial biomechanical characteristics when compared to single-row repair. With regard to clinical results, no significant differences were found while radiological data suggest a better structural tendon integrity following double-row fixation. Presently published clinical studies cannot emphasize a clearly superior technique at this time. Available biomechanical studies are in favour of double-row repair. Radiographic studies suggest a beneficial effect of double-row reconstruction on structural integrity of the reattached tendon or reduced recurrent defect rates, respectively.

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

Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.

PubMed

Sridhara, Rajeshwari; Johnson, John R; Justice, Robert; Keegan, Patricia; Chakravarty, Aloka; Pazdur, Richard

2010-02-24

The Office of Oncology Drug Products (OODP) in the Center for Drug Evaluation and Research at the US Food and Drug Administration began reviewing marketing applications for oncological and hematologic indications in July 2005. We conducted an overview of products that were reviewed by the OODP for marketing approval and the regulatory actions taken during July 2005 to December 2007. We identified all applications that were reviewed by the OODP from July 1, 2005, through December 31, 2007, and reviewed the actions that OODP took. We also sought the basis for the actions taken, including the clinical trial design, endpoints used, patient accrual in the trial(s) supporting approval, and the type of regulatory approval. During the study period, the OODP reviewed marketing applications for 60 new indications and took regulatory action on 58 indications. Regulatory action was based on a risk-benefit evaluation of the data submitted with each application. Products that demonstrated efficacy and had an acceptable risk-benefit ratio were granted either regular or accelerated marketing approval for use in the specific indication that was studied. Regular approval was based on endpoints that demonstrated that the drug provided clinical benefit as evidenced by a longer or better life or a favorable effect on an established surrogate for a longer or better life. Accelerated approval was based on a less well-established surrogate endpoint that was reasonably likely to predict a longer or better life. Of the 53 new indications that were approved during the study period, 39 received regular approval, nine received accelerated approval, and five were converted from accelerated to regular approval. Five applications were not approved, and two applications were withdrawn before any regulatory action was taken. Eighteen of the 53 indications that were approved were for new molecular entities. During the study period, regulatory action was taken on 58 of the 60 marketing applications. Fifty-three applications were approved. A variety of clinical trial endpoints were used in the approval trials.

Surrogate endpoints in clinical trials of chronic kidney disease progression: moving from single to multiple risk marker response scores.

PubMed

Schievink, Bauke; Mol, Peter G M; Lambers Heerspink, Hiddo J

2015-11-01

There is increased interest in developing surrogate endpoints for clinical trials of chronic kidney disease progression, as the established clinically meaningful endpoint end-stage renal disease requires large and lengthy trials to assess drug efficacy. We describe recent developments in the search for novel surrogate endpoints. Declines in estimated glomerular filtration rate (eGFR) of 30% or 40% and albuminuria have been proposed as surrogates for end-stage renal disease. However, changes in eGFR or albuminuria may not be valid under all circumstances as drugs always have effects on multiple renal risk markers. Changes in each of these other 'off-target' risk markers can alter renal risk (either beneficially or adversely), and can thereby confound the relationship between surrogates that are based on single risk markers and renal outcome. Risk algorithms that integrate the short-term drug effects on multiple risk markers to predict drug effects on hard renal outcomes may therefore be more accurate. The validity of these risk algorithms is currently investigated. Given that drugs affect multiple renal risk markers, risk scores that integrate these effects are a promising alternative to using eGFR decline or albuminuria. Proper validation is required before these risk scores can be implemented.

Elevated serum creatinine at baseline predicts poor outcome in patients receiving cardiac resynchronization therapy.

PubMed

Shalaby, Alaa; El-Saed, Aiman; Voigt, Andrew; Albany, Constantine; Saba, Samir

2008-05-01

Renal insufficiency is recognized as a predictor of mortality and poor outcome in heart failure patients. We sought to study the impact of baseline serum creatinine on subsequent outcome in cardiac resynchronization therapy (CRT) recipients. We retrospectively reviewed hospital records of all CRT recipients at Pittsburgh Veterans Affairs (VA) Healthcare System (2003-2005) and University of Pittsburgh Medical Center (2004). We recorded clinical characteristics at the time of implantation including demographics, New York Heart Association (NYHA) functional class, ejection fraction, QRS duration, cardiomyopathy etiology, medical history, medication use, and serum creatinine. Mortality alone and mortality combined with heart failure hospitalization were the study endpoints. Out of the 330 patients studied, a total of 66 (20.0%) patients died over a mean follow-up duration of 19.7 +/- 9.0 months (range 1-44). The cohort was studied by three creatinine tertiles (0.6-1.0, 1.1-1.3, 1.4-3.0 mg/dL). Both study endpoints were observed more frequently in patients in the highest creatinine tertile compared to others (28.7% vs 14.0%, P = 0.008 for death and 41.6% vs 21.5%, P = 0.001 for the combined endpoint). High creatinine remained an independent predictor of mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.06-3.39, P = 0.032) and the combined endpoint (HR 1.94, 95% CI 1.20-3.13, P = 0.007) in multivariate adjusted models. Studied as a continuous variable, increase in creatinine level by 0.1 mg/dL was associated with an 11% increase in mortality risk and a 7% increase in the combined endpoint. In an unselected cohort of CRT recipients, the baseline creatinine was found to predict worse survival and poor outcome over a modest follow-up duration.

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.

Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?

PubMed

Kemp, Robert; Prasad, Vinay

2017-07-21

Surrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies. In this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked. We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm. The use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited.

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.

Reliability of Chinese medicine diagnostic variables in the examination of patients with osteoarthritis of the knee.

PubMed

Hua, Bin; Abbas, Estelle; Hayes, Alan; Ryan, Peter; Nelson, Lisa; O'Brien, Kylie

2012-11-01

Chinese medicine (CM) has its own diagnostic indicators that are used as evidence of change in a patient's condition. The majority of studies investigating efficacy of Chinese herbal medicine (CHM) have utilized biomedical diagnostic endpoints. For CM clinical diagnostic variables to be incorporated into clinical trial designs, there would need to be evidence that these diagnostic variables are reliable. Previous studies have indicated that the reliability of CM syndrome diagnosis is variable. Little information is known about where the variability stems from--the basic data collection level or the synthesis of diagnostic data, or both. No previous studies have investigated systematically the reliability of all four diagnostic methods used in the CM diagnostic process (Inquiry, Inspection, Auscultation/Olfaction, and Palpation). The objective of this study was to assess the inter-rater reliability of data collected using the four diagnostic methods of CM in Australian patients with knee osteoarthritis (OA), in order to investigate if CM variables could be used with confidence as diagnostic endpoints in a clinical trial investigating the efficacy of a CHM in treating OA. An inter-rater reliability study was conducted as a substudy of a clinical trial investigating the treatment of knee OA with Chinese herbal medicine. Two (2) experienced CM practitioners conducted a CM examination separately, within 2 hours of each other, in 40 participants. A CM assessment form was utilized to record the diagnostic data. Cohen's κ coefficient was used as a measure of the level of agreement between 2 practitioners. There was a relatively good level of agreement for Inquiry and Auscultation variables, and, in general, a low level of agreement for (visual) Inspection and Palpation variables. There was variation in the level of agreement between 2 practitioners on clinical information collected using the Four Diagnostic Methods of a CM examination. Some aspects of CM diagnosis appear to be reliable, while others are not. Based on these results, it was inappropriate to use CM diagnostic variables as diagnostic endpoints in the main study, which was an investigation of efficacy of CHM treatment of knee OA.

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.

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.

Radiochemotherapy in Anal Cancer: cCR, clinical outcomes and quality of life using two different treatment schedules

PubMed Central

Di Santo, Sara; Trignani, Marianna; Neri, Matteo; Milano, Angelo; Innocenti, Paolo; Taraborrelli, Maria; Augurio, Antonietta; Vinciguerra, Annamaria; Di Tommaso, Monica; Ursini, Lucia Anna; Di Pilla, Angelo; Di Nicola, Marta; Genovesi, Domenico

2014-01-01

Aim Main endpoint was a response rate to therapy; secondary endpoints were disease-free survival, overall survival, acute and late toxicities, specially in terms of anorectal and urinary continence. Background Radiochemotherapy for anal cancer achieves a good clinical response, locoregional control, anal function preservation. However, oncologic outcomes can differ using radiotherapy plus fluorouracil and mytomicin vs. cisplatin and fluorouracil. Methods Between 2000 and 2012, 27 anal cancer patients receiving radiotherapy combined with two different radiochemotherapy schedules, fluorouracil and mytomicin (group A) and cisplatin plus fluorouracil (group B). The Kaplan–Meier method was also used to estimate local control, overall survival and disease free survival. Statistical significance between curves was evaluated using the Log-rank test. Results Complete pathological response was found in 85.2% of patients, with higher rates of response in the group A (100% vs. 63.6%, p = 0.039). No significantly difference was found between the two groups for the other endpoints. Low rates of both acute and late toxicities were recorded. Conclusion Radiotherapy plus fluorouracil and mytomicin provide a better complete pathological response than radiotherapy plus cisplatin and fluorouracil and a greater rate of anal sphincter function preservation. Globally, radiochemotherapy of the anal cancer provides excellent clinical outcomes with a good profile of acute and late toxicity, without difference between the two groups studied. PMID:25859401

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.

Benefit and harms of new anti-cancer drugs.

PubMed

Vera-Badillo, Francisco E; Al-Mubarak, Mustafa; Templeton, Arnoud J; Amir, Eitan

2013-06-01

Phase III randomized controlled trials (RCTs) assess clinically important differences in endpoints that reflect benefit to and harm of patients. Defining benefit of cancer drugs can be difficult. Overall survival and quality of life are the most relevant primary endpoints, but difficulty in measuring these mean that other endpoints are often used, although their surrogacy or clinical relevance has not always been established. In general, advances in drug development have led to numerous new drugs to enter the market. Pivotal RCT of several new drugs have shown that benefit appeared greater for targeted anticancer agents than for chemotherapeutic agents. This effect seems particularly evident with targeted agents evaluated in biomarker-driven studies. Unfortunately, new therapies have also shown an increase in toxicity. Such toxicity is not always evident in the initial reports of RCTs. This may be a result of a statistical inability to detect differences between arms of RCTs, or occasionally due to biased reporting. There are several examples where reports of new toxicities could only be found in drug labels. In some cases, the small improvement in survival has come at a cost of substantial excess toxicity, leading some to consider such therapy as having equipoise.

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

Usefulness of the Obesity Surgery Mortality Risk Score (OR-MRS) in choosing the laparoscopic bariatric procedure.

PubMed

Orłowski, Mikołaj; Janik, Michał R; Paśnik, Krzysztof; Jędrzejewski, Emil

2015-07-01

The most popular scale to stratify the postoperative risk is the Obesity Surgery Mortality Risk Score (OS-MRS). The design and ease of interpretation make the scale a potential tool for clinical use. To evaluate the usefulness of the OS-MRS scale in the enrollment of patients for laparoscopic bariatric procedures, including laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). The medical records of patients who underwent LSG or LRYGB due to obesity between January 2010 and December 2010 were reviewed retrospectively. The decision of choosing the surgical procedure was made on the basis of OS-MRS risk category. The primary endpoint of this study was the 90-day mortality, and the secondary endpoint was the presence of major complications. There were 107 patients including 66 women and 41 men. The OS-MRS classes were A (48%), B (47%) and C (5%). The LSG was applied to patients with higher body mass index and to patients of class C. The secondary endpoints occurred in 6 patients, distributed in 10% of class A, 2% of class B and 0% of class C patients (p < 0.05). In 5 of 6 cases the endpoint was observed after LRYGB. Fatal cases were not observed. The OS-MRS can be a useful clinical tool for choosing the appropriate laparoscopic bariatric procedure, depending on the risk of postoperative complications. Low risk of postoperative complications should not lower the watchfulness of the surgeon.

A double-blind randomized placebo-controlled clinical trial of squalamine ointment for tinea capitis treatment.

PubMed

Coulibaly, Oumar; Thera, Mahamadou A; Koné, Abdoulaye K; Siaka, Goïta; Traoré, Pierre; Djimdé, Abdoulaye A; Brunel, Jean-Michel; Gaudart, Jean; Piarroux, Renaud; Doumbo, Ogobara K; Ranque, Stéphane

2015-04-01

Novel treatments against for tinea capitis are needed, and the natural aminosterol squalamine is a potential topical antidermatophyte drug candidate. This phase II randomized double-blind placebo-controlled clinical trial aimed at testing the efficacy and safety of a three-week squalamine ointment regimen for the treatment of tinea capitis. Males aged 6-15 years presenting with tinea capitis were treated with either topical squalamine ointment or placebo for 3 weeks. The primary endpoint was complete clinical cure. The secondary endpoints were the occurrence of local and/or systemic adverse events, mycological cure, and partial clinical response. Prospective follow-up of clinical adverse events was performed daily. Five patients were treated with 1% squalamine ointment and 15 with placebo. No complete cure was observed. No clinical or biological adverse event was recorded. A significantly (p = 0.03) better hair-growth score, indicating a partial clinical improvement of the tinea capitis lesion, was observed in the patients treated with squalamine compared to those treated with placebo. This three-week squalamine ointment regimen was well tolerated and showed an encouraging partial clinical activity for the treatment of tinea capitis. Further studies are needed to evaluate the efficacy of topical squalamine alone against tinea corporis or in combination with a systemic antidermatophyte drug against tinea capitis.

Randomized controlled trials in mild cognitive impairment

PubMed Central

Thomas, Ronald G.; Aisen, Paul S.; Mohs, Richard C.; Carrillo, Maria C.; Albert, Marilyn S.

2017-01-01

Objective: To examine the variability in performance among placebo groups in randomized controlled trials for mild cognitive impairment (MCI). Methods: Placebo group data were obtained from 2 National Institute on Aging (NIA) MCI randomized controlled trials, the Alzheimer's Disease Cooperative Study (ADCS) MCI trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is a simulated clinical trial, in addition to industry-sponsored clinical trials involving rivastigmine, galantamine, rofecoxib, and donepezil. The data were collated for common measurement instruments. The performance of the placebo participants from these studies was tracked on the Alzheimer's Disease Assessment Scale–cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating–sum of boxes, and for progression on these measures to prespecified clinical study endpoints. APOE status, where available, was also analyzed for its effects. Results: The progression to clinical endpoints varied a great deal among the trials. The expected performances were seen for the participants in the 2 NIA trials, ADCS and ADNI, with generally worsening of performance over time; however, the industry-sponsored trials largely showed stable or improved performance in their placebo participants. APOE4 carrier status influenced results in an expected fashion on the study outcomes, including rates of progression and cognitive subscales. Conclusions: In spite of apparently similar criteria for MCI being adopted by the 7 studies, the implementation of the criteria varied a great deal. Several explanations including instruments used to characterize participants and variability among study populations contributed to the findings. PMID:28381516

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial.

PubMed

Brisco, Meredith A; Zile, Michael R; Hanberg, Jennifer S; Wilson, F Perry; Parikh, Chirag R; Coca, Steven G; Tang, W H Wilson; Testani, Jeffrey M

2016-10-01

Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001). The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical endpoints for developing pharmaceuticals to manage patients with sporadic or genetic risk of colorectal cancer

PubMed Central

Rial, Nathaniel S.; Zell, Jason A.; Cohen, Alfred M.; Gerner, Eugene W.

2013-01-01

To reduce the morbidity and mortality from colorectal cancer, current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients with risk of colorectal cancer. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with sporadic or genetic risk of colorectal cancer. It will also discuss therapeutic endpoints under evaluation in current efforts to develop drugs for treating colorectal cancer risk factors. PMID:22928902

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.

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.

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.

Pain management interventions in the nursing home: a structured review of the literature.

PubMed

Herman, Adam D; Johnson, Theodore M; Ritchie, Christine S; Parmelee, Patricia A

2009-07-01

Residents in nursing homes (NHs) experience pain that is underrecognized and undertreated. This pain contributes to a decline in quality of life. Although descriptive studies of pain assessment and management have been conducted, few have been published that critically evaluate interventions to improve pain management. Identification of the strengths and gaps in the current literature is required. A literature search was conducted of clinical trials that evaluated prospective interventions to improve pain management. Information on the intervention type, resident sample and setting, endpoints, and study design were extracted. Studies were classified based on a modification of Donabedian's model of healthcare quality. Four categories of interventions were identified: actor, decision support, treatment, and systems. The search strategy and selection criteria yielded 21 articles. Eleven studies used an actor intervention; of these, eight also employed a systems intervention, and one also used a treatment intervention. Two studies used a decision support intervention, seven used a treatment intervention, and one used a systems intervention. The overall quality of research was uneven in several areas: research design--nine studies were quasi-experimental in nature, endpoints measures were not consistent--three did not perform statistical analysis, and characteristics of the resident samples varied dramatically. In conclusion, the number of high-quality studies of pain management in NHs remains limited. Process endpoints are used as surrogate measures for resident endpoints. Systematic approaches are needed to understand how each type of intervention improves the quality of pain management at the resident level.

Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

PubMed Central

Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D.; d’Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

2014-01-01

An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed. PMID:25380523

Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention

PubMed Central

Kumar, Nagi B.; Pow-Sang, Julio; Egan, Kathleen M.; Spiess, Philippe E.; Dickinson, Shohreh; Salup, Raoul; Helal, Mohamed; McLarty, Jerry; Williams, Christopher R.; Schreiber, Fred; Parnes, Howard L.; Sebti, Said; Kazi, Aslam; Kang, Loveleen; Quinn, Gwen; Smith, Tiffany; Yue, Binglin; Diaz, Karen; Chornokur, Ganna; Crocker, Theresa; Schell, Michael J.

2015-01-01

Preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E® (PolyE), a proprietary mixture of GTCs, containing 400 mg (–)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year PCa rates on the two study arms. No differences in the number of PCa cases were observed: 5/49 (PolyE) versus 9/48 (placebo), P=0.25. A secondary endpoint comparing the cumulative rate of PCa plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3/26 (PolyE) versus 10/25 (placebo), P<0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared to the placebo arm (5/25). A decrease in serum prostate specific antigen (PSA) was observed on the PolyE arm [−0.87 ng/ml (95%CI: −1.66, −0.09)]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of PCa in men with baseline HGPIN or ASAP. PMID:25873370

The Sleep Apnea cardioVascular Endpoints (SAVE) Trial: Rationale, Ethics, Design, and Progress.

PubMed

Antic, Nick A; Heeley, Emma; Anderson, Craig S; Luo, Yuanming; Wang, Jiguang; Neal, Bruce; Grunstein, Ron; Barbe, Ferran; Lorenzi-Filho, Geraldo; Huang, Shaoguang; Redline, Susan; Zhong, Nanshan; McEvoy, R Doug

2015-08-01

The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed. NCT00738179. ACTRN12608000409370. © 2015 Associated Professional Sleep Societies, LLC.

Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data

PubMed Central

Mauguen, Audrey; Pignon, Jean-Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J; Belani, Chandra P; Shepherd, Frances A; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T; Dahlberg, Suzanne E; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E; Parmar, Mahesh; Tierney, Jayne F; Pechoux, Cécile Le; Michiels, Stefan

2013-01-01

Summary Background The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2=0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2=0·95, 0·91–0·98 for modified vs standard radiotherapy). Interpretation We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis. PMID:23680111

Thrombectomy in patients ineligible for iv tPA (THRILL).

PubMed

Bendszus, Martin; Thomalla, Götz; Knauth, Michael; Hacke, Werner; Bonekamp, Susanne; Fiehler, Jens

2015-08-01

A relevant proportion of patients with acute ischemic stroke are ineligible for intravenous thrombolysis with recombinant tissue plasminogen activator. Mechanical thrombectomy offers a treatment alternative for these patients; however, only few data are available on its safety and efficacy. The aim of this study was to compare safety and efficacy of stent retrievers as device class with best medical care alone in acute stroke patients with large intracranial vessel occlusion in the anterior circulation who are not eligible for intravenous thrombolysis with recombinant tissue plasminogen activator up to eight-hours of symptom onset. 'Thrombectomy in patients ineligible for iv tPA' is a prospective, open-label, blinded end-point, binational (Germany and Austria), two-arm, randomized, controlled, post-market study. Primary end-point is the modified Rankin Score shift analysis 90 days (±14) after stroke. Secondary end-points are excellent neurological outcomes (modified Rankin Score ≤ 1), good neurological outcomes (modified Rankin Score ≤ 2 or National Institutes of Health Stroke Scale improvement ≥ 10), difference between predicted infarct volume and actual core infarct volume (computed tomography or magnetic resonance imaging) at 30 (±6) h post-ictus, successful recanalization (thrombolysis in cerebral infarction score 2b or 3), functional health status 90 (±14) days after stroke (European Quality of Life-5 Dimensions) as well as common safety end-points (adverse event, serious adverse event, symptomatic intracranial haemorrhage at 30 (±6) h, death, or dependency). Whether mechanical thrombectomy in patients with acute ischemic stroke who are not eligible for intravenous thrombolysis with recombinant tissue plasminogen activator improves clinical outcomes is unclear. 'Thrombectomy in patients ineligible for iv tPA' may change clinical practice by providing evidence of an effective and safe treatment for such patients. © 2015 World Stroke Organization.

Rosemary oil vs minoxidil 2% for the treatment of androgenetic alopecia: a randomized comparative trial.

PubMed

Panahi, Yunes; Taghizadeh, Mohsen; Marzony, Eisa Tahmasbpour; Sahebkar, Amirhossein

2015-01-01

Rosmarinus officinalis L. is a medicinal plant with diverse activities including enhancement microcapillary perfusion. The present study aimed to investigate the clinical efficacy of rosemary oil in the treatment of androgenetic alopecia (AGA) and compare its effects with minoxidil 2%. Patients with AGA were randomly assigned to rosemary oil (n = 50) or minoxidil 2% (n = 50) for a period of 6 months. After a baseline visit, patients returned to the clinic for efficacy and safety evaluations every 3 months. A standardized professional microphotographic assessment of each volunteer was taken at the initial interview and after 3 and 6 months of the trial. No significant change was observed in the mean hair count at the 3-month endpoint, neither in the rosemary nor in the minoxidil group (P > .05). In contrast, both groups experienced a significant increase in hair count at the 6-month endpoint compared with the baseline and 3-month endpoint (P < .05). No significant difference was found between the study groups regarding hair count either at month 3 or month 6 (> .05). The frequencies of dry hair, greasy hair, and dandruff were not found to be significantly different from baseline at either month 3 or month 6 trial in the groups (P > .05). The frequency of scalp itching at the 3- and 6-month trial points was significantly higher compared with baseline in both groups (P < .05). Scalp itching, however, was more frequent in the minoxidil group at both assessed endpoints (P < .05). The findings of the present trial provided evidence with respect to the efficacy of rosemary oil in the treatment of AGA.

Cocaine and thrombosis: a narrative systematic review of clinical and in-vivo studies

PubMed Central

Wright, Nat MJ; Martin, Matthew; Goff, Tom; Morgan, John; Elworthy, Rebecca; Ghoneim, Shariffe

2007-01-01

Purpose To systematically review the literature pertaining to the link between cocaine and either arterial or venous thrombosis. Procedures Narrative systematic review of Medline, CINAHL, Embase, Psycinfo and Cochrane databases supplemented by hand trawling of relevant journals and reference lists up to April 2007. In-vivo studies and those with clinical endpoints were included in the review. Results A total of 2458 abstracts led to 186 full-text papers being retrieved. 15 met the criteria for inclusion in the review. The weight of evidence would support cocaine as a pro-thrombotic agent. There is evidence of it activating thrombotic pathways. The effect of cocaine upon clinical endpoints has not been quantified though there is evidence of an association between cocaine and myocardial infarction particularly amongst young adults. Cocaine may also be a causal agent in cerebrovascular accident though studies lacked sufficient power to determine a statistically significant effect. There is a gap in the evidence pertaining to the issue of cocaine and venous thrombosis. Conclusion Clinicians should consider questioning for cocaine use particularly amongst young adults who present with cardiac symptoms. More epidemiological work is required to quantify the effect of cocaine upon both arterial and venous clotting mechanisms. PMID:17880705

Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.

PubMed

Khan, Fakhar Z; Virdee, Mumohan S; Palmer, Christopher R; Pugh, Peter J; O'Halloran, Denis; Elsik, Maros; Read, Philip A; Begley, David; Fynn, Simon P; Dutka, David P

2012-04-24

This study sought to assess the impact of targeted left ventricular (LV) lead placement on outcomes of cardiac resynchronization therapy (CRT). Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care. A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of >10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure-related hospitalization. The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031). Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Using Standardized Interpretation of Chest Radiographs to Identify Adults with Bacterial Pneumonia--Guatemala, 2007-2012.

PubMed

Wortham, Jonathan M; Gray, Jennifer; Verani, Jennifer; Contreras, Carmen Lucia; Bernart, Chris; Moscoso, Fabiola; Moir, Juan Carlos; Reyes Marroquin, Emma Lissette; Castellan, Rigoberto; Arvelo, Wences; Lindblade, Kim; McCracken, John P

2015-01-01

Bacterial pneumonia is a leading cause of illness and death worldwide, but quantifying its burden is difficult due to insensitive diagnostics. Although World Health Organization (WHO) protocol standardizes pediatric chest radiograph (CXR) interpretation for epidemiologic studies of bacterial pneumonia, its validity in adults is unknown. Patients (age ≥ 15 years) admitted with respiratory infections to two Guatemalan hospitals between November 2007 and March 2012 had urine and nasopharyngeal/oropharyngeal (NP/OP) swabs collected; blood cultures and CXR were also performed at physician clinical discretion. 'Any bacterial infection' was defined as a positive urine pneumococcal antigen test, isolation of a bacterial pneumonia pathogen from blood culture, or detection of an atypical bacterial pathogen by polymerase chain reaction (PCR) of nasopharyngeal/oropharyngeal (NP/OP) specimens. 'Viral infection' was defined as detection of viral pathogens by PCR of NP/OP specimens. CXRs were interpreted according to the WHO protocol as having 'endpoint consolidation', 'other infiltrate', or 'normal' findings. We examined associations between bacterial and viral infections and endpoint consolidation. Urine antigen and/or blood culture results were available for 721 patients with CXR interpretations; of these, 385 (53%) had endpoint consolidation and 253 (35%) had other infiltrate. Any bacterial infection was detected in 119 (17%) patients, including 106 (89%) pneumococcal infections. Any bacterial infection (Diagnostic Odds Ratio [DOR] = 2.9; 95% confidence Interval (CI): 1.3-7.9) and pneumococcal infection (DOR = 3.4; 95% CI: 1.5-10.0) were associated with 'endpoint consolidation', but not 'other infiltrate' (DOR = 1.7; 95% CI: 0.7-4.9, and 1.7; 95% CI: 0.7-4.9 respectively). Viral infection was not significantly associated with 'endpoint consolidation', 'other infiltrate,' or 'normal' findings. 'Endpoint consolidation' was associated with 'any bacterial infection,' specifically pneumococcal infection. Therefore, endpoint consolidation may be a useful surrogate for studies measuring the impact of interventions, such as conjugate vaccines, against bacterial pneumonia.

Prognostic implications of epicardial fat volume quantification in acute pericarditis.

PubMed

Lazaros, George; Antonopoulos, Alexios S; Oikonomou, Evangelos K; Vasileiou, Panagiotis; Oikonomou, Evangelos; Stroumpouli, Evangelia; Karavidas, Apostolos; Antoniades, Charalambos; Tousoulis, Dimitris

2017-02-01

The pathophysiology of acute pericarditis remains largely unknown, and biomarkers are needed to identify patients susceptible to complications. As adipose tissue has a pivotal role in cardiovascular disease pathogenesis, we hypothesized that quantification of epicardial fat volume (EFV) provides prognostic information in patients with acute pericarditis. Fifty (n = 50) patients with first diagnosis of acute pericarditis were enrolled in this study. Patients underwent a cardiac computerized tomography (CT) scan to quantify EFV on a dedicated workstation. Patients were followed up in hospital for atrial fibrillation (AF) development and up to 18 months for the composite clinical endpoint of development of constrictive, recurrent or incessant pericarditis or poor response to nonsteroidal anti-inflammatory drugs. Patients presenting with chest pain had lower EFV vs. patients without chest pain (167·2 ± 21·7 vs. 105·1 ± 11·1 cm 3 , respectively, P < 0·01); EFV (but not body mass index) was strongly positively correlated with pericardial effusion size (r = 0·395, P = 0·007) and associated with in-hospital AF. At follow-up, patients that reached the composite clinical endpoint had lower EFV (P < 0·05). After adjustment for age, EFV was associated with lower odds ratio for the composite clinical endpoint point of poor response to NSAIDs or the development of constrictive, recurrent or incessant pericarditis during follow-up (per 20 cm 3 increase in EFV: OR = 0·802 [0·656-0·981], P < 0·05). We report for the first time a significant association of EFV with the clinical features and the outcome of patients with acute pericarditis. Measurement of EFV by CT may have important prognostic implications in these patients. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

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.

An exploration into study design for biomarker identification: issues and recommendations.

PubMed

Hall, Jacqueline A; Brown, Robert; Paul, Jim

2007-01-01

Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.

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 of a controlled clinical trial developed by consensus of an international study group. Part one: rationale and hypothesis.

PubMed

Lorenz, W; Stinner, B; Bauhofer, A; Rothmund, M; Celik, I; Fingerhut, A; Koller, M; Lorijn, R H; Nyström, P O; Sitter, H; Schein, M; Solomkin, J S; Troidl, H; Wyatt, J; Wittmann, D H

2001-03-01

Presentation of a novel study protocol to evalue the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). Part one of this protocol describes the concepts of three major sections of the study: Definition of optimum and sub-optimal recovery after operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i. e. death, complications and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patient and the surgeon (true endpoint). Its conventional early assessment within 14-28 days is artificial: longer periods (such as 6 months) are needed for the patient to state: "I am now as well as I was before". Identification of suitable target patients: the use of biological response modifiers (immune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropriate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cancer will be studied to prove this hypothesis. Choice of biological response modifier: Filgrastim has been chosen as an example of a biological response modifier because it was effective in a new study type, clinic-modelling randomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced host defence and has been anti-inflammatory in basic research. The following hypothesis will be tested in patients with operations for colorectal cancer and increased preoperative risk (ASA 3 and 4): is the outcome as evaluated by the hermeneutic endpoint (quality of life expressed by the patient) and mechanistic endpoints (mortality rate, complication rate, relative hospital stay, assessed by the doctor) improved in the group receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, statistical testing of confirmatory analysis.

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

One-Year Clinical Outcomes of Patients Presenting With ST-Segment Elevation Myocardial Infarction Caused by Bifurcation Culprit Lesions Treated With the Stentys Self-Apposing Coronary Stent: Results From the APPOSITION III Study.

PubMed

Grundeken, Maik J; Lu, Huangling; Vos, Nicola; IJsselmuiden, Alexander; van Geuns, Robert-Jan; Wessely, Rainer; Dengler, Thomas; La Manna, Alessio; Silvain, Johanne; Montalescot, Gilles; Spaargaren, René; Tijssen, Jan G P; de Winter, Robbert J; Wykrzykowska, Joanna J; Amoroso, Giovanni; Koch, Karel T

2017-08-01

To investigate outcomes in patients with ST-segment elevation myocardial infarction (STEMI) after treatment with the Stentys self-apposing stent (Stentys SAS; Stentys S.A.) for bifurcation culprit lesions. The nitinol, self-expanding Stentys was initially developed as a dedicated bifurcation stent. The stent facilitates a provisional strategy by accommodating its diameter to both the proximal and distal reference diameters and offering an opportunity to "disconnect" the interconnectors, opening the stent toward the side branch. The APPOSITION (a post-market registry to assess the Stentys self-expanding coronary stent in acute myocardial infarction) III study was a prospective, multicenter, international, observational study including STEMI patients undergoing primary percutaneous coronary intervention (PCI) with the Stentys SAS. Clinical endpoints were evaluated and stratified by bifurcation vs non-bifurcation culprit lesions. From 965 patients included, a total of 123 (13%) were documented as having a bifurcation lesion. Target-vessel revascularization (TVR) rates were higher in the bifurcation subgroup (16.4% vs 10.0%; P=.04). Although not statistically significant, other endpoints were numerically higher in the bifurcation subgroup: major adverse cardiac events (MACE; 12.7% vs 8.8%), myocardial infarction (MI; 3.4% vs 1.8%), and definite/probable stent thrombosis (ST; 5.8% vs 3.1%). However, when postdilation was performed, clinical endpoints were similar between bifurcation and non-bifurcation lesions: MACE (8.7% vs 8.4%), MI (1.2% vs 0.7%), and definite/probable ST (3.7% vs 2.4%). The use of the Stentys SAS was safe and feasible for the treatment of bifurcation lesions in the setting of primary PCI for STEMI treatment with acceptable 1-year cardiovascular event rates, which improved when postdilation was performed.

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.

Study Designs and Statistical Analyses for Biomarker Research

PubMed Central

Gosho, Masahiko; Nagashima, Kengo; Sato, Yasunori

2012-01-01

Biomarkers are becoming increasingly important for streamlining drug discovery and development. In addition, biomarkers are widely expected to be used as a tool for disease diagnosis, personalized medication, and surrogate endpoints in clinical research. In this paper, we highlight several important aspects related to study design and statistical analysis for clinical research incorporating biomarkers. We describe the typical and current study designs for exploring, detecting, and utilizing biomarkers. Furthermore, we introduce statistical issues such as confounding and multiplicity for statistical tests in biomarker research. PMID:23012528

Responders vs clinical response: a critical analysis of data from linaclotide phase 3 clinical trials in IBS-C.

PubMed

Lacy, B E; Lembo, A J; Macdougall, J E; Shiff, S J; Kurtz, C B; Currie, M G; Johnston, J M

2014-03-01

US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome-C (IBS-C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health-care practitioners to assess clinical response has not been determined. We analyzed pooled IBS-C linaclotide trial data to evaluate clinically significant responses in linaclotide-treated patients who did not meet the FDA responder definition. Percentages of FDA non-responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two linaclotide Phase 3 IBS-C trials. 1602 IBS-C patients enrolled; 34% of linaclotide-treated and 17% of placebo-treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non-responders at week 12, 63% of linaclotide-treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo-treated patients. For stool frequency, 62% of linaclotide-treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo-treated patients. For global IBS symptoms, 65% of linaclotide-treated patients reported at least some IBS-symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively. Most linaclotide-treated IBS-C patients who were FDA non-responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom-specific change from baseline should be considered by clinicians for a complete understanding of clinical response to linaclotide and other IBS-C therapies. © 2013 Ironwood Pharmaceuticals. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.

Time to improvement of pain and sleep quality in clinical trials of pregabalin for the treatment of fibromyalgia.

PubMed

Arnold, Lesley M; Emir, Birol; Pauer, Lynne; Resnick, Malca; Clair, Andrew

2015-01-01

To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia. A post hoc analysis of four 8- to 14-week phase 2-3, placebo-controlled trials of fixed-dose pregabalin (150-600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms. A total of 2,747 patients with fibromyalgia, aged 18-82 years. Pain and sleep quality scores, recorded daily on 11-point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of ≥2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a ≥1-point reduction of the baseline NRS score of patient responders who had a ≥30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at endpoint. Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo. Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo. Wiley Periodicals, Inc.

Structured personal care of type 2 diabetes: a 19 year follow-up of the study Diabetes Care in General Practice (DCGP).

PubMed

Hansen, L J; Siersma, V; Beck-Nielsen, H; de Fine Olivarius, N

2013-06-01

This study is a 19 year observational follow-up of a pragmatic open multicentre cluster-randomised controlled trial of 6 years of structured personal diabetes care starting from diagnosis. A total of 1,381 patients aged ≥ 40 years and newly diagnosed with type 2 diabetes were followed up in national registries for 19 years. Clinical follow-up was at 6 and 14 years after diabetes diagnosis. The original 6 year intervention included regular follow-up and individualised goal setting, supported by prompting of doctors, clinical guidelines, feedback and continuing medical education (ClinicalTrials.gov NCT01074762). The registry-based endpoints were: incidence of any diabetes-related endpoint; diabetes-related death; all-cause mortality; myocardial infarction (MI); stroke; peripheral vascular disease; and microvascular disease. At 14 year clinical follow-up, group differences in risk factors from the 6 year follow-up had levelled out, although the prevalence of (micro)albuminuria and level of triacylglycerols were lower in the intervention group. During 19 years of registry-based monitoring, all-cause mortality was not different between the intervention and comparison groups (58.9 vs 62.3 events per 1,000 patient-years, respectively; for structured personal care, HR 0.94, 95% CI 0.83, 1.08, p = 0.40), but a lower risk emerged for fatal and non-fatal MI (27.3 vs 33.5, HR 0.81, 95% CI 0.68, 0.98, p = 0.030) and any diabetes-related endpoint (69.5 vs 82.1, HR 0.83, 95% CI 0.72, 0.97, p = 0.016). These differences persisted after extensive multivariable adjustment. In concert with features such as prompting, feedback, clinical guidelines and continuing medical education, individualisation of goal setting and drug treatment may safely be applied to treat patients newly diagnosed with type 2 diabetes to lower the risk of diabetes complications.

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.

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.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

PubMed

Wang, Jianming; Ke, Chunlei; Yu, Zhinuan; Fu, Lei; Dornseif, Bruce

2016-05-01

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression-free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

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).

Primary transmission of chronic wasting disease versus scrapie prions from small ruminants to transgenic mice expressing ovine or cervid prion protein.

PubMed

Madsen-Bouterse, Sally A; Schneider, David A; Zhuang, Dongyue; Dassanayake, Rohana P; Balachandran, Aru; Mitchell, Gordon B; O'Rourke, Katherine I

2016-09-01

Development of mice expressing either ovine (Tg338) or cervid (TgElk) prion protein (PrP) have aided in characterization of scrapie and chronic wasting disease (CWD), respectively. Experimental inoculation of sheep with CWD prions has demonstrated the potential for interspecies transmission but, infection with CWD versus classical scrapie prions may be difficult to differentiate using validated diagnostic platforms. In this study, mouse bioassay in Tg338 and TgElk was utilized to evaluate transmission of CWD versus scrapie prions from small ruminants. Mice (≥5 per homogenate) were inoculated with brain homogenates from clinically affected sheep or goats with naturally acquired classical scrapie, white-tailed deer with naturally acquired CWD (WTD-CWD) or sheep with experimentally acquired CWD derived from elk (sheep-passaged-CWD). Survival time (time to clinical disease) and attack rates (brain accumulation of protease resistant PrP, PrPres) were determined. Inoculation with classical scrapie prions resulted in clinical disease and 100 % attack rates in Tg338, but no clinical disease at endpoint (>300 days post-inoculation, p.i.) and low attack rates (6.8 %) in TgElk. Inoculation with WTD-CWD prions yielded no clinical disease or brain PrPres accumulation in Tg338 at endpoint (>500 days p.i.), but rapid onset of clinical disease (~121 days p.i.) and 100 % attack rate in TgElk. Sheep-passaged-CWD resulted in transmission to both mouse lines with 100 % attack rates at endpoint in Tg338 and an attack rate of ~73 % in TgElk with some culled due to clinical disease. These primary transmission observations demonstrate the potential of bioassay in Tg338 and TgElk to help differentiate possible infection with CWD versus classical scrapie prions in sheep and goats.

A study to assess the value of bispectral analysis in intravenous sedation with midazolam during third molar surgery under local anaesthesia.

PubMed

Cheung, C W; Irwin, M G; Chiu, W K; Ying, C L A

2008-12-01

This study aimed to determine whether bispectral index (BIS) can be used as an indicator of sedation and recovery with intravenous midazolam. In Part A, 30 healthy patients undergoing third molar extraction under local anaesthesia were recruited. They were sedated with intravenous midazolam titrated to clinical endpoints. BIS values were recorded when adequately sedated (BIS(S)) and when clinical recovery criteria were met (BIS). In Part B, another 30 patients were sedated to the range of BIS(S) obtained in Part A. Recovery was assessed postoperatively when the range of BIS(R) from Part A was reached. BIS titrated patients required less midazolam (p < 0.001). Seventy percent of Part B patients required increments of midazolam during surgery, compared to 16.7% in Part A (p < 0.001). Total dose of midazolam given was lower in Part B (p = 0.025). BIS is not effective as a sole indicator of endpoint in sedation with intravenous midazolam.

Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

PubMed

Carrera, Gemma; Garcia-Albeniz, Xabier; Ayuso, Juan Ramón; Aparicio, Jorge; Castells, Antoni; Codony-Servat, Jordi; Feliu, Jaime; Fuster, David; Gallego, Rosa; Pagés, Mario; Torres, Ferran; Maurel, Joan

2011-05-01

Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

Safety and Effectiveness of Once-Daily Tadalafil (5 mg) Therapy in Korean Men with Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms in a Real-World Clinical Setting: Results from a Post-Marketing Surveillance Study.

PubMed

Won, Ji Eon; Chu, Ji Yeon; Choi, Hyunah Caroline; Chen, Yun; Park, Hyun Jun; Dueñas, Héctor José

2018-05-01

The aim of this study was to investigate the safety and effectiveness of tadalafil 5 mg once daily (quaque die [everyday], QD) among Korean men with benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in a real-world clinical setting. This was a single-country, prospective, observational cohort study in which patients newly prescribed tadalafil 5 mg QD for the treatment of BPH/LUTS were followed-up for 12±2 or 24±2 weeks, or to the last treatment, during post-marketing surveillance. Safety was evaluated in terms of the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Effectiveness was assessed by changes in the International Prostate Symptom Score (IPSS) from baseline to each endpoint. All patients receiving ≥1 dose of tadalafil 5 mg QD (N=637) were included in the safety population. Two percent of patients (n=13) experienced 15 TEAEs of mild (n=10; 66.7%) or moderate (n=5; 33.3%) severity. No severe TEAEs and no SAEs were reported. Effectiveness evaluations included all patients receiving tadalafil who had both baseline and endpoint observations (12-week, N=265; 24-week, N=44). Compared with baseline, the mean IPSS total score (±standard error) significantly improved by 4.7±0.3 and 6.4±0.7 points at the 12- and 24-week endpoints, respectively (p<0.0001), with significant improvements also observed on the storage, voiding, and quality of life subscores. In total, 69.1% of the patients had a clinically meaningful ≥3-point improvement in the IPSS total score. Tadalafil 5 mg QD was well tolerated and effective in Korean men with BPH/LUTS in a real-world clinical setting. Copyright © 2018 Korean Society for Sexual Medicine and Andrology.

Clinical and anatomic pathology effects of serial blood sampling in rat toxicology studies, using conventional or microsampling methods.

PubMed

Caron, Alexis; Lelong, Christine; Bartels, T; Dorchies, O; Gury, T; Chalier, Catherine; Benning, Véronique

2015-08-01

As a general practice in rodent toxicology studies, satellite animals are used for toxicokinetic determinations, because of the potential impact of serial blood sampling on toxicological endpoints. Besides toxicological and toxicokinetic determinations, blood samples obtained longitudinally from a same animal may be used for the assessment of additional parameters (e.g., metabolism, pharmacodynamics, safety biomarkers) to maximize information that can be deduced from rodents. We investigated whether removal of up to 6 × 200 μL of blood over 24h can be applied in GLP rat toxicology studies without affecting the scientific outcome. 8 week-old female rats (200-300 g) were dosed for up to 1 month with a standard vehicle and subjected or not (controls) to serial blood sampling for sham toxicokinetic/ancillary determinations, using miniaturized methods allowing collection of 6 × 50, 100 or 200 μL over 24h. In-life endpoints, clinical pathology parameters and histopathology of organs sensitive to blood volume reduction were evaluated at several time points after completion of sampling. In sampled rats, minimal and reversible changes in red blood cell mass (maximally 15%) and subtle variations in liver enzymes, fibrinogen and neutrophils were not associated with any organ/tissue macroscopic or microscopic correlate. Serial blood sampling (up to 6 × 200 μL over 24h) is compatible with the assessment of standard toxicity endpoints in adult rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Ophthalmic Start-Up Chief Executive Officers' Perceptions of Development Hurdles.

PubMed

Stewart, William C; Nelson, Lindsay A; Kruft, Bonnie; Stewart, Jeanette A

2018-01-01

To identify current challenges facing ophthalmic pharmaceutical start-ups in developing new products. Surveys were distributed to the chief executive officer (CEO) or president of ophthalmic start-ups. The survey attracted 24 responses from 78 surveys distributed (31%). The CEOs stated that a lack of financial capital (n = 18, 75%), FDA regulations (n = 6, 25%), and failure to meet clinical endpoints (n = 6, 25%) were their greatest development hurdles. Risk aversion to medicines in early development (n = 18, 75%), mergers and acquisitions reducing corporate choice for licensing agreements (n = 7, 29%), the emergence of large pharmaceutical-based venture capital funding groups (n = 12, 50%), and the failure of many large pharmaceutical companies to develop their own medicines (n = 10, 42%) were noted as recent prominent trends affecting fundraising. The study suggests that development funding, regulatory burden, and meeting clinical endpoints are the greatest development challenges faced by ophthalmic start-up CEOs. © 2017 S. Karger AG, Basel.

Effect of Obesity on the Prognostic Impact of Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction.

PubMed

Yagawa, Mayuko; Nagatomo, Yuji; Izumi, Yuki; Mahara, Keitaro; Tomoike, Hitonobu; Shiraishi, Yasuyuki; Kohno, Takashi; Mizuno, Atsushi; Goda, Ayumi; Kohsaka, Shun; Yoshikawa, Tsutomu

2017-06-23

Although obesity is associated with left ventricular hypertrophy, diastolic dysfunction, and occurrence of atrial fibrillation (AF), obese heart failure (HF) patients have a more favorable clinical outcome (obesity paradox). The clinical impact of AF on obese or lean HF patients has not been fully elucidated.Methods and Results:We analyzed 1,681 patients who were enrolled in the West Tokyo Heart Failure Registry (WET-HF Registry), a multicenter, prospective cohort registry from 2005 through 2014. We assigned them to 3 categories based on body mass index (BMI): low, BMI <18.5; medium, BMI ≥18.5 and <25; and high, BMI ≥25 (n=182/915/400). The clinical endpoint was all-cause death or readmission for acute decompensated HF. During 406 days of follow-up (IQR, 116-739 days), AF was associated with a higher risk of the endpoint in the HF with preserved ejection fraction (HFpEF) group (P<0.001, log-rank test), but not in the HF with reduced EF (HFrEF) group. AF was associated with a higher risk of the endpoint in low and medium BMI patients with HFpEF (P=0.016 and 0.009, respectively). On Multivariate Cox proportional hazards analysis, AF was an independent predictor of the endpoint in patients with BMI <25 from the HFpEF group (hazard ratio, 1.74; 95% CI: 1.21-2.54, P=0.003), but not in the other subgroups. AF had a negative impact on clinical outcome in non-obese patients with HFpEF.

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.

Association between frequent cardiac resynchronization therapy optimization and long-term clinical response: a post hoc analysis of the Clinical Evaluation on Advanced Resynchronization (CLEAR) pilot study.

PubMed

Delnoy, Peter Paul; Ritter, Philippe; Naegele, Herbert; Orazi, Serafino; Szwed, Hanna; Zupan, Igor; Goscinska-Bis, Kinga; Anselme, Frederic; Martino, Maria; Padeletti, Luigi

2013-08-01

The long-term clinical value of the optimization of atrioventricular (AVD) and interventricular (VVD) delays in cardiac resynchronization therapy (CRT) remains controversial. We studied retrospectively the association between the frequency of AVD and VVD optimization and 1-year clinical outcomes in the 199 CRT patients who completed the Clinical Evaluation on Advanced Resynchronization study. From the 199 patients assigned to CRT-pacemaker (CRT-P) (New York Heart Association, NYHA, class III/IV, left ventricular ejection fraction <35%), two groups were retrospectively composed a posteriori on the basis of the frequency of their AVD and VVD optimization: Group 1 (n = 66) was composed of patients 'systematically' optimized at implant, at 3 and 6 months; Group 2 (n = 133) was composed of all other patients optimized 'non-systematically' (less than three times) during the 1 year study. The primary endpoint was a composite of all-cause mortality, heart failure-related hospitalization, NYHA functional class, and Quality of Life score, at 1 year. Systematic CRT optimization was associated with a higher percentage of improved patients based on the composite endpoint (85% in Group 1 vs. 61% in Group 2, P < 0.001), with fewer deaths (3% in Group 1 vs. 14% in Group 2, P = 0.014) and fewer hospitalizations (8% in Group 1 vs. 23% in Group 2, P = 0.007), at 1 year. These results further suggest that AVD and VVD frequent optimization (at implant, at 3 and 6 months) is associated with improved long-term clinical response in CRT-P patients.

Comparative Effectiveness of Renin-Angiotensin System Antagonists in Maintenance Dialysis Patients

PubMed Central

Shireman, Theresa I.; Mahnken, Jonathan D.; Phadnis, Milind A.; Ellerbeck, Edward F.; Wetmore, James B.

2017-01-01

Background/Aims Whether angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) are differentially associated with reductions in cardiovascular events and mortality in patients receiving maintenance dialysis is uncertain. We compared outcomes between ACE and ARB users among hypertensive, maintenance dialysis patients. Methods National retrospective cohort study of hypertensive, Medicare-Medicaid eligible patients initiating chronic dialysis between 1/1/2000 to 12/31/2005. The exposure of interest was new use of either an ACEI or ARB. Outcomes were all-cause mortality (ACM) and combined cardiovascular hospitalization or death (CV-endpoint). Cox proportion hazards models were used to compare the effect of ACEI vs ARB use on ACM and, separately, CV-endpoint. Results ACM models were based on 3,555 ACEI and 1,442 ARB new users, while CV-endpoint models included 3,289 ACEI and 1,346 ARB new users. After statistical adjustments, ACEI users had higher hazard ratios for ACM (AHR = 1.22, 99% CI 1.05–1.42) and CV-endpoint (AHR = 1.12, 99% CI 0.99–1.27). Conclusions Patients initiating maintenance dialysis who received an ACEI faced an increased risk for mortality and a trend towards an increased risk for CV-endpoints when compared to patients who received an ARB. Validation of these results in a rigorous clinical trial is warranted. PMID:27871075

Comparative Effectiveness of Renin-Angiotensin System Antagonists in Maintenance Dialysis Patients.

PubMed

Shireman, Theresa I; Mahnken, Jonathan D; Phadnis, Milind A; Ellerbeck, Edward F; Wetmore, James B

2016-01-01

Whether angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) are differentially associated with reductions in cardiovascular events and mortality in patients receiving maintenance dialysis is uncertain. We compared outcomes between ACE and ARB users among hypertensive, maintenance dialysis patients. National retrospective cohort study of hypertensive, Medicare-Medicaid eligible patients initiating chronic dialysis between 1/1/2000 to 12/31/2005. The exposure of interest was new use of either an ACEI or ARB. Outcomes were all-cause mortality (ACM) and combined cardiovascular hospitalization or death (CV-endpoint). Cox proportion hazards models were used to compare the effect of ACEI vs ARB use on ACM and, separately, CV-endpoint. ACM models were based on 3,555 ACEI and 1,442 ARB new users, while CV-endpoint models included 3,289 ACEI and 1,346 ARB new users. After statistical adjustments, ACEI users had higher hazard ratios for ACM (AHR = 1.22, 99% CI 1.05-1.42) and CV-endpoint (AHR = 1.12, 99% CI 0.99-1.27). Patients initiating maintenance dialysis who received an ACEI faced an increased risk for mortality and a trend towards an increased risk for CV-endpoints when compared to patients who received an ARB. Validation of these results in a rigorous clinical trial is warranted. © 2016 The Author(s) Published by S. Karger AG, Basel.

Use of an activity monitor to detect response to treatment in dogs with osteoarthritis

PubMed Central

Brown, Dorothy Cimino; Boston, Raymond C.; Farrar, John T.

2010-01-01

Objective To determine whether an activity monitor (AM) could be used to detect changes in activity in dogs with osteoarthritis treated with carprofen or a placebo. Design Randomized controlled trial. Animals 70 dogs with no clinically important abnormalities other than osteoarthritis for which they were not currently being treated. Procedures Dogs wore an AM continuously for 21 days. On days 8 through 21, the dogs were treated with carprofen (n = 35) or a placebo (35). Total activity counts for days 1 through 7 (baseline) were compared with total activity counts for days 15 through 21 (endpoint). The change in total activity count from baseline to endpoint was assessed within each treatment group as well as between groups. Linear regression analysis was performed to test for an association between treatment and percentage change in activity counts while controlling for other variables. Results For placebo-treated dogs, median baseline total activity count was not significantly different from median endpoint total activity count (1,378,408 vs 1,310,112, respectively). For dogs receiving carprofen, there was a significant increase in median activity count from baseline to endpoint (1,276,427 vs 1,374,133). When age and baseline activity counts were controlled for, dogs in the carpofen-treated group had a 20% increase in activity counts, compared with placebo-treated dogs (95% confidence interval, 10% to 26%). Conclusions and Clinical Relevance Results suggested that the AM used in the present study may be a valid outcome assessment tool for documenting improved activity associated with treatment in dogs with osteoarthritis. PMID:20590496

Establishing Chinese medicine characteristic tumor response evaluation system is the key to promote internationalization of Chinese medicine oncology.

PubMed

Li, Jie; Li, Lei; Liu, Rui; Lin, Hong-sheng

2012-10-01

The features and advantages of Chinese medicine (CM) in cancer comprehensive treatment have been in the spotlight of experts both at home and abroad. However, how to evaluate the effect of CM more objectively, scientifically and systematically is still the key problem of clinical trial, and also a limitation to the development and internationalization of CM oncology. The change of tumor response evaluation system in conventional medicine is gradually consistent with the features of CM clinical effect, such as they both focus on a combination of soft endpoints (i.e. quality of life, clinical benefit, etc.) and hard endpoints (i.e. tumor remission rate, time to progress, etc.). Although experts have proposed protocols of CM tumor response evaluation criteria and come to an agreement in general, divergences still exist in the importance, quantification and CM feature of the potential endpoints. Thus, establishing a CM characteristic and wildly accepted tumor response evaluation system is the key to promote internationalization of CM oncology, and also provides a more convenient and scientific platform for CM international cooperation and communication.

Vapor Inhalation Exposure to Soman in Conscious Untreated Rats: Preliminary Assessment of Neurotoxicity

DTIC Science & Technology

2015-12-22

study, which did not survive until the 24 h post-exposure endpoint, experienced severe signs of cholin- ergic intoxication , resulting in mortality...following vapor inhalation exposure, to aid in the development of potential treatment strategies. Gross clinical signs of soman intoxication were...consistent with typical cholinergic-induced intoxication . The observed CWNA-induced cholinergic crises and clinical signs of toxicity such as straub tail

The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis

PubMed Central

2013-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival time of 2–5 years. The search for effective treatment has involved numerous clinical trials of investigational agents without significant success. However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Four key clinical trials supported the efficacy and tolerability of pirfenidone. In the two recently published Phase III CAPACITY trials evaluating pirfenidone (studies 004 and 006), patients with mild-to-moderate IPF were treated with pirfenidone or placebo. Study 004 and pooled analysis of primary endpoint data from both studies showed that pirfenidone significantly reduced decline in percent-predicted forced vital capacity (FVC) compared with placebo (p<0.005). Evidence of beneficial effects of pirfenidone treatment was also observed with regard to several secondary endpoints. Pirfenidone was generally well tolerated, with the most common side effects being gastrointestinal and photosensitivity. Data from the RECAP extension phase of the CAPACITY studies, where patients were treated with pirfenidone for up to three years, further support the manageable tolerability profile of pirfenidone. The efficacy data, coupled with long-term safety data, provide further evidence of a clinically-meaningful treatment effect with pirfenidone in patients with IPF. PMID:23734908

Sample size determination in group-sequential clinical trials with two co-primary endpoints

PubMed Central

Asakura, Koko; Hamasaki, Toshimitsu; Sugimoto, Tomoyuki; Hayashi, Kenichi; Evans, Scott R; Sozu, Takashi

2014-01-01

We discuss sample size determination in group-sequential designs with two endpoints as co-primary. We derive the power and sample size within two decision-making frameworks. One is to claim the test intervention’s benefit relative to control when superiority is achieved for the two endpoints at the same interim timepoint of the trial. The other is when the superiority is achieved for the two endpoints at any interim timepoint, not necessarily simultaneously. We evaluate the behaviors of sample size and power with varying design elements and provide a real example to illustrate the proposed sample size methods. In addition, we discuss sample size recalculation based on observed data and evaluate the impact on the power and Type I error rate. PMID:24676799

High-volume forced diuresis with matched hydration using the RenalGuard System to prevent contrast-induced nephropathy: A meta-analysis of randomized trials.

PubMed

Shah, Rahman; Wood, Sarah J; Khan, Sajjad A; Chaudhry, Amina; Rehan Khan, M; Morsy, Mohamed S

2017-12-01

Contrast-induced nephropathy (CIN) is a well-recognized complication of coronary angiography that is associated with poor outcomes. Several small randomized controlled trials (RCTs) have recently shown that in patients with chronic kidney disease (CKD), furosemide-induced forced diuresis with matched hydration using the RenalGuard system can prevent its occurrence. However, individual studies have been underpowered and thus cannot show significant differences in major clinical endpoints. Forced diuresis with matched hydration using the RenalGuard system improves clinical outcomes in patients undergoing coronary angiography. Scientific databases and websites were searched for relevant RCTs. The pooled risk ratios were calculated using random-effects models. The primary endpoint was CIN, and the secondary endpoints were major adverse clinical events (MACEs) and the need for renal replacement therapy. Data from 3 trials including 586 patients were analyzed. High-volume forced diuresis with matched hydration using the RenalGuard system decreased risk of CIN by 60% (risk ratio: 0.40, 95% confidence interval: 0.25 to 0.65, P < 0.001), MACE rate by 59%, and the need for renal replacement therapy by 78%, compared with the standard of care. In patients with CKD undergoing coronary angiography, high-volume forced diuresis with matched hydration using the RenalGuard system significantly reduces the risk of CIN, MACE rate, and the need for renal replacement therapy. Larger RCTs with sufficient power are needed to confirm these findings. © 2017 Wiley Periodicals, Inc.

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

PubMed

Opal, Steven M; Dellinger, R Phillip; Vincent, Jean-Louis; Masur, Henry; Angus, Derek C

2014-07-01

The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

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 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.

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.

78 FR 33421 - Availability of Masked and De-identified Non-Summary Safety and Efficacy Data; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-04

... endpoint for chronic hepatitis C trials has been based on detection of hepatitis C virus at week 24 of... as a primary endpoint in clinical trials and allows for hepatitis C virus treatment options to be... Selection of Hepatitis C Therapies.'' Gastroenterology, 2013 March 4 http://www.sciencedirect.com/science...

Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.

PubMed

Sufka, Kenneth J; Staszko, Stephanie M; Johnson, Ainslee P; Davis, Morgan E; Davis, Rachel E; Smitherman, Todd A

2016-01-01

This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

Elemental mercury neurotoxicity and clinical recovery of function: A review of findings, and implications for occupational health.

PubMed

Calabrese, Edward J; Iavicoli, Ivo; Calabrese, Vittorio; Cory-Slechta, Deborah A; Giordano, James

2018-05-01

This paper assessed approximately 30 studies, mostly involving occupationally exposed subjects, concerning the extent to which those who developed elemental mercury (Hg)-induced central and/or peripheral neurotoxicities from chronic or acute exposures recover functionality and/or performance. While some recovery occurred in the vast majority of cases, the extent of such recoveries varied considerably by individual and endpoint. Factors accounting for the extensive inter-individual variation in toxicity and recovery were not specifically assessed such as age, gender, diet, environmental enrichment, chelation strategies and dose-rate. While the data indicate that psychomotor endpoints often show substantial and relatively rapid (i.e., 2-6 months) recovery and that neuropsychological endpoints display slower and less complete recovery, generalizations are difficult due to highly variable study designs, use of different endpoints measured between studies, different Hg exposures based on blood/urine concentrations and Hg dose-rates, the poor capacity for replicating findings due to the unpredictable/episodic nature of harmful exposures to elemental Hg, and the inconsistency of the initiation of studies after induced toxicities and the differing periods of follow up during recovery periods. Finally, there is strikingly limited animal model literature on the topic of recovery/reversibility of elemental Hg toxicity, a factor which significantly contributes to the overall marked uncertainties for predicting the rate and magnitude of recovery and the factors that affect it. Copyright © 2018 Elsevier Inc. All rights reserved.

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

The Palliative Care in Heart Failure (PAL-HF) Trial: Rationale and Design

PubMed Central

Mentz, Robert J.; Tulsky, James A.; Granger, Bradi B.; Anstrom, Kevin J.; Adams, Patricia A.; Dodson, Gwen C.; Fiuzat, Mona; Johnson, Kimberly S.; Patel, Chetan B.; Steinhauser, Karen E.; Taylor, Donald H.; O’Connor, Christopher M.; Rogers, Joseph G.

2014-01-01

Background The progressive nature of heart failure (HF) coupled with high mortality and poor quality of life mandates greater attention to palliative care as a routine component of advanced HF management. Limited evidence exists from randomized, controlled trials supporting the use of interdisciplinary palliative care in HF. Methods The Palliative Care in Heart Failure trial (PAL-HF) is a prospective, controlled, unblinded, single-center study of an interdisciplinary palliative care intervention in 200 patients with advanced HF estimated to have a high likelihood of mortality or re-hospitalization in the ensuing 6 months. The 6-month PAL-HF intervention focuses on physical and psychosocial symptom relief, attention to spiritual concerns and advanced care planning. The primary endpoint is health-related quality of life measured by the Kansas City Cardiomyopathy Questionnaire and the Functional Assessment of Chronic Illness Therapy with Palliative Care Subscale score at 6 months. Secondary endpoints include changes in anxiety/depression, spiritual well-being, caregiver satisfaction, cost and resource utilization, and a composite of death, HF hospitalization and quality of life. Conclusions PAL-HF is a randomized, controlled clinical trial that will help evaluate the efficacy and cost-effectiveness of palliative care in advanced HF using a patient-centered outcome as well as clinical and economic endpoints. PMID:25440791

Expectations about insulin therapy, perceived insulin-delivery system social acceptability, and insulin treatment satisfaction contribute to decreases in insulin therapy self-efficacy in patients with type 2 diabetes after 36 weeks insulin therapy.

PubMed

Hayes, Risa P; Curtis, Bradley; Ilag, Liza; Nelson, David R; Wong, Mayme; Funnell, Martha

2013-09-01

Self-efficacy plays a critical role in diabetes self-care. Herein we explore factors contributing to decreased insulin therapy self-efficacy in insulin-naïve patients with type 2 diabetes mellitus (T2DM) initiating and managing insulin therapy over 36 weeks. The study was conducted within an international, randomized clinical trial comparing two insulin therapies administered by insulin pen in patients with T2DM inadequately controlled with oral antihyperglycemic medications. Patients completed the Self-Efficacy about Insulin Therapy Questionnaire (SEITQ) at baseline and endpoint. Patients also completed patient-reported measures assessing expectations about insulin therapy at baseline and perceptions about insulin therapy and insulin-delivery system (IDS) satisfaction at endpoint. Baseline and endpoint SEITQ scores were compared. Using prespecified criteria, patients were classified as having "decreased" or "no change/improved" insulin self-efficacy. Demographic, clinical, and patient-reported variables were entered into a logistic regression model with decreased insulin self-efficacy (yes or no) as the dependent variable. Baseline and endpoint SEITQ data were available for 450 insulin-naïve T2DM patients (mean age 59 years; 53% female; 57% Caucasian; mean baseline HbA1c 9.4%; 80.0 mmol/mol). Insulin therapy self-efficacy improved from baseline to endpoint (74.0 vs 77.5; P<0.001). Logistic regression analysis indicated that lower IDS satisfaction (P<0.0001), lower IDS social acceptability (P=0.004), and more positive expectations of insulin therapy (P<0.0001) were associated with decreased insulin self-efficacy. A candid discussion between clinicians and their insulin-naïve T2DM patients about the benefits and challenges of insulin therapy may prevent unrealistic expectations that could potentially undermine insulin self-efficacy. © 2013 Wiley Publishing Asia Pty Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.

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.

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.

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.

Patient-specific evolution of renal function in chronic heart failure patients dynamically predicts clinical outcome in the Bio-SHiFT study.

PubMed

Brankovic, Milos; Akkerhuis, K Martijn; van Boven, Nick; Anroedh, Sharda; Constantinescu, Alina; Caliskan, Kadir; Manintveld, Olivier; Cornel, Jan Hein; Baart, Sara; Rizopoulos, Dimitris; Hillege, Hans; Boersma, Eric; Umans, Victor; Kardys, Isabella

2018-04-01

Renal dysfunction is an important component of chronic heart failure (CHF), but its single assessment does not sufficiently reflect clinically silent progression of CHF prior to adverse clinical outcome. Therefore, we aimed to investigate temporal evolutions of glomerular and tubular markers in 263 stable patients with CHF, and to determine if their patient-specific evolutions during this clinically silent period can dynamically predict clinical outcome. We determined the risk of clinical outcome (composite endpoint of Heart Failure hospitalization, cardiac death, Left Ventricular Assist Device placement, and heart transplantation) in relation to marker levels, slopes and areas under their trajectories. In each patient, the trajectories were estimated using repeatedly measured glomerular markers: creatinine/estimated glomerular filtration rate (eGFR), cystatin C (CysC), and tubular markers: urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1, plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL). During 2.2 years of follow-up, we collected on average 8 urine and 9 plasma samples per patient. All glomerular markers predicted the endpoint (univariable hazard ratio [95% confidence interval] per 20% increase: creatinine: 1.18[1.07-1.31], CysC: 2.41[1.81-3.41], and per 20% eGFR decrease: 1.13[1.05-1.23]). Tubular markers, NAG, and KIM-1 also predicted the endpoint (NAG: 1.06[1.01-1.11] and KIM-1: 1.08[1.04-1.11]). Larger slopes were the strongest predictors (creatinine: 1.57[1.39-1.84], CysC: 1.76[1.52-2.09], eGFR: 1.59[1.37-1.90], NAG: 1.26[1.11-1.44], and KIM-1: 1.64[1.38-2.05]). Associations persisted after multivariable adjustment for clinical characteristics. Thus, during clinically silent progression of CHF, glomerular and tubular functions deteriorate, but not simultaneously. Hence, patient-specific evolutions of these renal markers dynamically predict clinical outcome in patients with CHF. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

A Comprehensive Review of mTOR-Inhibiting Pharmacotherapy for the Treatment of Non-Infectious Uveitis.

PubMed

Blair, Joshua; Barry, Robert; Moore, David J; Denniston, Alastair K

2017-01-01

Non-infectious uveitis is a sight-threatening inflammatory disease that often necessitates prolonged use of high-dose corticosteroids, resulting in significant systemic side effects. There is a need for efficacious steroid-sparing immunomodulatory therapy for these patients, and the mTOR inhibitors (sirolimus and everolimus) may be contenders for this role. A comprehensive review of preclinical and clinical research on mTOR inhibitors for non-infectious uveitis was performed. Articles were identified by a search of MEDLINE (PubMed/OVID) and EMBASE (OVID) the terms (uveitis OR non-infectious uveitis) AND (mTOR inhibitor OR sirolimus OR everolimus). Assessment of study aims, methods, efficacy outcomes and adverse events was performed. Seven pre-clinical and nine clinical studies were identified. One study in each group was on everolimus, the rest sirolimus. Preclinical studies have been performed in rabbit, rat, mouse and in-vitro models. Clinical studies range from comparative open-label trials to case reports, with reported clinical efficacy ranging from 40% to 100% depending on endpoint assessed. The overall rate of drug-related adverse events (such as ocular irritation, visual floaters, nausea and vomiting) was 0.640 events per patient-year with sirolimus, and 0.111 events per patient-year with everolimus. Published evidence suggests that sirolimus and everolimus may be useful in the management of noninfectious uveitis. Both appear to be well tolerated, especially when locally administered. Further high-quality RCTs adopting standardised end-points are required to definitively determine the efficacy of each agent. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Non-invasive prediction of forthcoming cirrhosis-related complications

PubMed Central

Kang, Wonseok; Kim, Seung Up; Ahn, Sang Hoon

2014-01-01

In patients with chronic liver diseases, identification of significant liver fibrosis and cirrhosis is essential for determining treatment strategies, assessing therapeutic response, and stratifying long-term prognosis. Although liver biopsy remains the reference standard for evaluating the extent of liver fibrosis in patients with chronic liver diseases, several non-invasive methods have been developed as alternatives to liver biopsies. Some of these non-invasive methods have demonstrated clinical accuracy for diagnosing significant fibrosis or cirrhosis in many cross-sectional studies with the histological fibrosis stage as a reference standard. However, non-invasive methods cannot be fully validated through cross-sectional studies since liver biopsy is not a perfect surrogate endpoint marker. Accordingly, recent studies have focused on assessing the performance of non-invasive methods through long-term, longitudinal, follow-up studies with solid clinical endpoints related to advanced stages of liver fibrosis and cirrhosis. As a result, current view is that these alternative methods can independently predict future cirrhosis-related complications, such as hepatic decompensation, liver failure, hepatocellular carcinoma, or liver-related death. The clinical role of non-invasive models seems to be shifting from a simple tool for predicting the extent of fibrosis to a surveillance tool for predicting future liver-related events. In this article, we will summarize recent longitudinal studies of non-invasive methods for predicting forthcoming complications related to liver cirrhosis and discuss the clinical value of currently available non-invasive methods based on evidence from the literature. PMID:24627597

78 FR 76443 - Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-17

... Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 5411, Silver... surrogate endpoints and study design issues for the in vivo testing of health care antiseptics (Ref. 3... addressed when designing a clinical outcome study of the effectiveness of antiseptic washes in the consumer...

High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial.

PubMed

Vial, Pablo A; Valdivieso, Francisca; Ferres, Marcela; Riquelme, Raul; Rioseco, M Luisa; Calvo, Mario; Castillo, Constanza; Díaz, Ricardo; Scholz, Luis; Cuiza, Analia; Belmar, Edith; Hernandez, Carla; Martinez, Jessica; Lee, Sang-Joon; Mertz, Gregory J

2013-10-01

Andes virus (ANDV)-related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. NCT00128180.

Non-muscle invasive bladder cancer: Are epicrises the ‘Bermuda Triangle’ of information transfer?

PubMed Central

May, Matthias; Wick, Anne-Kathrin; Roiner, Michael; Mathew, Marcella; Gilfrich, Christian; Schostak, Martin

2017-01-01

Introduction The aim of the study was to collect information regarding the quality of communication of risk-determining factors or risk profile, and the guideline conformity of recommendations for adjuvant treatment in patients with non-muscle invasive bladder cancer (NMIBC) between clinical and ambulatory urologists. Material and methods At three German urological clinics during the period between 2012-2014, epicrises of 1,033 NMIBC-patients were retrospectively summarised to 505 tumour episodes (tumour resection including any re-resections) and analysed regarding the endpoints 1) risk profile is explicitly named or recorded risk factors are sufficient for the determination of risk profile, and 2) guideline conformity of treatment recommendation. Independent factors influencing the endpoints were determined by means of multivariate logistic regression models. Results The risk profile was explicitly named for 3.6% of tumour episodes; for 68.9% a risk profile could be derived from the information in the epicrises. Treatment recommendations were given for 93.7% of tumour episodes, but only 17.8% were guideline compliant. 42.6% of the recommendations were not reliably effective; 33.1% and 0.2% resulted in under- and overtreatment respectively. Neither endpoint showed gender specific or regional differences, but both were considerably less likely to be achieved in case of recurrence. Conclusions The discrepancy between treatment recommendation (93.7%) and guideline compliance (17.8%) could indicate a lack of familiarity with guidelines. The quality of the epicrises of NMIBC-patients was poor and bore the potential risk of undertreatment. The results of this study are not necessarily applicable to other clinics, but could, however, prompt physicians to re-examine epicrises for the fulfillment of the quality criteria examined here. PMID:29104786

Non-muscle invasive bladder cancer: Are epicrises the 'Bermuda Triangle' of information transfer?

PubMed

Lebentrau, Steffen; May, Matthias; Wick, Anne-Kathrin; Roiner, Michael; Mathew, Marcella; Gilfrich, Christian; Schostak, Martin

2017-01-01

The aim of the study was to collect information regarding the quality of communication of risk-determining factors or risk profile, and the guideline conformity of recommendations for adjuvant treatment in patients with non-muscle invasive bladder cancer (NMIBC) between clinical and ambulatory urologists. At three German urological clinics during the period between 2012-2014, epicrises of 1,033 NMIBC-patients were retrospectively summarised to 505 tumour episodes (tumour resection including any re-resections) and analysed regarding the endpoints 1) risk profile is explicitly named or recorded risk factors are sufficient for the determination of risk profile, and 2) guideline conformity of treatment recommendation. Independent factors influencing the endpoints were determined by means of multivariate logistic regression models. The risk profile was explicitly named for 3.6% of tumour episodes; for 68.9% a risk profile could be derived from the information in the epicrises. Treatment recommendations were given for 93.7% of tumour episodes, but only 17.8% were guideline compliant. 42.6% of the recommendations were not reliably effective; 33.1% and 0.2% resulted in under- and overtreatment respectively. Neither endpoint showed gender specific or regional differences, but both were considerably less likely to be achieved in case of recurrence. The discrepancy between treatment recommendation (93.7%) and guideline compliance (17.8%) could indicate a lack of familiarity with guidelines. The quality of the epicrises of NMIBC-patients was poor and bore the potential risk of undertreatment. The results of this study are not necessarily applicable to other clinics, but could, however, prompt physicians to re-examine epicrises for the fulfillment of the quality criteria examined here.

Human Health Safety Evaluation of Halon Replacement Candidates

DTIC Science & Technology

2000-05-01

neurotoxicity, developmental neurotoxicity, immunotoxicity, and endocrine disruptor tests may be considered if there is reason to suspect alterations in...conclusion of the study), gross necropsy, and select organ weight measurements (e.g., liver, lungs, kidneys, adrenals, testes, brain) "* Preserve ...and evaluated in the study. The biological endpoints of a 90-day study include daily clinical observations; measurements of body weight, food

CHEMICAL EFFECTS IN BIOLOGICAL SYSTEMS – DATA DICTIONARY (CEBS-DD): A COMPENDIUM OF TERMS FOR THE CAPTURE AND INTEGRATION OF BIOLOGICAL STUDY DESIGN DESCRIPTION, CONVENTIONAL PHENOTYPES AND ‘OMICS’ DATA

EPA Science Inventory

A critical component in the design of the Chemical Effects in Biological Systems (CEBS) Knowledgebase is a strategy to capture toxicogenomics study protocols and the toxicity endpoint data (clinical pathology and histopathology). A Study is generally an experiment carried out du...

Real life juvenile toxicity case studies: the good, the bad and the ugly.

PubMed

De Schaepdrijver, Luc; Rouan, Marie-Claude; Raoof, Araz; Bailey, Graham P; De Zwart, Loeckie; Monbaliu, Johan; Coogan, Timothy P; Lammens, Lieve; Coussement, Werner

2008-09-01

With the growing experience in the conduct of juvenile toxicity studies for multiple classes of compound, the 'case-by-case' approach has become under much more pressure. Instead, a general screen or 'standard design' is now commonly expected by regulatory authorities with more routine inclusion of neurological and reproductive assessments. Minor modifications or additions can be made to the design to address specific questions according to the class of drug or intended clinical use. This drift from a 'case-by-case' approach to a 'standard design' approach is present within certain reviewing divisions of the FDA, often requesting by default a rodent and non-rodent juvenile animal study. However, juvenile animal studies should be designed thoughtfully to fulfil a purpose based on scientific rationale, with each endpoint carefully considered in terms of practicality and interpretability of data generated. Only when using the appropriate strategy and design may juvenile studies add value by (1) identifying potential safety or pharmacokinetic issues for drugs intended for paediatric use, (2) suggesting additional clinical endpoints and (3) adding new information to the product label. As the knowledge from juvenile animal studies in various species grows, a better understanding of the significance/relevance of findings will be achieved.

Epidemiology of Recurrent Acute and Chronic Pancreatitis: Similarities and Differences.

PubMed

Machicado, Jorge D; Yadav, Dhiraj

2017-07-01

Emerging data in the past few years suggest that acute, recurrent acute (RAP), and chronic pancreatitis (CP) represent a disease continuum. This review discusses the similarities and differences in the epidemiology of RAP and CP. RAP is a high-risk group, comprised of individuals at varying risk of progression. The premise is that RAP is an intermediary stage in the pathogenesis of CP, and a subset of RAP patients during their natural course transition to CP. Although many clinical factors have been identified, accurately predicting the probability of disease course in individual patients remains difficult. Future studies should focus on providing more precise estimates of the risk of disease transition in a cohort of patients, quantification of clinical events during the natural course of disease, and discovery of biomarkers of the different stages of the disease continuum. Availability of clinically relevant endpoints and linked biomarkers will allow more accurate prediction of the natural course of disease over intermediate- or long-term-based characteristics of an individual patient. These endpoints will also provide objective measures for use in clinical trials of interventions that aim to alter the natural course of disease.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials.

PubMed

Zink, Richard C; Marchenko, Olga; Sanchez-Kam, Matilde; Ma, Haijun; Jiang, Qi

2018-03-01

There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group.

Efficacy and Safety of Oritavancin Relative to Vancomycin for Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the Outpatient Setting: Results From the SOLO Clinical Trials.

PubMed

Lodise, Thomas P; Redell, Mark; Armstrong, Shannon O; Sulham, Katherine A; Corey, G Ralph

2017-01-01

The objective of this analysis was to evaluate the efficacy and safety of oritavancin compared with vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSIs) who received treatment in the outpatient setting in the Phase 3 SOLO clinical trials. SOLO I and SOLO II were 2 identically designed comparative, multicenter, double-blind, randomized studies to evaluate the efficacy and safety of a single 1200-mg dose of intravenous (IV) oritavancin versus 7-10 days of twice-daily IV vancomycin for the treatment of ABSSSI. Protocols were amended to allow enrolled patients to complete their entire course of antimicrobial therapy in an outpatient setting. The primary efficacy outcome was a composite endpoint (cessation of spread or reduction in size of the baseline lesion, absence of fever, and no rescue antibiotic at early clinical evaluation [ECE]) (48 to 72 hours). Key secondary endpoints included investigator-assessed clinical cure 7 to 14 days after end of treatment (posttherapy evaluation [PTE]) and 20% or greater reduction in lesion area at ECE. Safety was assessed until day 60. Seven hundred ninety-two patients (oritavancin, 392; vancomycin, 400) received entire course of treatment in the outpatient setting. Efficacy response rates at ECE and PTE were similar (primary composite endpoint at ECE: 80.4% vs 77.5% for oritavancin and vancomycin, respectively) as was incidence of adverse events. Five patients (1.3%) who received oritavancin and 9 (2.3%) vancomycin patients were subsequently admitted to a hospital. Oritavancin provides a single-dose alternative to multidose vancomycin for treatment of ABSSSI in the outpatient setting. © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Predictive factors for the placebo effect in clinical trials for dry eye: a pooled analysis of three clinical trials.

PubMed

Imanaka, Takahiro; Sato, Izumi; Tanaka, Shiro; Kawakami, Koji

2017-11-01

Placebo effect is one of the methodological difficulties in dry eye clinical trials. If we could elucidate the tendencies of the placebo response and find predictors, we could reduce the placebo response in clinical trials for dry eye. In this study, we investigated the predictive factors for the placebo effect in dry eye clinical trials. A total of 205 patients with dry eye assigned to the placebo arms of three placebo-controlled randomised clinical trials were analysed by simple and multivariable regression analysis. The corneal fluorescein (FL) staining score and dry eye symptoms were studied at week 4. The variables of interest included gender, age, complications of Sjögren's syndrome, Schirmer's test I value, tear break-up time and conjunctival hyperaemia score. We also conducted a stratified analysis according to the patients' age. Among all the studied endpoints, the baseline scores were significantly related to the corresponding placebo response. In addition, for the FL score and the dryness score, age was a significant predictor of the placebo response (p=0.04 and p<0.0001, respectively). Stratified analysis by age showed that patients more than 40 years of age are more likely to have a stronger placebo response in the FL and dryness scores. The baseline scores and age were predictive factors of the placebo response in frequently used endpoints, such as FL score or dryness symptoms. These patient characteristics can be controlled by study design, and our findings enable the design of more efficient placebo-controlled studies with good statistical power. © 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.

Hypoglycemia evaluation and reporting in diabetes: Importance for the development of new therapies.

PubMed

Klonoff, David C; Alexander Fleming, G; Muchmore, Douglas B; Frier, Brian M

2017-07-01

Hypoglycemia complicating diabetes therapy is well recognized to be an ever-present threat to patients, their families, providers, payers, and regulators. Despite this being widely acknowledged, the regulatory stance on hypoglycemia as an endpoint in clinical trials to support new product registration has not evolved in any meaningful way since the publication of a position paper by an American Diabetes Association (ADA) Workgroup in 2005. As the impact of hypoglycemia on persons affected by diabetes is of major importance when assessing new treatments, the historical position of regulatory agencies on hypoglycemia is reviewed with respect to product approvals. The purpose of this article is to present proposals for facilitating development of therapies that reduce hypoglycemia risk through (1) development of composite measures of benefit for regulatory endpoints and (2) facilitation of the fulfillment of an unmet clinical need for reducing hypoglycemia. In view of greater comprehension of the effects of hypoglycemia, coupled with improved methodology to assess its frequency, the authors recommend: (1) a numerical cut point of <54 mg/dl (<3.0 mmol/L) as a clinically relevant level with which to define meaningful hypoglycemia for trials of diabetes therapies; (2) utilization in clinical trials of mature glucose monitoring technologies for purposes of regulatory evaluation and clinical decision-making; and (3) development of primary efficacy endpoint composites that include hypoglycemia rates and glycemic control. Copyright © 2017 John Wiley & Sons, Ltd.

[Clinical end-points and surrogate markers of pulmonary arterial hypertension in the light of evidence-based treatment].

PubMed

Can, Mehmet Mustafa; Kaymaz, Cihangir

2010-08-01

Pulmonary arterial hypertension (PAH) is a rare, fatal and progressive disease. There is an acceleration in the advent of new therapies in parallel to the development of the knowledge about etiogenesis and pathogenesis of PAH. Therefore, to optimize the goals of PAH-specific treatment and to determine the time to shift from monotherapy to combination therapy, simple, objective and reproducible end-points, which may predict the disease severity, progression rate and life expectancy are needed. The adventure of end points in PAH has started with six minute walk distance and functional capacity, and continues with new parameters (biochemical marker, time to clinical worsening, echocardiography and magnetic resonance imaging etc.), which can better reflect the clinical outcome.

Early improvement with pregabalin predicts endpoint response in patients with generalized anxiety disorder: an integrated and predictive data analysis.

PubMed

Montgomery, Stuart A; Lyndon, Gavin; Almas, Mary; Whalen, Ed; Prieto, Rita

2017-01-01

Generalized anxiety disorder (GAD), a common mental disorder, has several treatment options including pregabalin. Not all patients respond to treatment; quickly determining which patients will respond is an important treatment goal. Patient-level data were pooled from nine phase II and III randomized, double-blind, short-term, placebo-controlled trials of pregabalin for the treatment of GAD. Efficacy outcomes included the change from baseline in the Hamilton Anxiety Scale (HAM-A) total score and psychic and somatic subscales. Predictive modelling assessed baseline characteristics and early clinical responses to determine those predictive of clinical improvement at endpoint. A total of 2155 patients were included in the analysis (1447 pregabalin, 708 placebo). Pregabalin significantly improved the HAM-A total score compared with the placebo at endpoint, treatment difference (95% confidence interval), -2.61 (-3.21 to -2.01), P<0.0001. Pregabalin significantly improved HAM-A psychic and somatic scores compared with placebo, -1.52 (-1.85 to -1.18), P<0.0001, and -1.10 (-1.41 to -0.80), P<0.0001, respectively. Response to pregabalin in the first 1-2 weeks (≥20 or ≥30% improvement in HAM-A total, psychic or somatic score) was predictive of an endpoint greater than or equal to 50% improvement in the HAM-A total score. Pregabalin is an effective treatment option for patients with GAD. Patients with early response to pregabalin are more likely to respond significantly at endpoint.

Safinamide: A Review in Parkinson's Disease.

PubMed

Blair, Hannah A; Dhillon, Sohita

2017-02-01

Safinamide (Xadago ® ) is an orally active, selective, reversible monoamine oxidase-B inhibitor with both dopaminergic and non-dopaminergic (glutamatergic) properties. In the EU, safinamide is approved for the treatment of mid- to late-stage fluctuating Parkinson's disease (PD) as add-on therapy to a stable dose of levodopa alone or in combination with other PD medications. Safinamide 50-100 mg/day administered as a fixed or flexible dose significantly increased daily 'on' time without dyskinesia (primary endpoint) in patients with mid- to late-stage PD with motor fluctuations in 24-week, placebo-controlled clinical trials. Other outcomes, including motor function, overall clinical status and health-related quality of life, were also generally improved with safinamide. Furthermore, in an 18-month extension of one study, although dyskinesia (primary endpoint) was not significantly improved with safinamide relative to placebo, treatment benefits in other outcomes were generally sustained over 24 months of treatment. Safinamide was generally well tolerated in clinical trials; dyskinesia was the most common adverse event. Although further studies are needed, including comparative and long-term studies, current evidence indicates that safinamide extends the treatment options available for use as add-on therapy to levodopa and other PD medications in patients with mid- to late-stage PD experiencing motor fluctuations.

Computational methods using genome-wide association studies to predict radiotherapy complications and to identify correlative molecular processes

NASA Astrophysics Data System (ADS)

Oh, Jung Hun; Kerns, Sarah; Ostrer, Harry; Powell, Simon N.; Rosenstein, Barry; Deasy, Joseph O.

2017-02-01

The biological cause of clinically observed variability of normal tissue damage following radiotherapy is poorly understood. We hypothesized that machine/statistical learning methods using single nucleotide polymorphism (SNP)-based genome-wide association studies (GWAS) would identify groups of patients of differing complication risk, and furthermore could be used to identify key biological sources of variability. We developed a novel learning algorithm, called pre-conditioned random forest regression (PRFR), to construct polygenic risk models using hundreds of SNPs, thereby capturing genomic features that confer small differential risk. Predictive models were trained and validated on a cohort of 368 prostate cancer patients for two post-radiotherapy clinical endpoints: late rectal bleeding and erectile dysfunction. The proposed method results in better predictive performance compared with existing computational methods. Gene ontology enrichment analysis and protein-protein interaction network analysis are used to identify key biological processes and proteins that were plausible based on other published studies. In conclusion, we confirm that novel machine learning methods can produce large predictive models (hundreds of SNPs), yielding clinically useful risk stratification models, as well as identifying important underlying biological processes in the radiation damage and tissue repair process. The methods are generally applicable to GWAS data and are not specific to radiotherapy endpoints.

Introduction: the goals of antimicrobial therapy.

PubMed

Song, Jae-Hoon

2003-03-01

Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demonstrating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy. However, large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and, generally, studies are powered to show only clinical equivalence. In addition, diagnosis is often based on clinical symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant pathogens are often excluded. Clinical efficacy can be achieved in some bacterial infections in which antimicrobials are suboptimal or even not prescribed. However, bacterial eradication maximizes clinical efficacy and may also reduce the development and spread of resistant organisms. The goal of antimicrobial therapy is, therefore, to eradicate bacteria at the site of infection. Bacterial eradication is not usually assessed as a primary endpoint within the limits of currently recommended clinical trial design. However, pharmacokinetic (PK) (serum concentration profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy. PK/PD predictions should be confirmed during all phases of antimicrobial development and throughout clinical use in response to changing patterns of resistance. A clear rationale for dose recommendations can be determined preclinically based on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials. The duration of treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well tolerated. Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for bacteriologic eradication. Recommendations for appropriate antimicrobial therapy should be based on PK/PD parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant pathogens.

Interactive associations of depression and sleep apnea with adverse clinical outcomes after acute myocardial infarction

PubMed Central

Hayano, Junichiro; Carney, Robert M.; Watanabe, Eiichi; Kawai, Kiyohiro; Kodama, Itsuo; Stein, Phyllis K.; Watkins, Lana L.; Freedland, Kenneth E.; Blumenthal, James A.

2012-01-01

Objective Depression and sleep apnea (SA) are common among patients after acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between depression and SA in relation to prognosis in post-AMI patients. Methods Participants were 337 depressed and 379 nondepressed post-AMI patients who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter ECG at the entry by an algorithm that detects cyclic variation of heart rate. Results During a median follow-up of 25 months, 43 (6.0%) of patients died and 83 (11.6%) either died or experienced a recurrent AMI. Among 94 patients with both depression and SA, these endpoints occurred in 20 (21.3%) and 25 (26.6%), the prevalence that was 6.9 and 3.9 times higher than predicted probabilities by ENRICHD clinical risk scores (P <.001 for both). In the patients with depression alone, SA alone, or neither, the frequencies did not differ significantly from the predicted probability. Although both depression and SA predicted death and the combined endpoint, we observed depression by SA interactions (P = .03 and .02). SA independently predicted these endpoints in depressed (P <.001 and P = .001), but not in nondepressed patients (P = .73 and .84). Similarly, depression independently predicted these endpoints in SA (P <.001 for both), but not in non-SA patients (P = .61 and .12). Conclusion The combination of depression and SA estimated by CVHR is associated with long-term adverse clinical outcomes after AMI. PMID:23023681

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

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

Clinical Trial Design Principles and Endpoint Definitions for Transcatheter Mitral Valve Repair and Replacement: Part 2: Endpoint Definitions: A Consensus Document From the Mitral Valve Academic Research Consortium.

PubMed

Stone, Gregg W; Adams, David H; Abraham, William T; Kappetein, Arie Pieter; Généreux, Philippe; Vranckx, Pascal; Mehran, Roxana; Kuck, Karl-Heinz; Leon, Martin B; Piazza, Nicolo; Head, Stuart J; Filippatos, Gerasimos; Vahanian, Alec S

2015-07-21

Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous etiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodeling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of micafungin for the treatment of patients with proven or probable invasive aspergillosis: A non-comparative, multicenter, phase IV, open-label study.

PubMed

Ji, Yu; Song, Yongping; Zhou, Fang; Liu, Ting; Jiang, Ming; Zhao, Xielan; Huang, Xiaojun

2017-12-01

Few studies have assessed the efficacy and safety of micafungin in patients with proven or probable invasive aspergillosis (IA). This was the aim of the current study, which was conducted in 22 hospitals in China, where micafungin was approved for treatment of IA in 2006. This was a non-comparative, phase IV open-label study (NCT02646774). Eligible patient were adults with proven or probable IA. Efficacy endpoints included rates of overall treatment success (primary endpoint) and clinical improvement, fungal clearance, mortality, and the site of Aspergillus infection (all secondary endpoints). Safety endpoints included incidences of treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and adverse drug reactions (ADRs). These endpoints were reported descriptively with associated 95% confidence intervals (CI); no hypotheses were tested. The study was discontinued early due to low patient recruitment, which did not allow for the planned sample size to be reached. In total, 68 patients were enrolled: 42 into the full analysis set (for efficacy) and 61 into the safety analysis set. All patients were Han Chinese; the majority were male (n = 26; 61.9%) and ≤60 years of age (n = 35; 83.3%). Rates of overall treatment success, clinical improvement, fungal clearance, and mortality were 45.2% (n = 19/42; 95% CI: 29.85-61.33); 59.5% (n = 25/42; 95% CI: 43.28-74.37), 80.0% (n = 4/5; 95% CI: 28.36-99.49), and 7.1% (n = 3/42; 95% CI: 1.50-19.48), respectively. All patients were diagnosed with pulmonary Aspergillus infection. Overall, 155 TEAEs and 8 SAEs were reported by 37 (60.7%) and 7 (11.5%) patients. The most common TEAEs were decreased platelet count and fatigue (both n = 5; 8.2%) and the most common SAEs were intracranial hemorrhage and lung infection (n = 3; 4.9% and n = 2; 3.3%). Eight ADRs (n = 6; 9.8%) were reported but all were completely remitted or remitting during follow-up. Results suggest that micafungin is efficacious and well-tolerated in patients with proven or probable IA in China. However, these findings should be interpreted with care, due to the small number of patients included in this study. Further comparative trials should be used to confirm the efficacy and safety of micafungin in patients with proven or probable IA. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Tafenoquine is not neurotoxic following supertherapeutic dosing in rats.

PubMed

Dow, Geoffrey S; Brown, Tracey; Reid, Mark; Smith, Bryan; Toovey, Stephen

Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7-8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

High-Dose Intravenous Methylprednisolone for Hantavirus Cardiopulmonary Syndrome in Chile: A Double-Blind, Randomized Controlled Clinical Trial

PubMed Central

Vial, Pablo A.; Valdivieso, Francisca; Ferres, Marcela; Riquelme, Raul; Rioseco, M. Luisa; Calvo, Mario; Castillo, Constanza; Díaz, Ricardo; Scholz, Luis; Cuiza, Analia; Belmar, Edith; Hernandez, Carla; Martinez, Jessica; Lee, Sang-Joon; Mertz, Gregory J.; Abarca, Juan; Tomicic, Vinko; Aracena, M. Eugenia; Rehbein, Ana Maria; Velásquez, Soledad; Lavin, Victoria; Garrido, Felipe; Godoy, Paula; Martinez, Constanza; Chamorro, Juan Carlos; Contreras, Jorge; Hernandez, Jury; Pino, Marcelo; Villegas, Paola; Zapata, Viviana; León, Marisol; Vega, Ivonne; Otarola, Irisol; Ortega, Carlos; Daube, Elizabeth; Huecha, Doris; Neira, Alda; Ruiz, Ines; Nuñez, M. Antonieta; Monsalve, Luz; Chabouty, Henriette; Riquelme, Lorena; Palma, Samia; Bustos, Raul; Miranda, Ruben; Mardones, Jovita; Hernandez, Nora; Betancur, Yasna; Sanhueza, Ligia; Inostroza, Jaime; Donoso, Solange; Navarrete, Maritza; Acuña, Lily; Manriquez, Paulina; Castillo, Fabiola; Unzueta, Paola; Aguilera, Teresa; Osorio, Carola; Yobanolo, Veronica; Mardones, Jorge; Aranda, Sandra; Carvajal, Soledad; Sandoval, Moisés; Daza, Soraya; Vargas, Felipe; Diaz, Violeta; Riquelme, Mauricio; Muñoz, Miriam; Carriel, Andrea; Lanino, Paola; Hernandez, Susana; Schumacher, Patricia; Yañez, Lia; Marco, Claudia; Ehrenfeld, Mildred; Delgado, Iris; Rios, Susana; Vial, Cecilia; Bedrick, Edward

2013-01-01

Background. Andes virus (ANDV)–related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. Methods. Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. Results. Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. Conclusions. Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. Clinical Trials Registration. NCT00128180. PMID:23784924

[Impact of plasma pro-B-type natriuretic peptide amino-terminal and galectin-3 levels on the predictive capacity of the LIPID Clinical Risk Scale in stable coronary disease].

PubMed

Higueras, Javier; Martín-Ventura, José Luis; Blanco-Colio, Luis; Cristóbal, Carmen; Tarín, Nieves; Huelmos, Ana; Alonso, Joaquín; Pello, Ana; Aceña, Álvaro; Carda, Rocío; Lorenzo, Óscar; Mahíllo-Fernández, Ignacio; Asensio, Dolores; Almeida, Pedro; Rodríguez-Artalejo, Fernando; Farré, Jerónimo; López Bescós, Lorenzo; Egido, Jesús; Tuñón, José

2015-01-01

At present, there is no tool validated by scientific societies for risk stratification of patients with stable coronary artery disease (SCAD). It has been shown that plasma levels of monocyte chemoattractant protein-1 (MCP-1), galectin-3 and pro-B-type natriuretic peptide amino-terminal (NT-proBNP) have prognostic value in this population. To analyze the prognostic value of a clinical risk scale published in Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study and determining its predictive capacity when combined with plasma levels of MCP-1, galectin-3 and NT-proBNP in patients with SCAD. A total of 706 patients with SCAD and a history of acute coronary syndrome (ACS) were analyzed over a follow up period of 2.2 ± 0.99 years. The primary endpoint was the occurrence of an ischemic event (any SCA, stroke or transient ischemic attack), heart failure, or death. A clinical risk scale derived from the LIPID study significantly predicted the development of the primary endpoint, with an area under the ROC curve (Receiver Operating Characteristic) of 0.642 (0.579 to 0.705); P<0.001. A composite score was developed by adding the scores of the LIPID and scale decile levels of MCP -1, galectin -3 and NT-proBNP. The predictive value improved with an area under the curve of 0.744 (0.684 to 0.805); P<0.001 (P=0.022 for comparison). A score greater than 21.5 had a sensitivity of 74% and a specificity of 61% for the development of the primary endpoint (P<0.001, log -rank test). Plasma levels of MCP-1, galectin -3 and NT-proBNP improve the ability of the LIPID clinical scale to predict the prognosis of patients with SCAD. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

An evaluation of motor evoked potential surrogate endpoints during intracranial vascular procedures.

PubMed

Holdefer, R N; MacDonald, D B; Guo, L; Skinner, S A

2016-02-01

MEPs are used as surrogate endpoints to predict the effectiveness of interventions, made in response to MEP deterioration, in avoiding new postoperative deficits. MEP performance in capturing intervention effects on these outcomes was investigated. A meta-analysis of studies using MEPs during intracranial vascular surgeries between 2003 and 2014 was performed. MEP diagnostic performance and relative risk of new postoperative deficits for reversible compared with irreversible MEP changes were determined. Intervention efficacy in reversing MEP deterioration and postoperative outcomes was compared across studies. MEP diagnostic performance compared favorably with that of other tests used in medicine, with all likelihood ratios >10. The summary relative risk comparing reversible and irreversible changes was 0.40, indicating a 60% decrease in new deficits for reversible MEP changes. The proportion of MEP deteriorations which recovered was negatively correlated with the proportion of new postoperative deficits (r=-0.81, p<.005). The effectiveness of interventions in recovering an MEP decline was predictive of preserved neurologic status. MEPs are provisionally qualified as surrogate endpoints given potentially major harms to the patient if they are not used, compared to the minimal harms and costs associated with their use. The performance of MEPs as substitute, or surrogate, endpoints during intracranial vascular surgeries for new deficits in motor strength in the immediate postoperative period was directly assessed for ten recent studies. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Study design of the influence of SErotonin inhibition on patients with RENAl impairment or diabetes undergoing drug-eluting stent implantation (SERENADE) study: A multicenter, open-label, prospective, randomized study.

PubMed

Lee, Seung-Ah; Suh, Jung-Won; Park, Jin Joo; Yoon, Chang-Hwan; Cho, Young-Suk; Youn, Tae-Jin; Chae, In-Ho; Kim, Hyo-Soo; Kim, Sang-Hyun; Choi, Dong-Ju

2015-07-01

The rates of stent failure after percutaneous coronary intervention have decreased since the introduction of the drug-eluting stent (DES). However, chronic kidney disease (CKD) and diabetes mellitus (DM) remain strong clinical predictors of poor prognosis despite DES implantation. Sarpogrelate, a selective serotonin (5-hydroxytryptamine (HT)2a [5-HT2A]) receptor antagonist, has antiproliferative effects, reducing neointimal hyperplasia and smooth muscle cell proliferation, as well as potent antiplatelet action, inhibiting 5-HT-induced platelet aggregation. However, efficacy and safety data for sarpogrelate in patients with CKD or DM are limited. We aim to determine whether sarpogrelate has beneficial effects in patients with CDK or DM treated with DES implantation. The SERENADE trial is a multicenter, open-label, prospective, randomized study that will test the superiority of triple anti-platelet therapy (TAT; aspirin, clopidogrel, and sarpogrelate) to conventional dual antiplatelet therapy (DAT; aspirin and clopidogrel) in preventing late lumen loss 9 months after the index procedure in patients with CKD or DM. A total of 220 patients diagnosed with coronary artery disease with DM or CKD will be randomized to the TAT or DAT groups (1:1 ratio) after DES implantation. The primary endpoint is late lumen loss at 9 months assessed by quantitative coronary angiography. Secondary efficacy endpoints are composites of major adverse cardiovascular events including cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Secondary safety endpoints are major bleeding events and hepatic or renal impairment. The SERENADE trial will provide insight on the efficacy of adjunctive therapy with sarpogrelate after DES implantation for patients with high-risk profiles such as CKD or DM. National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov NCT02294643). Copyright © 2015. Published by Elsevier Inc.

Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial.

PubMed

Smith, Larry R; Wloch, Mary K; Chaplin, Jennifer A; Gerber, Michele; Rolland, Alain P

2013-09-25

2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK) delivery system designed to enhance plasmid expression. The vaccine's planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV⁺) recipients of an allogeneic hematopoietic stem cell transplant (HCT). A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV⁺ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial.

Current challenges for clinical trials of cardiovascular medical devices.

PubMed

Zannad, Faiez; Stough, Wendy Gattis; Piña, Ileana L; Mehran, Roxana; Abraham, William T; Anker, Stefan D; De Ferrari, Gaetano M; Farb, Andrew; Geller, Nancy L; Kieval, Robert S; Linde, Cecilia; Redberg, Rita F; Stein, Kenneth; Vincent, Alphons; Woehrle, Holger; Pocock, Stuart J

2014-07-15

Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Clinical Outcome Assessments: Conceptual Foundation-Report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force.

PubMed

Walton, Marc K; Powers, John H; Hobart, Jeremy; Patrick, Donald; Marquis, Patrick; Vamvakas, Spiros; Isaac, Maria; Molsen, Elizabeth; Cano, Stefan; Burke, Laurie B

2015-09-01

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient's health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment's benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment's intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient's typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

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

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

Success and failure of biological treatment in systemic lupus erythematosus: A critical analysis.

PubMed

Gatto, Mariele; Saccon, Francesca; Zen, Margherita; Bettio, Silvano; Iaccarino, Luca; Punzi, Leonardo; Doria, Andrea

2016-11-01

Patients affected with systemic lupus erythematosus (SLE) still display increased mortality and decreased quality of life in respect to general population. The major determinant of poor long term prognosis is organ damage, which is predictive of more damage and death. Damage is in turn triggered by uncontrolled disease activity and especially by the long-standing corticosteroid use which often accompanies SLE patients over their disease course, owing both to the need of reaching disease remission and to the habit of keeping patients on a small steroid dose for an indefinite period of time. Hence, the need for new drugs and therapeutic strategies aiming at minimizing damage accrual through a better control of disease activity and a steroid-sparing potential is paramount. So far, however, the therapeutic strategy in SLE requires a multitarget approach which is not devoid of widespread immunesuppression. In fact, several studies have been carried out in recent years targeting both the adaptive and the innate immune system, the majority of which did not achieve their primary endpoint, being often divergent from successful clinical experience and thereby committing physician to off-label use of targeted therapies in face of refractory SLE manifestations. The study designs and the chosen endpoints were often blamed for inadequacy, being at least in part responsible for study failures. In this review, we go over major clinical trials conducted in SLE by analyzing any critical aspects related to study design, predefined endpoints and biological activity of novel compounds that may have hampered study outcome, despite the great effort of providing less toxic drugs within a targeted, pathogenic-based approach. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endovascular Management of Patients with Head and Neck Cancers Presenting with Acute Hemorrhage: A Single-Center Retrospective Study

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

Vilas Boas, P. P.; Castro-Afonso, L. H. de; Monsignore, L. M.

PurposeAcute hemorrhage associated with cancers of the head and neck is a life-threatening condition that requires immediate action. The aim of this study was to assess the safety and efficacy of endovascular embolization for acute hemorrhage in patients with head and neck cancers.Materials and MethodsData were retrospectively collected from patients with head and neck cancers who underwent endovascular embolization to treat acute hemorrhage. The primary endpoint was the rate of immediate control of hemorrhage during the first 24 h after embolization. The secondary endpoints were technical or clinical complications, rate of re-hemorrhage 24 h after the procedure, time from embolization to re-hemorrhage,more » hospitalization time, mortality rate, and time from embolization to death.ResultsFifty-one patients underwent endovascular embolization. The primary endpoint was achieved in 94% of patients. The rate of technical complications was 5.8%, and no clinical complication was observed. Twelve patients (23.5%) had hemorrhage recurrence after an average time of 127.5 days. The average hospitalization time was 7.4 days, the mortality rate during the follow-up period was 66.6%, and the average time from embolization to death was 132.5 days.ConclusionEndovascular embolization to treat acute hemorrhage in patients with head and neck cancers is a safe and effective method for the immediate control of hemorrhage and results in a high rate of hemorrhage control. Larger studies are necessary to determine which treatment strategy is best for improving patient outcomes.« less

Health economic evaluation of treatments for Alzheimer's disease: impact of new diagnostic criteria.

PubMed

Wimo, A; Ballard, C; Brayne, C; Gauthier, S; Handels, R; Jones, R W; Jonsson, L; Khachaturian, A S; Kramberger, M

2014-03-01

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered. © 2014 The Association for the Publication of the Journal of Internal Medicine.

Weighting Composite Endpoints in Clinical Trials: Essential Evidence for the Heart Team

PubMed Central

Tong, Betty C.; Huber, Joel C.; Ascheim, Deborah D.; Puskas, John D.; Ferguson, T. Bruce; Blackstone, Eugene H.; Smith, Peter K.

2013-01-01

Background Coronary revascularization trials often use a composite endpoint of major adverse cardiac and cerebrovascular events (MACCE). The usual practice in analyzing data with a composite endpoint is to assign equal weights to each of the individual MACCE elements. Non-inferiority margins are used to offset effects of presumably less important components, but their magnitudes are subject to bias. This study describes the relative importance of MACCE elements from a patient perspective. Methods A discrete choice experiment was conducted. Survey respondents were presented with a scenario that would make them eligible for the SYNTAX 3-Vessel Disease cohort. Respondents chose among pairs of procedures that differed on the 3-year probability of MACCE, potential for increased longevity, and procedure/recovery time. Conjoint analysis derived relative weights for these attributes. Results In all, 224 respondents completed the survey. The attributes did not have equal weight. Risk of death was most important (relative weight 0.23), followed by stroke (.18), potential increased longevity and recovery time (each 0.17), MI (0.14) and risk of repeat revascularization (0.11). Applying these weights to the SYNTAX 3-year endpoints resulted in a persistent, but decreased margin of difference in MACCE favoring CABG compared to PCI. When labeled only as “Procedure A” and “B,” 87% of respondents chose CABG over PCI. When procedures were labeled as “Coronary Stent” and “Coronary Bypass Surgery,” only 73% chose CABG. Procedural preference varied with demographics, gender and familiarity with the procedures. Conclusions MACCE elements do not carry equal weight in a composite endpoint, from a patient perspective. Using a weighted composite endpoint increases the validity of statistical analyses and trial conclusions. Patients are subject to bias by labels when considering coronary revascularization. PMID:22795064

The Use of a Binary Composite Endpoint and Sample Size Requirement: Influence of Endpoints Overlap.

PubMed

Marsal, Josep-Ramon; Ferreira-González, Ignacio; Bertran, Sandra; Ribera, Aida; Permanyer-Miralda, Gaietà; García-Dorado, David; Gómez, Guadalupe

2017-05-01

Although composite endpoints (CE) are common in clinical trials, the impact of the relationship between the components of a binary CE on the sample size requirement (SSR) has not been addressed. We performed a computational study considering 2 treatments and a CE with 2 components: the relevant endpoint (RE) and the additional endpoint (AE). We assessed the strength of the components' interrelation by the degree of relative overlap between them, which was stratified into 5 groups. Within each stratum, SSR was computed for multiple scenarios by varying the events proportion and the effect of the therapy. A lower SSR using CE was defined as the best scenario for using the CE. In 25 of 66 scenarios the degree of relative overlap determined the benefit of using CE instead of the RE. Adding an AE with greater effect than the RE leads to lower SSR using the CE regardless of the AE proportion and the relative overlap. The influence of overlapping decreases when the effect on RE increases. Adding an AE with lower effect than the RE constitutes the most uncertain situation. In summary, the interrelationship between CE components, assessed by the relative overlap, can help to define the SSR in specific situations and it should be considered for SSR computation. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Power Calculations to Select Instruments for Clinical Trial Secondary Endpoints. A Case Study of Instrument Selection for Post-Traumatic Stress Symptoms in Subjects with Acute Respiratory Distress Syndrome.

PubMed

Sjoding, Michael W; Schoenfeld, David A; Brown, Samuel M; Hough, Catherine L; Yealy, Donald M; Moss, Marc; Angus, Derek C; Iwashyna, Theodore J

2017-01-01

After the sample size of a randomized clinical trial (RCT) is set by the power requirement of its primary endpoint, investigators select secondary endpoints while unable to further adjust sample size. How the sensitivity and specificity of an instrument used to measure these outcomes, together with their expected underlying event rates, affect an RCT's power to measure significant differences in these outcomes is poorly understood. Motivated by the design of an RCT of neuromuscular blockade in acute respiratory distress syndrome, we examined how power to detect a difference in secondary endpoints varies with the sensitivity and specificity of the instrument used to measure such outcomes. We derived a general formula and Stata code for calculating an RCT's power to detect differences in binary outcomes when such outcomes are measured with imperfect sensitivity and specificity. The formula informed the choice of instrument for measuring post-traumatic stress-like symptoms in the Reevaluation of Systemic Early Neuromuscular Blockade RCT ( www.clinicaltrials.gov identifier NCT02509078). On the basis of published sensitivities and specificities, the Impact of Events Scale-Revised was predicted to measure a 36% symptom rate, whereas the Post-Traumatic Stress Symptoms instrument was predicted to measure a 23% rate, if the true underlying rate of post-traumatic stress symptoms were 25%. Despite its lower sensitivity, the briefer Post-Traumatic Stress Symptoms instrument provided superior power to detect a difference in rates between trial arms, owing to its higher specificity. Examining instruments' power to detect differences in outcomes may guide their selection when multiple instruments exist, each with different sensitivities and specificities.

Power Calculations to Select Instruments for Clinical Trial Secondary Endpoints. A Case Study of Instrument Selection for Post-Traumatic Stress Symptoms in Subjects with Acute Respiratory Distress Syndrome

PubMed Central

Schoenfeld, David A.; Brown, Samuel M.; Hough, Catherine L.; Yealy, Donald M.; Moss, Marc; Angus, Derek C.; Iwashyna, Theodore J.

2017-01-01

Rationale: After the sample size of a randomized clinical trial (RCT) is set by the power requirement of its primary endpoint, investigators select secondary endpoints while unable to further adjust sample size. How the sensitivity and specificity of an instrument used to measure these outcomes, together with their expected underlying event rates, affect an RCT’s power to measure significant differences in these outcomes is poorly understood. Objectives: Motivated by the design of an RCT of neuromuscular blockade in acute respiratory distress syndrome, we examined how power to detect a difference in secondary endpoints varies with the sensitivity and specificity of the instrument used to measure such outcomes. Methods: We derived a general formula and Stata code for calculating an RCT’s power to detect differences in binary outcomes when such outcomes are measured with imperfect sensitivity and specificity. The formula informed the choice of instrument for measuring post-traumatic stress–like symptoms in the Reevaluation of Systemic Early Neuromuscular Blockade RCT (www.clinicaltrials.gov identifier NCT02509078). Measurements and Main Results: On the basis of published sensitivities and specificities, the Impact of Events Scale-Revised was predicted to measure a 36% symptom rate, whereas the Post-Traumatic Stress Symptoms instrument was predicted to measure a 23% rate, if the true underlying rate of post-traumatic stress symptoms were 25%. Despite its lower sensitivity, the briefer Post-Traumatic Stress Symptoms instrument provided superior power to detect a difference in rates between trial arms, owing to its higher specificity. Conclusions: Examining instruments’ power to detect differences in outcomes may guide their selection when multiple instruments exist, each with different sensitivities and specificities. PMID:27788018

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.

A new method of applying randomised control study data to the individual patient: A novel quantitative patient-centred approach to interpreting composite end points.

PubMed

Ahmad, Yousif; Nijjer, Sukhjinder; Cook, Christopher M; El-Harasis, Majd; Graby, John; Petraco, Ricardo; Kotecha, Tushar; Baker, Christopher S; Malik, Iqbal S; Bellamy, Michael F; Sethi, Amarjit; Mikhail, Ghada W; Al-Bustami, Mahmud; Khan, Masood; Kaprielian, Raffi; Foale, Rodney A; Mayet, Jamil; Davies, Justin E; Francis, Darrel P; Sen, Sayan

2015-09-15

Modern randomised controlled trials typically use composite endpoints. This is only valid if each endpoint is equally important to patients but few trials document patient preference and seek the relative importance of components of combined endpoints. If patients weigh endpoints differentially, our interpretation of trial data needs to be refined. We derive a quantitative, structured tool to determine the relative importance of each endpoint to patients. We then apply this tool to data comparing angioplasty with drug-eluting stents to bypass surgery. The survey was administered to patients undergoing cardiac catheterisation. A meta-analysis comparing coronary artery bypass grafting (CABG) to percutaneous coronary interventuin (PCI) was then performed using (a) standard MACE and (b) patient-centred MACE. Patients considered stroke worse than death (stroke 102.3 ± 19.6%, p < 0.01), and MI and repeat revascularisation less severe than death (61.9 ± 26.8% and 41.9 ± 25.4% respectively p < 0.01 for both). 7 RCTs (5251 patients) were eligible. Meta-analysis demonstrated that standard MACE occurs more frequently with PCI than surgery (OR 1.44; 95% CI 1.10 to 1.87; p = 0.007). Re-analysis using patient-centred MACE found no significant difference between PCI and CABG (OR 1.22, 95% CI 0.97 to 1.53; p = 0.10). Patients do not consider the constituent endpoints of MACE equal. We derive a novel patient-centred metric that recognises and quantifies the differences attributed to each endpoint. When patient preference data are applied to contemporary trial results, there is no significant difference between PCI and CABG. Responses from individual patients in clinic could be used to give individual patients a recommendation that is truly personalised. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[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.

Natriuretic Peptides, 6-Min Walk Test, and Quality-of-Life Questionnaires as Clinically Meaningful Endpoints in HF Trials.

PubMed

Ferreira, João Pedro; Duarte, Kevin; Graves, Todd L; Zile, Michael R; Abraham, William T; Weaver, Fred A; Lindenfeld, JoAnn; Zannad, Faiez

2016-12-20

The Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions document was issued as a guidance for industry and for the Food and Drug Administration. The Expedited Access Pathway was designed as a new program for medical devices that demonstrated the potential to address unmet medical needs for life threatening or irreversibly debilitating conditions. The Food and Drug Administration would consider assessments of a device's effect on intermediate endpoints that, when improving in a congruent fashion, are reasonably likely to predict clinical benefit. The purpose of this review is to provide evidence to support the use of 3 such intermediate endpoints: natriuretic peptides, such as N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide, the 6-min walk test distance, and health-related quality of life in heart failure. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Abdominal pain endpoints currently recommended by the FDA and EMA for adult patients with irritable bowel syndrome may not be reliable in children.

PubMed

Saps, M; Lavigne, J V

2015-06-01

The Food and Drug Administration (FDA) recommended ≥30% decrease on patient-reported outcomes for pain be considered clinically significant in clinical trials for adults with irritable bowel syndrome. This percent change approach may not be appropriate for children. We compared three alternate approaches to determining clinically significant reductions in pain among children. 80 children with functional abdominal pain participated in a study of the efficacy of amitriptyline. Endpoints included patient-reported estimates of feeling better, and pain Visual Analog Scale (VAS). The minimum clinically important difference in pain report was calculated as (i) mean change in VAS score for children reporting being 'better'; (ii) percent changes in pain (≥30% and ≥50%) on the VAS; and (iii) statistically reliable changes on the VAS for 68% and 95% confidence intervals. There was poor agreement between the three approaches. 43.6% of the children who met the FDA ≥30% criterion for clinically significant change did not achieve a reliable level of improvement (95% confidence interval). Children's self-reported ratings of being better may not be statistically reliable. A combined approach in which children must report improvement as better and achieve a statistically significant change may be more appropriate for outcomes in clinical trials. © 2015 John Wiley & Sons Ltd.

International multicentre trial protocol to assess the efficacy and safety of tenecteplase during cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest: the Thrombolysis in Cardiac Arrest (TROICA) Study.

PubMed

Spöhr, F; Arntz, H R; Bluhmki, E; Bode, C; Carli, P; Chamberlain, D; Danays, T; Poth, J; Skamira, C; Wenzel, V; Böttiger, B W

2005-05-01

Prehospital cardiac arrest has been associated with a very poor prognosis. Acute myocardial infarction and massive pulmonary embolism are the underlying causes of out-of-hospital cardiac arrest in 50-70% of patients. Although fibrinolysis is an effective treatment strategy for both myocardial infarction and pulmonary embolism, clinical experience for this therapy performed during resuscitation has been limited owing to the anticipated risk of severe bleeding complications. The TROICA study is planned as one of the largest randomized, double-blind, placebo-controlled trials to assess the efficacy and safety of prehospital thrombolytic therapy in cardiac arrest of presumed cardiac origin. Approximately 1000 patients with cardiac arrest will be randomized at approximately 60 international study centres to receive either a weight-adjusted dose of tenecteplase or placebo after the first dose of a vasopressor. Patients can be included if they are at least 18 years, presenting with a witnessed cardiac arrest of presumed cardiac origin, and if either basic life support had started within 10 min of onset and had been performed up to 10 min or advanced life support is started within 10 min of onset of cardiac arrest. Primary endpoint of the study is the 30-day survival rate, and the coprimary endpoint is hospital admission. Secondary endpoints are the return of spontaneous circulation (ROSC), survival after 24 h, survival to hospital discharge, and neurological performance. Safety endpoints include major bleeding complications and symptomatic intracranial haemorrhage.

Is automated kinetic measurement superior to end-point for advanced oxidation protein product?

PubMed

Oguz, Osman; Inal, Berrin Bercik; Emre, Turker; Ozcan, Oguzhan; Altunoglu, Esma; Oguz, Gokce; Topkaya, Cigdem; Guvenen, Guvenc

2014-01-01

Advanced oxidation protein product (AOPP) was first described as an oxidative protein marker in chronic uremic patients and measured with a semi-automatic end-point method. Subsequently, the kinetic method was introduced for AOPP assay. We aimed to compare these two methods by adapting them to a chemistry analyzer and to investigate the correlation between AOPP and fibrinogen, the key molecule responsible for human plasma AOPP reactivity, microalbumin, and HbA1c in patients with type II diabetes mellitus (DM II). The effects of EDTA and citrate-anticogulated tubes on these two methods were incorporated into the study. This study included 93 DM II patients (36 women, 57 men) with HbA1c levels > or = 7%, who were admitted to the diabetes and nephrology clinics. The samples were collected in EDTA and in citrate-anticoagulated tubes. Both methods were adapted to a chemistry analyzer and the samples were studied in parallel. In both types of samples, we found a moderate correlation between the kinetic and the endpoint methods (r = 0.611 for citrate-anticoagulated, r = 0.636 for EDTA-anticoagulated, p = 0.0001 for both). We found a moderate correlation between fibrinogen-AOPP and microalbumin-AOPP levels only in the kinetic method (r = 0.644 and 0.520 for citrate-anticoagulated; r = 0.581 and 0.490 for EDTA-anticoagulated, p = 0.0001). We conclude that adaptation of the end-point method to automation is more difficult and it has higher between-run CV% while application of the kinetic method is easier and it may be used in oxidative stress studies.

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.

Implementation of a Bayesian design in a dose-escalation study of an experimental agent in healthy volunteers.

PubMed

Zhou, Yinghui; Whitehead, John; Korhonen, Pasi; Mustonen, Mika

2008-03-01

Bayesian decision procedures have recently been developed for dose escalation in phase I clinical trials concerning pharmacokinetic responses observed in healthy volunteers. This article describes how that general methodology was extended and evaluated for implementation in a specific phase I trial of a novel compound. At the time of writing, the study is ongoing, and it will be some time before the sponsor will wish to put the results into the public domain. This article is an account of how the study was designed in a way that should prove to be safe, accurate, and efficient whatever the true nature of the compound. The study involves the observation of two pharmacokinetic endpoints relating to the plasma concentration of the compound itself and of a metabolite as well as a safety endpoint relating to the occurrence of adverse events. Construction of the design and its evaluation via simulation are presented.

Genetics of Triglycerides and the Risk of Atherosclerosis.

PubMed

Dron, Jacqueline S; Hegele, Robert A

2017-07-01

Plasma triglycerides are routinely measured with a lipid profile, and elevated plasma triglycerides are commonly encountered in the clinic. The confounded nature of this trait, which is correlated with numerous other metabolic perturbations, including depressed high-density lipoprotein cholesterol (HDL-C), has thwarted efforts to directly implicate triglycerides as causal in atherogenesis. Human genetic approaches involving large-scale populations and high-throughput genomic assessment under a Mendelian randomization framework have undertaken to sort out questions of causality. We review recent large-scale meta-analyses of cohorts and population-based sequencing studies designed to address whether common and rare variants in genes whose products are determinants of plasma triglycerides are also associated with clinical cardiovascular endpoints. The studied loci include genes encoding lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and angiopoietin-like proteins 3 and 4, and common polymorphisms identified in genome-wide association studies. Triglyceride-raising variant alleles of these genes showed generally strong associations with clinical cardiovascular endpoints. However, in most cases, a second lipid disturbance-usually depressed HDL-C-was concurrently associated. While the findings collectively shift our understanding towards a potential causal role for triglycerides, we still cannot rule out the possibilities that triglycerides are a component of a joint phenotype with low HDL-C or that they are but markers of deeper causal metabolic disturbances that are not routinely measured in epidemiological-scale genetic studies.

Recommendations for pharmacological clinical trials in children with irritable bowel syndrome: the Rome foundation pediatric subcommittee on clinical trials.

PubMed

Saps, M; van Tilburg, M A L; Lavigne, J V; Miranda, A; Benninga, M A; Taminiau, J A; Di Lorenzo, C

2016-11-01

There is little published evidence of efficacy for the most commonly used treatments. Thus, there is an urgent need to conduct clinical trials on existing and novel therapies. In order to address these issues the Rome Foundation and members of the Pediatric Committee of the European Medicines Agency formed a subcommittee on clinical trials to develop guidelines for the design of clinical trials in children with irritable bowel syndrome (IBS). The following recommendations are based on evidence from published data when available and expert opinion. The subcommittee recommends randomized, double-blind, placebo-controlled, parallel-group, clinical trials to assess the efficacy of new drugs. The combined endpoints for abdominal pain are a decrease in intensity of at least 30% compared with baseline and to meet or exceed the Reliable Change Index (RCI) for the sample. Stool consistency is measured with the Bristol Stool Scale Form (BSFS). The subcommittee recommends as entry criteria for abdominal pain a weekly average of worst abdominal pain in past 24 h of at least 3.0 on a 0-10 point scale or at least 30 mm in 100 mm Visual Analog Scale. For stool endpoints the committee recommends an average stool consistency lower than 3 in the BSFS during the run-in period for clinical trials on IBS-C and an average stool consistency greater than 5 in the BSFS during the run-in period for clinical trials on IBS-D. Changes in stool consistency are the primary endpoints for both IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). © 2016 John Wiley & Sons Ltd.

Randomized Clinical Trials of Gene Transfer for Heart Failure with Reduced Ejection Fraction.

PubMed

Penny, William F; Hammond, H Kirk

2017-05-01

Despite improvements in drug and device therapy for heart failure, hospitalization rates and mortality have changed little in the past decade. Randomized clinical trials using gene transfer to improve function of the failing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with reduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic HFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid. The initial CUPID trial randomized 14 subjects to placebo and 25 subjects to escalating doses of adeno-associated virus type 1 encoding sarcoplasmic reticulum calcium ATPase (AAV1.SERCA2a). AAV1.SERCA2a was well tolerated, and the high-dose group met a 6 month composite endpoint. In the subsequent CUPID-2 study, 243 subjects received either placebo or the high dose of AAV1.SERCA2a. AAV1.SERCA2a administration, while safe, failed to meet the primary or any secondary endpoints. STOP-HF used plasmid endocardial injection of stromal cell-derived factor-1 to promote stem-cell recruitment. In a 93-subject trial of patients with ischemic etiology heart failure, the primary endpoint (symptoms and 6 min walk distance) failed, but subgroup analyses showed improvements in subjects with the lowest ejection fractions. A fourth trial randomized 14 subjects to placebo and 42 subjects to escalating doses of adenovirus-5 encoding adenylyl cyclase 6 (Ad5.hAC6). There were no safety concerns, and patients in the two highest dose groups (combined) showed improvements in left ventricular function (left ventricular ejection fraction and -dP/dt). The safety data from four randomized clinical trials of gene transfer in patients with symptomatic HFrEF suggest that this approach can be conducted with acceptable risk, despite invasive delivery techniques in a high-risk population. Additional trials are necessary before the approach can be endorsed for clinical practice.

[The Probabilistic Efficiency Frontier: A Value Assessment of Treatment Options in Hepatitis C].

PubMed

Mühlbacher, Axel C; Sadler, Andrew

2017-06-19

Background The German Institute for Quality and Efficiency in Health Care (IQWiG) recommends the concept of the efficiency frontier to assess health care interventions. The efficiency frontier supports regulatory decisions on reimbursement prices for the appropriate allocation of health care resources. Until today this cost-benefit assessment framework has only been applied on the basis of individual patient-relevant endpoints. This contradicts the reality of a multi-dimensional patient benefit. Objective The objective of this study was to illustrate the operationalization of multi-dimensional benefit considering the uncertainty in clinical effects and preference data in order to calculate the efficiency of different treatment options for hepatitis C (HCV). This case study shows how methodological challenges could be overcome in order to use the efficiency frontier for economic analysis and health care decision-making. Method The operationalization of patient benefit was carried out on several patient-relevant endpoints. Preference data from a discrete choice experiment (DCE) study and clinical data based on clinical trials, which reflected the patient and the clinical perspective, respectively, were used for the aggregation of an overall benefit score. A probabilistic efficiency frontier was constructed in a Monte Carlo simulation with 10000 random draws. Patient-relevant endpoints were modeled with a beta distribution and preference data with a normal distribution. The assessment of overall benefit and costs provided information about the adequacy of the treatment prices. The parameter uncertainty was illustrated by the price-acceptability-curve and the net monetary benefit. Results Based on the clinical and preference data in Germany, the interferon-free treatment options proved to be efficient for the current price level. The interferon-free therapies of the latest generation achieved a positive net cost-benefit. Within the decision model, these therapies showed a maximum overall benefit. Due to their high additional benefit and approved prices, the therapies lie above of the extrapolated efficiency frontier, which suggests that these options have efficient reimbursement prices. Considering uncertainty, even a higher price would have resulted in a positive cost-benefit ratio. Conclusion IQWiG's efficiency frontier was used to assess the value of different treatment options in HCV. This study demonstrates that the probabilistic efficiency frontier, price-acceptability-curve and the net monetary benefit can contribute essential information to reimbursement decisions and price negotiations. © Georg Thieme Verlag KG Stuttgart · New York.

Implications of Pain in Generalized Anxiety Disorder: Efficacy of Duloxetine

PubMed Central

Hartford, James T.; Endicott, Jean; Kornstein, Susan G.; Allgulander, Christer; Wohlreich, Madelaine M.; Russell, James M.; Perahia, David G. S.; Erickson, Janelle S.

2008-01-01

Objective: To conduct a post hoc evaluation of the prevalence of clinically significant pain and the efficacy of duloxetine in patients with generalized anxiety disorder (GAD) and concurrent pain. Method: Data from two 9- to 10-week double-blind, placebo-controlled, randomized clinical trials of duloxetine (60 to 120 mg) in DSM-IV–defined GAD were analyzed (study 1 was conducted from July 2004 to September 2005; study 2 was conducted from August 2004 to June 2005). Efficacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A), visual analog scales (VAS) for pain, the Hospital Anxiety Depression Scale (HADS), the Clinical Global Impressions-Improvement of Illness (CGI-I) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and the Sheehan Disability Scale (SDS) global functional impairment scale. Results: Of 840 patients randomly assigned to treatment, 61.3% (302 duloxetine, 213 placebo) had VAS scores ≥ 30 mm on at least 1 of the pain scales, indicating clinically significant pain. Among those patients with concurrent pain at baseline, change from baseline to endpoint in the HAM-A total score (42.9% change in mean scores for duloxetine, 31.4% for placebo), HADS anxiety scale (40.3% vs. 22.8%), HADS depression scale (36.1% vs. 20.5%), HAM-A psychic factor (45.9% vs. 29.9%), and SDS global functional improvement score (45.5% vs. 22.1%) was significantly (all p's < .001) greater for duloxetine compared with placebo. Improvement on the CGI-I (p = .003) and PGI-I (p < .001) was also significantly greater for duloxetine. Response (HAM-A total score decrease ≥ 50%) (49% vs. 29%) and remission (HAM-A total score ≤ 7 at endpoint) (29% vs. 18%) rates were significantly greater for duloxetine compared with placebo (p < .001 and p = .041, respectively). Duloxetine demonstrated statistically significantly greater reduction in pain on all 6 VAS pain scales (all p's < .001 except headaches with p < .002) (for duloxetine, percent change in means from baseline to endpoint ranged from 40.1% to 45.2% across the 6 VAS scales; for placebo, 22.0% to 26.3%). Conclusion: Duloxetine, relative to placebo, improves anxiety symptoms, pain, and functional impairment among patients with GAD with concurrent clinically significant pain. Trial Registration: clinicaltrials.gov Identifiers: NCT00122824 (study 1) and NCT00475969 (study 2) PMID:18615176

Evaluating markers for the early detection of cancer: overview of study designs and methods.

PubMed

Baker, Stuart G; Kramer, Barnett S; McIntosh, Martin; Patterson, Blossom H; Shyr, Yu; Skates, Steven

2006-01-01

The field of cancer biomarker development has been evolving rapidly. New developments both in the biologic and statistical realms are providing increasing opportunities for evaluation of markers for both early detection and diagnosis of cancer. To review the major conceptual and methodological issues in cancer biomarker evaluation, with an emphasis on recent developments in statistical methods together with practical recommendations. We organized this review by type of study: preliminary performance, retrospective performance, prospective performance and cancer screening evaluation. For each type of study, we discuss methodologic issues, provide examples and discuss strengths and limitations. Preliminary performance studies are useful for quickly winnowing down the number of candidate markers; however their results may not apply to the ultimate target population, asymptomatic subjects. If stored specimens from cohort studies with clinical cancer endpoints are available, retrospective studies provide a quick and valid way to evaluate performance of the markers or changes in the markers prior to the onset of clinical symptoms. Prospective studies have a restricted role because they require large sample sizes, and, if the endpoint is cancer on biopsy, there may be bias due to overdiagnosis. Cancer screening studies require very large sample sizes and long follow-up, but are necessary for evaluating the marker as a trigger of early intervention.

Improving data transparency in clinical trials using blockchain smart contracts.

PubMed

Nugent, Timothy; Upton, David; Cimpoesu, Mihai

2016-01-01

The scientific credibility of findings from clinical trials can be undermined by a range of problems including missing data, endpoint switching, data dredging, and selective publication. Together, these issues have contributed to systematically distorted perceptions regarding the benefits and risks of treatments. While these issues have been well documented and widely discussed within the profession, legislative intervention has seen limited success. Recently, a method was described for using a blockchain to prove the existence of documents describing pre-specified endpoints in clinical trials. Here, we extend the idea by using smart contracts - code, and data, that resides at a specific address in a blockchain, and whose execution is cryptographically validated by the network - to demonstrate how trust in clinical trials can be enforced and data manipulation eliminated. We show that blockchain smart contracts provide a novel technological solution to the data manipulation problem, by acting as trusted administrators and providing an immutable record of trial history.

Bilateral implantation of +2.5 D multifocal intraocular lens and contralateral implantation of +2.5 D and +3.0 D multifocal intraocular lenses: Clinical outcomes.

PubMed

Nuijts, Rudy M M A; Jonker, Soraya M R; Kaufer, Robert A; Lapid-Gortzak, Ruth; Mendicute, Javier; Martinez, Cristina Peris; Schmickler, Stefanie; Kohnen, Thomas

2016-02-01

To assess the clinical visual outcomes of bilateral implantation of Restor +2.5 diopter (D) multifocal intraocular lenses (IOLs) and contralateral implantation of a Restor +2.5 D multifocal IOL in the dominant eye and Restor +3.0 D multifocal IOL in the fellow eye. Multicenter study at 8 investigative sites. Prospective randomized parallel-group patient-masked 2-arm study. This study comprised adults requiring bilateral cataract extraction followed by multifocal IOL implantation. The primary endpoint was corrected intermediate visual acuity (CIVA) at 60 cm, and the secondary endpoint was corrected near visual acuity (CNVA) at 40 cm. Both endpoints were measured 3 months after implantation with a noninferiority margin of Δ = 0.1 logMAR. In total, 103 patients completed the study (53 bilateral, 50 contralateral). At 3 months, the mean CIVA at 60 cm was 0.13 logMAR and 0.10 logMAR in the bilateral group and contralateral group, respectively (difference 0.04 logMAR), achieving noninferiority. Noninferiority was not attained for CNVA at 40 cm; mean values at 3 months for bilateral and contralateral implantation were 0.26 logMAR and 0.11 logMAR, respectively (difference 0.15 logMAR). Binocular defocus curves suggested similar performance in distance vision between the 2 groups. Treatment-emergent ocular adverse events rates were similar between the groups. Bilateral implantation of the +2.5 D multifocal IOL resulted in similar distance as contralateral implantation of the +2.5 D multifocal IOL and +3.0 D multifocal IOL for intermediate vision (60 cm), while noninferiority was not achieved for near distances (40 cm). Copyright © 2016 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

Safety and feasibility of pulmonary artery pressure-guided heart failure therapy: rationale and design of the prospective CardioMEMS Monitoring Study for Heart Failure (MEMS-HF).

PubMed

Angermann, Christiane E; Assmus, Birgit; Anker, Stefan D; Brachmann, Johannes; Ertl, Georg; Köhler, Friedrich; Rosenkranz, Stephan; Tschöpe, Carsten; Adamson, Philip B; Böhm, Michael

2018-05-19

Wireless monitoring of pulmonary artery (PA) pressures with the CardioMEMS HF™ system is indicated in patients with New York Heart Association (NYHA) class III heart failure (HF). Randomized and observational trials have shown a reduction in HF-related hospitalizations and improved quality of life in patients using this device in the United States. MEMS-HF is a prospective, non-randomized, open-label, multicenter study to characterize safety and feasibility of using remote PA pressure monitoring in a real-world setting in Germany, The Netherlands and Ireland. After informed consent, adult patients with NYHA class III HF and a recent HF-related hospitalization are evaluated for suitability for permanent implantation of a CardioMEMS™ sensor. Participation in MEMS-HF is open to qualifying subjects regardless of left ventricular ejection fraction (LVEF). Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy as tolerated. The study will enroll 230 patients in approximately 35 centers. Expected duration is 36 months (24-month enrolment plus ≥ 12-month follow-up). Primary endpoints are freedom from device/system-related complications and freedom from pressure sensor failure at 12-month post-implant. Secondary endpoints include the annualized rate of HF-related hospitalization at 12 months versus the rate over the 12 months preceding implant, and health-related quality of life. Endpoints will be evaluated using data obtained after each subject's 12-month visit. The MEMS-HF study will provide robust evidence on the clinical safety and feasibility of implementing haemodynamic monitoring as a novel disease management tool in routine out-patient care in selected European healthcare systems. ClinicalTrials.gov; NCT02693691.

Bladder wall thickness in women with symptoms of overactive bladder and detrusor overactivity: Results from the randomised, placebo-controlled shrink study.

PubMed

Robinson, Dudley; Oelke, Matthias; Khullar, Vik; Wijkstra, Hessel; Tretter, Reiner; Stow, Bridget; Compion, Gerhard; Tubaro, Andrea

2016-09-01

Measurement of bladder wall thickness (BWT) by transvaginal ultrasound (TVUS) may be a less invasive method to diagnose overactive bladder (OAB) or detrusor overactivity (DO) and monitor response to therapy. This study assessed whether treatment with solifenacin affects BWT. This was a double-blind, randomised, placebo-controlled, phase 4 study. Adult women with OAB symptoms received solifenacin 5 or 10 mg or placebo once daily for 12 weeks. The co-primary endpoints were change from baseline to Week 12 in TVUS-measured BWT and urinary nerve growth factor. Only results for BWT are presented here. Overall, 547 patients were randomised, 501 patients had a baseline BWT measurement, and change from baseline could be calculated for 478 patients. Mean BWT at baseline was 5.08 mm (range 2.2-11.1, SD = 1.14) and was normally distributed. A significant reduction in BWT from baseline to 12 weeks versus placebo was observed with solifenacin 5 mg (-0.42 vs. -0.16 mm, P = 0.03), but not with the 10 mg dose or with pooled solifenacin, considered the primary comparison. Both solifenacin doses were associated with improvements in efficacy and patient satisfaction endpoints versus placebo. Solifenacin was well tolerated, with dry mouth being the most common adverse event. There was no consistent effect of solifenacin on BWT in women with OAB/DO, despite improvements in efficacy endpoints. This study suggests that routine clinical assessment of BWT with TVUS for monitoring the effects of OAB/DO treatment is not clinically useful. Neurourol. Urodynam. 35:819-825, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R and Lactobacillus rhamnosus CLR2 improve quality-of-life and IBS symptoms: a double-blind, randomised, placebo-controlled study.

PubMed

Preston, K; Krumian, R; Hattner, J; de Montigny, D; Stewart, M; Gaddam, S

2018-06-11

A combination of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R and Lactobacillus rhamnosus CLR2 was compared to placebo for relief of symptoms of irritable bowel syndrome (IBS). A total of 113 subjects at 3 clinical sites were randomised in a 2:1 ratio and followed for 12 weeks. Subjects ingested either 2 capsules of active study product, containing 50×10 9 cfu of live organisms, or 2 placebo capsules daily. Endpoints included improvement in abdominal pain, days of pain, distention, stool consistency and frequency, quality of life (QOL), and adequate relief (AR) of IBS symptoms. IBS subtypes constipation (IBS-C), diarrhoea (IBS-D), and mixed (IBS-M) were evaluated separately; the effect of gender was also examined. For all efficacy endpoints improvement of 30% or more vs placebo was considered clinically significant. With the exception of pain intensity and AR, the endpoints demonstrated a therapeutic advantage of active over placebo for IBS symptoms in at least some subject subgroups. The IBS-D and female subgroups showed the largest and most consistent effects. Stool frequency and consistency were evaluated in the IBS-C and IBS-D subgroups, and improvement of active vs placebo was noted in both. QOL improvement was seen overall and in specific domains. Adverse events (AEs) were limited to 7 subjects; all were of mild or moderate intensity except one, severe cramping. Four AEs in the same subject in the placebo group were judged to be related to study product; these resolved by the end of study. There were no serious AEs.

Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia.

PubMed

Saccà, Francesco; Puorro, Giorgia; Marsili, Angela; Antenora, Antonella; Pane, Chiara; Casali, Carlo; Marcotulli, Christian; Defazio, Giovanni; Liuzzi, Daniele; Tatillo, Chiara; Cambriglia, Donata Maria; Schiano di Cola, Giuseppe; Giuliani, Luigi; Guardasole, Vincenzo; Salzano, Andrea; Ruvolo, Antonio; De Rosa, Anna; Cittadini, Antonio; De Michele, Giuseppe; Filla, Alessandro

2016-05-01

Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown. We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks. A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [-0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (-17.24 sec. [-31.5 to -3.0]; P = .018). The treatment was safe and well tolerated. Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

The limits of evidence in drug approval and availability: a case study of cilostazol and naftidrofuryl for the treatment of intermittent claudication.

PubMed

Hong, Haeyeon; Mackey, William C

2014-08-01

Despite numerous efforts to develop effective medications for the treatment of intermittent claudication (IC) over the past 4 decades, a gold standard medical management option has yet to be defined. Although not life-threatening, IC interferes with mobility and activities of daily living, significantly impairing quality of life and potentially causing depression. Cilostazol, the leading pharmacologic agent for IC in the United States, was approved by the US Food and Drug Administration (FDA) in 1999 based on controversial data. Meanwhile, naftidrofuryl, the first-line pharmacologic agent for IC in the United Kingdom and Europe, has never been approved by the FDA and therefore is not available in the United States. The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect impossible. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted, because the manufacturers of these agents have much to lose and little to gain from such a study. This article provides an overview of the pharmacology of cilostazol and naftidrofuryl, and the clinical studies leading to their approval and clinical acceptance. It further explores the possible sources of bias in analyzing these clinical trials, some of which have been brought to light by the National Institute for Health and Clinical Excellence (NICE) of the United Kingdom in its technology appraisal guidance. It also speculates the ways in which economic incentives may affect drug-marketing decisions. A literature review of pharmacology and clinical trials for cilostazol and naftidrofuryl was performed in PubMed. The majority of included clinical trials were initially identified through the most recent Cochrane review articles as well as the FDA's approval packet for cilostazol. The technology appraisal guidance of the National Institute for Health and Care Excellence of the United Kingdom and the manufacturer's response to this guidance document were located via an online search engine. The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect difficult. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted. The history of the evaluation, approval, and marketing of these drugs illustrates the limitations of data in the regulatory approval and marketing of agents whose benefit is subjective and difficult to quantify. Implementation of a standardized protocol with strict eligibility criteria, objective quantifiable measurement of drug effect, and validated endpoints will eventually allow development of an ideal pharmacotherapy for IC. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Novel insights on diagnosis, cause and treatment of diabetic neuropathy: focus on painful diabetic neuropathy

PubMed Central

Tavakoli, Mitra; Asghar, Omar; Alam, Uazman; Petropoulos, Ioannis N.; Fadavi, Hassan; Malik, Rayaz A.

2010-01-01

Diabetic neuropathy is common, under or misdiagnosed, and causes substantial morbidity with increased mortality. Defining and developing sensitive diagnostic tests for diabetic neuropathy is not only key to implementing earlier interventions but also to ensure that the most appropriate endpoints are employed in clinical intervention trials. This is critical as many potentially effective therapies may never progress to the clinic, not due to a lack of therapeutic effect, but because the endpoints were not sufficiently sensitive or robust to identify benefit. Apart from improving glycaemic control, there is no licensed treatment for diabetic neuropathy, however, a number of pathogenetic pathways remain under active study. Painful diabetic neuropathy is a cause of considerable morbidity and whilst many pharmacological and nonpharmacological interventions are currently used, only two are approved by the US Food and Drug Administration. We address the important issue of the ‘placebo effect’ and also consider potential new pharmacological therapies as well as nonpharmacological interventions in the treatment of painful diabetic neuropathy. PMID:23148152

Self-expandable metal stents for relieving malignant colorectal obstruction: short-term safety and efficacy within 30 days of stent procedure in 447 patients.

PubMed

Meisner, Søren; González-Huix, Ferran; Vandervoort, Jo G; Goldberg, Paul; Casellas, Juan A; Roncero, Oscar; Grund, Karl E; Alvarez, Alberto; García-Cano, Jesús; Vázquez-Astray, Enrique; Jiménez-Pérez, Javier

2011-10-01

The self-expandable metal stent (SEMS) can alleviate malignant colonic obstruction and avoid emergency decompressive surgery. To document performance, safety, and effectiveness of colorectal stents used per local standards of practice in patients with malignant large-bowel obstruction to avoid palliative stoma surgery in incurable patients (PAL) and facilitate bowel decompression as a bridge to surgery for curable patients (BTS). Prospective clinical cohort study. Two global registries with 39 academic and community centers. This study involved 447 patients with malignant colonic obstruction who received stents (255 PAL, 182 BTS, 10 no indication specified). Colorectal through-the-scope SEMS placement. The primary endpoint was clinical success at 30 days, defined as the patient's ability to maintain bowel function without adverse events related to the procedure or stent. Secondary endpoints were procedural success, defined as successful stent placement in the correct position, symptoms of persistent or recurrent colonic obstruction, and complications. The procedural success rate was 94.8% (439/463), and the clinical success rates were 90.5% (313/346) as assessed on a per protocol basis and 71.6% (313/437) as assessed on an intent-to-treat basis. Complications included 15 (3.9%) perforations, 3 resulting in death, 7 (1.8%) migrations, 7 (1.8%) cases of pain, and 2 (0.5%) cases of bleeding. No control group. No primary endpoint analysis data for 25% of patients. This largest multicenter, prospective study of colonic SEMS placement demonstrates that colonic SEMSs are safe and highly effective for the short-term treatment of malignant colorectal obstruction, allowing most curable patients to have 1-step resection without stoma and providing most incurable patients minimally invasive palliation instead of surgery. The risk of complications, including perforation, was low. Copyright © 2011 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study.

PubMed

Vuilleumier, Pascal H; Besson, Marie; Desmeules, Jules; Arendt-Nielsen, Lars; Curatolo, Michele

2013-01-01

Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain. In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry. For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed. Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds. ClinicalTrials.gov NCT01011036.

Evaluation of Anti-Hyperalgesic and Analgesic Effects of Two Benzodiazepines in Human Experimental Pain: A Randomized Placebo-Controlled Study

PubMed Central

Vuilleumier, Pascal H.; Besson, Marie; Desmeules, Jules; Arendt-Nielsen, Lars; Curatolo, Michele

2013-01-01

Background and Aims Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain. Methods In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry. Results For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed. Conclusions Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds. Trial Registration ClinicalTrials.gov NCT01011036 PMID:23554851

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.

Relationship between time to clinical response and outcomes among Pneumonia Outcomes Research Team (PORT) risk class III and IV hospitalized patients with community-acquired pneumonia who received ceftriaxone and azithromycin.

PubMed

Zasowski, Evan; Butterfield, Jill M; McNutt, Louise-Ann; Cohen, Jason; Cosler, Leon; Pai, Manjunath P; Gottwald, Joseph; Chen, Wen Zhen; Lodise, Thomas P

2014-07-01

Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P = 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indicator of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Identifying a system of predominant negative symptoms: Network analysis of three randomized clinical trials.

PubMed

Levine, Stephen Z; Leucht, Stefan

2016-12-01

Reasons for the recent mixed success of research into negative symptoms may be informed by conceptualizing negative symptoms as a system that is identifiable from network analysis. We aimed to identify: (I) negative symptom systems; (I) central negative symptoms within each system; and (III) differences between the systems, based on network analysis of negative symptoms for baseline, endpoint and change. Patients with chronic schizophrenia and predominant negative symptoms participated in three clinical trials that compared placebo and amisulpride to 60days (n=487). Networks analyses were computed from the Scale for the Assessment of Negative Symptoms (SANS) scores for baseline and endpoint for severity, and estimated change based on mixed models. Central symptoms to each network were identified. The networks were contrasted for connectivity with permutation tests. Network analysis showed that the baseline and endpoint symptom severity systems formed symptom groups of Affect, Poor responsiveness, Lack of interest, and Apathy-inattentiveness. The baseline and endpoint networks did not significantly differ in terms of connectivity, but both significantly (P<0.05) differed to the change network. In the change network the apathy-inattentiveness symptom group split into three other groups. The most central symptoms were Decreased Spontaneous Movements at baseline and endpoint, and Poverty of Speech for estimated change. Results provide preliminary evidence for: (I) a replicable negative symptom severity system; and (II) symptoms with high centrality (e.g., Decreased Spontaneous Movement), that may be future treatment targets following replication to ensure the curent results generalize to other samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis.

PubMed

Oulhaj, Abderrahim; El Ghouch, Anouar; Holman, Rury R

2017-01-01

Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease.

Regular aquatic exercise for chronic kidney disease patients: a 10-year follow-up study.

PubMed

Pechter, Ülle; Raag, Mait; Ots-Rosenberg, Mai

2014-09-01

Chronic kidney disease (CKD) patients not yet in dialysis can benefit from increased physical activity; however, the safety and outcomes of aquatic exercise have not been investigated in observational studies. The aim of this study was to analyze association of 10 years of regularly performed aquatic exercise with the study endpoint--that is, all-cause death or start of dialysis. Consecutive CKD patients were included in the study in January 2002. The exercise group (n=7) exercised regularly under the supervision of physiotherapist for 10 years; the control group (n=9), matched in terms of age and clinical parameters, remained sedentary. Low-intensity aerobic aquatic exercise was performed regularly twice a week; 32 weeks or more of exercise therapy sessions were conducted annually. None of the members of the aquatic exercise group reached dialysis or died in 10 years. In the sedentary control group, 55% reached the study endpoint--renal replacement therapy (n=2) or all-cause death (n=3). Occurrence of the study endpoint, compared using the exact multinomial test with unconditional margins, was statistically significantly different (P-value: 0.037) between the study groups. Regular supervised aquatic exercise arrested CKD progression. There was a statistically significant difference between the sedentary group and the exercise group in reaching renal replacement therapy or all-cause death in a follow-up time of 10 years.

Design and analysis of three-arm trials with negative binomially distributed endpoints.

PubMed

Mütze, Tobias; Munk, Axel; Friede, Tim

2016-02-20

A three-arm clinical trial design with an experimental treatment, an active control, and a placebo control, commonly referred to as the gold standard design, enables testing of non-inferiority or superiority of the experimental treatment compared with the active control. In this paper, we propose methods for designing and analyzing three-arm trials with negative binomially distributed endpoints. In particular, we develop a Wald-type test with a restricted maximum-likelihood variance estimator for testing non-inferiority or superiority. For this test, sample size and power formulas as well as optimal sample size allocations will be derived. The performance of the proposed test will be assessed in an extensive simulation study with regard to type I error rate, power, sample size, and sample size allocation. For the purpose of comparison, Wald-type statistics with a sample variance estimator and an unrestricted maximum-likelihood estimator are included in the simulation study. We found that the proposed Wald-type test with a restricted variance estimator performed well across the considered scenarios and is therefore recommended for application in clinical trials. The methods proposed are motivated and illustrated by a recent clinical trial in multiple sclerosis. The R package ThreeArmedTrials, which implements the methods discussed in this paper, is available on CRAN. Copyright © 2015 John Wiley & Sons, Ltd.

Medication Use in Early-HD Participants in Track-HD: an Investigation of its Effects on Clinical Performance.

PubMed

Keogh, Ruth; Frost, Chris; Owen, Gail; Daniel, Rhian M; Langbehn, Doug R; Leavitt, Blair; Durr, Alexandra; Roos, Raymund A C; Landwehrmeyer, G Bernhard; Reilmann, Ralf; Borowsky, Beth; Stout, Julie; Craufurd, David; Tabrizi, Sarah J

2016-01-11

 Insufficient evidence exists to guide the long-term pharmacological management of Huntington's disease (HD) although most current interventions rely on symptomatic management. The effect of many frontline treatments on potential endpoints for HD clinical trials remains unknown. Our objective was to investigate how therapies widely used to manage HD affect the symptom for which they are prescribed and other endpoints using data from TRACK-HD. We used longitudinal models to estimate effects of medication use on performance on tests of motor, cognitive and neuropsychiatric function using data from 123 TRACK-HD stage 1/2 participants across four study visits. Adjustment for confounding by prior medication use, prior clinical performance, concomitant use of other medications, and baseline variables (sex, disease group, age, CAG, study site, education) enabled a closer-to-causal interpretation of the associations. Adjusting for baseline variables only, medication use was typically associated with worse clinical performance, reflecting greater medication use in more advanced patients. After additional adjustment for longitudinal confounders such "inverse" associations were generally eliminated and in the expected directions: participants taking neuroleptics tended to have better motor performance, improved affect and poorer cognitive performance, and those taking SSRI/SNRIs had less apathy, less affect and better total behaviour scores. However, we uncovered few statistically significant associations. Limitations include sample size and unmeasured confounding. In conclusion, adjustment for confounding by prior measurements largely eliminated associations between medication use and poorer clinical performance from simple analyses. However, there was little convincing evidence of causal effects of medication on clinical performance and larger cohorts or trials are needed.

Achieving consensus for clinical trials

PubMed Central

Blakeley, Jaishri O.; Dombi, Eva; Fisher, Michael J.; Hanemann, C. Oliver; Walsh, Karin S.; Wolters, Pamela L.; Widemann, Brigitte C.

2013-01-01

The neurofibromatoses (NF)—including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis—are related tumor-suppressor syndromes characterized by a predisposition to multiple tumor types and other disease manifestations, which often result in functional disability, reduced quality of life, pain, and, in some cases, malignancy. With increasing knowledge of the biology and pathogenesis of NF, clinical trials with targeted agents directed at NF tumors have become available. Most clinical trials for patients with NF have used designs and endpoints similar to oncology trials. However, differences in the disease manifestations and natural history of NF (compared to cancers) require the development of new designs and endpoints to perform meaningful NF clinical trials. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established in 2011 at the Children's Tumor Foundation meeting to achieve consensus within the NF community about the design of future clinical trials, with a specific emphasis on endpoints. The REiNS Collaboration includes 7 working groups that focus on imaging of tumor response; functional, visual, patient-reported, and neurocognitive outcomes; whole-body MRI; and disease biomarkers. This supplement includes the first series of recommendations by the REiNS Collaboration. The hope is that these recommendations will be used by members of the group and by researchers outside of the REiNS International Collaboration to standardize the measurement of outcomes and thus improve clinical trials for patients with NF. Ultimately, we plan to engage industry partners and national regulatory agencies in this process to facilitate the approval of drugs for patients with NF. PMID:24249801

Adalimumab in active ulcerative colitis: a "real-life" observational study.

PubMed

Armuzzi, Alessandro; Biancone, Livia; Daperno, Marco; Coli, Alessandra; Pugliese, Daniela; Annese, Vito; Aratari, Annalisa; Ardizzone, Sandro; Balestrieri, Paola; Bossa, Fabrizio; Cappello, Maria; Castiglione, Fabiana; Cicala, Michele; Danese, Silvio; D'Incà, Renata; Dulbecco, Pietro; Feliciangeli, Giuseppe; Fries, Walter; Genise, Stefania; Gionchetti, Paolo; Gozzi, Stefano; Kohn, Anna; Lorenzetti, Roberto; Milla, Monica; Onali, Sara; Orlando, Ambrogio; Papparella, Luigi Giovanni; Renna, Sara; Ricci, Chiara; Rizzello, Fernando; Sostegni, Raffaello; Guidi, Luisa; Papi, Claudio

2013-09-01

The effectiveness of adalimumab in the treatment of ulcerative colitis is under debate. Although controlled trials have shown that adalimumab is significantly better than placebo, the absolute clinical benefit is modest. We report data on the effectiveness of adalimumab in a cohort of ulcerative colitis patients treated in 22 Italian centres. All patients with active disease treated with adalimumab were retrospectively reviewed. Co-primary endpoints were clinical remission at weeks 4, 12, 24 and 54. Secondary endpoints were sustained clinical remission, steroid discontinuation, endoscopic remission and need for colectomy. Eighty-eight patients were included. Most patients had received previous infliximab treatment. Clinical remission rates were 17%, 28.4%, 36.4% and 43.2% at 4, 12, 24 and 54 weeks respectively. Twenty-two patients required colectomy. Clinical remission and low C-reactive protein at week 12 predicted clinical remission at week 54 (OR 4.17, 95% CI 2.36-19.44; OR 2.63, 95% CI 2.32-14.94, respectively). Previous immunosuppressant use was associated with a lower probability of clinical remission at week 54 (OR 0.67, 95% CI 0.08-0.66) and with a higher rate of colectomy (HR 9.7, 95% CI 1.46-9.07). In this large "real-life" experience adalimumab appears effective in patients with otherwise medically refractory ulcerative colitis. Patients achieving early remission can expect a better long-term outcome. Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial.

PubMed

Vinereanu, Dragos; Stevens, Susanna R; Alexander, John H; Al-Khatib, Sana M; Avezum, Alvaro; Bahit, Marıa Cecilia; Granger, Christopher B; Lopes, Renato D; Halvorsen, Sigrun; Hanna, Michael; Husted, Steen; Hylek, Elaine M; Mărgulescu, Andrei D; Wallentin, Lars; Atar, Dan

2015-12-07

To assess clinical outcomes, efficacy, and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a randomized, double-blind, placebo-controlled, multicentre trial that included 11 785 (64.7%) men and 6416 (35.3%) women with atrial fibrillation or flutter randomized to receive either warfarin or apixaban. The primary efficacy endpoint was stroke or systemic embolism; secondary efficacy endpoints were death from any cause and cardiovascular death. The primary safety endpoint was major bleeding; secondary safety endpoints were a composite of major bleeding and non-major clinically relevant bleeding. The risk of stroke or systemic embolism was similar in women vs. men [adjusted hazard ratio (adjHR): 0.91; 95% confidence interval (CI): 0.74-1.12; P = 0.38]. However, among patients with history of stroke or transient ischaemic attack, women had a lower risk of recurrent stroke compared with men (adjHR: 0.70; 95% CI: 0.50-0.97; P = 0.036). Women also had a lower risk of all-cause death (adjHR: 0.63; 95% CI: 0.55-0.73; P < 0.0001) and cardiovascular death (adjHR: 0.62; 95% CI: 0.51-0.75; P < 0.0001), and a trend towards less major bleeding (adjHR: 0.86; 95% CI: 0.74-1.01; P = 0.066) and major or non-major clinically relevant bleeding (adjHR: 0.89; 95% CI: 0.80-1.00; P = 0.049). The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex. In the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinically relevant bleeding than men. The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women. ARISTOTLE ClinicalTrials.gov number, NCT00412984. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study.

PubMed

Stallmach, A; Langbein, C; Atreya, R; Bruns, T; Dignass, A; Ende, K; Hampe, J; Hartmann, F; Neurath, M F; Maul, J; Preiss, J C; Schmelz, R; Siegmund, B; Schulze, H; Teich, N; von Arnim, U; Baumgart, D C; Schmidt, C

2016-12-01

Vedolizumab, a monoclonal antibody targeting the α4β7-integrin, is effective in inducing and maintaining clinical remission in Crohn's disease and ulcerative colitis according to randomised clinical trials. To determine the long-term effectiveness of vedolizumab in a real-world clinical setting. This observational registry assessed the clinical outcome in patients treated with vedolizumab for clinically active Crohn's disease (n = 67) or ulcerative colitis (n = 60). Primary endpoint was clinical remission (HBI ≤ 4/pMayo ≤ 1) at week 54. Secondary endpoints included clinical response rates (HBI/pMayo score drop ≥3) and steroid-free clinical remission at weeks 30 and 54. Vedolizumab was stopped in 69/127 (56%) patients after a median time of 18 weeks (range 2-49) predominantly owing to lack or loss of response. Using nonresponder imputation analysis, clinical remission and steroid-free remission rates were 21% and 15% in Crohn's disease and 25% and 22% in ulcerative colitis, respectively. Lack of clinical remission was associated with prior treatment with anti-TNF or with steroids for more than 3 months in the last 6 months in ulcerative colitis. At week 14, the absence of remission in Crohn's disease or nonresponse in ulcerative colitis indicated a low likelihood of clinical remission at week 54 [2/31 (7%) in Crohn's disease, 4/41 (10%) in ulcerative colitis]. Accordingly, declining C-reactive protein in inflammatory bowel disease and/or lower faecal calprotectin in ulcerative colitis at week 14 predicted remission at week 54. Among patients who started vedolizumab for active inflammatory bowel disease, clinical remission rates are 21-25% after 54 weeks. © 2016 John Wiley & Sons Ltd.

The Relationship between Urban Sprawl and Coronary Heart Disease in Women

PubMed Central

Griffin, Beth Ann; Eibner, Christine; Bird, Chloe E.; Jewell, Adria; Margolis, Karen; Shih, Regina; Slaughter, Mary Ellen; Whitsel, Eric A.; Allison, Matthew; Escarce, Jose J.

2013-01-01

Studies have reported relationships between urban sprawl, physical activity, and obesity, but—to date—no studies have considered the relationship between sprawl and coronary heart disease (CHD) endpoints. In this analysis, we use longitudinal data on post-menopausal women from the Women’s Health Initiative (WHI) Clinical Trial to analyze the relationship between metropolitan statistical area (MSA)-level urban compactness (the opposite of sprawl) and CHD endpoints including death, any CHD event, and myocardial infarction. Models control for individual and neighborhood sociodemographic characteristics. Women who lived in more compact communities at baseline had a lower probability of experiencing a CHD event and CHD death or MI during the study follow-up period. One component of compactness, high residential density, had a particularly noteworthy effect on outcomes. Finally, exploratory analyses showed evidence that the effects of compactness were moderated by race and region. PMID:23376728

The relationship between urban sprawl and coronary heart disease in women.

PubMed

Griffin, Beth Ann; Eibner, Christine; Bird, Chloe E; Jewell, Adria; Margolis, Karen; Shih, Regina; Ellen Slaughter, Mary; Whitsel, Eric A; Allison, Matthew; Escarce, Jose J

2013-03-01

Studies have reported relationships between urban sprawl, physical activity, and obesity, but - to date - no studies have considered the relationship between sprawl and coronary heart disease (CHD) endpoints. In this analysis, we use longitudinal data on post-menopausal women from the Women's Health Initiative (WHI) Clinical Trial to analyze the relationship between metropolitan statistical area (MSA)-level urban compactness (the opposite of sprawl) and CHD endpoints including death, any CHD event, and myocardial infarction. Models control for individual and neighborhood socio-demographic characteristics. Women who lived in more compact communities at baseline had a lower probability of experiencing a CHD event and CHD death or MI during the study follow-up period. One component of compactness, high residential density, had a particularly noteworthy effect on outcomes. Finally, exploratory analyses showed evidence that the effects of compactness were moderated by race and region. Copyright © 2012 Elsevier Ltd. All rights reserved.

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.

Assessing correlations between the spatial distribution of the dose to the rectal wall and late rectal toxicity after prostate radiotherapy: an analysis of data from the MRC RT01 trial (ISRCTN 47772397)

NASA Astrophysics Data System (ADS)

Buettner, Florian; Gulliford, Sarah L.; Webb, Steve; Sydes, Matthew R.; Dearnaley, David P.; Partridge, Mike

2009-11-01

Many studies have been performed to assess correlations between measures derived from dose-volume histograms and late rectal toxicities for radiotherapy of prostate cancer. The purpose of this study was to quantify correlations between measures describing the shape and location of the dose distribution and different outcomes. The dose to the rectal wall was projected on a two-dimensional map. In order to characterize the dose distribution, its centre of mass, longitudinal and lateral extent, and eccentricity were calculated at different dose levels. Furthermore, the dose-surface histogram (DSH) was determined. Correlations between these measures and seven clinically relevant rectal-toxicity endpoints were quantified by maximally selected standardized Wilcoxon rank statistics. The analysis was performed using data from the RT01 prostate radiotherapy trial. For some endpoints, the shape of the dose distribution is more strongly correlated with the outcome than simple DSHs. Rectal bleeding was most strongly correlated with the lateral extent of the dose distribution. For loose stools, the strongest correlations were found for longitudinal extent; proctitis was most strongly correlated with DSH. For the other endpoints no statistically significant correlations could be found. The strengths of the correlations between the shape of the dose distribution and outcome differed considerably between the different endpoints. Due to these significant correlations, it is desirable to use shape-based tools in order to assess the quality of a dose distribution.

Standardized definitions and clinical endpoints in carotid artery and supra-aortic trunk revascularization trials.

PubMed

Nedeltchev, Krassen; Pattynama, Peter M; Biaminoo, Giancarlo; Diehm, Nicolas; Jaff, Michael R; Hopkins, L Nelson; Ramee, Stephen; van Sambeek, Marc; Talen, Aly; Vermassen, Frank; Cremonesi, Alberto

2010-09-01

Endovascular therapy has emerged as a promising alternative to open surgery for stroke prevention in patients with obstructive disease of the supra-aortic arteries. Although most previous studies have used similar safety and efficacy endpoints, differences in definitions, timing of assessments, and standards of reporting have hampered direct comparisons across various trials. The DEFINE group, an informal collaboration of multidisciplinary physicians, involved in the therapy of patients with obstructive disease of the supra-aortic arteries in Europe and the United States reviewed the current literature and, after extensive correspondence and meetings, proposed the definitions outlined in the present manuscript. Three meetings including all authors of the manuscript, along with representatives of the United States Food and Drug Administration (FDA) and commercial device manufacturers were held in Barcelona, Spain, in May 2008, in Munich, Germany, in July 2008, and in New York in November 2008. The proposed definitions encompass baseline clinical and anatomic characteristics, clinical and radiologic outcomes, complications, standards of reporting, and timing of assessment. Considering the broad consensus between the multidisciplinary scientific members and the regulatory authorities, the proposed definitions are expected to find adoption in future clinical investigations. These definitions can be applied to both endovascular and open surgery trials and will allow reliable comparisons between these two revascularization methods.

Using Outcomes to Analyze Patients Rather than Patients to Analyze Outcomes: A Step toward Pragmatism in Benefit:risk Evaluation.

PubMed

Evans, Scott R; Follmann, Dean

2016-01-01

In the future, clinical trials will have an increased emphasis on pragmatism, providing a practical description of the effects of new treatments in realistic clinical settings. Accomplishing pragmatism requires better summaries of the totality of the evidence in ways that clinical trials consumers---patients, physicians, insurers---find transparent and allow for informed benefit:risk decision-making. The current approach to the analysis of clinical trials is to analyze efficacy and safety separately and then combine these analyses into a benefit:risk assessment. Many assume that this will effectively describe the impact on patients. But this approach is suboptimal for evaluating the totality of effects on patients. We discuss methods for benefit:risk assessment that have greater pragmatism than methods that separately analyze efficacy and safety. These include the concepts of within-patient analyses and composite benefit:risk endpoints with a goal of understanding how to analyze one patient before trying to figure out how to analyze many. We discuss the desirability of outcome ranking (DOOR) and introduce the partial credit strategy using an example in a clinical trial evaluating the effects of a new antibiotic. As part of the example we introduce a strategy to engage patients as a resource to inform benefit:risk analyses consistent with the goal of measuring and weighing outcomes that are most important from the patient's perspective. We describe a broad vision for the future of clinical trials consistent with increased pragmatism. Greater focus on using endpoints to analyze patients rather than patients to analyze endpoints particularly in late-phase/stage clinical trials is an important part of this vision.

Using Outcomes to Analyze Patients Rather than Patients to Analyze Outcomes: A Step toward Pragmatism in Benefit:risk Evaluation

PubMed Central

Evans, Scott R.; Follmann, Dean

2016-01-01

In the future, clinical trials will have an increased emphasis on pragmatism, providing a practical description of the effects of new treatments in realistic clinical settings. Accomplishing pragmatism requires better summaries of the totality of the evidence in ways that clinical trials consumers---patients, physicians, insurers---find transparent and allow for informed benefit:risk decision-making. The current approach to the analysis of clinical trials is to analyze efficacy and safety separately and then combine these analyses into a benefit:risk assessment. Many assume that this will effectively describe the impact on patients. But this approach is suboptimal for evaluating the totality of effects on patients. We discuss methods for benefit:risk assessment that have greater pragmatism than methods that separately analyze efficacy and safety. These include the concepts of within-patient analyses and composite benefit:risk endpoints with a goal of understanding how to analyze one patient before trying to figure out how to analyze many. We discuss the desirability of outcome ranking (DOOR) and introduce the partial credit strategy using an example in a clinical trial evaluating the effects of a new antibiotic. As part of the example we introduce a strategy to engage patients as a resource to inform benefit:risk analyses consistent with the goal of measuring and weighing outcomes that are most important from the patient’s perspective. We describe a broad vision for the future of clinical trials consistent with increased pragmatism. Greater focus on using endpoints to analyze patients rather than patients to analyze endpoints particularly in late-phase/stage clinical trials is an important part of this vision. PMID:28435515

[What is the perception of the 10-point plan of the German Federal Ministry of Health against multidrug-resistant pathogens and measures of antibiotic stewardship? : An interdisciplinary analysis among German clinicians and development of a decision tool for urologists].

PubMed

May, M; Vetterlein, M W; Wagenlehner, F M; Brookman-May, S D; Gilfrich, C; Fritsche, H-M; Spachmann, P J; Burger, M; Schostak, M; Lebentrau, S

2017-10-01

Due to increasing antibiotic resistances, relevant treatment problems are currently emerging in clinical practice. In March 2015, the German Federal Ministry of Health (BMG) published a 10-point plan designed to combat this development. Furthermore, the first German guideline on antibiotic stewardship (ABS) was implemented in 2013 and instructs physicians of different specialties about several treatment considerations. Evidence is scarce on how such concepts (10-point plan/BMG, ABS) are perceived among clinicians. Within the MR2 study (Multiinstitutional Reconnaissance of practice with MultiResistant bacteria - a survey focusing on German hospitals), a questionnaire including 4 + 35 items was sent to 18 German hospitals between August and October 2015, surveying internists, gynecologists, general surgeons, and urologists. Using multivariate logistic regression models (MLRM), the impact of medical specialty and further criteria on the endpoints (1) awareness of the 10-point plan/BMG and (2) knowledge of ABS measures were assessed. Fulfillment of endpoints was predefined when average or full knowledge was reported (reference: poor to no knowledge). Overall response rate was 43% (456/1061) for fully evaluable questionnaires. Only 63.0 and 53.6% of urologists and nonurologists (internists, gynecologists, and general surgeons), respectively, attended training courses regarding multidrug-resistance or antibiotic prescribing in the 12 months prior to the study (P = 0.045). The endpoints average and full knowledge regarding 10-point plan/BMG and ABS measures were fulfilled in only 31.4 and 32.8%, respectively. In MLRM, clinicians with at least one previous training course (reference: no training course) were 2.5- and 3.8-fold more likely to meet respective endpoint criteria (all P < 0.001). Medical specialty (urologists vs. nonurologists) did not significantly impact the endpoints in both MLRM. The 10-point plan/BMG and ABS programs should be implemented into clinical practice, but awareness and knowledge of both is insufficient. Thus, it stands to reason that the actual realization of such measures is inadequate and continuous training towards rational prescription of antibiotics is necessary, regardless of medical specialty.

Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy.

PubMed

Polydefkis, Michael; Arezzo, Joseph; Nash, Marshall; Bril, Vera; Shaibani, Aziz; Gordon, Robert J; Bradshaw, Kate L; Junor, Roderick W J

2015-12-01

We examined the efficacy and safety of ranirestat in patients with diabetic sensorimotor polyneuropathy (DSPN). Patients (18-75 years) with stable type 1/2 diabetes mellitus and DSPN were eligible for this global, double-blind, phase II/III study (ClinicalTrials.gov NCT00927914). Patients (n = 800) were randomized 1 : 1 : 1 to placebo, ranirestat 40 mg/day or 80 mg/day (265 : 264 : 271). Change in peroneal motor nerve conduction velocity (PMNCV) from baseline to 24 months was the primary endpoint with a goal improvement vs. placebo ≥1.2 m/s. Other endpoints included symptoms, quality-of-life, and safety. Six hundred thirty-three patients completed the study. The PMNCV difference from placebo was significant at 6, 12, and 18 months in both ranirestat groups, but <1.2 m/s. The mean improvement from baseline at 24 months was +0.49, +0.95, and +0.90 m/s for placebo, ranirestat 40 mg and 80 mg, respectively (NS). The treatment difference vs. placebo reached significance when ranirestat groups were combined in a post hoc analysis (+0.44 m/s; p = 0.0237). There was no effect of ranirestat on safety assessments, secondary or exploratory endpoints vs. placebo. Ranirestat was well tolerated and improved PMNCV, but did not achieve any efficacy endpoints. The absence of PMNCV worsening in the placebo group underscores the challenges of DSPN studies in patients with well-controlled diabetes. © 2015 Peripheral Nerve Society.

Adaptive servo-ventilation therapy for patients with chronic heart failure in a confirmatory, multicenter, randomized, controlled study.

PubMed

Momomura, Shin-Ichi; Seino, Yoshihiko; Kihara, Yasuki; Adachi, Hitoshi; Yasumura, Yoshio; Yokoyama, Hiroyuki; Wada, Hiroshi; Ise, Takayuki; Tanaka, Koichi

2015-01-01

Adaptive servo-ventilation (ASV) therapy is expected to be novel nonpharmacotherapy with hemodynamic effects on patients with chronic heart failure (CHF), but sufficient evidence has not been obtained. A 24-week, open-label, randomized, controlled study was performed to confirm the cardiac function-improving effect of ASV therapy on CHF patients. At 39 institutions, 213 outpatients with CHF, whose left ventricular ejection fraction (LVEF) was <40% and who had mild to severe symptoms [New York Heart Association (NYHA) class: ≥II], were enrolled. After excluding 8 patients, 102 and 103 underwent ASV plus guideline-directed medical therapy (GDMT) [ASV group] and GDMT only [control group], respectively. The primary endpoint was LVEF, and the secondary endpoints were HF deterioration, B-type natriuretic peptide (BNP), and clinical composite response (CCR: NYHA class+HF deterioration). LVEF and BNP improved significantly at completion against the baseline values in the 2 groups. However, no significant difference was found between these groups. HF deterioration tended to be suppressed. The ASV group showed a significant improvement in CCR corroborated by significant improvements in NYHA class and ADL against the control group. Under the present study's conditions, ASV therapy was not superior to GDMT in the cardiac function-improving effect but showed a clinical status-improving effect, thus indicating a given level of clinical benefit.

Use of Atorvastatin in Lipid Disorders and Cardiovascular Disease in Chinese Patients

PubMed Central

Ye, Yi-Cong; Zhao, Xi-Liang; Zhang, Shu-Yang

2015-01-01

Objective: Statins are still underused for the prevention of cardiovascular disease (CVD) in China. Hence, we conducted a systemic review on the pharmacology, clinical efficacy, and adverse events of atorvastatin, as well as on patient adherence. Data Sources: We conducted a systemic search in PubMed with the following keywords: “atorvastatin” (Supplementary concept) or “atorvastatin” (All field) and (“China” [AD] or “China” [all field] or “Chinese” [All field]). Study Selection: Clinical or basic research articles on atorvastatin were included. Results: Atorvastatin is a reversible and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, decreasing the de novo cholesterol synthesis. The pharmacokinetics of atorvastatin among Chinese is similar to those in Caucasians, and several gene polymorphisms have proved to be associated with the metabolism of atorvastatin in the Chinese population. Several international multiple-center randomized control trials have demonstrated the benefit of atorvastatin for primary and secondary prevention of CVD. None of them, however, included the Chinese, and current evidence in the population is still inadequate, due to the small sample size, low study quality, short study duration, and the use of surrogate endpoints instead of clinical endpoints. The overall incidence of adverse events observed with atorvastatin did not increase in the 10–80 mg dose range, and was similar to that observed with placebo and in patients treated with other statins, which makes atorvastatin well-tolerated in the Chinese population. Moreover, high patient adherence was observed in clinical studies. Conclusions: Based on the current available evidence, there is no significant difference between Chinese and non-Chinese population in term of pharmacology and clinical efficacy/safety. High-quality evidence is still needed to support the use of atorvastatin in high-risk Chinese population. PMID:25591572

Liraglutide 3.0 mg for weight management: weight-loss dependent and independent effects.

PubMed

Bays, Harold; Pi-Sunyer, Xavier; Hemmingsson, Joanna Uddén; Claudius, Birgitte; Jensen, Christine B; Van Gaal, Luc

2017-02-01

As an adjunct to a reduced-calorie diet and increased physical activity, treatment with liraglutide 3.0 mg for weight management provides a statistically significant and clinically meaningful weight loss of 5.7%-8.0% compared to 1.6%-2.6% with placebo. The objective of this post hoc analysis was to quantify the relative contribution of weight loss to the treatment effects of liraglutide 3.0 mg on key efficacy endpoints. The analysis utilized data from 4725 participants across three randomized, placebo-controlled, double-blind trials that evaluated the efficacy and safety of liraglutide 3.0 mg versus placebo, as an adjunct to a reduced-calorie diet and increased physical activity (ClinicalTrials.gov identifiers: NCT01272219, NCT01272232 and NCT01557166). The duration of two of the trials was 56 weeks; one trial was of 32 weeks' duration. A mediation analysis was performed, which ranked the relative contribution of weight loss to the treatment effects of liraglutide 3.0 mg on key cardiometabolic efficacy endpoints, Apnea-Hypopnea Index (AHI) and health-related quality of life (QoL). A limitation of this type of analysis is that it cannot conclusively prove a causal relationship. In individuals without type 2 diabetes mellitus (T2DM), endpoints predominantly driven by liraglutide-induced weight loss included waist circumference, diastolic blood pressure, triglycerides, high density lipoprotein cholesterol, AHI, and Impact of Weight on Quality of Life-Lite total and physical function scores. Endpoints predominantly independent of weight loss included the glycemic endpoints hemoglobin A1c and fasting plasma glucose in individuals with and without T2DM. Regardless of the degree of dependence on weight loss according to the mediation analysis, greater weight loss was associated with greater improvement in all endpoints. Treatment with liraglutide 3.0 mg contributes to improved cardiometabolic parameters, AHI and health-related QoL through both weight-loss dependent and weight-loss independent mechanisms.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.

PubMed

Lambertus, Stanley; Bax, Nathalie M; Fakin, Ana; Groenewoud, Joannes M M; Klevering, B Jeroen; Moore, Anthony T; Michaelides, Michel; Webster, Andrew R; van der Wilt, Gert Jan; Hoyng, Carel B

2017-01-01

Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

PubMed Central

Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

2017-01-01

Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders. PMID:28355279

Rasagiline: a review of its use in the treatment of idiopathic Parkinson's disease.

PubMed

Hoy, Sheridan M; Keating, Gillian M

2012-03-26

Rasagiline (Azilect®), a selective, irreversible, monoamine oxidase-B inhibitor, is available in the EU, the US and in several other countries worldwide, including Canada and Israel. It is indicated for the treatment of idiopathic Parkinson's disease as monotherapy or as adjunctive therapy to levodopa in patients [corrected]with end-of-dose fluctuations in the EU and for the treatment of adult patients with the signs and symptoms of idiopathic Parkinson's disease in the US. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of rasagiline as monotherapy or as adjunctive therapy to levodopa in patients with Parkinson's disease. Oral rasagiline as monotherapy or as adjunctive therapy to levodopa was effective in the symptomatic treatment of adult patients with Parkinson's disease participating in double-blind, placebo-controlled, multinational studies. In patients with early Parkinson's disease, monotherapy with rasagiline 1 mg/day (recommended dosage) significantly slowed the rate of worsening (i.e. an increase in the Unified Parkinson's Disease Rating Scale [UPDRS] score) in the ADAGIO and TEMPO studies, with the results from the ADAGIO study for rasagiline 1 mg/day suggesting a slowing of clinical progression. However, at the higher dosage of 2 mg/day, rasagiline met the primary endpoint in the TEMPO study and the first, but not the second, of three hierarchical primary endpoints in the ADAGIO study. Compared with delayed-start rasagiline monotherapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson's disease in the TEMPO study. As adjunctive therapy to levodopa in the LARGO and PRESTO studies, rasagiline 0.5 and/or 1 mg/day significantly reduced the total daily 'off' time (primary efficacy endpoint) and significantly improved the Clinical Global Impression score, the UPDRS activities of daily living subscale score during 'off' time and the UPDRS motor subscale score during 'on' time compared with placebo in patients with advanced Parkinson's disease. Although rasagiline showed neuroprotective properties both in vitro and in vivo, identifying its potential to slow clinical progression in the clinical setting has been elusive to date and was not definitively demonstrated in the studies discussed in this article. Additional rasagiline studies specifically designed to assess the clinical progression of Parkinson's disease while addressing the potentially confounding factors of the delayed-start study design would therefore be of interest. As monotherapy or as adjunctive therapy to levodopa, rasagiline was generally well tolerated, with the frequency and nature of treatment-emergent adverse events generally similar across clinical studies and between rasagiline and placebo groups. Therapy with rasagiline appears to be associated with a low incidence of cognitive and behavioural adverse events. Thus, oral rasagiline as monotherapy or as adjunctive therapy to levodopa provides a useful option in the treatment of adult patients with Parkinson's disease.

The Use of Surrogate Endpoints in Regulating Medicines for Cardio-Renal Disease: Opinions of Stakeholders

PubMed Central

Schievink, Bauke; Lambers Heerspink, Hiddo; Leufkens, Hubert; De Zeeuw, Dick; Hoekman, Jarno

2014-01-01

Aim There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. Methods We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Results Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Conclusion Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them. PMID:25268242

The use of surrogate endpoints in regulating medicines for cardio-renal disease: opinions of stakeholders.

PubMed

Schievink, Bauke; Lambers Heerspink, Hiddo; Leufkens, Hubert; De Zeeuw, Dick; Hoekman, Jarno

2014-01-01

There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them.

Clinical trials with multiple endpoints can establish a correlation, but not (yet) causality, between dietary supplementation with omega-3 fatty acids and keratoconjunctivitis sicca.

PubMed

Mendoza, Roger Lee

2018-06-13

We review clinical evidence of therapeutic efficacy and effectiveness of omega-3 fatty acids (omega-3s) in keratoconjunctivitis sicca, colloquially known as dry eye disease. In doing so, we identify relevant literature to address the following questions: (1) What definitive guidance can clinical evidence offer eye physicians and their patients? (2) What aspects of omega-3 supplementation lack definitive evidence, and how might economic assessments help? A targeted and systematic search strategy based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) was designed in this study for refereed clinical trials of omega-3s in dry eye treatment. Four key databases were accessed. Records were filtered through a three-step process using predetermined inclusion criteria. Data was extracted for experimental design, sample population characteristics, content of test and control groups, symptoms and associated opthalmologic conditions, diagnostic measures, patient health outcomes, adverse events, and model time horizon. A total of 219 records were initially identified, of which 21 prospective clinical trials, with a total of 2,973 participants, were admitted for review. Clinical evidence indicates that daily oral supplementation with omega-3s statistically correlates with dry eye treatment in the general symptomatic population as well as induced sub-populations. Reported adverse events are minimal. These trials nonetheless exhibit considerable heterogeneity in clinical endpoints, particularly as a result of the multi-factorial character of dry eye as well as continuous advances in scientific knowledge and technology. Their findings and recommendations appear to be of limited external validity. And causal inferences are needed, but difficult to establish. These have encouraged and sustained wide variations in ophthalmologic practice and normative decision-making. Comparability of omega-3 therapeutic efficacy and effectiveness remains a major challenge in dry eye disease management. Notwithstanding its multi-factorial character, addressing prevailing methodological and empirical issues in clinical trials will help reduce knowledge gaps and normative choices among eye physicians and patients alike. In this regard, pharmacoeconomics offers a useful and robust toolset through which analysis of cost-minimization, cost-effectiveness, and cost-utility as well as meta-analysis can be comparatively pursued. Blending measures of costs and outcomes puts in perspective the heterogeneity of clinical endpoints in keratoconjunctivitis sicca.

The Average Hazard Ratio - A Good Effect Measure for Time-to-event Endpoints when the Proportional Hazard Assumption is Violated?

PubMed

Rauch, Geraldine; Brannath, Werner; Brückner, Matthias; Kieser, Meinhard

2018-05-01

In many clinical trial applications, the endpoint of interest corresponds to a time-to-event endpoint. In this case, group differences are usually expressed by the hazard ratio. Group differences are commonly assessed by the logrank test, which is optimal under the proportional hazard assumption. However, there are many situations in which this assumption is violated. Especially in applications were a full population and several subgroups or a composite time-to-first-event endpoint and several components are considered, the proportional hazard assumption usually does not simultaneously hold true for all test problems under investigation. As an alternative effect measure, Kalbfleisch and Prentice proposed the so-called 'average hazard ratio'. The average hazard ratio is based on a flexible weighting function to modify the influence of time and has a meaningful interpretation even in the case of non-proportional hazards. Despite this favorable property, it is hardly ever used in practice, whereas the standard hazard ratio is commonly reported in clinical trials regardless of whether the proportional hazard assumption holds true or not. There exist two main approaches to construct corresponding estimators and tests for the average hazard ratio where the first relies on weighted Cox regression and the second on a simple plug-in estimator. The aim of this work is to give a systematic comparison of these two approaches and the standard logrank test for different time-toevent settings with proportional and nonproportional hazards and to illustrate the pros and cons in application. We conduct a systematic comparative study based on Monte-Carlo simulations and by a real clinical trial example. Our results suggest that the properties of the average hazard ratio depend on the underlying weighting function. The two approaches to construct estimators and related tests show very similar performance for adequately chosen weights. In general, the average hazard ratio defines a more valid effect measure than the standard hazard ratio under non-proportional hazards and the corresponding tests provide a power advantage over the common logrank test. As non-proportional hazards are often met in clinical practice and the average hazard ratio tests often outperform the common logrank test, this approach should be used more routinely in applications. Schattauer GmbH.

Clinicopathological Features to Predict Progression of IgA Nephropathy with Mild Proteinuria.

PubMed

Chen, Ding; Liu, Jian; Duan, Shuwei; Chen, Pu; Tang, Li; Zhang, Li; Feng, Zhe; Cai, Guangyan; Wu, Jie; Chen, Xiangmei

2018-03-06

In the past, little attention has been paid to patients with IgA nephropathy (IgAN) who had minimal proteinuria upon the onset. The aim of this study was to analyze the clinicopathological features and the prognostic factors in patients with IgA nephropathy. Data of patients that had their first renal biopsy in our hospital and were diagnosed with primary IgAN with proteinuria <1 g/d from January 1995 to December 2014 were retrospectively examined. Clinical records of the clinicopathological features, renal function, and proteinuria were collected and investigated. The factors affecting the renal function and proteinuria were analyzed by Cox regression. The predictive efficiencies of clinical and pathological models were evaluated by Harrell concordance index (C-index). A total of 506 patients with IgA nephropathy were included in this study. (1) Baseline proteinuria greater than 0.5 g/d was positively associated with Oxford M, S, and T lesions. eGFR less than 90 mL/min/1.73 m2 were positively associated with Oxford T. (2) In the follow-up with a median of 50 months, 82 patients (16.2%) achieved complete clinical remission (CCR), whereas 54 patients (10.6%) showed an increase in creatinine by more than 50% (not progressing to end-stage renal disease). The cumulative proportion of creatinine increased >50%, and the values obtained by life-table analysis in 10, 15, and 20 years were 15%, 21%, and 22%, respectively. Significant differences were found in baseline age, proteinuria, and Oxford T between the group of creatinine increase >50% and the CCR group. (4) Multivariate COX regression showed that baseline age and proteinuria > 0.5 g/d were independent risk factors of adverse outcome. C-index suggested that the clinical model was more effective than the pathological models in predicting endpoint events. (5) Effect of the mean value during the follow-up on adverse endpoint events: Multivariate COX regression found that the mean proteinuria during follow-up was an independent influencing factor for the increase of creatinine by more than 50%. (1) Proteinuria > 0.5g/d and eGFR < 90 mL/min/1.73 m2 may predict more severe pathological changes; (2) With the increase in age and baseline proteinuria, the risks of adverse endpoint events would increase significantly; (3) Pathology could roughly predict the adverse endpoint events but is less efficient than the clinical indicators; (4) Data during follow-up suggested that the patients should regularly test their renal function and proactively control their proteinuria. © 2018 The Author(s). Published by S. Karger AG, Basel.

Clinical progression of ocular injury following arsenical vesicant lewisite exposure.

PubMed

Tewari-Singh, Neera; Croutch, Claire R; Tuttle, Richard; Goswami, Dinesh G; Kant, Rama; Peters, Eric; Culley, Tara; Ammar, David A; Enzenauer, Robert W; Petrash, J Mark; Casillas, Robert P; Agarwal, Rajesh

2016-12-01

Ocular injury by lewisite (LEW), a potential chemical warfare and terrorist agent, results in edema of eyelids, inflammation, massive corneal necrosis and blindness. To enable screening of effective therapeutics to treat ocular injury from LEW, useful clinically-relevant endpoints are essential. Hence, we designed an efficient exposure system capable of exposing up to six New-Zealand white rabbits at one time, and assessed LEW vapor-induced progression of clinical ocular lesions mainly in the cornea. The right eye of each rabbit was exposed to LEW (0.2 mg/L) vapor for 2.5, 5.0, 7.5 and 10.0 min and clinical progression of injury was observed for 28 days post-exposure (dose-response study), or exposed to same LEW dose for 2.5 and 7.5 min and clinical progression of injury was observed for up to 56 days post-exposure (time-response study); left eye served as an unexposed control. Increasing LEW exposure caused corneal opacity within 6 h post-exposure, which increased up to 3 days, slightly reduced thereafter till 3 weeks, and again increased thereafter. LEW-induced corneal ulceration peaked at 1 day post-exposure and its increase thereafter was observed in phases. LEW exposure induced neovascularization starting at 7 days which peaked at 22-35 days post-exposure, and remained persistent thereafter. In addition, LEW exposure caused corneal thickness, iris redness, and redness and swelling of the conjunctiva. Together, these findings provide clinical sequelae of ocular injury following LEW exposure and for the first time establish clinically-relevant quantitative endpoints, to enable the further identification of histopathological and molecular events involved in LEW-induced ocular injury.

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.

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.

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.

Clinical efficacy and safety of an implantable cardioverter-defibrillator lead with a floating atrial sensing dipole.

PubMed

Safak, Erdal; Schmitz, Dietmar; Konorza, Thomas; Wende, Christian; De Ros, Jose Olague; Schirdewan, Alexander

2013-08-01

The concept of a single-lead implantable cardioverter-defibrillator (ICD), with a floating dipole, has been proven safe and functional. The studied active-fixation, steroid-eluting lead (Linox(smart) S DX, BIOTRONIK SE & Co KG, Berlin, Germany) is one French thinner than its predecessor and coated with lubricious SilGlide to improve lead handling. A dedicated ICD device has a self-adaptive atrial input stage including a fourfold amplifier. The amplification, filtering, and adapted atrial input stage are located in the Lumax 540 VR-T DX (BIOTRONIK). The Linox(smart) S DX ICD lead delivers only the signal. The lead was evaluated during implantation; at predischarge; and 1-, 3-, and 6-month follow-up examinations. The primary endpoint (efficacy) was the rate of appropriate atrial sensing tests. The secondary endpoint (safety) was freedom from lead-related invasive reinterventions. Both safety and efficacy were expected to be significantly higher than 90%. The study enrolled 116 patients at 25 clinical sites. Skin-to-skin operation time was 52.4 ± 26.2 minutes. The investigators graded lead insertion as "easy" in 87% of patients. Mean P-wave amplitudes (preamplified) varied from 5.0 to 6.1 mV in different body positions. Both primary and secondary endpoints were met, as 93.8% (364/388; P = 0.005) of specific sensing tests indicated appropriate atrial sensing, and 94.8% (110/116; P = 0.048) of patients were free from reinterventions (lead dislodgement). Analysis of arrhythmia episodes stored in ICDs and elective 24-hour Holter electrocardiogram tests raised no concerns about lead functionality. The studied ICD lead with a floating atrial sensing dipole met the predefined safety expectation and demonstrated appropriate atrial sensing performance. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.

Clinical and prognostic role of ammonia in advanced decompensated heart failure. The cardio-abdominal syndrome?

PubMed

Frea, Simone; Bovolo, Virginia; Pidello, Stefano; Canavosio, Federico G; Botta, Michela; Bergerone, Serena; Gaita, Fiorenzo

2015-09-15

Advanced heart failure is associated with end-organ damage. Recent literature suggested an intriguing crosstalk between failing heart, abdomen and kidneys. Venous ammonia, as a by-product of the gut, could be a marker of abdominal injury in heart failure patients. The aim of the study was to investigate the clinical and prognostic role of ammonia in patients with advanced decompensated heart failure (ADHF). 90 patients admitted with ADHF were prospectively studied. The prognostic role of ammonia at admission was evaluated. Primary end-points were: a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 3 months and need for renal replacement therapies (RRT). In the study cohort (age 59.0 ± 12.0 years, FE 21.6 ± 9.0%, INTERMACS profile 3.7 ± 0.9, creatinine 1.71 ± 0.95 mg/dl) 27 patients (30%) underwent the cardiac composite endpoint, while 9 patients (10%) needed RRT. At ROC curve analysis ammonia ≥ 130 μg/dl (abdominal damage) showed the best diagnostic accuracy. At multivariate analysis abdominal damage predicted the cardiac composite endpoint. Abdominal damage further increased risk among patient with cold profile at admission (HR 2.7, 95% CI 1.1-7.0, p = 0.046). At multivariate analysis abdominal damage also predicted need for RRT (OR 10.8, 95% CI 1.5-75.8, p = 0.017). The combined use of estimated right atrial pressure and ammonia showed the highest diagnostic accuracy and a very high specificity in prediction of need for RRT. In a selected population admitted for ADHF ammonia, as a marker of abdominal derangement, predicted adverse cardiac events and need for RRT. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effect of transcutaneous electrical stimulation treatment on lower urinary tract symptoms after class III radical hysterectomy in cervical cancer patients: study protocol for a multicentre, randomized controlled trial.

PubMed

Sun, Xiu-Li; Wang, Hai-Bo; Wang, Zhi-Qi; Cao, Ting-Ting; Yang, Xin; Han, Jing-Song; Wu, Yang-Feng; Reilly, Kathleen H; Wang, Jian-Liu

2017-06-15

Class III radical hysterectomy (RH III)_plus pelvic lymphadenectomy is the standard surgery for early stage cervical cancer (CC) patients, the 5 year survival rate is about 90%, but pelvic floor disorders especially bladder dysfunction are common due to damaged vessels and nerve fibers following surgery. Transcutaneous electrical stimulation (TENS) treatment has been used to treat bladder disorders for many years, but its effect on cervical cancer patients, the best treatment time point and stimulated protocol, had never been assessed. The aim of this study is to investigate the efficacy of TENS treatment on lower urinary tract symptoms (LUTS) after RH III in CC patients. The study will be conducted as a clinical, multicentre, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 208 participants (at 1:1 ratio, 104 subjects in each group). At 5-7 days after RH III, patients are screened according to operative and pathological findings. Enrolled participants are randomised into an intervention group (TENS plus conventional clinical care) or control group (conventional clinical care), with stratification by menopausal status (menopause vs. non-menopause) and surgical modality (laparoscopic RH or abdominal RH). Participants in both groups will be followed up at 14 days, 21 days, 28 days, 3 months, 6 months, 12 months, 18 months and 24 months after surgery. The primary endpoint is improvement rate of urination function which is defined as recovery (residual urine ≤50 ml) or improvement (residual urine 50-100 ml). Secondary endpoints include urodynamic parameter, urinary incontinence, anorectal function, pelvic function, quality of life (QOL), disease-free survival and adverse events. Primary endpoint analyses will be carried out by Cochran-Mantel-Haenszel tests taking into center effect. To our knowledge this is the first trial to investigate the effect of TENS treatment on bladder function recovery after RH III among CC patients. This study will provide new information on TENS efficacy for bladder function recovery. Once confirmed, it may help to provide a new, non-invisive treatment for those postoperative CC patients with poor pelvic function, which would help improve their quality of life. The study is registered to Clinical Trials.gov ( NCT02492542 ) on June 25, 2015.

Drug-Coated Balloon Treatment of Femoropopliteal Lesions for Patients With Intermittent Claudication and Ischemic Rest Pain: 2-Year Results From the IN.PACT Global Study.

PubMed

Micari, Antonio; Brodmann, Marianne; Keirse, Koen; Peeters, Patrick; Tepe, Gunnar; Frost, Martin; Wang, Hong; Zeller, Thomas

2018-05-28

The IN.PACT Global Study is the largest prospective, multicenter, independently adjudicated trial to evaluate a paclitaxel drug-coated balloon in patients with lifestyle-limiting claudication and/or ischemic rest pain due to atherosclerotic disease of the femoropopliteal artery and includes complex lesions beyond what are typically included in randomized controlled trials. Randomized controlled trials have demonstrated the safety and efficacy of drug-coated balloons for the treatment of Trans-Atlantic Inter-Society Consensus Document II A and B lesions, but there is a need for large-scale prospective studies to evaluate a broader range of lesions. The IN.PACT Global Study enrolled 1,535 subjects, and 1,406 (1,773 lesions) were included in the pre-defined clinical cohort analysis. Freedom from clinically driven target lesion revascularization was evaluated at 24 months. The safety composite endpoint was freedom from device- and procedure-related death through 30 days and freedom from target limb major amputation and clinically driven target vessel revascularization within 24 months. Mean lesion length was 12.1 cm, 35.5% were total occlusions, and 18.0% had in-stent restenosis. Freedom from clinically driven target lesion revascularization at 24 months was 83.3%, the composite safety endpoint was met in 81.7%, the 2-year all-cause mortality rate was 7.0%, and the major target limb amputation rate was 0.7%. Increased lesion length and the presence of de novo in-stent restenosis or coronary artery disease were associated with increased risk for clinically driven target lesion revascularization by 24 months. This real-world study of femoropopliteal artery disease treatment with drug-coated balloons confirmed positive findings reported from more strictly designed randomized controlled trials and showed that outcomes are durable in this population up to 2 years after treatment. (IN.PACT Global Clinical Study; NCT01609296). Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

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.

New antirheumatic drugs: any real added value? A critical overview of regulatory criteria for their marketing approval.

PubMed

Bertele', Vittorio; Assisi, Alessandro; Di Muzio, Valeria; Renzo, Danila; Garattini, Silvio

2007-09-01

Rheumatoid arthritis (RA) is a systemic autoimmune disorder causing chronic polyarticular synovial inflammation and progressive joint damage. New anti-rheumatic drugs, such as leflunomide, infliximab, etanercept, adalimumab and anakinra, have recently become available. The aim of this paper is to summarize and critically evaluate the type of studies and clinical endpoints accepted by the European Medicines Agency (EMEA) to approve these new drugs. Information regarding the approval of antirheumatic drugs was obtained from European Public Assessment Reports (EPARs) and published pivotal studies. Leflunomide is the only non-biological disease-modifying anti-rheumatic drug (DMARD) to receive recent approval for RA treatment, but strong evidence of its superiority over conventional therapies is lacking. Anakinra in combination with methotrexate received approval as a DMARD for RA on the basis of two pivotal trials in which American College of Rheumatology response criteria (ACR 20 response) were used as the sole primary endpoint. For easier demonstration of efficacy, studies leading to first approval of etanercept, infliximab and adalimumab were carried out on non-responders to DMARDs. Once on the market, these drugs gained an extension of the indication to methotrexate-naïve patients. Studies that provided the basis for approval were not adequately designed, given the lack of an active control and the choice of ACR response as the only clinical endpoint. Consequently, only a weak proof of efficacy emerged for the treatment of signs and symptoms of RA, and these drugs failed to show real benefit in slowing radiographic progression. Serious infections, changes in blood cell counts, severe skin and hepatic infections were the main adverse events that emerged from the clinical studies. Therefore, the unconvincing benefit of the new antirheumatic drugs can scarcely outweigh the risk associated with their use. Moreover, the monthly costs in Italy of the new biological preparations are several fold higher than those of the reference drugs. Recently approved anti-RA products should be a therapeutic option only for patients refractory to conventional drugs.

Rifaximin and eluxadoline - newly approved treatments for diarrhea-predominant irritable bowel syndrome: what is their role in clinical practice alongside alosetron?

PubMed

Cash, Brooks D; Lacy, Brian E; Rao, Tharaknath; Earnest, David L

2016-01-01

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal condition in which patients experience abdominal pain, diarrhea, bloating, cramps, flatulence, fecal urgency, and incontinence. We review two recently approved therapies that focus on treating underlying pathogenic mechanisms of IBS-D: (1) the non-absorbable antibiotic rifaximin, and (2) the opioid receptor agonist/antagonist eluxadoline. We compare the safety and efficacy data emerging from rifaximin and eluxadoline registration trials with safety and efficacy data from the alosetron clinical development program. The rifaximin and eluxadoline clinical development programs for IBS-D have demonstrated significant improvement in IBS-D endpoints compared to placebo. Direct comparison of primary endpoint results from the alosetron, rifaximin, and eluxadoline pivotal trials is not possible; however, general estimates of efficacy can be made, and these demonstrate similar and significantly greater responses to 'adequate relief' and a composite endpoint of abdominal pain/stool form for each agent compared to placebo. With the recent approval in the United States of rifaximin and eluxadoline for IBS-D, how should clinicians employ these agents? We suggest that they be utilized sequentially, taking into consideration patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles.

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).

Robenacoxib vs. carprofen for the treatment of canine osteoarthritis; a randomized, noninferiority clinical trial.

PubMed

Reymond, N; Speranza, C; Gruet, P; Seewald, W; King, J N

2012-04-01

Robenacoxib is a member of the coxib class of nonsteroidal anti-inflammatory drugs (NSAID), with high selectivity for the cyclooxygenase (COX)-2 isoform of COX. In this study, the efficacy and tolerability of robenacoxib were compared with those of carprofen in canine osteoarthritis in a multi-centre, prospective, randomized, blinded, positive-controlled noninferiority clinical trial. Both drugs were administered orally once daily at recommended dosages: robenacoxib at 1-2 mg/kg (n = 125 dogs) and racemic carprofen at 2-4 mg/kg (n = 63 dogs) for a total of 12 weeks. The efficacy of the test compounds was assessed by veterinary investigators and owners using numerical rating scales at baseline and days 7, 14, 28, 56 and 84. In both groups, all scores were significantly (P < 0.0001) improved compared with baseline at all time points (days 7-84). Robenacoxib had noninferior efficacy to carprofen for the primary endpoint, the global functional disability, both for all dogs and for the subgroup of dogs in which robenacoxib was not administered during meals. Noninferiority was also demonstrated for three of six veterinary investigator secondary endpoints and four of six owner efficacy endpoints. For haematology and clinical chemistry variables, there were some significant differences from baseline levels but no differences between groups. There were no differences between groups in the frequencies of adverse events, which were reported in 46% dogs with robenacoxib and 52% with carprofen (P = 0.44), which were most frequently mild events affecting the gastrointestinal tract. In conclusion, noninferior efficacy and tolerability of robenacoxib compared with carprofen was demonstrated in dogs with osteoarthritis. © 2011 Blackwell Publishing Ltd.

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.

Comparing and combining biomarkers as principle surrogates for time-to-event clinical endpoints.

PubMed

Gabriel, Erin E; Sachs, Michael C; Gilbert, Peter B

2015-02-10

Principal surrogate endpoints are useful as targets for phase I and II trials. In many recent trials, multiple post-randomization biomarkers are measured. However, few statistical methods exist for comparison of or combination of biomarkers as principal surrogates, and none of these methods to our knowledge utilize time-to-event clinical endpoint information. We propose a Weibull model extension of the semi-parametric estimated maximum likelihood method that allows for the inclusion of multiple biomarkers in the same risk model as multivariate candidate principal surrogates. We propose several methods for comparing candidate principal surrogates and evaluating multivariate principal surrogates. These include the time-dependent and surrogate-dependent true and false positive fraction, the time-dependent and the integrated standardized total gain, and the cumulative distribution function of the risk difference. We illustrate the operating characteristics of our proposed methods in simulations and outline how these statistics can be used to evaluate and compare candidate principal surrogates. We use these methods to investigate candidate surrogates in the Diabetes Control and Complications Trial. Copyright © 2014 John Wiley & Sons, Ltd.

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.

Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints.

PubMed

Macklin, Eric A; Blacker, Deborah; Hyman, Bradley T; Betensky, Rebecca A

2013-01-01

Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a "mid-risk" subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases.

Improved design of prodromal Alzheimer’s disease trials through cohort enrichment and surrogate endpoints

PubMed Central

Macklin, Eric A.; Blacker, Deborah; Hyman, Bradley T.; Betensky, Rebecca A.

2013-01-01

Summary Alzheimer’s disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: (1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and (2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n=358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n=6,243). To identify a “mid-risk” subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. PMID:23629586

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.

Assessment and treatment relevance in elderly glioblastoma patients

PubMed Central

Bauchet, Luc; Zouaoui, Sonia; Darlix, Amélie; Menjot de Champfleur, Nicolas; Ferreira, Ernestine; Fabbro, Michel; Kerr, Christine; Taillandier, Luc

2014-01-01

Glioblastoma (GBM) is the most common malignant primary brain tumor. Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and “standards of care” do not exist for GBM patients aged >70 years. We review epidemiology, tumor biology/molecular factors, prognostic factors (clinical, imaging data, therapeutics), and their assessments as well as classic and specific endpoints plus recent and ongoing clinical trials for elderly GBM patients. This work includes perspectives and personal opinions on this topic. Although there are no standards of care for elderly GBM patients, we can hypothesize that (i) Karnofsky performance status (KPS), probably after steroid treatment, is one of the most important clinical factors for determining our oncological strategy; (ii) resection is superior to biopsy, at least in selected patients (depending on location of the tumor and associated comorbidities); (iii) specific schedules of radiotherapy yield a modest but significant improvement; (iv) temozolomide has an acceptable tolerance, even when KPS <70, and could be proposed for methylated elderly GBM patients; and (v) the addition of concomitant temozolomide to radiotherapy has not yet been validated but shows promising results in some studies, yet the optimal schedule of radiotherapy remains to be determined. In the future, specific assessments (geriatric, imaging, biology) and use of new endpoints (quality of life and toxicity measures) will aid clinicians in determining the balance of potential benefits and risks of each oncological strategy. PMID:24792440

[Development of Peptide Vaccines for Triple-Negative Breast Cancer Treatment].

PubMed

Toh, Uhi; Saku, Shuko; Okabe, Mina; Iwakuma, Nobutaka; Kimitsuki, Yuko; Akashi, Momoko; Ogo, Etsuyo; Yamada, Akira; Shichijo, Shigeki; Itoh, Kyogo; Akagi, Yoshito

2016-10-01

Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open-label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated.

A prospective evaluation of a standardized strategy for the use of a polymeric everolimus-eluting bioresorbable scaffold in ST-segment elevation myocardial infarction: Rationale and design of the BVS STEMI STRATEGY-IT study.

PubMed

Ielasi, Alfonso; Varricchio, Attilio; Campo, Gianluca; Leoncini, Massimo; Cortese, Bernardo; Vicinelli, Paolo; Brugaletta, Salvatore; di Uccio, Fortunato Scotto; Latib, Azeem; Tespili, Maurizio

2017-06-01

To assess the feasibility and the clinical results following a prespecified bioresorbable vascular scaffold (Absorb BVS) implantation strategy in ST-elevation myocardial infarction (STEMI) patients. Concerns raised about the BVS safety in STEMI setting because a not negligible thrombosis rate was reported within 30 days and 12 months after implantation. Technical procedural issues related to the structural BVS features were advocated as probable causes for the thrombotic events. This is an investigators-owned and -directed, prospective, nonrandomized, single-arm multicenter registry intended to obtain data from 500 consecutive STEMI patients undergoing primary PCI with BVS (1.1 or GT1) following a prespecified implantation protocol. The study is recorded in ClinicalTrials.gov with the identifier: NCT02601781. The primary endpoint is a device-oriented composite end-point (DOCE) of cardiac death, any myocardial infarction clearly attributable to the intervention culprit vessel and ischemic-driven target lesion revascularization within 30 days after the index procedure. The DOCE will be assessed even at 6-month, 1-, 3-, and 5-year follow-up. This will be the first study investigating the feasibility and the early- and long-term clinical impact of a prespecified BVS implantation protocol in thrombotic lesions causing STEMI. Here, we describe the rationale and the design of the study. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Clinical significance of tumor necrosis factor-α inhibitors in the treatment of sciatica: a systematic review and meta-analysis.

PubMed

Wang, Yun Fu; Chen, Ping You; Chang, Wei; Zhu, Fi Qi; Xu, Li Li; Wang, Song Lin; Chang, Li Ying; Luo, Jie; Liu, Guang Jian

2014-01-01

Currently, no satisfactory treatment is available for sciatica caused by herniated discs and/or spinal stenosis. The objective of this study is to assess the value of tumor necrosis factor (TNF)-α inhibitors in the treatment of sciatica. Without language restrictions, we searched PubMed, OVID, EMBASE, the Web of Science, the Clinical Trials Registers, the Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. We then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria. Nine prospective randomized controlled trials (RCTs) and two before-after controlled trials involving 531 patients met our inclusion criteria and were included in this study. Our systematic assessment and meta-analysis demonstrated that in terms of the natural course of the disease, compared with the control condition, TNF-α inhibitors neither significantly relieved lower back and leg pain (both p > 0.05) nor enhanced the proportion of patients who felt overall satisfaction (global perceived effect (satisfaction)) or were able to return to work (return to work) (combined endpoint; p > 0.05) at the short-term, medium-term and long-term follow-ups. In addition, compared with the control condition, TNF-α inhibitors could reduce the risk ratio (RR) of discectomy or radicular block (combined endpoint; RR = 0.51, 95% CI 0.26 to 1.00, p = 0.049) at medium-term follow-up, but did not decrease RR at the short-term (RR = 0.64, 95% CI 0.17 to 2.40, p = 0.508) and long-term follow-ups (RR = 0.64, 95% CI 0.40 to 1.03, p = 0.065). The currently available evidence demonstrated that other than reducing the RR of discectomy or radicular block (combined endpoint) at medium-term follow-up, TNF-α inhibitors showed limited clinical value in the treatment of sciatica caused by herniated discs and/or spinal stenosis.

Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial

PubMed Central

McGarvey, Lorcan; Pavord, Ian D.; Higgins, Bernard; Chung, Kian Fan; Birring, Surinder S.

2017-01-01

Background To investigate the effect of BC1036 on health-related quality of life (QOL) in subjects with persistent cough. The secondary objective was to investigate the effect of BC1036 on subjective cough severity. Methods This was a randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 289 subjects with persistent cough. Subjects received BC1036 or placebo twice daily for 14 days. The primary endpoint comprised cough-related QOL assessed using the validated Leicester Cough Questionnaire (LCQ) at Day 14. Secondary endpoints comprised the LCQ scores at Day 7 and Day 28, cough severity VAS scores at each visit and pulmonary function tests. Results At baseline, mean total LCQ score in the BC1036 group was lower (i.e., worse QOL) than placebo (P<0.001), indicating significant between-group heterogeneity. Mean baseline-adjusted change in LCQ score at Day 14 was greater for BC1036 [mean (SD) 2.4±3.5] compared to placebo [mean (SD) score 2.2±3.0], but did not reach statistical significance (P=0.60). Mean cough severity VAS score decreased to a greater extent in the BC1036 group compared to placebo, but again the results were not statistically significant (−12.2±23.28 in BC1036 group and −11.0±21.34 in placebo group at Day 14, P=0.688). There was no significant change in pulmonary function measurements. The adverse event (AE) profile was similar in both groups. Conclusions This study showed that BC1036 was well tolerated and, although the primary endpoint did not achieve statistical significance, the magnitude of improvement was greater with BC1036 compared to placebo with respect to improving QOL and reducing cough severity. Clinical trial registration ClinicalTrials.gov: NCT01656668. PMID:28839984

The rationale and design of the Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study.

PubMed

Roberts, Matthew A; Pilmore, Helen L; Ierino, Francesco L; Badve, Sunil V; Cass, Alan; Garg, Amit X; Hawley, Carmel M; Isbel, Nicole M; Krum, Henry; Pascoe, Elaine M; Tonkin, Andrew M; Vergara, Liza A; Perkovic, Vlado

2015-03-01

The Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study aims to determine the feasibility of a large-scale randomized controlled trial with clinical endpoints comparing the beta-blocking agent carvedilol with placebo in patients receiving dialysis. The BLOCADE Feasibility Study is a randomized, double-blind, placebo-controlled, parallel group feasibility study comparing the beta-blocking agent carvedilol with placebo. Patients receiving dialysis for ≥3 months and who are aged ≥50 years, or who are ≥18 years and have diabetes or cardiovascular disease, were eligible. The primary outcome was the proportion of participants who complete a 6-week run-in phase in which all participants received carvedilol titrated from 3.125 mg twice daily to 6.25 mg twice daily. Other measures included how many patients are screened, the proportion recruited, the overall recruitment rate, the proportion of participants who remain on study drug for 12 months and the incidence of intra-dialytic hypotension while on randomized treatment. The BLOCADE Feasibility Study commenced recruiting in May 2011 and involves 11 sites in Australia and New Zealand. The BLOCADE Feasibility Study will inform the design of a larger clinical endpoint study to determine whether beta-blocking agents provide benefit to patients receiving dialysis, and define whether such a study is feasible. © 2014 Asian Pacific Society of Nephrology.

The role of imperfect surrogate endpoint information in drug approval and reimbursement decisions.

PubMed

Bognar, Katalin; Romley, John A; Bae, Jay P; Murray, James; Chou, Jacquelyn W; Lakdawalla, Darius N

2017-01-01

Approval of new drugs is increasingly reliant on "surrogate endpoints," which correlate with but imperfectly predict clinical benefits. Proponents argue surrogate endpoints allow for faster approval, but critics charge they provide inadequate evidence. We develop an economic framework that addresses the value of improvement in the predictive power, or "quality," of surrogate endpoints, and clarifies how quality can influence decisions by regulators, payers, and manufacturers. For example, the framework shows how lower-quality surrogates lead to greater misalignment of incentives between payers and regulators, resulting in more drugs that are approved for use but not covered by payers. Efficient price-negotiation in the marketplace can help align payer incentives for granting access based on surrogates. Higher-quality surrogates increase manufacturer profits and social surplus from early access to new drugs. Since the return on better quality is shared between manufacturers and payers, private incentives to invest in higher-quality surrogates are inefficiently low. Copyright © 2016 The Author(s). Published by Elsevier B.V. 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.

The First Cut Is the Deepest: The History and Development of Safe Treatments for Wound Healing and Tissue Repair.

PubMed

Hobson, David W; Schuh, JoAnn C L; Zurawski, Daniel V; Wang, Jianyong; Arbabi, Sam; McVean, Maralee; Funk, Kathleen A

2016-09-01

As the skin is the primary barrier to infection, the importance of wound healing has been understood since ancient times. This article provides a synopsis on the symposium presentations focusing on how wounds were traditionally treated, what models and pathology endpoints exist to study wound healing, special considerations for wound healing studies, an overview of regulatory aspects of new pharmaceutical and medical device development, and the clinical relevance of such models. The clinical treatment of small and large wounds is also considered. © The Author(s) 2016.

The value of telemonitoring and ICT-guided disease management in heart failure: Results from the IN TOUCH study.

PubMed

Kraai, Imke; de Vries, Arjen; Vermeulen, Karin; van Deursen, Vincent; van der Wal, Martje; de Jong, Richard; van Dijk, René; Jaarsma, Tiny; Hillege, Hans; Lesman, Ivonne

2016-01-01

It is still unclear whether telemonitoring reduces hospitalization and mortality in heart failure (HF) patients and whether adding an Information and Computing Technology-guided-disease-management-system (ICT-guided-DMS) improves clinical and patient reported outcomes or reduces healthcare costs. A multicenter randomized controlled trial was performed testing the effects of INnovative ICT-guided-DMS combined with Telemonitoring in OUtpatient clinics for Chronic HF patients (IN TOUCH) with in total 179 patients (mean age 69 years; 72% male; 77% in New York Heart Association Classification (NYHA) III-IV; mean left ventricular ejection fraction was 28%). Patients were randomized to ICT-guided-DMS or to ICT-guided-DMS+telemonitoring with a follow-up of nine months. The composite endpoint included mortality, HF-readmission and change in health-related quality of life (HR-QoL). In total 177 patients were eligible for analyses. The mean score of the primary composite endpoint was -0.63 in ICT-guided-DMS vs. -0.73 in ICT-guided-DMS+telemonitoring (mean difference 0.1, 95% CI: -0.67 +0.82, p=0.39). All-cause mortality in ICT-guided-DMS was 12% versus 15% in ICT-guided-DMS+telemonitoring (p=0.27); HF-readmission 28% vs. 27% p=0.87; all-cause readmission was 49% vs. 51% (p=0.78). HR-QoL improved in most patients and was equal in both groups. Incremental costs were €1360 in favor of ICT-guided-DMS. ICT-guided-DMS+telemonitoring had significantly fewer HF-outpatient-clinic visits (p<0.01). ICT-guided-DMS+telemonitoring for the management of HF patients did not affect the primary and secondary endpoints. However, we did find a reduction in visits to the HF-outpatient clinic in this group suggesting that telemonitoring might be safe to use in reorganizing HF-care with relatively low costs. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

A Pilot Study to Evaluate the Safety and Clinical Outcomes of Vaccination with Recombinant CEA-MUC-1-TRICOM (PANVAC) Poxviral-based Vaccines in Patients with Metastatic Carcinoma

PubMed Central

Gulley, James L.; Arlen, Philip M.; Tsang, Kwong-Yok; Yokokawa, Junko; Palena, Claudia; Poole, Diane J.; Remondo, Cinzia; Cereda, Vittore; Jones, Jacquin L.; Pazdur, Mary P.; Higgins, Jack P.; Hodge, James W.; Steinberg, Seth M.; Kotz, Herbert; Dahut, William L.; Schlom, Jeffrey

2009-01-01

Purpose: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary endpoint of this study was vaccine safety, with immunologic and clinical responses as secondary endpoints. Experimental Design: We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM, composed of B7.1, ICAM-1, and LFA-3) engineered into vaccinia (PANVAC-V) as a prime and fowlpox (PANVAC-F) as booster vaccinations. Results: The vaccine was well-tolerated. Apart from injection-site reaction, no grade II or greater toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccine in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of > 20% in the size of large liver metastasis. Conclusions: This vaccine strategy appears to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. PMID:18483372

Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

PubMed

Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

2016-12-01

Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

PubMed

Lassen, M R; Fisher, W; Mouret, P; Agnelli, G; George, D; Kakkar, A; Mismetti, P; Turpie, A G G

2012-05-01

Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles. © 2012 International Society on Thrombosis and Haemostasis.

A new proportion measure of the treatment effect captured by candidate surrogate endpoints.

PubMed

Kobayashi, Fumiaki; Kuroki, Manabu

2014-08-30

The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut-off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non-captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half-range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. Copyright © 2014 John Wiley & Sons, Ltd.

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.

Prospective, Multi-Centre, Single-Arm Study of Mechanical Thrombectomy using Solitaire FR in Acute Ischemic Stroke-STAR

PubMed Central

Pereira, Vitor M; Gralla, Jan; Davalos, Antoni; Bonafé, Alain; Castaño, Carlos; Chapot, Rene; Liebeskind, David S; Nogueira, Raul G; Arnold, Marcel; Sztajzel, Roman; Liebig, Thomas; Goyal, Mayank; Besselmann, Michael; Moreno, Alfredo; Schroth, Gerhard

2013-01-01

Background and Purpose Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire FR in patients with acute ischemic stroke. Methods STAR was an international, multicenter, prospective, single-arm study of Solitaire FR thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary endpoint was the revascularization rate (3TICI 2b) of the occluded vessel as determined by an independent core lab. The secondary endpoint was the rate of good functional outcome (defined as 90-day modified Rankin scale (mRS) 0–2). Results A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale (NIHSS) was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and/or procedure related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic. Conclusions In this single arm study, treatment with the Solitaire™ FR device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days. Clinical Trial Registration This study is registered with ClinicalTrials.gov, number NCT01327989. PMID:23908066

Empiric versus imaging guided left ventricular lead placement in cardiac resynchronization therapy (ImagingCRT): study protocol for a randomized controlled trial.

PubMed

Sommer, Anders; Kronborg, Mads Brix; Poulsen, Steen Hvitfeldt; Böttcher, Morten; Nørgaard, Bjarne Linde; Bouchelouche, Kirsten; Mortensen, Peter Thomas; Gerdes, Christian; Nielsen, Jens Cosedis

2013-04-26

Cardiac resynchronization therapy (CRT) is an established treatment in heart failure patients. However, a large proportion of patients remain nonresponsive to this pacing strategy. Left ventricular (LV) lead position is one of the main determinants of response to CRT. This study aims to clarify whether multimodality imaging guided LV lead placement improves clinical outcome after CRT. The ImagingCRT study is a prospective, randomized, patient- and assessor-blinded, two-armed trial. The study is designed to investigate the effect of imaging guided left ventricular lead positioning on a clinical composite primary endpoint comprising all-cause mortality, hospitalization for heart failure, or unchanged or worsened functional capacity (no improvement in New York Heart Association class and <10% improvement in six-minute-walk test). Imaging guided LV lead positioning is targeted to the latest activated non-scarred myocardial region by speckle tracking echocardiography, single-photon emission computed tomography, and cardiac computed tomography. Secondary endpoints include changes in LV dimensions, ejection fraction and dyssynchrony. A total of 192 patients are included in the study. Despite tremendous advances in knowledge with CRT, the proportion of patients not responding to this treatment has remained stable since the introduction of CRT. ImagingCRT is a prospective, randomized study assessing the clinical and echocardiographic effect of multimodality imaging guided LV lead placement in CRT. The results are expected to make an important contribution in the pursuit of increasing response rate to CRT. Clinicaltrials.gov identifier NCT01323686. The trial was registered March 25, 2011 and the first study subject was randomized April 11, 2011.

Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.

PubMed

Siddiqui, Mohammad Shadab; Harrison, Stephen A; Abdelmalek, Manal F; Anstee, Quentin M; Bedossa, Pierre; Castera, Laurent; Dimick-Santos, Lara; Friedman, Scott L; Greene, Katherine; Kleiner, David E; Megnien, Sophie; Neuschwander-Tetri, Brent A; Ratziu, Vlad; Schabel, Elmer; Miller, Veronica; Sanyal, Arun J

2018-05-01

Nonalcoholic steatohepatitis (NASH) is an important cause of liver-related morbidity and mortality. There are no approved therapies, and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized, particularly with respect to the contributions of underlying obesity, type 2 diabetes, and other comorbidities and the treatments provided for these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multistakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations, and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study. (Hepatology 2018;67:2001-2012). © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

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.

Vitamin K Nutrition, Metabolism, and Requirements: Current Concepts and Future Research12

PubMed Central

Shearer, Martin J.; Fu, Xueyan; Booth, Sarah L.

2012-01-01

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults. PMID:22516726

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.

Coriolis-force-induced trajectory and endpoint deviations in the reaching movements of labyrinthine-defective subjects

NASA Technical Reports Server (NTRS)

DiZio, P.; Lackner, J. R.

2001-01-01

When reaching movements are made during passive constant velocity body rotation, inertial Coriolis accelerations are generated that displace both movement paths and endpoints in their direction. These findings directly contradict equilibrium point theories of movement control. However, it has been argued that these movement errors relate to subjects sensing their body rotation through continuing vestibular activity and making corrective movements. In the present study, we evaluated the reaching movements of five labyrinthine-defective subjects (lacking both semicircular canal and otolith function) who cannot sense passive body rotation in the dark and five age-matched, normal control subjects. Each pointed 40 times in complete darkness to the location of a just extinguished visual target before, during, and after constant velocity rotation at 10 rpm in the center of a fully enclosed slow rotation room. All subjects, including the normal controls, always felt completely stationary when making their movements. During rotation, both groups initially showed large deviations of their movement paths and endpoints in the direction of the transient Coriolis forces generated by their movements. With additional per-rotation movements, both groups showed complete adaptation of movement curvature (restoration of straight-line reaches) during rotation. The labyrinthine-defective subjects, however, failed to regain fully accurate movement endpoints after 40 reaches, unlike the control subjects who did so within 11 reaches. Postrotation, both groups' movements initially had mirror image curvatures to their initial per-rotation reaches; the endpoint aftereffects were significantly different from prerotation baseline for the control subjects but not for the labyrinthine-defective subjects reflecting the smaller amount of endpoint adaptation they achieved during rotation. The labyrinthine-defective subjects' movements had significantly lower peak velocity, higher peak elevation, lower terminal velocity, and a more vertical touchdown than those of the control subjects. Thus the way their reaches terminated denied them the somatosensory contact cues necessary for full endpoint adaptation. These findings fully contradict equilibrium point theories of movement control. They emphasize the importance of contact cues in adaptive movement control and indicate that movement errors generated by Coriolis perturbations of limb movements reveal characteristics of motor planning and adaptation in both healthy and clinical populations.

Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G-CSF in Breast Cancer Patients.

PubMed

Li, Liang; Ma, Lian; Schrieber, Sarah J; Rahman, Nam Atiqur; Deisseroth, Albert; Farrell, Ann T; Wang, Yaning; Sinha, Vikram; Marathe, Anshu

2018-02-02

The aim of the study was to evaluate the quantitative relationship between duration of severe neutropenia (DSN, the efficacy endpoint) and area under effect curve of absolute neutrophil counts (ANC-AUEC, the pharmacodynamic endpoint), based on data from filgrastim products, a human granulocyte colony-stimulating factor (G-CSF). Clinical data from filgrastim product comparator and test arms of two randomized, parallel-group, phase III studies in breast cancer patients treated with myelosuppressive chemotherapy were utilized. A zero-inflated Poisson regression model best described the negative correlation between DSN and ANC-AUEC. The models predicted that with 10 × 10 9 day/L of increase in ANC-AUEC, the mean DSN would decrease from 1.1 days to 0.93 day in Trial 1 and from 1.2 days to 1.0 day in Trial 2. The findings of the analysis provide useful information regarding the relationship between ANC and DSN that can be used for dose selection and optimization of clinical trial design for G-CSF. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: analyses of data from clinical trials of duloxetine in pain disorders.

PubMed

Farrar, John T; Pritchett, Yili L; Robinson, Michael; Prakash, Apurva; Chappell, Amy

2010-02-01

Data on 1,700 patients pooled from 5 randomized, placebo-controlled duloxetine studies (3 in diabetic peripheral neuropathic pain and 2 in fibromyalgia) were analyzed to determine clinically important differences (CIDs) in the 0 to 10 Numeric Rating Scale-Pain Intensity (NRS-PI) for patient-reported "worst" and "least" pain intensity while validating the previously published level for "average" pain. The correspondence between the baseline-to-endpoint raw and percentage change in the NRS-PI for the worst, least, and average pain were compared to patients' perceived improvements at endpoint as measured by the 7-point Patient Global Impression of Improvement (PGI-I) scales. Stratification by baseline pain separated the raw but not the percent change scores. The PGI-I category of "much better" or above was our a priori definition of a CID. Cutoff points for the NRS-PI change scores were determined using a receiver operator curve analysis. A consistent relationship between the worst and average NRS-PI percent change and the PGI-I was demonstrated regardless of the study, pain type, age, sex, or treatment group with a reduction of approximately 34%. The least pain item CID was slightly higher at 41%. Raw change CID cutoff points were approximately -2, -2.5 and -3 for least, average, and worst pain respectively. We determined an anchor-based value for the change in the worst, least, and average pain intensity items of the Brief Pain Inventory that best represents a clinically important difference. Our findings support a standard definition of a clinically important difference in clinical trials of chronic-pain therapies. Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.