A web-based screening and accrual strategy for a cancer prevention clinical trial in healthy smokers

PubMed Central

Mohebati, Arash; Knutson, Allison; Zhou, Xi Kathy; Smith, Judith J.; Brown, Powel H.; Dannenberg, Andrew J.; Szabo, Eva

2012-01-01

Screening and recruitment of qualified subjects for clinical trials is an essential component of translational research, and it can be quite challenging if the most efficient recruitment method is not utilized. In this report, we describe a successful web-based screening and accrual method used in a randomized prospective chemoprevention clinical trial with urinary biomarker endpoints. The targeted study population was a group of at-risk healthy current smokers with no evidence of lung disease. Craigslist was used as the sole recruitment modality for this study. All interested subjects were directed to a pre-screening website, in which subject questionnaire responses were linked to the study coordinator's secure e-mail account. Of the 429 initial inquiries, 189 individuals were initially eligible based on the questionnaire response. One hundred twenty-two people were telephone-screened, of whom 98 subjects were consented, 84 were randomized and 77 subjects completed the study successfully. Utilizing this single web-based advertising strategy, accrual for the trial was completed 7 months prior to the projected date. Craigslist is a cost effective and efficient web-based resource that can be utilized in accruing subjects to some chemoprevention trials. PMID:22771576

Can the FDA improve oversight of foreign clinical trials?: Closing the information gap and moving towards a globalized regulatory scheme.

PubMed

Ourso, André

2012-01-01

Currently, pharmaceutical companies' utilization of foreign clinical trial data is a ubiquitous and indispensable aspect of gaining approval to market drugs in the United States. Cost benefits, a larger pool of ready volunteer subjects, and greater efficiency in clinical testing are some of the reasons for conducting clinical trials overseas. Despite these advantages, lack of proper oversight may have serious public health implications regarding the integrity of clinical research, ethical treatment of human subjects, and drug safety. Due to the expansive global nature of foreign clinical trials, there are concerns with the FDA's ability to monitor and regulate these trials. This article examines the FDA's oversight of foreign clinical trials and the agency's limitations regulating these trials. In addition to looking at steps the FDA is taking to address these limitations, the article examines other potential regulatory and cooperative actions that can be taken to effectively monitor foreign clinical trials and to ensure data integrity and patient safety.

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

Organizational structure and communication strategies of the bypass angioplasty revascularization investigation: a multicenter clinical trial.

PubMed

Naydeck, B L; Sutton-Tyrrell, K; Burek, K; Sopko, G S

1996-06-01

Efficient communication is a challenge for the many operating components of a multicenter randomized clinical trial. Traditional management theory states that communications generally flow along a path established by a hierarchical organizational structure. A multicenter clinical trial does not fit traditional organizational models well and requires modification of traditional communication techniques. While the scientific community typically views a clinical trial as one large and cohesive enterprise, at each site the trial may actually be conducted as a small project related to the medical specialty of the investigator. Therefore overall trial management must be accomplished through collaboration rather than through direct management. In the Bypass Angioplasty Revascularization Investigation (BARI), the BARI clinical coordinating center has designed and utilized several mechanisms that facilitate effective communication and administrative control of a multicenter clinical trial. These mechanisms provide a framework of communication techniques that accommodate the specific needs of a complex organization.

Changes in geographic variation in the use of percutaneous coronary intervention for stable ischemic heart disease after publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.

PubMed

Mohan, Arun V; Fazel, Reza; Huang, Pei-Hsiu; Shen, Yu-Chu; Howard, David

2014-01-01

Clinical uncertainty is cited as a cause of geographic variation. However, little is known about the effect of comparative effectiveness research on variation. We examined whether geographic variation in the use of percutaneous coronary intervention (PCI) for stable ischemic heart disease (SIHD) declined after publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. We examined changes in utilization and geographic variation in 67 hospital referral regions using the State Inpatient Databases. We compared age- and sex-adjusted rates of PCI for SIHD before (2006) and after (2008) publication of the COURAGE trial and compared those with contemporaneous changes in PCI volume for acute coronary syndrome. A total of 272,659 PCIs for SIHD from 526 hospitals were included in the analysis. After the publication of the COURAGE trial, PCI volume for SIHD declined by 25% (P<0.001) and decreased by 12% for acute coronary syndrome (P<0.001). This was predominantly attributable to changes in hospital referral regions with the highest levels of utilization pre-COURAGE trial (35% decline in the highest tertile versus 18% in the lowest). As measured by the systematic component of variation, there was substantial geographic variation in the use of PCI for SIHD preceding the publication of the COURAGE trial. Variation declined by 28% (0.53 versus 0.40) after publication, but geographic variation remained higher for SIHD than acute coronary syndrome (0.40 versus 0.17). There was a substantial decline in the use of and geographic variation in PCI for SIHD after the publication of the COURAGE trial. However, geographic variation in the use of PCI for SIHD remained high.

From ClinicalTrials.gov trial registry to an analysis-ready database of clinical trial results.

PubMed

Cepeda, M Soledad; Lobanov, Victor; Berlin, Jesse A

2013-04-01

The ClinicalTrials.gov web site provides a convenient interface to look up study results, but it does not allow downloading data in a format that can be readily used for quantitative analyses. To develop a system that automatically downloads study results from ClinicalTrials.gov and provides an interface to retrieve study results in a spreadsheet format ready for analysis. Sherlock(®) identifies studies by intervention, population, or outcome of interest and in seconds creates an analytic database of study results ready for analyses. The outcome classification algorithms used in Sherlock were validated against a classification by an expert. Having a database ready for analysis that can be updated automatically, dramatically extends the utility of the ClinicalTrials.gov trial registry. It increases the speed of comparative research, reduces the need for manual extraction of data, and permits answering a vast array of questions.

Behavioral aspects of clinical trials. An integrated framework from behavior theory.

PubMed

Morrow, G R; Hickok, J T; Burish, T G

1994-11-01

A less-than-optimal proportion of patients with cancer are entered into National Cancer Institute-sponsored clinical trials. This article reviews the literature on accrual in oncology clinical trials to characterize the extent of the problem, identify reasons for low accrual, and suggest ways to promote accrual. Four well known theories of health behavior (the Health Belief Model, Subjective Expected Utility Theory, Protection Motivation Theory, and the Theory of Reasoned Action) point to central concepts involved in understanding patient health-related behavior: (1) the probability that an unwelcomed health event will happen to a patient, (2) the severity of that event if it does occur, (3) the effectiveness of a particular behavior (such as taking part in a clinical trial) to modify the severity, and (4) the cost of adopting that behavior. These concepts form a framework for integrating the available information about accrual to clinical oncology trials. Patient and physician factors previously related to clinical trials suggest specific recommendations for increasing accrual to clinical oncology trials.

Development of a manualized protocol of massage therapy for clinical trials in osteoarthritis.

PubMed

Ali, Ather; Kahn, Janet; Rosenberger, Lisa; Perlman, Adam I

2012-10-04

Clinical trial design of manual therapies may be especially challenging as techniques are often individualized and practitioner-dependent. This paper describes our methods in creating a standardized Swedish massage protocol tailored to subjects with osteoarthritis of the knee while respectful of the individualized nature of massage therapy, as well as implementation of this protocol in two randomized clinical trials. The manualization process involved a collaborative process between methodologic and clinical experts, with the explicit goals of creating a reproducible semi-structured protocol for massage therapy, while allowing some latitude for therapists' clinical judgment and maintaining consistency with a prior pilot study. The manualized protocol addressed identical specified body regions with distinct 30- and 60-min protocols, using standard Swedish strokes. Each protocol specifies the time allocated to each body region. The manualized 30- and 60-min protocols were implemented in a dual-site 24-week randomized dose-finding trial in patients with osteoarthritis of the knee, and is currently being implemented in a three-site 52-week efficacy trial of manualized Swedish massage therapy. In the dose-finding study, therapists adhered to the protocols and significant treatment effects were demonstrated. The massage protocol was manualized, using standard techniques, and made flexible for individual practitioner and subject needs. The protocol has been applied in two randomized clinical trials. This manualized Swedish massage protocol has real-world utility and can be readily utilized both in the research and clinical settings. Clinicaltrials.gov NCT00970008 (18 August 2009).

Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials.

PubMed

Wolters, Pamela L; Martin, Staci; Merker, Vanessa L; Gardner, Kathy L; Hingtgen, Cynthia M; Tonsgard, James H; Schorry, Elizabeth K; Baldwin, Andrea

2013-11-19

Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity. The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process. Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages ≥ 8 years. The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials.

Drug-resistant tuberculosis clinical trials: proposed core research definitions in adults.

PubMed

Furin, J; Alirol, E; Allen, E; Fielding, K; Merle, C; Abubakar, I; Andersen, J; Davies, G; Dheda, K; Diacon, A; Dooley, K E; Dravnice, G; Eisenach, K; Everitt, D; Ferstenberg, D; Goolam-Mahomed, A; Grobusch, M P; Gupta, R; Harausz, E; Harrington, M; Horsburgh, C R; Lienhardt, C; McNeeley, D; Mitnick, C D; Nachman, S; Nahid, P; Nunn, A J; Phillips, P; Rodriguez, C; Shah, S; Wells, C; Thomas-Nyang'wa, B; du Cros, P

2016-03-01

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

Toward an information-motivation-behavioral skills model of microbicide adherence in clinical trials.

PubMed

Ferrer, Rebecca A; Morrow, Kathleen M; Fisher, William A; Fisher, Jeffrey D

2010-08-01

Unless optimal adherence in microbicide clinical trials is ensured, an efficacious microbicide may be rejected after trial completion, or development of a promising microbicide may be stopped, because low adherence rates create the illusion of poor efficacy. We provide a framework with which to conceptualize and improve microbicide adherence in clinical trials, supported by a critical review of the empirical literature. The information-motivation-behavioral skills (IMB) model of microbicide adherence conceptualizes microbicide adherence in clinical trials and highlights factors that can be addressed in behavioral interventions to increase adherence in such trials. This model asserts that microbicide adherence-related information, motivation, and behavioral skills are fundamental determinants of adherent microbicide utilization. Specifically, information consists of objective facts about microbicide use (e.g., administration and dosage) as well as heuristics that facilitate use (e.g., microbicides must be used with all partners). Motivation to adhere consists of attitudes toward personal use of microbicides (e.g., evaluating the consequences of using microbicides as good or pleasant) as well as social norms that support their use (e.g., beliefs that a sexual partner approves use of microbicides). Behavioral skills consist of objective skills necessary for microbicide adherence (e.g., the ability to apply the microbicide correctly and consistently). Empirical evidence concerning microbicide acceptability and adherence to spermicides, medication, and condom use regimens support the utility of this model for understanding and promoting microbicide adherence in clinical trials.

Divalproex Sodium for the Treatment of PTSD and Conduct Disordered Youth: A Pilot Randomized Controlled Clinical Trial

ERIC Educational Resources Information Center

Steiner, Hans; Saxena, Kirti S.; Carrion, Victor; Khanzode, Leena A.; Silverman, Melissa; Chang, Kiki

2007-01-01

We examined the efficacy of divalproex sodium (DVP) for the treatment of PTSD in conduct disorder, utilizing a previous study in which 71 youth were enrolled in a randomized controlled clinical trial. Twelve had PTSD. Subjects (all males, mean age 16, SD 1.0) were randomized into high and low dose conditions. Clinical Global Impression (CGI)…

Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients.

PubMed

Kim, Kelly Y; Le, Quynh-Thu; Yom, Sue S; Ng, Raymond H W; Chan, K C Allen; Bratman, Scott V; Welch, John J; Divi, Rao L; Petryshyn, Raymond A; Conley, Barbara A

2017-08-01

Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion. Published by Elsevier Inc.

Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials

PubMed Central

Martin, Staci; Merker, Vanessa L.; Gardner, Kathy L.; Hingtgen, Cynthia M.; Tonsgard, James H.; Schorry, Elizabeth K.; Baldwin, Andrea

2013-01-01

Objectives: Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity. Methods: The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process. Results: Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages ≥8 years. Conclusions: The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials. PMID:24249806

Protecting patient privacy when sharing patient-level data from clinical trials.

PubMed

Tucker, Katherine; Branson, Janice; Dilleen, Maria; Hollis, Sally; Loughlin, Paul; Nixon, Mark J; Williams, Zoë

2016-07-08

Greater transparency and, in particular, sharing of patient-level data for further scientific research is an increasingly important topic for the pharmaceutical industry and other organisations who sponsor and conduct clinical trials as well as generally in the interests of patients participating in studies. A concern remains, however, over how to appropriately prepare and share clinical trial data with third party researchers, whilst maintaining patient confidentiality. Clinical trial datasets contain very detailed information on each participant. Risk to patient privacy can be mitigated by data reduction techniques. However, retention of data utility is important in order to allow meaningful scientific research. In addition, for clinical trial data, an excessive application of such techniques may pose a public health risk if misleading results are produced. After considering existing guidance, this article makes recommendations with the aim of promoting an approach that balances data utility and privacy risk and is applicable across clinical trial data holders. Our key recommendations are as follows: 1. Data anonymisation/de-identification: Data holders are responsible for generating de-identified datasets which are intended to offer increased protection for patient privacy through masking or generalisation of direct and some indirect identifiers. 2. Controlled access to data, including use of a data sharing agreement: A legally binding data sharing agreement should be in place, including agreements not to download or further share data and not to attempt to seek to identify patients. Appropriate levels of security should be used for transferring data or providing access; one solution is use of a secure 'locked box' system which provides additional safeguards. This article provides recommendations on best practices to de-identify/anonymise clinical trial data for sharing with third-party researchers, as well as controlled access to data and data sharing agreements. The recommendations are applicable to all clinical trial data holders. Further work will be needed to identify and evaluate competing possibilities as regulations, attitudes to risk and technologies evolve.

RARtool: A MATLAB Software Package for Designing Response-Adaptive Randomized Clinical Trials with Time-to-Event Outcomes.

PubMed

Ryeznik, Yevgen; Sverdlov, Oleksandr; Wong, Weng Kee

2015-08-01

Response-adaptive randomization designs are becoming increasingly popular in clinical trial practice. In this paper, we present RARtool , a user interface software developed in MATLAB for designing response-adaptive randomized comparative clinical trials with censored time-to-event outcomes. The RARtool software can compute different types of optimal treatment allocation designs, and it can simulate response-adaptive randomization procedures targeting selected optimal allocations. Through simulations, an investigator can assess design characteristics under a variety of experimental scenarios and select the best procedure for practical implementation. We illustrate the utility of our RARtool software by redesigning a survival trial from the literature.

Applying Probabilistic Decision Models to Clinical Trial Design

PubMed Central

Smith, Wade P; Phillips, Mark H

2018-01-01

Clinical trial design most often focuses on a single or several related outcomes with corresponding calculations of statistical power. We consider a clinical trial to be a decision problem, often with competing outcomes. Using a current controversy in the treatment of HPV-positive head and neck cancer, we apply several different probabilistic methods to help define the range of outcomes given different possible trial designs. Our model incorporates the uncertainties in the disease process and treatment response and the inhomogeneities in the patient population. Instead of expected utility, we have used a Markov model to calculate quality adjusted life expectancy as a maximization objective. Monte Carlo simulations over realistic ranges of parameters are used to explore different trial scenarios given the possible ranges of parameters. This modeling approach can be used to better inform the initial trial design so that it will more likely achieve clinical relevance. PMID:29888075

The experience of older patients with cancer in phase 1 clinical trials: a qualitative case series.

PubMed

Kvale, Elizabeth A; Woodby, Lesa; Williams, Beverly Rosa

2010-11-01

This article explores the experiences of older patients with cancer in phase 1 clinical trials. Conducting a case series of face-to-face, in-depth, open-ended interviews and using qualitative methods of analysis, we find that the psychosocial process of social comparison is relevant for understanding older adults' phase 1 clinical trial participation. Social comparison influences decisions to enroll in a phase 1 clinical trial, shapes perceptions of supportive care needs, and encourages the utilization of hope. Additional research should develop strategies for addressing supportive care needs among this patient cohort whose use of social comparison can inhibit articulation of pain, suffering, and symptom burden as well as use of informal support systems.

Utility-based designs for randomized comparative trials with categorical outcomes

PubMed Central

Murray, Thomas A.; Thall, Peter F.; Yuan, Ying

2016-01-01

A general utility-based testing methodology for design and conduct of randomized comparative clinical trials with categorical outcomes is presented. Numerical utilities of all elementary events are elicited to quantify their desirabilities. These numerical values are used to map the categorical outcome probability vector of each treatment to a mean utility, which is used as a one-dimensional criterion for constructing comparative tests. Bayesian tests are presented, including fixed sample and group sequential procedures, assuming Dirichlet-multinomial models for the priors and likelihoods. Guidelines are provided for establishing priors, eliciting utilities, and specifying hypotheses. Efficient posterior computation is discussed, and algorithms are provided for jointly calibrating test cutoffs and sample size to control overall type I error and achieve specified power. Asymptotic approximations for the power curve are used to initialize the algorithms. The methodology is applied to re-design a completed trial that compared two chemotherapy regimens for chronic lymphocytic leukemia, in which an ordinal efficacy outcome was dichotomized and toxicity was ignored to construct the trial’s design. The Bayesian tests also are illustrated by several types of categorical outcomes arising in common clinical settings. Freely available computer software for implementation is provided. PMID:27189672

Clinical Trials of Precision Medicine through Molecular Profiling: Focus on Breast Cancer.

PubMed

Zardavas, Dimitrios; Piccart-Gebhart, Martine

2015-01-01

High-throughput technologies of molecular profiling in cancer, such as gene-expression profiling and next-generation sequencing, are expanding our knowledge of the molecular landscapes of several cancer types. This increasing knowledge coupled with the development of several molecularly targeted agents hold the promise for personalized cancer medicine to be fully realized. Moreover, an expanding armamentarium of targeted agents has been approved for the treatment of specific molecular cancer subgroups in different diagnoses. According to this paradigm, treatment selection should be dictated by the specific molecular aberrations found in each patient's tumor. The classical clinical trials paradigm of patients' eligibility being based on clinicopathologic parameters is being abandoned, with current clinical trials enrolling patients on the basis of specific molecular aberrations. New, innovative trial designs have been generated to better tackle the multiple challenges induced by the increasing molecular fragmentation of cancer, namely: (1) longitudinal cohort studies with or without downstream trials, (2) studies assessing the clinical utility of molecular profiling, (3) master or umbrella trials, (4) basket trials, (5) N-of-1 trials, and (6) adaptive design trials. This article provides an overview of the challenges for clinical trials in the era of molecular profiling of cancer. Subsequently, innovative trial designs with respective examples and their potential to expedite efficient clinical development of targeted anticancer agents is discussed.

An Update on Renal Artery Denervation and Its Clinical Impact on Hypertensive Disease

PubMed Central

Kuang, Ye Min; Gan, Gary C. H.; Burgess, David; Denniss, Alan Robert

2015-01-01

Hypertension is a globally prevalent condition, with a heavy clinical and economic burden. It is the predominant risk factor for premature cardiovascular and cerebrovascular disease, and is associated with a variety of clinical disorders including stroke, congestive cardiac failure, ischaemic heart disease, chronic renal failure, and peripheral arterial disease. A significant subset of hypertensive patients have resistant hypertensive disease. In this group of patients, catheter-based renal artery denervation has emerged as a potential therapy, with favourable clinical efficacy and safety in early trials. Additional benefits of this therapy are also being identified and include effects on left ventricular remodeling, cardiac performance, and symptom status in congestive cardiac failure. Utility of renal denervation for the management of resistant hypertension, however, has become controversial since the release of the Symplicity HTN-3 trial, the first large-scale blinded randomised study investigating the efficacy and safety of renal artery denervation. The aim of this paper is to evaluate the history, utility, and clinical efficacy of renal artery denervation technology, including an in-depth appraisal of the current literature and principal trials. PMID:26495305

Enrolling Minority and Underserved Populations in Cancer Clinical Research

PubMed Central

Wallington, Sherrie Flynt; Dash, Chiranjeev; Sheppard, Vanessa B.; Goode, Tawara D.; Oppong, Bridget A.; Dodson, Everett E.; Hamilton, Rhonda N.; Adams-Campbell, Lucile L.

2015-01-01

Research suggests that community involvement is integral to solving public health problems, including involvement in clinical trials—a “gold standard.” Significant racial/ethnic disparities exist in the accrual of participants for clinical trials. Location and cultural aspects of clinical trials influence recruitment and accrual to clinical trials. It is increasingly necessary to be aware of defining characteristics such as location and culture of the populations from which research participants are enrolled. Little research has examined the effect of location and cultural competency in adapting clinical trial research for minority and underserved communities on accrual for clinical trials. Utilizing embedded community academic sites, the authors applied cultural competency frameworks to adapt clinical trial research in order to increase minority participation in nontherapeutic cancer clinical trials. This strategy resulted in successful accrual of participants to new clinical research trials, specifically targeting participation from minority and underserved communities in metropolitan Washington, DC. From 2012 to 2014, a total of 559 participants enrolled across six non-therapeutic clinical trials, representing a 62% increase in the enrollment of blacks in clinical research. Embedding cancer prevention programs and research in the community was shown to be yet another important strategy in the arsenal of approaches that can potentially enhance clinical research enrollment and capacity. The analyses showed that the capacity to acquire cultural knowledge about patients—their physical locales, cultural values, and environments in which they live—is essential to recruiting culturally and ethnically diverse population samples. PMID:26470805

Preliminary Evidence on the Effectiveness of Psychological Treatments Delivered at a University Counseling Center

ERIC Educational Resources Information Center

Minami, Takuya; Davies, D. Robert; Tierney, Sandra Callen; Bettmann, Joanna E.; McAward, Scott M.; Averill, Lynnette A.; Huebner, Lois A.; Weitzman, Lauren M.; Benbrook, Amy R.; Serlin, Ronald C.; Wampold, Bruce E.

2009-01-01

Treatment data from a university counseling center (UCC) that utilized the Outcome Questionnaire-45.2 (OQ-45; M. J. Lambert et al., 2004), a self-report general clinical symptom measure, was compared against treatment efficacy benchmarks from clinical trials of adult major depression that utilized similar measures. Statistical analyses suggested…

Enrolling Minority and Underserved Populations in Cancer Clinical Research.

PubMed

Wallington, Sherrie F; Dash, Chiranjeev; Sheppard, Vanessa B; Goode, Tawara D; Oppong, Bridget A; Dodson, Everett E; Hamilton, Rhonda N; Adams-Campbell, Lucile L

2016-01-01

Research suggests that community involvement is integral to solving public health problems, including involvement in clinical trials-a gold standard. Significant racial/ethnic disparities exist in the accrual of participants for clinical trials. Location and cultural aspects of clinical trials influence recruitment and accrual to clinical trials. It is increasingly necessary to be aware of defining characteristics, such as location and culture of the populations from which research participants are enrolled. Little research has examined the effect of location and cultural competency in adapting clinical trial research for minority and underserved communities on accrual for clinical trials. Utilizing embedded community academic sites, the authors applied cultural competency frameworks to adapt clinical trial research in order to increase minority participation in nontherapeutic cancer clinical trials. This strategy resulted in successful accrual of participants to new clinical research trials, specifically targeting participation from minority and underserved communities in metropolitan Washington, DC. From 2012 to 2014, a total of 559 participants enrolled across six nontherapeutic clinical trials, representing a 62% increase in the enrollment of blacks in clinical research. Embedding cancer prevention programs and research in the community was shown to be yet another important strategy in the arsenal of approaches that can potentially enhance clinical research enrollment and capacity. The analyses showed that the capacity to acquire cultural knowledge about patients-their physical locales, cultural values, and environments in which they live-is essential to recruiting culturally and ethnically diverse population samples. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

OARSI Clinical Trials Recommendations: Soluble biomarker assessments in clinical trials in osteoarthritis.

PubMed

Kraus, V B; Blanco, F J; Englund, M; Henrotin, Y; Lohmander, L S; Losina, E; Önnerfjord, P; Persiani, S

2015-05-01

The objective of this work was to describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from both academia and industry, convened to discuss issues related to soluble biomarkers and to make recommendations for their use in OA clinical trials based on current knowledge and anticipated benefits. This document summarizes current guidance on use of biomarkers in OA clinical trials and their utility at five stages, including preclinical development and phase I to phase IV trials. As demonstrated by this summary, biomarkers can provide value at all stages of therapeutics development. When resources permit, we recommend collection of biospecimens in all OA clinical trials for a wide variety of reasons but in particular, to determine whether biomarkers are useful in identifying those individuals most likely to receive clinically important benefits from an intervention; and to determine whether biomarkers are useful for identifying individuals at earlier stages of OA in order to institute treatment at a time more amenable to disease modification. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Feasibility of feature-based indexing, clustering, and search of clinical trials: A case study of breast cancer trials from ClinicalTrials.gov

PubMed Central

Boland, Mary Regina; Miotto, Riccardo; Gao, Junfeng; Weng, Chunhua

2013-01-01

Summary Background When standard therapies fail, clinical trials provide experimental treatment opportunities for patients with drug-resistant illnesses or terminal diseases. Clinical Trials can also provide free treatment and education for individuals who otherwise may not have access to such care. To find relevant clinical trials, patients often search online; however, they often encounter a significant barrier due to the large number of trials and in-effective indexing methods for reducing the trial search space. Objectives This study explores the feasibility of feature-based indexing, clustering, and search of clinical trials and informs designs to automate these processes. Methods We decomposed 80 randomly selected stage III breast cancer clinical trials into a vector of eligibility features, which were organized into a hierarchy. We clustered trials based on their eligibility feature similarities. In a simulated search process, manually selected features were used to generate specific eligibility questions to filter trials iteratively. Results We extracted 1,437 distinct eligibility features and achieved an inter-rater agreement of 0.73 for feature extraction for 37 frequent features occurring in more than 20 trials. Using all the 1,437 features we stratified the 80 trials into six clusters containing trials recruiting similar patients by patient-characteristic features, five clusters by disease-characteristic features, and two clusters by mixed features. Most of the features were mapped to one or more Unified Medical Language System (UMLS) concepts, demonstrating the utility of named entity recognition prior to mapping with the UMLS for automatic feature extraction. Conclusions It is feasible to develop feature-based indexing and clustering methods for clinical trials to identify trials with similar target populations and to improve trial search efficiency. PMID:23666475

Feasibility of feature-based indexing, clustering, and search of clinical trials. A case study of breast cancer trials from ClinicalTrials.gov.

PubMed

Boland, M R; Miotto, R; Gao, J; Weng, C

2013-01-01

When standard therapies fail, clinical trials provide experimental treatment opportunities for patients with drug-resistant illnesses or terminal diseases. Clinical Trials can also provide free treatment and education for individuals who otherwise may not have access to such care. To find relevant clinical trials, patients often search online; however, they often encounter a significant barrier due to the large number of trials and in-effective indexing methods for reducing the trial search space. This study explores the feasibility of feature-based indexing, clustering, and search of clinical trials and informs designs to automate these processes. We decomposed 80 randomly selected stage III breast cancer clinical trials into a vector of eligibility features, which were organized into a hierarchy. We clustered trials based on their eligibility feature similarities. In a simulated search process, manually selected features were used to generate specific eligibility questions to filter trials iteratively. We extracted 1,437 distinct eligibility features and achieved an inter-rater agreement of 0.73 for feature extraction for 37 frequent features occurring in more than 20 trials. Using all the 1,437 features we stratified the 80 trials into six clusters containing trials recruiting similar patients by patient-characteristic features, five clusters by disease-characteristic features, and two clusters by mixed features. Most of the features were mapped to one or more Unified Medical Language System (UMLS) concepts, demonstrating the utility of named entity recognition prior to mapping with the UMLS for automatic feature extraction. It is feasible to develop feature-based indexing and clustering methods for clinical trials to identify trials with similar target populations and to improve trial search efficiency.

Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe.

PubMed

Blok, E J; Bastiaannet, E; van den Hout, W B; Liefers, G J; Smit, V T H B M; Kroep, J R; van de Velde, C J H

2018-01-01

Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Recommendations for Soluble Biomarker Assessments in Osteoarthritis Clinical Trials

PubMed Central

Kraus, Virginia Byers; Blanco, Francisco J; Englund, Martin; Henrotin, Yves; Lohmander, L Stefan; Losina, Elena; Önnerfjord, Patrik; Persiani, Stefano

2015-01-01

Objective To describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. Methods The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from both academia and industry, convened to discuss issues related to soluble biomarkers and to make recommendations for their use in OA clinical trials based on current knowledge and anticipated benefits. Results This document summarizes current guidance on use of biomarkers in OA clinical trials and their utility at 5 stages, including preclinical development and phase I to phase IV trials. Conclusions Biomarkers can provide value at all stages of therapeutics development. When resources permit, we recommend collection of biospecimens in all OA clinical trials for a wide variety of reasons but in particular, to determine whether biomarkers are useful in identifying those individuals most likely to receive clinically important benefits from an intervention; and to determine whether biomarkers are useful for identifying individuals at earlier stages of OA in order to institute treatment at a time more amenable to disease modification. PMID:25952342

How redesigning AD clinical trials might increase study partners’ willingness to participate

PubMed Central

Karlawish, Jason; Cary, Mark S.; Rubright, Jonathan; TenHave, Tom

2008-01-01

Background: Timely recruiting and retaining participants into Alzheimer disease (AD) clinical trials is a challenge. We used conjoint analysis to identify how alterations in attributes of clinical trial design improve willingness to participate: risk, home visits, car service, or increased chance of receiving intervention. Method: A total of 108 study partners of patients with very mild to severe stage AD rated willingness to allow their relative to participate in eight clinical trials that varied combinations of the four attributes. Results: The highest utility was for home visits (0.89) which essentially compensated for the disutility of high risk (−0.85). The combination of home visits and car service was redundant, with almost no increase in utility over home visits alone. Seventeen percent were willing to participate in a trial with no amenities; the addition of home visits increased predicted willingness to participate to 27%; low risk, home visits, and higher chance of active treatment increased predicted willingness to 60%. The value of reducing the hassles of travel correlated well with measures of AD severity (activities of daily living r = 0.41, p < 0.001; basic activities of daily living r = 0.38, p < 0.001; Neuropsychiatric Inventory severity p = 0.24, p = 0.01; Neuropsychiatric Inventory distress r = 0.23, p < 0.02). No association was found between degree of study partner burden and willingness to tolerate risk of an intervention. Conclusion: Clinical trials that reduce travel inconvenience may offset the disincentive of study features such as the risk of intervention and may also increase willingness to participate. Redesigning trials may also help recruit patients with more severe Alzheimer disease. Shorter recruitment periods and increased retention rates may offset costs of these changes. GLOSSARY AD = Alzheimer disease; BLUP = best linear unbiased prediction; RAQ = Research Attitude Questionnaire. PMID:19047560

How redesigning AD clinical trials might increase study partners' willingness to participate.

PubMed

Karlawish, Jason; Cary, Mark S; Rubright, Jonathan; Tenhave, Tom

2008-12-02

Timely recruiting and retaining participants into Alzheimer disease (AD) clinical trials is a challenge. We used conjoint analysis to identify how alterations in attributes of clinical trial design improve willingness to participate: risk, home visits, car service, or increased chance of receiving intervention. A total of 108 study partners of patients with very mild to severe stage AD rated willingness to allow their relative to participate in eight clinical trials that varied combinations of the four attributes. The highest utility was for home visits (0.89) which essentially compensated for the disutility of high risk (-0.85). The combination of home visits and car service was redundant, with almost no increase in utility over home visits alone. Seventeen percent were willing to participate in a trial with no amenities; the addition of home visits increased predicted willingness to participate to 27%; low risk, home visits, and higher chance of active treatment increased predicted willingness to 60%. The value of reducing the hassles of travel correlated well with measures of AD severity (activities of daily living r = 0.41, p < 0.001; basic activities of daily living r = 0.38, p < 0.001; Neuropsychiatric Inventory severity p = 0.24, p = 0.01; Neuropsychiatric Inventory distress r = 0.23, p < 0.02). No association was found between degree of study partner burden and willingness to tolerate risk of an intervention. Clinical trials that reduce travel inconvenience may offset the disincentive of study features such as the risk of intervention and may also increase willingness to participate. Redesigning trials may also help recruit patients with more severe Alzheimer disease. Shorter recruitment periods and increased retention rates may offset costs of these changes.

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.

Does information from ClinicalTrials.gov increase transparency and reduce bias? Results from a five-report case series.

PubMed

Adam, Gaelen P; Springs, Stacey; Trikalinos, Thomas; Williams, John W; Eaton, Jennifer L; Von Isenburg, Megan; Gierisch, Jennifer M; Wilson, Lisa M; Robinson, Karen A; Viswanathan, Meera; Middleton, Jennifer Cook; Forman-Hoffman, Valerie L; Berliner, Elise; Kaplan, Robert M

2018-04-16

We investigated whether information in ClinicalTrials.gov would impact the conclusions of five ongoing systematic reviews. We considered five reviews that included 495 studies total. Each review team conducted a search of ClinicalTrials.gov up to the date of the review's last literature search, screened the records using the review's eligibility criteria, extracted information, and assessed risk of bias and applicability. Each team then evaluated the impact of the evidence found in ClinicalTrials.gov on the conclusions in the review. Across the five reviews, the number of studies that had both a registry record and a publication varied widely, from none in one review to 43% of all studies identified in another. Among the studies with both a record and publication, there was also wide variability in the match between published outcomes and those listed in ClinicalTrials.gov. Of the 173 total ClinicalTrials.gov records identified across the five projects, between 11 and 43% did not have an associated publication. In the 14% of records that contained results, the new data provided in the ClinicalTrials.gov records did not change the results or conclusions of the reviews. Finally, a large number of published studies were not registered in ClinicalTrials.gov, but many of these were published before ClinicalTrials.gov's inception date of 2000. Improved prospective registration of trials and consistent reporting of results in ClinicalTrials.gov would help make ClinicalTrials.gov records more useful in finding unpublished information and identifying potential biases. In addition, consistent indexing in databases, such as MEDLINE, would allow for better matching of records and publications, leading to increased utility of these searches for systematic review projects.

ClinicalTrials.gov as a data source for semi-automated point-of-care trial eligibility screening.

PubMed

Pfiffner, Pascal B; Oh, JiWon; Miller, Timothy A; Mandl, Kenneth D

2014-01-01

Implementing semi-automated processes to efficiently match patients to clinical trials at the point of care requires both detailed patient data and authoritative information about open studies. To evaluate the utility of the ClinicalTrials.gov registry as a data source for semi-automated trial eligibility screening. Eligibility criteria and metadata for 437 trials open for recruitment in four different clinical domains were identified in ClinicalTrials.gov. Trials were evaluated for up to date recruitment status and eligibility criteria were evaluated for obstacles to automated interpretation. Finally, phone or email outreach to coordinators at a subset of the trials was made to assess the accuracy of contact details and recruitment status. 24% (104 of 437) of trials declaring on open recruitment status list a study completion date in the past, indicating out of date records. Substantial barriers to automated eligibility interpretation in free form text are present in 81% to up to 94% of all trials. We were unable to contact coordinators at 31% (45 of 146) of the trials in the subset, either by phone or by email. Only 53% (74 of 146) would confirm that they were still recruiting patients. Because ClinicalTrials.gov has entries on most US and many international trials, the registry could be repurposed as a comprehensive trial matching data source. Semi-automated point of care recruitment would be facilitated by matching the registry's eligibility criteria against clinical data from electronic health records. But the current entries fall short. Ultimately, improved techniques in natural language processing will facilitate semi-automated complex matching. As immediate next steps, we recommend augmenting ClinicalTrials.gov data entry forms to capture key eligibility criteria in a simple, structured format.

Using information technology to improve the quality and efficiency of clinical trial research in academic medical centers.

PubMed

Hardison, C D; Schnetzer, T

1999-01-01

In the area of clinical trial research, academic medical centers (AMCs) need to create additional capacity and improve performance on vital indicators to attract more studies, as they are currently losing their share to stand-alone research sites. Through the utilization of information technology, AMCs will be in a better position to fend off the competitive threats to their clinical research dollars. Most AMCs are in an enviable position to leverage the value of information technology because of the existing people, processes, and technologies that probably already exist throughout the AMC. The challenge, then, is to deploy these resources in a different manner to support clinical trial research.

The application of disease management to clinical trial designs.

PubMed

Puterman, Jared; Alter, David A

2009-08-01

The utilization of disease management (DM) as a minimum standard of care is believed to facilitate pronounced benefits in overall patient outcome and cost management. Randomized clinical trials remain the gold standard evaluative tool in clinical medicine. However, the extent to which contemporary cardiovascular clinical trials incorporate DM components into their treatment or control arms is unknown. Our study is the first to evaluate the extent to which clinical trials incorporate DM as a minimum standard of care for both the intervention and control groups. In total, 386 clinical trials published in 3 leading medical journals between 2003 and 2006 were evaluated. For each study, elements related to DM care, as defined using the American Heart Association Taxonomy, were abstracted and characterized. Our results demonstrate that while the application of DM has increased over time, only 3.4% of the clinical trials examined incorporated all 8 DM elements (and only 11% of such trials incorporated 4 DM elements). A significant association was found between study year and the inclusion of more than 3 elements of DM (chi(2) = 10.10 (3); p = 0.018). In addition, associations were found between study objective and DM criteria, as well as between cohort type and domains described. Our study serves as a baseline reference for the tracking of DM within, and its application to, randomized clinical trials. Moreover, our results underscore the need for broader implementation and evaluation of DM as a minimum care standard within clinical trial research.

The utility of Bayesian predictive probabilities for interim monitoring of clinical trials

PubMed Central

Connor, Jason T.; Ayers, Gregory D; Alvarez, JoAnn

2014-01-01

Background Bayesian predictive probabilities can be used for interim monitoring of clinical trials to estimate the probability of observing a statistically significant treatment effect if the trial were to continue to its predefined maximum sample size. Purpose We explore settings in which Bayesian predictive probabilities are advantageous for interim monitoring compared to Bayesian posterior probabilities, p-values, conditional power, or group sequential methods. Results For interim analyses that address prediction hypotheses, such as futility monitoring and efficacy monitoring with lagged outcomes, only predictive probabilities properly account for the amount of data remaining to be observed in a clinical trial and have the flexibility to incorporate additional information via auxiliary variables. Limitations Computational burdens limit the feasibility of predictive probabilities in many clinical trial settings. The specification of prior distributions brings additional challenges for regulatory approval. Conclusions The use of Bayesian predictive probabilities enables the choice of logical interim stopping rules that closely align with the clinical decision making process. PMID:24872363

Controlled trials to improve antibiotic utilization: a systematic review of experience, 1984-2004.

PubMed

Parrino, Thomas A

2005-02-01

To review the effectiveness of interventions designed to improve antibiotic prescribing patterns in clinical practice and to draw inferences about the most practical methods for optimizing antibiotic utilization in hospital and ambulatory settings. A literature search using online databases for the years 1975-2004 identified controlled trials of strategies for improving antibiotic utilization. Due to variation in study settings and design, quantitative meta-analysis was not feasible. Therefore, a qualitative literature review was conducted. Forty-one controlled trials met the search criteria. Interventions consisted of education, peer review and feedback, physician participation, rewards and penalties, administrative methods, and combined approaches. Social marketing directed at patients and prescribers was effective in varying contexts, as was implementation of practice guidelines. Authorization systems with structured order entry, formulary restriction, and mandatory consultation were also effective. Peer review and feedback were more effective when combined with dissemination of relevant information or social marketing than when used alone. Several practices were effective in improving antibiotic utilization: social marketing, practice guidelines, authorization systems, and peer review and feedback. Online systems providing clinical information, structured order entry, and decision support may be the most promising approach. Further studies, including economic analyses, are needed to confirm or refute this hypothesis.

Assessing cognitive function in clinical trials: latest developments and future directions.

PubMed

Wesnes, Keith

2002-01-01

Properly developed automated test systems are of value for assessing changes in cognitive function in clinical trials. Besides the other advantages that automation brings to trials, such as increased reliability and utility, it is shown that such systems are also more sensitive to change in cognitive function than traditional nonautomated procedures. Data from a variety of topical areas in drug development are presented to illustrate the added value such techniques have brought. The latest developments in automation include remote testing via the Internet and telephone.

The Strategies to Homogenize PET/CT Metrics: The Case of Onco-Haematological Clinical Trials

PubMed Central

Chauvie, Stephane; Bergesio, Fabrizio

2016-01-01

Positron emission tomography (PET) has been a widely used tool in oncology for staging lymphomas for a long time. Recently, several large clinical trials demonstrated its utility in therapy management during treatment, paving the way to personalized medicine. In doing so, the traditional way of reporting PET based on the extent of disease has been complemented by a discrete scale that takes in account tumour metabolism. However, due to several technical, physical and biological limitations in the use of PET uptake as a biomarker, stringent rules have been used in clinical trials to reduce the errors in its evaluation. Within this manuscript we will describe shortly the evolution in PET reporting, examine the main errors in uptake measurement, and analyse which strategy the clinical trials applied to reduce them. PMID:28536393

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

“Entering a Clinical Trial: Is it Right For You?"-- A Randomized Study of The Clinical Trials Video and Its Impact on the Informed Consent Process

PubMed Central

Hoffner, Brianna; Bauer-Wu, Susan; Hitchcock-Bryan, Suzanne; Powell, Mark; Wolanski, Andrew; Joffe, Steven

2011-01-01

PURPOSE This randomized study was designed to assess the utility of an educational video in preparing cancer patients for decisions about clinical trial participation. The study assessed the effect of the video on patients’ understanding and perceptions of clinical trials, its impact on decision making and patient-provider communication, and patients’ satisfaction with the video. METHODS Ninety adults considering cancer clinical trials were randomized to receive (n=45) or not receive (n=45) the video. Using the validated Quality of Informed Consent (QuIC), respondents’ knowledge about clinical trial participation was assessed. All subjects completed additional questions about satisfaction with the video, decision making, and patient-provider communication. Data were analyzed using the Wilcoxon rank-sum test, regression model and descriptive statistics. RESULTS Although intent-to-treat analysis found no significant group differences in objective understanding between those randomized to view or not view the video, the majority of participants reported favorable experiences with regard to watching the video: 85% found the video was an important source of information about clinical trials; 81% felt better prepared to discuss the trial with their physician; 89% of those who watched the video with family indicated that it helped family better understand clinical trials; and 73% indicated it helped family accept their decision about participation. CONCLUSIONS Although the video did not measurably improve patients’ knowledge about clinical trials, it was an important source of information, helped educate families, and enhanced patient communication with their oncology providers. PMID:22009665

The use of the sexual function questionnaire as a screening tool for women with sexual dysfunction.

PubMed

Quirk, Frances; Haughie, Scott; Symonds, Tara

2005-07-01

To determine if the validated Sexual Function Questionnaire (SFQ), developed to assess efficacy in female sexual dysfunction (FSD) clinical trials, may also have utility in identifying target populations for such studies. Data from five clinical trials and two general population surveys were used to analyze the utility of the SFQ as a tool to discriminate between the presence of specific components of FSD (i.e., hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and dyspareunia). Sensitivity/specificity analysis and logistic regression analysis, using data from all five clinical studies and the general population surveys, confirmed that the SFQ domains have utility in detecting the presence of specific components of FSD and provide scores indicative of the presence of a specific sexual disorder. The SFQ is a valuable new tool for detecting the presence of FSD and identifying the specific components of sexual functions affected (desire, arousal, orgasm, or dyspareunia).

Enhancing clinical evidence by proactively building quality into clinical trials.

PubMed

Meeker-O'Connell, Ann; Glessner, Coleen; Behm, Mark; Mulinde, Jean; Roach, Nancy; Sweeney, Fergus; Tenaerts, Pamela; Landray, Martin J

2016-08-01

Stakeholders across the clinical trial enterprise have expressed concern that the current clinical trial enterprise is unsustainable. The cost and complexity of trials have continued to increase, threatening our ability to generate reliable evidence essential for making appropriate decisions concerning the benefits and harms associated with clinical interventions. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight. The Clinical Trials Transformation Initiative convened a project to evaluate methods to prospectively build quality into the scientific and operational design of clinical trials ("quality-by-design"), such that trials are feasible to conduct and important errors are prevented rather than remediated. A working group evaluated aspects of trial design and oversight and developed the Clinical Trials Transformation Initiative quality-by-design principles document, outlining a series of factors generally relevant to the reliability of trial conclusions and to patient safety. These principles were then applied and further refined during a series of hands-on workshops to evaluate their utility in facilitating proactive, cross-functional dialogue, and decision-making about trial design and planning. Following these workshops, independent qualitative interviews were conducted with 19 workshop attendees to explore the potential challenges for implementing a quality-by-design approach to clinical trials. The Clinical Trials Transformation Initiative project team subsequently developed recommendations and an online resource guide to support implementation of this approach. The Clinical Trials Transformation Initiative quality-by-design principles provide a framework for assuring that clinical trials adequately safeguard participants and provide reliable information on which to make decisions on the effects of treatments. The quality-by-design workshops highlighted the value of active discussions incorporating the different perspectives within and external to an organization (e.g. clinical investigators, research site staff, and trial participants) in improving trial design. Workshop participants also recognized the value of focusing oversight on those aspects of the trial where errors would have a major impact on participant safety and reliability of results. Applying the Clinical Trials Transformation Initiative quality-by-design recommendations and principles should enable organizations to prioritize the most critical determinants of a trial's quality, identify non-essential activities that can be eliminated to streamline trial conduct and oversight, and formulate appropriate plans to define, avoid, mitigate, monitor, and address important errors. © The Author(s) 2016.

Prospective registration of clinical trials in India: strategies, achievements & challenges.

PubMed

Tharyan, Prathap

2009-02-01

This paper traces the development of the Clinical Trial Registry-India (CTRI) against the backdrop of the inequities in healthcare and the limitations in the design, conduct, regulation, oversight and reporting of clinical trials in India. It describes the scope and goals of the CTRI, the data elements it seeks and the process of registering clinical trials. It reports progress in trial registration in India and discusses the challenges in ensuring that healthcare decisions are informed by all the evidence. A descriptive survey of developments in clinical trial registration in India from publications in the Indian medical literature supplemented by first hand knowledge of these developments and an evaluation of how well clinical trials registered in the CTRI up to 10 January, 2009 comply with the requirements of the CTRI and the World Health Organization's International Clinical Trial Registry (WHO ICTRP). Considerable inequities exist within the Indian health system. Deficiencies in healthcare provision and uneven regulation of, and access to, affordable healthcare co-exists with a large private health system of uneven quality. India is now a preferred destination for outsourced clinical trials but is plagued by poor ethical oversight of the many trial sites and scant information of their existence. The CTRI's vision of conforming to international requirements for transparency and accountability but also using trial registration as a means of improving trial design, conduct and reporting led to the selection of registry-specific dataset items in addition to those endorsed by the WHO ICTRP. Compliance with these requirements is good for the trials currently registered but these trials represent only a fraction of the trials in progress in India. Prospective trial registration is a reality in India. The challenges facing the CTRI include better engagement with key stakeholders to ensure increased prospective registration of clinical trials and utilization of existing legislative opportunities to complement these efforts. © 2009 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University.

Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran.

PubMed

Lewis, J H; Larrey, D; Olsson, R; Lee, W M; Frison, L; Keisu, M

2008-07-01

Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

Asthma Outcomes: Healthcare Utilization and Costs

PubMed Central

Akinbami, Lara J.; Sullivan, Sean D.; Campbell, Jonathan D.; Grundmeier, Robert W.; Hartert, Tina V.; Lee, Todd A.; Smith, Robert A.

2014-01-01

Background Measures of healthcare utilization and indirect impact of asthma morbidity are used to assess clinical interventions and estimate cost. Objective National Institutes of Health (NIH) institutes and other federal agencies convened an expert group to propose standardized measurement, collection, analysis, and reporting of healthcare utilization and cost outcomes in future asthma studies. Methods We used comprehensive literature reviews and expert opinion to compile a list of asthma healthcare utilization outcomes that we classified as core (required in future studies), supplemental (used according to study aims and standardized) and emerging (requiring validation and standardization). We also have identified methodology to assign cost to these outcomes. This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Results We identified 3 ways to promote comparability across clinical trials for measures of healthcare utilization, resource use, and cost: (1) specify the study perspective (patient, clinician, payer, society), (2) standardize the measurement period (ideally, 12 months), and (3) use standard units to measure healthcare utilization and other asthma-related events. Conclusions Large clinical trials and observational studies should collect and report detailed information on healthcare utilization, intervention resources, and indirect impact of asthma, so that costs can be calculated and cost-effectiveness analyses can be conducted across several studies. Additional research is needed to develop standard, validated survey instruments for collection of provider-reported and participant-reported data regarding asthma-related health care. PMID:22386509

Implementing a low-cost web-based clinical trial management system for community studies: a case study.

PubMed

Geyer, John; Myers, Kathleen; Vander Stoep, Ann; McCarty, Carolyn; Palmer, Nancy; DeSalvo, Amy

2011-10-01

Clinical trials with multiple intervention locations and a single research coordinating center can be logistically difficult to implement. Increasingly, web-based systems are used to provide clinical trial support with many commercial, open source, and proprietary systems in use. New web-based tools are available which can be customized without programming expertise to deliver web-based clinical trial management and data collection functions. To demonstrate the feasibility of utilizing low-cost configurable applications to create a customized web-based data collection and study management system for a five intervention site randomized clinical trial establishing the efficacy of providing evidence-based treatment via teleconferencing to children with attention-deficit hyperactivity disorder. The sites are small communities that would not usually be included in traditional randomized trials. A major goal was to develop database that participants could access from computers in their home communities for direct data entry. Discussed is the selection process leading to the identification and utilization of a cost-effective and user-friendly set of tools capable of customization for data collection and study management tasks. An online assessment collection application, template-based web portal creation application, and web-accessible Access 2007 database were selected and customized to provide the following features: schedule appointments, administer and monitor online secure assessments, issue subject incentives, and securely transmit electronic documents between sites. Each tool was configured by users with limited programming expertise. As of June 2011, the system has successfully been used with 125 participants in 5 communities, who have completed 536 sets of assessment questionnaires, 8 community therapists, and 11 research staff at the research coordinating center. Total automation of processes is not possible with the current set of tools as each is loosely affiliated, creating some inefficiency. This system is best suited to investigations with a single data source e.g., psychosocial questionnaires. New web-based applications can be used by investigators with limited programming experience to implement user-friendly, efficient, and cost-effective tools for multi-site clinical trials with small distant communities. Such systems allow the inclusion in research of populations that are not usually involved in clinical trials.

Patient-reported outcomes (PROs): the significance of using humanistic measures in clinical trial and clinical practice.

PubMed

Refolo, P; Minacori, R; Mele, V; Sacchini, D; Spagnolo, A G

2012-10-01

Patient-reported outcome (PRO) is an "umbrella term" that covers a whole range of potential types of measurement but it is used specifically to refer to all measures quantifying the state of health through the evaluation of outcomes reported by the patient himself/herself. PROs are increasingly seen as complementary to biomedical measures and they are being incorporated more frequently into clinical trials and clinical practice. After considering the cultural background of PROs - that is the well known patient-centered model of medicine -, their historical profile (since 1914, the year of the first outcome measure) and typologies, the paper aims at debating their methodological complexity and implementation into practice. Some clinical trials and therapeutic managements utilizing patient-centered measures will be also analyzed.

Decision theory and the evaluation of risks and benefits of clinical trials.

PubMed

Bernabe, Rosemarie D C; van Thiel, Ghislaine J M W; Raaijmakers, Jan A M; van Delden, Johannes J M

2012-12-01

Research ethics committees (RECs) are tasked to assess the risks and the benefits of a clinical trial. In previous studies, it was shown that RECs find this task difficult, if not impossible, to do. The current approaches to benefit-risk assessment (i.e. Component Analysis and the Net Risk Test) confound the various risk-benefit tasks, and as such, make balancing impossible. In this article, we show that decision theory, specifically through the expected utility theory and multiattribute utility theory, enable for an explicit and ethically weighted risk-benefit evaluation. This makes a balanced ethical justification possible, and thus a more rationally defensible decision making. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Microdose clinical trial--impact of PET molecular imaging].

PubMed

Yano, Tsuneo; Watanabe, Yasuyoshi

2010-10-01

Microdose (MD) clinical trial and exploratory IND study including sub-therapeutic dose and therapeutic dose which are higher than microdoses are expected to bring about innovations in drug development. The outlines of guidances for microdose clinical trial and ICH-M3 (R2) issued by the MHLW in June, 2008, and February, 2010, are first explained, respectively, and some examples of their application to clinical developments of therapeutic drugs in the infection and cancer fields are introduced. Especially, thanks to the progress of molecular imaging research, a new field of drug development is explored by using imaging biomarkers for efficacy or safety evaluation which visualize biomarkers by PET imaging agents. Finally, the roadmap for drug development in infection and cancer fields utilizing PET molecular imaging is discussed.

Clinical trial designs incorporating predictive biomarkers☆

PubMed Central

Renfro, Lindsay A.; Mallick, Himel; An, Ming-Wen; Sargent, Daniel J.; Mandrekar, Sumithra J.

2016-01-01

Development of oncologic therapies has traditionally been performed in a sequence of clinical trials intended to assess safety (phase I), preliminary efficacy (phase II), and improvement over the standard of care (phase III) in homogeneous (in terms of tumor type and disease stage) patient populations. As cancer has become increasingly understood on the molecular level, newer “targeted” drugs that inhibit specific cancer cell growth and survival mechanisms have increased the need for new clinical trial designs, wherein pertinent questions on the relationship between patient biomarkers and response to treatment can be answered. Herein, we review the clinical trial design literature from initial to more recently proposed designs for targeted agents or those treatments hypothesized to have enhanced effectiveness within patient subgroups (e.g., those with a certain biomarker value or who harbor a certain genetic tumor mutation). We also describe a number of real clinical trials where biomarker-based designs have been utilized, including a discussion of their respective advantages and challenges. As cancers become further categorized and/or reclassified according to individual patient and tumor features, we anticipate a continued need for novel trial designs to keep pace with the changing frontier of clinical cancer research. PMID:26827695

EQ-5D-5L and SF-6D Utility Measures in Symptomatic benign Thyroid Nodules: Acceptability and Psychometric Evaluation.

PubMed

Wong, Carlos K H; Lang, Brian H H; Yu, Hill M S; Lam, Cindy L K

2017-08-01

The aim of this study was to examine the acceptability, validity, and reliability of the EuroQoL Five-Dimension Five-Level (EQ-5D-5L) and Short-Form Six-Dimension (SF-6D) health utility measures in patients with symptomatic benign thyroid nodules. Data from a randomized controlled trial (ClinicalTrials.gov identifier: NCT02398721) of 294 patients with symptomatic benign thyroid nodules were utilized for this psychometric evaluation of health-related quality of life (HR-QOL) measurement. Three HR-QOL questionnaires-the generic 12-item Short Form Health Survey (SF-12v2), EQ-5D-5L, and SF-6D-were interviewer-administered at baseline and 2 weeks afterwards. Responses to SF-6D were transformed to SF-6D utility scores using a Hong Kong population scoring algorithm derived by standard gamble, whereas responses to EQ-5D-5L were mapped onto EQ-5D-3L response via interim mapping algorithms and then converted to EQ-5D-5L utility scores using a Chinese-specific value set. Construct validity was determined by evaluating Spearman correlation between SF-12v2 scores and utility scores. Two-week test-retest reliability was assessed using intra-class correlation coefficient. No significant (>15%) floor and ceiling effects were observed for SF-6D utility scores. The SF-6D utility scores had a moderate Spearman rank correlation with the SF-12v2 domain score providing evidence for adequate construct validity. The SF-6D utility scores showed good test-retest reliability (0.794; range 0.696-0.860). Better reliability was observed in SF-6D utility scores than in EQ-5D-5L utility scores. While the EQ-5D-5L instrument was less reproducible, the SF-6D instrument appeared to be an applicable, valid, and reliable measure in assessing the HR-QOL of Chinese patients with symptomatic benign thyroid nodules. The impact of utility score selection on the effectiveness and cost effectiveness of clinical interventions targeted to these patients needs further exploration. NCT02398721, ClinicalTrials.gov.

Building trust and diversity in patient-centered oncology clinical trials: An integrated model.

PubMed

Hurd, Thelma C; Kaplan, Charles D; Cook, Elise D; Chilton, Janice A; Lytton, Jay S; Hawk, Ernest T; Jones, Lovell A

2017-04-01

Trust is the cornerstone of clinical trial recruitment and retention. Efforts to decrease barriers and increase clinical trial participation among diverse populations have yielded modest results. There is an urgent need to better understand the complex interactions between trust and clinical trial participation. The process of trust-building has been a focus of intense research in the business community. Yet, little has been published about trust in oncology clinical trials or the process of building trust in clinical trials. Both clinical trials and business share common dimensions. Business strategies for building trust may be transferable to the clinical trial setting. This study was conducted to understand and utilize contemporary thinking about building trust to develop an Integrated Model of Trust that incorporates both clinical and business perspectives. A key word-directed literature search of the PubMed, Medline, Cochrane, and Google Search databases for entries dated between 1 January 1985 and 1 September 2015 was conducted to obtain information from which to develop an Integrated Model of Trust. Successful trial participation requires both participants and clinical trial team members to build distinctly different types of interpersonal trust to effect recruitment and retention. They are built under conditions of significant emotional stress and time constraints among people who do not know each other and have never worked together before. Swift Trust and Traditional Trust are sequentially built during the clinical trial process. Swift trust operates during the recruitment and very early active treatment phases of the clinical trial process. Traditional trust is built over time and operates during the active treatment and surveillance stages of clinical trials. The Psychological Contract frames the participants' and clinical trial team members' interpersonal trust relationship. The "terms" of interpersonal trust are negotiated through the psychological contract. Contract renegotiation occurs in response to cyclical changes within the trust relationship throughout trial participation. The Integrated Model of Trust offers a novel framework to interrogate the process by which diverse populations and clinical trial teams build trust. To our knowledge, this is the first model of trust-building in clinical trials that frames trust development through integrated clinical and business perspectives. By focusing on the process, rather than outcomes of trust-building diverse trial participants, clinical trials teams, participants, and cancer centers may be able to better understand, measure, and manage their trust relationships in real time. Ultimately, this may foster increased recruitment and retention of diverse populations to clinical trials.

The impact of RTOG 0614 and RTOG 0933 trials in routine clinical practice: The US Survey of Utilization of Memantine and IMRT planning for hippocampus sparing in patients receiving whole brain radiotherapy for brain metastases.

PubMed

Slade, Alexander N; Stanic, Sinisa

2016-03-01

Two recent clinical trials, phase III RTOG 0614 and phase II RTOG 0933, showed some effectiveness of Memantine and IMRT planning for hippocampus sparing, among patients receiving whole brain radiotherapy (WBRT) for brain metastases; however, their use in routine clinical practice is unknown. A survey was sent to 1933 radiation oncologists in the US. Data collected included utilization of Memantine and hippocampus sparing, reasons for adoption and non-adoption, and demographic variables. A total of 196 radiation oncologists responded to the survey, with 64% reporting using Memantine in almost none of the patients receiving WBRT for brain metastases, and only 11% considering Memantine for <10% of their patients. The most common reason for not using Memantine was a poor patient performance status, and limited life expectancy. Likewise, 56% of radiation oncologists would not change their clinical practice to include hippocampus sparing IMRT in patients receiving WBRT based on the results of RTOG 0933. Further validation of hippocampus sparing in a phase III trial was supported by 71% of radiation oncologists, whereas further exploration of Memantine for this purpose in a phase III trial was supported by 42%. At this time, the majority of surveyed radiation oncologists in the US do not use Memantine, or IMRT planning for hippocampus sparing in patients receiving WBRT. Further validation of the hippocampus sparing concept in a phase III trial was supported, before adopting it in routine clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.

Malaria vaccine clinical trials: what’s on the horizon

PubMed Central

Moreno, Alberto; Joyner, Chester

2015-01-01

Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been made in the past few years with the completion of numerous clinical trials. Each trial has utilized a unique combination of antigens, delivery platforms, and adjuvants, and the data that has been obtained provides critical information that has poises the research community for the development of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P. vivax vaccine research requires more momentum and additional investigations to identify novel vaccine candidates. In this review, recently completed and ongoing malaria vaccine clinical trials as well as vaccine candidates that are in the development pipeline are reviewed. Perspectives for future research using post-genomic mining, nonhuman primate models, and systems biology are also discussed. PMID:26172291

Cost utility analysis of caudal epidural injections in the treatment of lumbar disc herniation, axial or discogenic low back pain, central spinal stenosis, and post lumbar surgery syndrome.

PubMed

Manchikanti, Laxmaiah; Falco, Frank J E; Pampati, Vidyasagar; Cash, Kimberly A; Benyamin, Ramsin M; Hirsch, Joshua A

2013-01-01

In this era of escalating health care costs and the questionable effectiveness of multiple interventions, cost effectiveness or cost utility analysis has become the cornerstone of evidence-based medicine, and has an influence coverage decisions. Even though multiple cost effectiveness analysis studies have been performed over the years, extensive literature is lacking for interventional techniques. Cost utility analysis studies of epidural injections for managing chronic low back pain demonstrated highly variable results including a lack of cost utility in randomized trials and contrasting results in observational studies. There has not been any cost utility analysis studies of epidural injections in large randomized trials performed in interventional pain management settings. To assess the cost utility of caudal epidural injections in managing chronic low back pain secondary to lumbar disc herniation, axial or discogenic low back pain, lumbar central spinal stenosis, and lumbar post surgery syndrome. This analysis is based on 4 previously published randomized trials. A private, specialty referral interventional pain management center in the United States. Four randomized trials were conducted assessing the clinical effectiveness of caudal epidural injections with or without steroids for lumbar disc herniation, lumbar discogenic or axial low back pain, lumbar central spinal stenosis, and post surgery syndrome. A cost utility analysis was performed with direct payment data for a total of 480 patients over a period of 2 years from these 4 trials. Outcome included various measures with significant improvement defined as at least a 50% improvement in pain reduction and disability status. The results of 4 randomized controlled trials of low back pain with 480 patients with a 2 year follow-up with the actual reimbursement data showed cost utility for one year of quality-adjusted life year (QALY) of $2,206 for disc herniation, $2,136 for axial or discogenic pain without disc herniation, $2,155 for central spinal stenosis, and $2,191 for post surgery syndrome. All patients showed significant improvement clinically and showed positive results in the cost utility analysis with an average cost per one year QALY of $2,172.50 for all patients and $1,966.03 for patients judged to be successful. The results of this assessment show a better cost utility or lower cost of managing chronic, intractable low back pain with caudal epidural injections at a QALY that is similar or lower in price than medical therapy only, physical therapy, manipulation, and surgery in most cases. The limitations of this cost utility analysis include that it is a single center evaluation, even though 480 patients were included in the analysis. Further, only the costs of interventional procedures and physician visits were included. The benefits of returning to work were not assessed.   This cost utility analysis of caudal epidural injections in the treatment of disc herniation, axial or discogenic low back pain, central spinal stenosis, and post surgery syndrome in the lumbar spine shows the clinical effectiveness and cost utility of these injections at less than $2,200 per one year of QALY.

Utilization of Clinical Trials Registries in Obstetrics and Gynecology Systematic Reviews.

PubMed

Bibens, Michael E; Chong, A Benjamin; Vassar, Matt

2016-02-01

To evaluate the use of clinical trials registries in published obstetrics and gynecologic systematic reviews and meta-analyses. We performed a metaepidemiologic study of systematic reviews between January 1, 2007, and December 31, 2015, from six obstetric and gynecologic journals (Obstetrics & Gynecology, Obstetrical & Gynecological Survey, Human Reproduction Update, Gynecologic Oncology, British Journal of Obstetrics and Gynaecology, and American Journal of Obstetrics & Gynecology). All systematic reviews included after exclusions were independently reviewed to determine whether clinical trials registries had been included as part of the search process. Studies that reported using a trials registry were further examined to determine whether trial data were included in the analysis of these systematic reviews. Our initial search resulted in 292 articles, which was narrowed to 256 after exclusions. Of the 256 systematic reviews meeting our selection criteria, 47 (18.4%) used a clinical trials registry. Eleven of the 47 (23.4%) systematic reviews found unpublished data and two included unpublished data in their results. A majority of systematic reviews in clinical obstetrics and gynecology journals do not conduct searches of clinical trials registries or do not make use of data obtained from these searches. Failure to make use of such data may lead to an inaccurate summary of available evidence and may contribute to an overrepresentation of published, statistically significant outcomes.

Utility analysis and calibration of QOL assessment in disease management.

PubMed

Liu, Mo

2018-05-02

In clinical trials, the assessment of health-related quality of life (QOL) (or patient-reported outcome [PRO] measure) has become very popular especially for clinical studies conducted for evaluating clinical benefits of patients with chronic, severe, and/or life threatening diseases. Health-related QOL information and PRO measures are useful for disease management for achieving best clinical practice. In this article, we will focus on health-related QOL assessment. The concept, design, and analysis of health-related QOL in clinical trials are reviewed. Validation of the use of health-related QOL instrument in terms of some key performance characteristics such as accuracy, reliability, sensitivity, and responsibility for assuring quality, integrity, and validity of collected QOL data are discussed. The concept of utility analysis and calibration (e.g., with respect to life events) for achieving the optimization of disease management are proposed. The change of the QOL could be translated into different life events for effective disease management. These translations could evaluate the treatment effect by more directly displaying the change of the QOL.

An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

PubMed

Barajaz, Ashley M; Kliethermes, Christopher L

2017-12-01

Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov.

PubMed

Su, Eric Wen; Sanger, Todd M

2017-01-01

Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts "Serious Adverse Events" (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer).

Basket Studies: Redefining Clinical Trials in the Era of Genome-Driven Oncology.

PubMed

Tao, Jessica J; Schram, Alison M; Hyman, David M

2018-01-29

Understanding a tumor's detailed molecular profile has become increasingly necessary to deliver the standard of care for patients with advanced cancer. Innovations in both tumor genomic sequencing technology and the development of drugs that target molecular alterations have fueled recent gains in genome-driven oncology care. "Basket studies," or histology-agnostic clinical trials in genomically selected patients, represent one important research tool to continue making progress in this field. We review key aspects of genome-driven oncology care, including the purpose and utility of basket studies, biostatistical considerations in trial design, genomic knowledgebase development, and patient matching and enrollment models, which are critical for translating our genomic knowledge into clinically meaningful outcomes.

Pharmacogenetics in Cardiovascular Medicine

PubMed Central

Tuteja, Sony; Limdi, Nita

2017-01-01

Purpose of review Pharmacogenetics is an important component of precision medicine. Even within the genomic era, several challenges lie ahead in the road towards clinical implementation of pharmacogenetics in the clinic. This review will summarize the current state of knowledge regarding pharmacogenetics of cardiovascular drugs, focusing on those with the most evidence supporting clinical implementation- clopidogrel, warfarin and simvastatin. Recent findings There is limited translation of pharmacogenetics into clinical practice primarily due to the absence of outcomes data from prospective, randomized, genotype-directed clinical trials. There are several ongoing randomized controlled trials that will provide some answers as to the clinical utility of genotype-directed strategies. Several academic medical centers have pushed towards clinical implementation where the clinical validity data are strong. Their experiences will inform operational requirements of a clinical pharmacogenetics testing including the timing of testing, incorporation of test results into the electronic health record, reimbursement and ethical issues. Summary Pharmacogenetics of clopidogrel, warfarin and simvastatin are three examples where pharmacogenetics testing may provide added clinical value. Continued accumulation of evidence surrounding clinical utility of pharmacogenetics markers is imperative as this will inform reimbursement policy and drive adoption of pharamcogenetics into routine care. PMID:29057167

Treatment Algorithms Based on Tumor Molecular Profiling: The Essence of Precision Medicine Trials.

PubMed

Le Tourneau, Christophe; Kamal, Maud; Tsimberidou, Apostolia-Maria; Bedard, Philippe; Pierron, Gaëlle; Callens, Céline; Rouleau, Etienne; Vincent-Salomon, Anne; Servant, Nicolas; Alt, Marie; Rouzier, Roman; Paoletti, Xavier; Delattre, Olivier; Bièche, Ivan

2016-04-01

With the advent of high-throughput molecular technologies, several precision medicine (PM) studies are currently ongoing that include molecular screening programs and PM clinical trials. Molecular profiling programs establish the molecular profile of patients' tumors with the aim to guide therapy based on identified molecular alterations. The aim of prospective PM clinical trials is to assess the clinical utility of tumor molecular profiling and to determine whether treatment selection based on molecular alterations produces superior outcomes compared with unselected treatment. These trials use treatment algorithms to assign patients to specific targeted therapies based on tumor molecular alterations. These algorithms should be governed by fixed rules to ensure standardization and reproducibility. Here, we summarize key molecular, biological, and technical criteria that, in our view, should be addressed when establishing treatment algorithms based on tumor molecular profiling for PM trials. © The Author 2015. Published by Oxford University Press.

Assessing Clinical Trial-Associated Workload in Community-Based Research Programs Using the ASCO Clinical Trial Workload Assessment Tool.

PubMed

Good, Marjorie J; Hurley, Patricia; Woo, Kaitlin M; Szczepanek, Connie; Stewart, Teresa; Robert, Nicholas; Lyss, Alan; Gönen, Mithat; Lilenbaum, Rogerio

2016-05-01

Clinical research program managers are regularly faced with the quandary of determining how much of a workload research staff members can manage while they balance clinical practice and still achieve clinical trial accrual goals, maintain data quality and protocol compliance, and stay within budget. A tool was developed to measure clinical trial-associated workload, to apply objective metrics toward documentation of work, and to provide clearer insight to better meet clinical research program challenges and aid in balancing staff workloads. A project was conducted to assess the feasibility and utility of using this tool in diverse research settings. Community-based research programs were recruited to collect and enter clinical trial-associated monthly workload data into a web-based tool for 6 consecutive months. Descriptive statistics were computed for self-reported program characteristics and workload data, including staff acuity scores and number of patient encounters. Fifty-one research programs that represented 30 states participated. Median staff acuity scores were highest for staff with patients enrolled in studies and receiving treatment, relative to staff with patients in follow-up status. Treatment trials typically resulted in higher median staff acuity, relative to cancer control, observational/registry, and prevention trials. Industry trials exhibited higher median staff acuity scores than trials sponsored by the National Institutes of Health/National Cancer Institute, academic institutions, or others. The results from this project demonstrate that trial-specific acuity measurement is a better measure of workload than simply counting the number of patients. The tool was shown to be feasible and useable in diverse community-based research settings. Copyright © 2016 by American Society of Clinical Oncology.

Issues and controversies of hepatocellular carcinoma-targeted therapy clinical trials in Asia: experts' opinion.

PubMed

Chen, Pei-Jer; Furuse, Junji; Han, Kwang-Hyub; Hsu, Chiun; Lim, Ho-Yeong; Moon, Hanlim; Qin, Shukui; Ye, Sheng-Long; Yeoh, Ee-Min; Yeo, Winnie

2010-11-01

Asia has a disproportionate share of the world's burden of hepatocellular carcinoma (HCC). However, the highly regarded clinical practice guidelines and recommendations for the design and conduct of clinical trials for HCC largely reflect Western practice. In order to design mutually beneficial international clinical trials of promising targeted therapies, it is imperative to understand how the aetiology, staging and treatment of HCC differ between Asian and Western countries. Our group, comprising experts in oncology and hepatology from countries that constitute the Eastern Asian region, convened to compare and contrast our current practices, evaluate potential compliance with the clinical trial recommendations, and offer suggestions for modifications that would enhance international collaboration. Here, we describe the results of our discussions, including recommendations for appropriate patient stratification based on potentially important differences in HCC aetiology, identification of practices that may confound interpretation of clinical trial outcomes (traditional Chinese medicine; antivirals that target hepatitis B virus; heterogeneous embolization procedures), suggestions for utilizing a common staging system in study protocols, recognition that sorafenib usage is limited by financial constraints and potentially increased toxicity in Asian patients, and expansion of patient populations that should be eligible for initial clinical trials with new agents. © 2010 John Wiley & Sons A/S.

Effort-Based Decision-Making Paradigms for Clinical Trials in Schizophrenia: Part 1—Psychometric Characteristics of 5 Paradigms

PubMed Central

Reddy, L. Felice; Horan, William P.; Barch, Deanna M.; Buchanan, Robert W.; Dunayevich, Eduardo; Gold, James M.; Lyons, Naomi; Marder, Stephen R.; Treadway, Michael T.; Wynn, Jonathan K.; Young, Jared W.; Green, Michael F.

2015-01-01

Impairments in willingness to exert effort contribute to the motivational deficits characteristic of the negative symptoms of schizophrenia. The current study evaluated the psychometric properties of 5 new or adapted paradigms to determine their suitability for use in clinical trials of schizophrenia. This study included 94 clinically stable participants with schizophrenia and 40 healthy controls. The effort-based decision-making battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 5 paradigms included 1 that assesses cognitive effort, 1 perceptual effort, and 3 that assess physical effort. Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure (ie, practice effects), and (4) tolerability. The 5 paradigms showed varying psychometric strengths and weaknesses. The Effort Expenditure for Rewards Task showed the best reliability and utility as a repeated measure, while the Grip Effort Task had significant patient-control group differences, and superior tolerability and administration duration. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting effort and motivation paradigms for use in clinical trials. PMID:26142081

Industry Perspective of Pediatric Drug Development in the United States: Involvement of the European Union Countries.

PubMed

Onishi, Taku; Tsukamoto, Katsura; Matsumaru, Naoki; Waki, Takashi

2018-01-01

Efforts to promote the development of pediatric pharmacotherapy include regulatory frameworks and close collaboration between the US Food and Drug Administration and the European Medicines Agency. We characterized the current status of pediatric clinical trials conducted in the United States by the pharmaceutical industry, focusing on the involvement of the European Union member countries, to clarify the industry perspective. Data on US pediatric clinical trials were obtained from ClinicalTrials.gov . Binary regression analysis was performed to identify what factors influence the likelihood of involvement of European Union countries. A total of 633 US pediatric clinical trials that met inclusion criteria were extracted and surveyed. Of these, 206 (32.5%) involved a European Union country site(s). The results of binary regression analysis indicated that attribution of industry, phase, disease area, and age of pediatric participants influenced the likelihood of the involvement of European Union countries in US pediatric clinical trials. Relatively complicated or large pediatric clinical trials, such as phase II and III trials and those that included a broad age range of participants, had a significantly greater likelihood of the involvement of European Union countries ( P < .05). Our results suggest that (1) the pharmaceutical industry utilizes regulatory frameworks in making business decisions regarding pediatric clinical trials, (2) disease area affects the involvement of European Union countries, and (3) feasibility of clinical trials is mainly concerned by pharmaceutical industry for pediatric drug development. Additional incentives for high marketability may further motivate pharmaceutical industry to develop pediatric drugs.

Unfulfilled translation opportunities in industry sponsored clinical trials.

PubMed

Smed, Marie; Getz, Kenneth A

2013-05-01

Knowledge generated by site representatives through their participation in clinical trials is valuable for testing new products in use and obtaining final market approval. The leverage of this important knowledge is however challenged as the former direct relationships between in-house staff in the industry and site representatives are changing. The process of clinical trials has increased in complexity over the years, resulting in additional management layers. Besides an increase in internal management layers, sponsors often also outsource various tasks related to clinical trials to a CRO (Contract Research Organization) and thereby adding another link in the relationships between site and sponsor. These changes are intended to optimize the time-consuming and costly trial phases; however, there is a need to study whether valuable knowledge and experience is compromised in the process. Limited research exists on the full range of clinical practice insights obtained by investigators during and after clinical trials and how well these insights are transferred to study sponsors. This study explores the important knowledge-transfer processes between sites and sponsors and to what extent sites' knowledge gained in clinical trials is utilized by the industry. Responses from 451 global investigative site representatives are included in the study. The analysis of the extensive dataset reveals that the current processes of collaboration between sites and the industry restrict the leverage of valuable knowledge gained by physicians in the process of clinical trials. These restrictions to knowledge-transfer between site and sponsor are further challenged if CRO partners are integrated in the trial process. Copyright © 2013 Elsevier Inc. All rights reserved.

The nature of placebo response in clinical studies of major depressive disorder.

PubMed

Papakostas, George I; Østergaard, Søren D; Iovieno, Nadia

2015-04-01

To review factors influencing placebo response and clinical trial outcome in depression, and suggest ways to optimize trial success in mood disorders. PubMed searches were conducted by cross-referencing the terms depression, depressive with placebo, clinical trial, and clinical trials for studies published in English between 1970 and September 2013. Relevant abstracts were identified in PubMed, including clinical trials, quantitative studies, and qualitative research. We obtained and reviewed relevant articles and utilized their information to synthesize the present review. Included articles were grouped in the following areas of relevance: (1) biological validity of illness, (2) baseline severity of illness, (3) chronicity of the index episode of depression, (4) age of participants, (5) medical and psychiatric comorbidity, (6) probability of receiving placebo, (7) use of prospective treatment phases (lead-in) (8) dosing schedule, (9) trial duration, (10) frequency of follow-up assessments, and (11) study outcome measure. Several key elements emerge as critical to the ultimate success of a clinical trial, including the probability of receiving placebo, study duration, dosing schedule, visit frequency, the use of blinded lead-in phases, the use of centralized raters, illness severity and duration, and comorbid anxiety. Our increasing understanding of the placebo response in clinical trials of major depressive disorder lends to a, gradually, more predictable phenomenon and, hopefully, to one that becomes lesser in magnitude and variability. Several elements have emerged that seem to play a critical role in trial success, gradually reshaping the design of clinical, translational, as well as mechanistic studies in depression. © Copyright 2015 Physicians Postgraduate Press, Inc.

Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials.

PubMed

Figueroa, Xavier A; Wright, James K

2016-09-27

First, to demonstrate that B-level evidence exists for the use of hyperbaric oxygen therapy (HBOT) as an effective treatment in mild to moderate traumatic brain injury/persistent postconcussion syndrome (mTBI/PPCS). Second, to alert readers and researchers that currently used pressurized air controls (≥21% O2, >1.0 ATA) are therapeutically active and cannot be utilized as sham controls without further validation. Review of published, peer-reviewed articles of HBOT prospective and controlled clinical trials of mTBI/PPCS symptoms. Published results demonstrate that HBOT is effective in the treatment of mTBI/PPCS symptoms. Doses of oxygen that are applied at ≥21% O2 and at pressures of >1.0 ATA produce improvements from baseline measures. Some of the recently published clinical trials are mischaracterized as sham-controlled clinical trials (i.e., sham = 21% O2/1.2-1.3 ATA), but are best characterized as dose-varying (variation in oxygen concentration, pressure applied, or both) clinical trials. Hyperbaric oxygen and hyperbaric air have demonstrated therapeutic effects on mTBI/PPCS symptoms and can alleviate posttraumatic stress disorder symptoms secondary to a brain injury in 5 out of 5 peer-reviewed clinical trials. The current use of pressurized air (1.2-1.3 ATA) as a placebo or sham in clinical trials biases the results due to biological activity that favors healing. © 2016 American Academy of Neurology.

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.

INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): study protocol for a mixed methods study to assess the feasibility of a future randomised controlled trial of the clinical utility of invasive urodynamic testing

PubMed Central

2011-01-01

Background Urinary incontinence is an important health problem to the individual sufferer and to health services. Stress and stress predominant mixed urinary incontinence are increasingly managed by surgery due to advances in surgical techniques. Despite the lack of evidence for its clinical utility, most clinicians undertake invasive urodynamic testing (IUT) to confirm a functional diagnosis of urodynamic stress incontinence before offering surgery for this condition. IUT is expensive, embarrassing and uncomfortable for women and carries a small risk. Recent systematic reviews have confirmed the lack of high quality evidence of effectiveness. The aim of this pilot study is to test the feasibility of a future definitive randomised control trial that would address whether IUT alters treatment decisions and treatment outcome in these women and would test its clinical and cost effectiveness. Methods/design This is a mixed methods pragmatic multicentre feasibility pilot study with four components:- (a) A multicentre, external pilot randomised trial comparing basic clinical assessment with non-invasive tests and IUT. The outcome measures are rates of recruitment, randomisation and data completion. Data will be used to estimate sample size necessary for the definitive trial. (b) Qualitative interviews of a purposively sampled sub-set of women eligible for the pilot trial will explore willingness to participate, be randomised and their overall trial experience. (c) A national survey of clinicians to determine their views of IUT in this context, the main outcome being their willingness to randomise patients into the definitive trial. (d) Qualitative interviews of a purposively sampled group of these clinicians will explore whether and how they use IUT to inform their decisions. Discussion The pilot trial will provide evidence of feasibility and acceptability and therefore inform the decision whether to proceed to the definitive trial. Results will inform the design and conduct of the definitive trial and ensure its effectiveness in achieving its research aim. Trial registration number Current Controlled Trials ISRCTN71327395 assigned 7th June 2010. PMID:21733166

Immune Recognition of Gene Transfer Vectors: Focus on Adenovirus as a Paradigm

PubMed Central

Aldhamen, Yasser Ali; Seregin, Sergey S.; Amalfitano, Andrea

2011-01-01

Recombinant Adenovirus (Ad) based vectors have been utilized extensively as a gene transfer platform in multiple pre-clinical and clinical applications. These applications are numerous, and inclusive of both gene therapy and vaccine based approaches to human or animal diseases. The widespread utilization of these vectors in both animal models, as well as numerous human clinical trials (Ad-based vectors surpass all other gene transfer vectors relative to numbers of patients treated, as well as number of clinical trials overall), has shed light on how this virus vector interacts with both the innate and adaptive immune systems. The ability to generate and administer large amounts of this vector likely contributes not only to their ability to allow for highly efficient gene transfer, but also their elicitation of host immune responses to the vector and/or the transgene the vector expresses in vivo. These facts, coupled with utilization of several models that allow for full detection of these responses has predicted several observations made in human trials, an important point as lack of similar capabilities by other vector systems may prevent detection of such responses until only after human trials are initiated. Finally, induction of innate or adaptive immune responses by Ad vectors may be detrimental in one setting (i.e., gene therapy) and be entirely beneficial in another (i.e., prophylactic or therapeutic vaccine based applications). Herein, we review the current understanding of innate and adaptive immune responses to Ad vectors, as well some recent advances that attempt to capitalize on this understanding so as to further broaden the safe and efficient use of Ad-based gene transfer therapies in general. PMID:22566830

Mixture-based gatekeeping procedures in adaptive clinical trials.

PubMed

Kordzakhia, George; Dmitrienko, Alex; Ishida, Eiji

2018-01-01

Clinical trials with data-driven decision rules often pursue multiple clinical objectives such as the evaluation of several endpoints or several doses of an experimental treatment. These complex analysis strategies give rise to "multivariate" multiplicity problems with several components or sources of multiplicity. A general framework for defining gatekeeping procedures in clinical trials with adaptive multistage designs is proposed in this paper. The mixture method is applied to build a gatekeeping procedure at each stage and inferences at each decision point (interim or final analysis) are performed using the combination function approach. An advantage of utilizing the mixture method is that it enables powerful gatekeeping procedures applicable to a broad class of settings with complex logical relationships among the hypotheses of interest. Further, the combination function approach supports flexible data-driven decisions such as a decision to increase the sample size or remove a treatment arm. The paper concludes with a clinical trial example that illustrates the methodology by applying it to develop an adaptive two-stage design with a mixture-based gatekeeping procedure.

Clinical studies and anti-inflammatory mechanisms of treatments

PubMed Central

French, Jacqueline A.; Koepp, Matthias; Naegelin, Yvonne; Vigevano, Federico; Auvin, Stéphane; Rho, Jong M.; Rosenberg, Evan; Devinsky, Orrin; Olofsson, Peder S.; Dichter, Marc A.

2017-01-01

Summary In this exciting era, we are coming closer and closer to bringing an anti-inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti-inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both “conventional, broad spectrum” anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain. PMID:28675558

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?

PubMed

Hamaker, M E; Stauder, R; van Munster, B C

2014-03-01

Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population.

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?†

PubMed Central

Hamaker, M. E.; Stauder, R.; van Munster, B. C.

2014-01-01

Background Cancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients. Method The United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. Results In the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies. Conclusion Currently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population. PMID:24458474

Selection and utilization of assessment instruments in substance abuse treatment trials: the National Drug Abuse Treatment Clinical Trials Network experience.

PubMed

Rosa, Carmen; Ghitza, Udi; Tai, Betty

2012-07-17

Based on recommendations from a US Institute of Medicine report, the National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999, to accelerate the translation of science-based addiction treatment research into community-based practice, and to improve the quality of addiction treatment, using science as the vehicle. One of the CTN's primary tasks is to serve as a platform to forge bi-directional communications and collaborations between providers and scientists, to enhance the relevance of research, which generates empirical results that impact practice. Among many obstacles in moving research into real-world settings, this commentary mainly describes challenges and iterative experiences in regard to how the CTN develops its research protocols, with focus on how the CTN study teams select and utilize assessment instruments, which can reasonably balance the interests of both research scientists and practicing providers when applied in CTN trials. This commentary also discusses the process by which the CTN further selects a core set of common assessment instruments that may be applied across all trials, to allow easier cross-study analyses of comparable data.

Drug designs fulfilling the requirements of clinical trials aiming at personalizing medicine

PubMed Central

Mandrekar, Sumithra J.; Sargent, Daniel J.

2014-01-01

In the current era of stratified medicine and biomarker-driven therapies, the focus has shifted from predictions based on the traditional anatomic staging systems to guide the choice of treatment for an individual patient to an integrated approach using the genetic makeup of the tumor and the genotype of the patient. The clinical trial designs utilized in the developmental pathway for biomarkers and biomarker-directed therapies from discovery to clinical practice are rapidly evolving. While several issues need careful consideration, two critical issues that surround the validation of biomarkers are the choice of the clinical trial design (which is based on the strength of the preliminary evidence and marker prevalence), and biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. In this review, we focus on trial designs aiming at personalized medicine in the context of early phase trials for initial marker validation, as well as in the context of larger definitive trials. Designs for biomarker validation are broadly classified as retrospective (i.e., using data from previously well-conducted randomized controlled trials (RCTs) versus prospective (enrichment, all-comers, hybrid or adaptive). We believe that the systematic evaluation and implementation of these design strategies are essential to accelerate the clinical validation of biomarker guided therapy. PMID:25414851

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

PubMed

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

A Randomized Trial of Probation Case Management for Drug-Involved Women Offenders

ERIC Educational Resources Information Center

Guydish, Joseph; Chan, Monica; Bostrom, Alan; Jessup, Martha A.; Davis, Thomas B.; Marsh, Cheryl

2011-01-01

This article reports findings from a clinical trial of a probation case management (PCM) intervention for drug-involved women offenders. Participants were randomly assigned to PCM (n = 92) or standard probation (n = 91) and followed for 12 months using measures of substance abuse, psychiatric symptoms, social support, and service utilization.…

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib

PubMed Central

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L.

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug’s known mechanism of action. Also, the models predict each drug’s potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets. PMID:26107615

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib.

PubMed

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.

Complete hazard ranking to analyze right-censored data: An ALS survival study.

PubMed

Huang, Zhengnan; Zhang, Hongjiu; Boss, Jonathan; Goutman, Stephen A; Mukherjee, Bhramar; Dinov, Ivo D; Guan, Yuanfang

2017-12-01

Survival analysis represents an important outcome measure in clinical research and clinical trials; further, survival ranking may offer additional advantages in clinical trials. In this study, we developed GuanRank, a non-parametric ranking-based technique to transform patients' survival data into a linear space of hazard ranks. The transformation enables the utilization of machine learning base-learners including Gaussian process regression, Lasso, and random forest on survival data. The method was submitted to the DREAM Amyotrophic Lateral Sclerosis (ALS) Stratification Challenge. Ranked first place, the model gave more accurate ranking predictions on the PRO-ACT ALS dataset in comparison to Cox proportional hazard model. By utilizing right-censored data in its training process, the method demonstrated its state-of-the-art predictive power in ALS survival ranking. Its feature selection identified multiple important factors, some of which conflicts with previous studies.

The Clinical Research Landscape in Rhode Island.

PubMed

Mao, George; Ramratnam, Bharat

2017-01-06

To present an overview of clinical research activity and the state of medical research funding in Rhode Island. We utilized clinicaltrials.gov registry to profile clinical studies between 2011 to 2016. NIH RePORT and other federal databases were used to extract information on levels of federal funding. Previously published hospital financial reports were reviewed for data on hospital-specific total external research funding. During 2011-2016, 1651 clinical studies were registered in clinicaltrials.gov. Nearly a third of all clinical studies were in oncology (21%) and cardiovascular diseases (10%). Alzheimer's dementia, breast cancer, HIV, and hepatitis C accounted for nearly 17% of all clinical trials. Seventy-five percent (75%) of clinical trials in RI were conducted in hospitals affiliated with Lifespan or Care New England. Financial support for clinical trials largely came from industry (60%) with 23% being supported by the National Institutes of Health (NIH). The rest are funded by nonprofit organizations, charitable foundations, educational institutions, and unlisted concerns. [Full article available at http://rimed.org/rimedicaljournal-2017-01.asp].

Feasibility, acceptability and clinical utility of the Cultural Formulation Interview: mixed-methods results from the DSM-5 international field trial.

PubMed

Lewis-Fernández, Roberto; Aggarwal, Neil Krishan; Lam, Peter C; Galfalvy, Hanga; Weiss, Mitchell G; Kirmayer, Laurence J; Paralikar, Vasudeo; Deshpande, Smita N; Díaz, Esperanza; Nicasio, Andel V; Boiler, Marit; Alarcón, Renato D; Rohlof, Hans; Groen, Simon; van Dijk, Rob C J; Jadhav, Sushrut; Sarmukaddam, Sanjeev; Ndetei, David; Scalco, Monica Z; Bassiri, Kavoos; Aguilar-Gaxiola, Sergio; Ton, Hendry; Westermeyer, Joseph; Vega-Dienstmaier, Johann M

2017-04-01

Background There is a need for clinical tools to identify cultural issues in diagnostic assessment. Aims To assess the feasibility, acceptability and clinical utility of the DSM-5 Cultural Formulation Interview (CFI) in routine clinical practice. Method Mixed-methods evaluation of field trial data from six countries. The CFI was administered to diagnostically diverse psychiatric out-patients during a diagnostic interview. In post-evaluation sessions, patients and clinicians completed debriefing qualitative interviews and Likert-scale questionnaires. The duration of CFI administration and the full diagnostic session were monitored. Results Mixed-methods data from 318 patients and 75 clinicians found the CFI feasible, acceptable and useful. Clinician feasibility ratings were significantly lower than patient ratings and other clinician-assessed outcomes. After administering one CFI, however, clinician feasibility ratings improved significantly and subsequent interviews required less time. Conclusions The CFI was included in DSM-5 as a feasible, acceptable and useful cultural assessment tool. © The Royal College of Psychiatrists 2017.

Patient navigation for American Indians undergoing cancer treatment: utilization and impact on care delivery in a regional healthcare center.

PubMed

Guadagnolo, B Ashleigh; Boylan, Amy; Sargent, Michele; Koop, David; Brunette, Deb; Kanekar, Shalini; Shortbull, Vanessa; Molloy, Kevin; Petereit, Daniel G

2011-06-15

A study was undertaken to assess patient navigation utilization and its impact on treatment interruptions and clinical trial enrollment among American Indian cancer patients. Between February 2004 and September 2009, 332 American Indian cancer patients received patient navigation services throughout cancer treatment. The patient navigation program provided culturally competent navigators to assist patients with navigating cancer therapy, obtaining medications, insurance issues, communicating with medical providers, and travel and lodging logistics. Data on utilization and trial enrollment were prospectively collected. Data for a historical control group of 70 American Indian patients who did not receive patient navigation services were used to compare treatment interruptions among those undergoing patient navigation during curative radiation therapy (subgroup of 123 patients). The median number of contacts with a navigator was 12 (range, 1-119). The median time spent with the navigator at first contact was 40 minutes (range, 10-250 minutes), and it was 15 minutes for subsequent contacts. Patients treated with radiation therapy with curative intent who underwent patient navigation had fewer days of treatment interruption (mean, 1.7 days; 95% confidence interval [CI], 1.1-2.2 days) than historical controls who did not receive patient navigation services (mean, 4.9 days; 95% CI, 2.9-6.9 days). Of the 332 patients, 72 (22%; 95% CI, 17%-26%) were enrolled on a clinical treatment trial or cancer control protocol. Patient navigation was associated with fewer treatment interruptions and relatively high rates of clinical trial enrollment among American Indian cancer patients compared with national reports. Copyright © 2010 American Cancer Society.

Methodological issues associated with preclinical drug development and increased placebo effects in schizophrenia clinical trials.

PubMed

Brown, Matt A; Bishnoi, Ram J; Dholakia, Sara; Velligan, Dawn I

2016-01-20

Recent failures to detect efficacy in clinical trials investigating pharmacological treatments for schizophrenia raise concerns regarding the potential contribution of methodological shortcomings to this research. This review provides an examination of two key methodological issues currently suspected of playing a role in hampering schizophrenia drug development; 1) limitations on the translational utility of preclinical development models, and 2) methodological challenges posed by increased placebo effects. Recommendations for strategies to address these methodological issues are addressed.

A highly sensitive search strategy for clinical trials in Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) was developed.

PubMed

Manríquez, Juan J

2008-04-01

Systematic reviews should include as many articles as possible. However, many systematic reviews use only databases with high English language content as sources of trials. Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) is an underused source of trials, and there is not a validated strategy for searching clinical trials to be used in this database. The objective of this study was to develop a sensitive search strategy for clinical trials in LILACS. An analytical survey was performed. Several single and multiple-term search strategies were tested for their ability to retrieve clinical trials in LILACS. Sensitivity, specificity, and accuracy of each single and multiple-term strategy were calculated using the results of a hand-search of 44 Chilean journals as gold standard. After combining the most sensitive, specific, and accurate single and multiple-term search strategy, a strategy with a sensitivity of 97.75% (95% confidence interval [CI]=95.98-99.53) and a specificity of 61.85 (95% CI=61.19-62.51) was obtained. LILACS is a source of trials that could improve systematic reviews. A new highly sensitive search strategy for clinical trials in LILACS has been developed. It is hoped this search strategy will improve and increase the utilization of LILACS in future systematic reviews.

Sacubitril/Valsartan: From Clinical Trials to Real-world Experience.

PubMed

Joly, Joanna M; Desai, Akshay S

2018-04-23

Compared to enalapril, use of angiotensin-receptor blocker and neprilysin inhibitor sacubitril/valsartan to treat patients with heart failure and reduced ejection fraction (HFrEF) is associated with substantial reductions in both cardiovascular mortality and heart failure progression. The purpose of this review is to discuss the real-world experience of sacubitril/valsartan. In the years following the publication of the landmark PARADIGM-HF trial in 2014 and its subsequent FDA approval, a growing evidence base supports the safety and efficacy of sacubitril/valsartan in a broad spectrum of patients with HFrEF. Updated clinical practice guidelines have embraced the use of sacubitril/valsartan in preference to ACE inhibitors or ARBs in selected patients. In this review, we highlight the clinical trials that led to these key updates to clinical guidelines, offer practical strategies for patient selection and utilization in clinical practice, and identify important areas of uncertainty that require future research.

Correlates of immune protection: Standardized and automated assays to interrogate correlates of immunity--Phacilitate Vaccine Forum Washington 2011. The Grand Hyatt, Washington, DC January 24–26, 2011.

PubMed

Bolton, Wade

2011-06-01

The utility of functional cell mediated immune assays in the assessment of immune response or immunogenicity is increasing significantly as we search for surrogates to determine vaccine efficacy or therapeutic response. No definitive reports to date have demonstrated that CMI assays in human clinical trials correlate with clinical outcome, although animal and non human primate studies have reported surrogacy in varying degrees. This report discusses the approaches identified, their advantages and disadvantages, and their justification for inclusion in the clinical trial setting.

Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD—‘Assessing QbTest Utility in ADHD’ (AQUA): a randomised controlled trial

PubMed Central

Hall, Charlotte L; Walker, Gemma M; Valentine, Althea Z; Guo, Boliang; Kaylor-Hughes, Catherine; James, Marilyn; Daley, David; Sayal, Kapil; Hollis, Chris

2014-01-01

Introduction The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current ‘gold standard’ ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. Methods and analysis This multisite randomised controlled trial will recruit young people (aged 6–17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. Ethics and dissemination The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. Trial registration number NCT02209116. PMID:25448628

Translating U-500R Randomized Clinical Trial Evidence to the Practice Setting: A Diabetes Educator/Expert Prescriber Team Approach

PubMed Central

Bergen, Paula M.; Kruger, Davida F.; Taylor, April D.; Eid, Wael E.; Bhan, Arti; Jackson, Jeffrey A.

2017-01-01

Purpose The purpose of this article is to provide recommendations to the diabetes educator/expert prescriber team for the use of human regular U-500 insulin (U-500R) in patients with severely insulin-resistant type 2 diabetes, including its initiation and titration, by utilizing dosing charts and teaching materials translated from a recent U-500R clinical trial. Conclusions Clinically relevant recommendations and teaching materials for the optimal use and management of U-500R in clinical practice are provided based on the efficacy and safety results of and lessons learned from the U-500R clinical trial by Hood et al, current standards of practice, and the authors’ clinical expertise. This trial was the first robustly powered, randomized, titration-to-target trial to compare twice-daily and three-times-daily U-500R dosing regimens. Modifications were made to the initiation and titration dosing algorithms used in this trial to simplify dosing strategies for the clinical setting and align with current glycemic targets recommended by the American Diabetes Association. Leveraging the expertise, resources, and patient interactions of the diabetes educator who can provide diabetes self-management education and support in collaboration with the multidisciplinary diabetes team is strongly recommended to ensure patients treated with U-500R receive the timely and comprehensive care required to safely and effectively use this highly concentrated insulin. PMID:28427304

Translating U-500R Randomized Clinical Trial Evidence to the Practice Setting: A Diabetes Educator/Expert Prescriber Team Approach.

PubMed

Bergen, Paula M; Kruger, Davida F; Taylor, April D; Eid, Wael E; Bhan, Arti; Jackson, Jeffrey A

2017-06-01

Purpose The purpose of this article is to provide recommendations to the diabetes educator/expert prescriber team for the use of human regular U-500 insulin (U-500R) in patients with severely insulin-resistant type 2 diabetes, including its initiation and titration, by utilizing dosing charts and teaching materials translated from a recent U-500R clinical trial. Conclusions Clinically relevant recommendations and teaching materials for the optimal use and management of U-500R in clinical practice are provided based on the efficacy and safety results of and lessons learned from the U-500R clinical trial by Hood et al, current standards of practice, and the authors' clinical expertise. This trial was the first robustly powered, randomized, titration-to-target trial to compare twice-daily and three-times-daily U-500R dosing regimens. Modifications were made to the initiation and titration dosing algorithms used in this trial to simplify dosing strategies for the clinical setting and align with current glycemic targets recommended by the American Diabetes Association. Leveraging the expertise, resources, and patient interactions of the diabetes educator who can provide diabetes self-management education and support in collaboration with the multidisciplinary diabetes team is strongly recommended to ensure patients treated with U-500R receive the timely and comprehensive care required to safely and effectively use this highly concentrated insulin.

Advances in the development of new tuberculosis drugs and treatment regimens.

PubMed

Zumla, Alimuddin; Nahid, Payam; Cole, Stewart T

2013-05-01

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

Potential Psychiatric Uses for MDMA.

PubMed

Yazar-Klosinski, B B; Mithoefer, M C

2017-02-01

Phase II trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of posttraumatic stress disorder (PTSD), with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as the US Food and Drug Administration (FDA) Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches. © 2016, The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Cost-utility Analysis of Supported Self-management with Motiva-tional Interviewing for Patients with Psoriasis.

PubMed

Larsen, Marie H; Wahl, Astrid K; Krogstad, Anne-Lene; Aas, Eline

2016-06-15

There are few studies evaluating the cost-effectiveness of self-management interventions for patients with psoriasis. Motivational interviewing (MI) as a telephone follow-up after climate-heliotherapy was effective on several clinical parameters, but its cost-effectiveness is unknown. A cost-utility analysis was conducted alongside a randomized controlled trial (RCT) comparing MI with usual care. A total of 169 Norwegian patients were included. A within-trial analysis compared the costs and quality-adjusted life years (QALYs). Utilities were measured with the 15D instrument, supplemented with Dermatological Life Quality Index (DLQI). A time-integrated summary score defined the clinical effects. QALYs were adjusted for baseline differences. MI provided equivalent quality of life and utility (15D: -0.0022 QALYs (95% Cl -0.02, 0.01), p = 0.77, and DLQI: -0.62 QALYs (95%CI -0.65, 0.41), p = 0.24, at lower costs €-1103 (-2293, 87), p = 0.058, compared with treatment-as-usual. The MI intervention was thus cost-effective. This result was more evident when using the DLQI as outcome measure compared with 15D.

Independent data monitoring committees: Preparing a path for the future

PubMed Central

Hess, Connie N.; Roe, Matthew T.; Gibson, C. Michael; Temple, Robert J.; Pencina, Michael J.; Zarin, Deborah A.; Anstrom, Kevin J.; Alexander, John H.; Sherman, Rachel E.; Fiedorek, Fred T.; Mahaffey, Kenneth W.; Lee, Kerry L.; Chow, Shein-Chung; Armstrong, Paul W.; Califf, Robert M.

2014-01-01

Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs. PMID:25066551

Data Quality Monitoring in Clinical Trials: Has It Been Worth It? An Evaluation and Prediction of the Future by All Stakeholders

PubMed Central

Kalali, Amir; West, Mark; Walling, David; Hilt, Dana; Engelhardt, Nina; Alphs, Larry; Loebel, Antony; Vanover, Kim; Atkinson, Sarah; Opler, Mark; Sachs, Gary; Nations, Kari; Brady, Chris

2016-01-01

This paper summarizes the results of the CNS Summit Data Quality Monitoring Workgroup analysis of current data quality monitoring techniques used in central nervous system (CNS) clinical trials. Based on audience polls conducted at the CNS Summit 2014, the panel determined that current techniques used to monitor data and quality in clinical trials are broad, uncontrolled, and lack independent verification. The majority of those polled endorse the value of monitoring data. Case examples of current data quality methodology are presented and discussed. Perspectives of pharmaceutical companies and trial sites regarding data quality monitoring are presented. Potential future developments in CNS data quality monitoring are described. Increased utilization of biomarkers as objective outcomes and for patient selection is considered to be the most impactful development in data quality monitoring over the next 10 years. Additional future outcome measures and patient selection approaches are discussed. PMID:27413584

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures.

PubMed

Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R; Schreiber, Fred; Anderson, Kyle

2012-01-21

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention.

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures

PubMed Central

Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E.; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R.; Schreiber, Fred; Anderson, Kyle

2014-01-01

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention. PMID:24533253

Circulating tumor cells: clinical validity and utility.

PubMed

Cabel, Luc; Proudhon, Charlotte; Gortais, Hugo; Loirat, Delphine; Coussy, Florence; Pierga, Jean-Yves; Bidard, François-Clément

2017-06-01

Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed-(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.

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

Efficacy and enlightenment: LSD psychotherapy and the Drug Amendments of 1962.

PubMed

Oram, Matthew

2014-04-01

The decline in therapeutic research with lysergic acid diethylamide (LSD) in the United States over the course of the 1960s has commonly been attributed to the growing controversy surrounding its recreational use. However, research difficulties played an equal role in LSD psychotherapy's demise, as they frustrated researchers' efforts to clearly establish the efficacy of treatment. Once the Kefauver Harris Drug Amendments of 1962 introduced the requirement that proof of efficacy be established through controlled clinical trials before a drug could be approved to market, the value of clinical research became increasingly dependent on the scientific rigor of the trial's design. LSD psychotherapy's complex method of utilizing drug effects to catalyze a psychological treatment clashed with the controlled trial methodology on both theoretical and practical levels, making proof of efficacy difficult to obtain. Through a close examination of clinical trials performed after 1962, this article explores how the new emphasis on controlled clinical trials frustrated the progress of LSD psychotherapy research by focusing researchers' attention on trial design to the detriment of their therapeutic method. This analysis provides a new perspective on the death of LSD psychotherapy and explores the implications of the Drug Amendments of 1962.

Bayesian methodology for the design and interpretation of clinical trials in critical care medicine: a primer for clinicians.

PubMed

Kalil, Andre C; Sun, Junfeng

2014-10-01

To review Bayesian methodology and its utility to clinical decision making and research in the critical care field. Clinical, epidemiological, and biostatistical studies on Bayesian methods in PubMed and Embase from their inception to December 2013. Bayesian methods have been extensively used by a wide range of scientific fields, including astronomy, engineering, chemistry, genetics, physics, geology, paleontology, climatology, cryptography, linguistics, ecology, and computational sciences. The application of medical knowledge in clinical research is analogous to the application of medical knowledge in clinical practice. Bedside physicians have to make most diagnostic and treatment decisions on critically ill patients every day without clear-cut evidence-based medicine (more subjective than objective evidence). Similarly, clinical researchers have to make most decisions about trial design with limited available data. Bayesian methodology allows both subjective and objective aspects of knowledge to be formally measured and transparently incorporated into the design, execution, and interpretation of clinical trials. In addition, various degrees of knowledge and several hypotheses can be tested at the same time in a single clinical trial without the risk of multiplicity. Notably, the Bayesian technology is naturally suited for the interpretation of clinical trial findings for the individualized care of critically ill patients and for the optimization of public health policies. We propose that the application of the versatile Bayesian methodology in conjunction with the conventional statistical methods is not only ripe for actual use in critical care clinical research but it is also a necessary step to maximize the performance of clinical trials and its translation to the practice of critical care medicine.

Effort-Based Decision-Making Paradigms for Clinical Trials in Schizophrenia: Part 1—Psychometric Characteristics of 5 Paradigms.

PubMed

Reddy, L Felice; Horan, William P; Barch, Deanna M; Buchanan, Robert W; Dunayevich, Eduardo; Gold, James M; Lyons, Naomi; Marder, Stephen R; Treadway, Michael T; Wynn, Jonathan K; Young, Jared W; Green, Michael F

2015-09-01

Impairments in willingness to exert effort contribute to the motivational deficits characteristic of the negative symptoms of schizophrenia. The current study evaluated the psychometric properties of 5 new or adapted paradigms to determine their suitability for use in clinical trials of schizophrenia. This study included 94 clinically stable participants with schizophrenia and 40 healthy controls. The effort-based decision-making battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 5 paradigms included 1 that assesses cognitive effort, 1 perceptual effort, and 3 that assess physical effort. Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure (ie, practice effects), and (4) tolerability. The 5 paradigms showed varying psychometric strengths and weaknesses. The Effort Expenditure for Rewards Task showed the best reliability and utility as a repeated measure, while the Grip Effort Task had significant patient-control group differences, and superior tolerability and administration duration. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting effort and motivation paradigms for use in clinical trials. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2015.

Preferential Cyclooxygenase 2 Inhibitors as a Nonhormonal Method of Emergency Contraception: A Look at the Evidence.

PubMed

Weiss, Erich A; Gandhi, Mona

2016-04-01

To review the literature surrounding the use of preferential cyclooxygenase 2 (COX-2) inhibitors as an alternative form of emergency contraception. MEDLINE (1950 to February 2014) was searched using the key words cyclooxygenase or COX-2 combined with contraception, emergency contraception, or ovulation. Results were limited to randomized control trials, controlled clinical trials, and clinical trials. Human trials that measured the effects of COX inhibition on female reproductive potential were included for review. The effects of the COX-2 inhibitors rofecoxib, celecoxib, and meloxicam were evaluated in 6 trials. Each of which was small in scope, enrolled women of variable fertility status, used different dosing regimens, included multiple end points, and had variable results. Insufficient evidence exists to fully support the use of preferential COX-2 inhibitors as a form of emergency contraception. Although all trials resulted in a decrease in ovulatory cycles, outcomes varied between dosing strategies and agents used. A lack of homogeneity in these studies makes comparisons difficult. However, success of meloxicam in multiple trials warrants further study. Larger human trials are necessary before the clinical utility of this method of emergency contraception can be fully appreciated. © The Author(s) 2014.

The Database for Aggregate Analysis of ClinicalTrials.gov (AACT) and Subsequent Regrouping by Clinical Specialty

PubMed Central

Tasneem, Asba; Aberle, Laura; Ananth, Hari; Chakraborty, Swati; Chiswell, Karen; McCourt, Brian J.; Pietrobon, Ricardo

2012-01-01

Background The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. Methods/Principal Results The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. Conclusions/Significance The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups. PMID:22438982

The database for aggregate analysis of ClinicalTrials.gov (AACT) and subsequent regrouping by clinical specialty.

PubMed

Tasneem, Asba; Aberle, Laura; Ananth, Hari; Chakraborty, Swati; Chiswell, Karen; McCourt, Brian J; Pietrobon, Ricardo

2012-01-01

The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups.

Development of a dynamic quality assurance testing protocol for multisite clinical trial DCE-CT accreditation

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

Driscoll, B.; Keller, H.; Jaffray, D.

2013-08-15

Purpose: Credentialing can have an impact on whether or not a clinical trial produces useful quality data that is comparable between various institutions and scanners. With the recent increase of dynamic contrast enhanced-computed tomography (DCE-CT) usage as a companion biomarker in clinical trials, effective quality assurance, and control methods are required to ensure there is minimal deviation in the results between different scanners and protocols at various institutions. This paper attempts to address this problem by utilizing a dynamic flow imaging phantom to develop and evaluate a DCE-CT quality assurance (QA) protocol.Methods: A previously designed flow phantom, capable of producingmore » predictable and reproducible time concentration curves from contrast injection was fully validated and then utilized to design a DCE-CT QA protocol. The QA protocol involved a set of quantitative metrics including injected and total mass error, as well as goodness of fit comparison to the known truth concentration curves. An additional region of interest (ROI) sensitivity analysis was also developed to provide additional details on intrascanner variability and determine appropriate ROI sizes for quantitative analysis. Both the QA protocol and ROI sensitivity analysis were utilized to test variations in DCE-CT results using different imaging parameters (tube voltage and current) as well as alternate reconstruction methods and imaging techniques. The developed QA protocol and ROI sensitivity analysis was then applied at three institutions that were part of clinical trial involving DCE-CT and results were compared.Results: The inherent specificity of robustness of the phantom was determined through calculation of the total intraday variability and determined to be less than 2.2 ± 1.1% (total calculated output contrast mass error) with a goodness of fit (R{sup 2}) of greater than 0.99 ± 0.0035 (n= 10). The DCE-CT QA protocol was capable of detecting significant deviations from the expected phantom result when scanning at low mAs and low kVp in terms of quantitative metrics (Injected Mass Error 15.4%), goodness of fit (R{sup 2}) of 0.91, and ROI sensitivity (increase in minimum input function ROI radius by 146 ± 86%). These tests also confirmed that the ASIR reconstruction process was beneficial in reducing noise without substantially increasing partial volume effects and that vendor specific modes (e.g., axial shuttle) did not significantly affect the phantom results. The phantom and QA protocol were finally able to quickly (<90 min) and successfully validate the DCE-CT imaging protocol utilized at the three separate institutions of a multicenter clinical trial; thereby enhancing the confidence in the patient data collected.Conclusions: A DCE QA protocol was developed that, in combination with a dynamic multimodality flow phantom, allows the intrascanner variability to be separated from other sources of variability such as the impact of injection protocol and ROI selection. This provides a valuable resource that can be utilized at various clinical trial institutions to test conformance with imaging protocols and accuracy requirements as well as ensure that the scanners are performing as expected for dynamic scans.« less

An analysis of current pharmaceutical industry practices for making clinical trial results publicly accessible.

PubMed

Viereck, Christopher; Boudes, Pol

2009-07-01

We compared the clinical trial transparency practices of US/European pharma by analyzing the publicly-accessible clinical trial results databases of major drugs (doripenem, varenicline, lapatinib, zoledronic acid, adalimumab, insulin glargine, raltegravir, gefitinib). We evaluated their accessibility and utility from the perspective of the lay public. We included databases on company websites, http://www.clinicalstudyresults.org, http://www.clinicaltrials.gov and http://clinicaltrials.ifpma.org. Only 2 of 8 company homepages provide a direct link to the results. While the use of common terms on company search engines led to results for 5 of the 8 drugs following 2-4 clicks, no logical pathway was identified. The number of clinical trials in the databases was inconsistent: 0 for doripenem to 45 for insulin glargine. Results from all phases of clinical development were provided for 2 (insulin glargine and gefitinib) of the 8 drugs. Analyses of phase III reports revealed that most critical elements of the International Conference of Harmonization E3 Structure and Content of Synopses for Clinical Trial Reports were provided for 2 (varenicline, lapatinib) of the 8 drugs. For adalimumab and zoledronic acid, only citations were provided, which the lay public would be unable to access. None of the clinical trial reports was written in lay language. User-friendly support, when provided, was of marginal benefit. Only 1 of the databases (gefitinib) permitted the user to find the most recently updated reports. None of the glossaries included explanations for adverse events or statistical methodology. In conclusion, our study indicates that the public faces significant hurdles in finding and understanding clinical trial results databases.

Accuracy of point-of-care serum creatinine devices for detecting patients at risk of contrast-induced nephropathy: a critical overview.

PubMed

Martínez Lomakin, Felipe; Tobar, Catalina

2014-12-01

Contrast-induced nephropathy (CIN) is a common event in hospitals, with reported incidences ranging from 1 to 30%. Patients with underlying kidney disease have an increased risk of developing CIN. Point-of-care (POC) creatinine devices are handheld devices capable of providing quantitative data on a patient's kidney function that could be useful in stratifying preventive measures. This overview aims to synthesize the current evidence on diagnostic accuracy and clinical utility of POC creatinine devices in detecting patients at risk of CIN. Five databases were searched for diagnostic accuracy studies or clinical trials that evaluated the usefulness of POC devices in detecting patients at risk of CIN. Selected articles were critically appraised to assess their individual risk of bias by the use of standard criteria; 13 studies were found that addressed the diagnostic accuracy or clinical utility of POC creatinine devices. Most studies incurred a moderate to high risk of bias. Overall concordance between POC devices and reference standards (clinical laboratory procedures) was found to be moderate, with 95% limits of agreement often lying between -35.4 and +35.4 µmol/L (-0.4 and +0.4 mg/dL). Concordance was shown to decrease with worsening kidney function. Data on the clinical utility of these devices were limited, but a significant reduction in time to diagnosis was reported in two studies. Overall, POC creatinine devices showed a moderate concordance with standard clinical laboratory creatinine measurements. Several biases could have induced optimism in these estimations. Results obtained from these devices may be unreliable in cases of severe kidney failure. Randomized trials are needed to address the clinical utility of these devices.

Reinforcement Learning Strategies for Clinical Trials in Non-small Cell Lung Cancer

PubMed Central

Zhao, Yufan; Zeng, Donglin; Socinski, Mark A.; Kosorok, Michael R.

2010-01-01

Summary Typical regimens for advanced metastatic stage IIIB/IV non-small cell lung cancer (NSCLC) consist of multiple lines of treatment. We present an adaptive reinforcement learning approach to discover optimal individualized treatment regimens from a specially designed clinical trial (a “clinical reinforcement trial”) of an experimental treatment for patients with advanced NSCLC who have not been treated previously with systemic therapy. In addition to the complexity of the problem of selecting optimal compounds for first and second-line treatments based on prognostic factors, another primary goal is to determine the optimal time to initiate second-line therapy, either immediately or delayed after induction therapy, yielding the longest overall survival time. A reinforcement learning method called Q-learning is utilized which involves learning an optimal regimen from patient data generated from the clinical reinforcement trial. Approximating the Q-function with time-indexed parameters can be achieved by using a modification of support vector regression which can utilize censored data. Within this framework, a simulation study shows that the procedure can extract optimal regimens for two lines of treatment directly from clinical data without prior knowledge of the treatment effect mechanism. In addition, we demonstrate that the design reliably selects the best initial time for second-line therapy while taking into account the heterogeneity of NSCLC across patients. PMID:21385164

Clinical outcomes research in gynecologic oncology.

PubMed

Melamed, Alexander; Rauh-Hain, J Alejandro; Schorge, John O

2017-09-01

Clinical outcomes research seeks to understand the real-world manifestations of clinical care. In particular, outcomes research seeks to reveal the effects of pharmaceutical, procedural, and structural aspects of healthcare on patient outcomes, including mortality, disease control, toxicity, cost, and quality of life. Although outcomes research can utilize interventional study designs, insightful use of observational data is a defining feature of this field. Many questions in gynecologic oncology are not amenable to investigation in randomized clinical trials due to cost, feasibility, or ethical concerns. When a randomized trial is not practical or has not yet been conducted, well-designed observational studies have the potential to provide the best available evidence about the effects of clinical care. Such studies may use surveys, medical records, disease registries, and a variety of administrative data sources. Even when a randomized trial has been conducted, observational studies can be used to estimate the real-world effect of an intervention, which may differ from the results obtained in the controlled setting of a clinical trial. This article reviews the goals, methodologies, data sources, and limitations of clinical outcomes research, with a focus on gynecologic oncology. Copyright © 2017. Published by Elsevier Inc.

Clinical studies and anti-inflammatory mechanisms of treatments.

PubMed

French, Jacqueline A; Koepp, Matthias; Naegelin, Yvonne; Vigevano, Federico; Auvin, Stéphane; Rho, Jong M; Rosenberg, Evan; Devinsky, Orrin; Olofsson, Peder S; Dichter, Marc A

2017-07-01

In this exciting era, we are coming closer and closer to bringing an anti-inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti-inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both "conventional, broad spectrum" anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

PubMed

Harris, Lyndsay N; Ismaila, Nofisat; McShane, Lisa M; Andre, Fabrice; Collyar, Deborah E; Gonzalez-Angulo, Ana M; Hammond, Elizabeth H; Kuderer, Nicole M; Liu, Minetta C; Mennel, Robert G; Van Poznak, Catherine; Bast, Robert C; Hayes, Daniel F

2016-04-01

To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences. © 2016 by American Society of Clinical Oncology.

A generic minimization random allocation and blinding system on web.

PubMed

Cai, Hongwei; Xia, Jielai; Xu, Dezhong; Gao, Donghuai; Yan, Yongping

2006-12-01

Minimization is a dynamic randomization method for clinical trials. Although recommended by many researchers, the utilization of minimization has been seldom reported in randomized trials mainly because of the controversy surrounding the validity of conventional analyses and its complexity in implementation. However, both the statistical and clinical validity of minimization were demonstrated in recent studies. Minimization random allocation system integrated with blinding function that could facilitate the implementation of this method in general clinical trials has not been reported. SYSTEM OVERVIEW: The system is a web-based random allocation system using Pocock and Simon minimization method. It also supports multiple treatment arms within a trial, multiple simultaneous trials, and blinding without further programming. This system was constructed with generic database schema design method, Pocock and Simon minimization method and blinding method. It was coded with Microsoft Visual Basic and Active Server Pages (ASP) programming languages. And all dataset were managed with a Microsoft SQL Server database. Some critical programming codes were also provided. SIMULATIONS AND RESULTS: Two clinical trials were simulated simultaneously to test the system's applicability. Not only balanced groups but also blinded allocation results were achieved in both trials. Practical considerations for minimization method, the benefits, general applicability and drawbacks of the technique implemented in this system are discussed. Promising features of the proposed system are also summarized.

A data-driven approach to quality risk management.

PubMed

Alemayehu, Demissie; Alvir, Jose; Levenstein, Marcia; Nickerson, David

2013-10-01

An effective clinical trial strategy to ensure patient safety as well as trial quality and efficiency involves an integrated approach, including prospective identification of risk factors, mitigation of the risks through proper study design and execution, and assessment of quality metrics in real-time. Such an integrated quality management plan may also be enhanced by using data-driven techniques to identify risk factors that are most relevant in predicting quality issues associated with a trial. In this paper, we illustrate such an approach using data collected from actual clinical trials. Several statistical methods were employed, including the Wilcoxon rank-sum test and logistic regression, to identify the presence of association between risk factors and the occurrence of quality issues, applied to data on quality of clinical trials sponsored by Pfizer. ONLY A SUBSET OF THE RISK FACTORS HAD A SIGNIFICANT ASSOCIATION WITH QUALITY ISSUES, AND INCLUDED: Whether study used Placebo, whether an agent was a biologic, unusual packaging label, complex dosing, and over 25 planned procedures. Proper implementation of the strategy can help to optimize resource utilization without compromising trial integrity and patient safety.

A Pilot Study of a Culturally Targeted Video Intervention to Increase Participation of African American Patients in Cancer Clinical Trials

PubMed Central

Libin, Alexander V.; Wang, Hong; Swain, Sandra M.

2012-01-01

Purpose. Barriers to clinical trial participation among African American cancer patients are well characterized in the literature. Attitudinal barriers encompassing fear, distrust, and concerns about ethical misconduct are also well documented. To increase trial accrual, these attitudes must be adequately addressed, yet there remains a lack of targeted interventions toward this end. We developed a 15-minute culturally targeted video designed to impact six specific attitudes of African American cancer patients toward therapeutic trials. We conducted a pilot study to test in the first such intervention to increase intention to enroll. Patients and Methods. The primary study outcome was self-reported likelihood to participate in a therapeutic trial. Using a mixed methods approach, we developed the Attitudes and Intention to Enroll in Therapeutic Clinical Trials (AIET) instrument, a 30-item questionnaire measuring six attitudinal barriers to African American trial participation. We enrolled 108 eligible active treatment patients at a large urban cancer institute. McNemar's test for matched pairs was used to assess changes in attitudes and likelihood to enroll in a clinical trial at baseline and immediately after the video. Pre- and post-video AIET summative scores were analyzed by paired t-test for each attitudinal barrier. Results. Patients' likelihood of enrolling in a clinical trial significantly increased post-video with 36% of the sample showing positive changes in intention [McNemar's χ2 = 33.39, p < .001]. Paired t-tests showed significant changes in all six attitudinal barriers measured via AIET summative scores from pre- to post-video. Conclusion. These data suggest utility of our video for increasing African American participation in clinical trials. PMID:22639112

Lost in translation: neuropsychiatric drug development.

PubMed

Becker, Robert E; Greig, Nigel H

2010-12-08

Recent studies have identified troubling method and practice lapses in neuropsychiatric drug developments. These problems have resulted in errors that are of sufficient magnitude to invalidate clinical trial data and interpretations. We identify two potential sources for these difficulties: investigators selectively choosing scientific practices for demonstrations of efficacy in human-testing phases of drug development and investigators failing to anticipate the needs of practitioners who must optimize treatment for the individual patient. When clinical investigators neglect to use clinical trials as opportunities to test hypotheses of disease mechanisms in humans, the neuropsychiatric knowledge base loses both credibility and scope. When clinical investigators do not anticipate the need to translate discoveries into applications, the practitioner cannot provide optimal care for the patient. We conclude from this evidence that clinical trials, and other aspects of neuropsychiatric drug development, must adopt more practices from basic science and show greater responsiveness to conditions of clinical practice. We feel that these changes are necessary to overcome current threats to the validity and utility of studies of neurological and psychiatric drugs.

Cervical auscultation in the diagnosis of oropharyngeal aspiration in children: a study protocol for a randomised controlled trial

PubMed Central

2013-01-01

Background Oropharyngeal aspiration (OPA) can lead to recurrent respiratory illnesses and chronic lung disease in children. Current clinical feeding evaluations performed by speech pathologists have poor reliability in detecting OPA when compared to radiological procedures such as the modified barium swallow (MBS). Improved ability to diagnose OPA accurately via clinical evaluation potentially reduces reliance on expensive, less readily available radiological procedures. Our study investigates the utility of adding cervical auscultation (CA), a technique of listening to swallowing sounds, in improving the diagnostic accuracy of a clinical evaluation for the detection of OPA. Methods We plan an open, unblinded, randomised controlled trial at a paediatric tertiary teaching hospital. Two hundred and sixteen children fulfilling the inclusion criteria will be randomised to one of the two clinical assessment techniques for the clinical detection of OPA: (1) clinical feeding evaluation only (CFE) group or (2) clinical feeding evaluation with cervical auscultation (CFE + CA) group. All children will then undergo an MBS to determine radiologically assessed OPA. The primary outcome is the presence or absence of OPA, as determined on MBS using the Penetration-Aspiration Scale. Our main objective is to determine the sensitivity, specificity, negative and positive predictive values of ‘CFE + CA’ versus ‘CFE’ only compared to MBS-identified OPA. Discussion Early detection and appropriate management of OPA is important to prevent chronic pulmonary disease and poor growth in children. As the reliability of CFE to detect OPA is low, a technique that can improve the diagnostic accuracy of the CFE will help minimise consequences to the paediatric respiratory system. Cervical auscultation is a technique that has previously been documented as a clinical adjunct to the CFE; however, no published RCTs addressing the reliability of this technique in children exist. Our study will be the first to establish the utility of CA in assessing and diagnosing OPA risk in young children. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12613000589785. PMID:24199872

Incremental validity of estimated cannabis grams as a predictor of problems and cannabinoid biomarkers: Evidence from a clinical trial.

PubMed

Tomko, Rachel L; Baker, Nathaniel L; McClure, Erin A; Sonne, Susan C; McRae-Clark, Aimee L; Sherman, Brian J; Gray, Kevin M

2018-01-01

Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams. This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N=300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder. Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X 2 =98.3; p<0.05) and in the model predicting problems due to cannabis use (X 2 =6.4; p<0.05), relative to a model that contained only simpler measures of quantity and frequency. This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial). Copyright © 2017 Elsevier B.V. All rights reserved.

Advances in the management of multiple sclerosis spasticity: recent clinical trials.

PubMed

Fernández, Oscar

2014-01-01

Most patients with multiple sclerosis (MS) experience spasticity as the clinical course evolves. Associated symptoms include (often painful) spasms, urinary dysfunction and sleep disturbances. THC:CBD oromucosal spray (Sativex®) is approved for symptom improvement in adult patients with moderate to severe MS-related spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In pivotal clinical trials of THC:CBD oromucosal spray, a meaningful proportion of patients with treatment-resistant MS spasticity achieved clinically relevant improvement with active treatment versus placebo. The utility of a 4-week trial of therapy to identify patients who respond to treatment was demonstrated in an enriched-design study. THC:CBD oromucosal spray was well tolerated in these studies, with no evidence of effects typically associated with recreational cannabis use. In a subsequent post approval clinical trial, THC:CBD oromucosal spray had no statistically significant effect on cognition and mood compared with placebo. Moreover, after 50 weeks' treatment, approximately two-thirds of patients, physicians and caregivers reported improvement from baseline in spasticity based on global impressions of change. Key Messages: In phase III clinical trials, approximately one-third of MS patients with treatment-resistant spasticity had a clinically relevant and statistically significant response to THC:CBD oromucosal spray. In addition to a reduction in spasticity, responders experienced meaningful relief from associated symptoms. THC:CBD oromucosal spray was generally well tolerated and efficacy was maintained over the longer term. A post-approval clinical trial indicated no effect of THC:CBD oromucosal spray on cognition or mood after 50 weeks of use. © 2014 S. Karger AG, Basel.

Efficacy of Individualized Clinical Coaching in a Virtual Reality Classroom for Increasing Teachers' Fidelity of Implementation of Discrete Trial Teaching

ERIC Educational Resources Information Center

Garland, Krista Vince; Vasquez, Eleazar, III; Pearl, Cynthia

2012-01-01

Discrete-trials teaching (DTT) is an evidence-based practice used in educational programs for children with autism spectrum disorders (ASD). Although there is strong demand for preparing teachers to effectively implement DTT, there is a scarcity of published research on such studies. A multiple baseline across participants design was utilized to…

Liquid biopsy and its role in an advanced clinical trial for lung cancer.

PubMed

Johann, Donald J; Steliga, Mathew; Shin, Ik J; Yoon, Donghoon; Arnaoutakis, Konstantinos; Hutchins, Laura; Liu, Meeiyueh; Liem, Jason; Walker, Karl; Pereira, Andy; Yang, Mary; Jeffus, Susanne K; Peterson, Erich; Xu, Joshua

2018-02-01

Liquid biopsy methodologies, for the purpose of plasma genotyping of cell-free DNA (cfDNA) of solid tumors, are a new class of novel molecular assays. Such assays are rapidly entering the clinical sphere of research-based monitoring in translational oncology, especially for thoracic malignancies. Potential applications for these blood-based cfDNA assays include: (i) initial diagnosis, (ii) response to therapy and follow-up, (iii) tumor evolution, and (iv) minimal residual disease evaluation. Precision medicine will benefit from cutting-edge molecular diagnostics, especially regarding treatment decisions in the adjuvant setting, where avoiding over-treatment and unnecessary toxicity are paramount. The use of innovative genetic analysis techniques on individual patient tumor samples is being pursued in several advanced clinical trials. Rather than using a categorical treatment plan, the next critical step of therapeutic decision making is providing the "right" cancer therapy for an individual patient, including correct dose and timeframe based on the molecular analysis of the tumor in question. Per the 21st Century Cures Act, innovative clinical trials are integral for biomarker and drug development. This will include advanced clinical trials utilizing: (i) innovative assays, (ii) molecular profiling with cutting-edge bioinformatics, and (iii) clinically relevant animal or tissue models. In this paper, a mini-review addresses state-of-the-art liquid biopsy approaches. Additionally, an on-going advanced clinical trial for lung cancer with novelty through synergizing liquid biopsies, co-clinical trials, and advanced bioinformatics is also presented. Impact statement Liquid biopsy technology is providing a new source for cancer biomarkers, and adds new dimensions in advanced clinical trials. Utilizing a non-invasive routine blood draw, the liquid biopsy provides abilities to address perplexing issues of tumor tissue heterogeneity by identifying mutations in both primary and metastatic lesions. Regarding the assessment of response to cancer therapy, the liquid biopsy is not ready to replace medical imaging, but adds critical new information; for instance, through a temporal assessment of quantitative circulating tumor DNA (ctDNA) assay results, and importantly, the ability to monitor for signs of resistance, via emerging clones. Adjuvant therapy may soon be considered based on a quantitative cfDNA assay. As sensitivity and specificity of the technology continue to progress, cancer screening and prevention will improve and save countless lives by finding the cancer early, so that a routine surgery may be all that is required for a definitive cure.

Medicare long-term CPAP coverage policy: a cost-utility analysis.

PubMed

Billings, Martha E; Kapur, Vishesh K

2013-10-15

CPAP is an effective treatment for OSA that may reduce health care utilization and costs. Medicare currently reimburses the costs of long-term CPAP therapy only if the patient is adherent during a 90-day trial. If not, Medicare requires a repeat polysomnogram (PSG) and another trial which seems empirically not cost-effective. We modeled the cost-effectiveness of current Medicare policy compared to an alternative policy (clinic-only) without the adherence criterion and repeat PSG. Cost-utility and cost-effectiveness analysis. U.S. Medicare Population. N/A. N/A. We created a decision tree modeling (1) clinic only follow-up vs. (2) current Medicare policy. Costs were assigned based on Medicare reimbursement rates in 2012. Sensitivity analyses were conducted to test our assumptions. We estimated cumulative costs, overall adherence, and QALY gained for a 5-year time horizon from the perspective of Medicare as the payer. Current Medicare policy is more costly than the clinic-only policy but has higher net adherence and improved utility. Current Medicare policy compared to clinic-only policy costs $30,544 more per QALY. Current CMS policy promotes early identification of those more likely to adhere to CPAP therapy by requiring strict adherence standards. The policy effect is to deny coverage to those unlikely to use CPAP long-term and prevent wasted resources. Future studies are needed to measure long-term adherence in an elderly population with and without current adherence requirements to verify the cost-effectiveness of a policy change.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

PubMed Central

Harris, Lyndsay N.; McShane, Lisa M.; Andre, Fabrice; Collyar, Deborah E.; Gonzalez-Angulo, Ana M.; Hammond, Elizabeth H.; Kuderer, Nicole M.; Liu, Minetta C.; Mennel, Robert G.; Van Poznak, Catherine; Bast, Robert C.; Hayes, Daniel F.

2016-01-01

Purpose To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. Methods A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. Recommendations In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences. PMID:26858339

Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.

PubMed

Dubovsky, Jason A; Beckwith, Kyle A; Natarajan, Gayathri; Woyach, Jennifer A; Jaglowski, Samantha; Zhong, Yiming; Hessler, Joshua D; Liu, Ta-Ming; Chang, Betty Y; Larkin, Karilyn M; Stefanovski, Matthew R; Chappell, Danielle L; Frissora, Frank W; Smith, Lisa L; Smucker, Kelly A; Flynn, Joseph M; Jones, Jeffrey A; Andritsos, Leslie A; Maddocks, Kami; Lehman, Amy M; Furman, Richard; Sharman, Jeff; Mishra, Anjali; Caligiuri, Michael A; Satoskar, Abhay R; Buggy, Joseph J; Muthusamy, Natarajan; Johnson, Amy J; Byrd, John C

2013-10-10

Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.

Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes

PubMed Central

Dubovsky, Jason A.; Beckwith, Kyle A.; Natarajan, Gayathri; Woyach, Jennifer A.; Jaglowski, Samantha; Zhong, Yiming; Hessler, Joshua D.; Liu, Ta-Ming; Chang, Betty Y.; Larkin, Karilyn M.; Stefanovski, Matthew R.; Chappell, Danielle L.; Frissora, Frank W.; Smith, Lisa L.; Smucker, Kelly A.; Flynn, Joseph M.; Jones, Jeffrey A.; Andritsos, Leslie A.; Maddocks, Kami; Lehman, Amy M.; Furman, Richard; Sharman, Jeff; Mishra, Anjali; Caligiuri, Michael A.; Satoskar, Abhay R.; Buggy, Joseph J.; Muthusamy, Natarajan; Johnson, Amy J.

2013-01-01

Given its critical role in T-cell signaling, interleukin-2–inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749. PMID:23886836

Considerations and challenges in defining optimal iron utilization in hemodialysis.

PubMed

Charytan, David M; Pai, Amy Barton; Chan, Christopher T; Coyne, Daniel W; Hung, Adriana M; Kovesdy, Csaba P; Fishbane, Steven

2015-06-01

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population. Copyright © 2015 by the American Society of Nephrology.

Patient-oriented randomisation: A new trial design applied in the Neuroleptic Strategy Study.

PubMed

Schulz, Constanze; Timm, Jürgen; Cordes, Joachim; Gründer, Gerhard; Mühlbauer, Bernd; Rüther, Eckart; Heinze, Martin

2016-06-01

The 'gold standard' for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians' preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types. The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients' needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia. In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians' preferences for specific drugs used for the respective patients were analysed. The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient-drug interaction, this design should prove particularly useful. © The Author(s) 2016.

Assessing Clinical Trial–Associated Workload in Community-Based Research Programs Using the ASCO Clinical Trial Workload Assessment Tool

PubMed Central

Hurley, Patricia; Woo, Kaitlin M.; Szczepanek, Connie; Stewart, Teresa; Robert, Nicholas; Lyss, Alan; Gönen, Mithat; Lilenbaum, Rogerio

2016-01-01

Purpose: Clinical research program managers are regularly faced with the quandary of determining how much of a workload research staff members can manage while they balance clinical practice and still achieve clinical trial accrual goals, maintain data quality and protocol compliance, and stay within budget. A tool was developed to measure clinical trial–associated workload, to apply objective metrics toward documentation of work, and to provide clearer insight to better meet clinical research program challenges and aid in balancing staff workloads. A project was conducted to assess the feasibility and utility of using this tool in diverse research settings. Methods: Community-based research programs were recruited to collect and enter clinical trial–associated monthly workload data into a web-based tool for 6 consecutive months. Descriptive statistics were computed for self-reported program characteristics and workload data, including staff acuity scores and number of patient encounters. Results: Fifty-one research programs that represented 30 states participated. Median staff acuity scores were highest for staff with patients enrolled in studies and receiving treatment, relative to staff with patients in follow-up status. Treatment trials typically resulted in higher median staff acuity, relative to cancer control, observational/registry, and prevention trials. Industry trials exhibited higher median staff acuity scores than trials sponsored by the National Institutes of Health/National Cancer Institute, academic institutions, or others. Conclusion: The results from this project demonstrate that trial-specific acuity measurement is a better measure of workload than simply counting the number of patients. The tool was shown to be feasible and useable in diverse community-based research settings. PMID:27006354

Quality Management Tools: Facilitating Clinical Research Data Integrity by Utilizing Specialized Reports with Electronic Case Report Forms

PubMed Central

Trocky, NM; Fontinha, M

2005-01-01

Data collected throughout the course of a clinical research trial must be reviewed for accuracy and completeness continually. The Oracle Clinical® (OC) data management application utilized to capture clinical data facilitates data integrity through pre-programmed validations, edit and range checks, and discrepancy management modules. These functions were not enough. Coupled with the use of specially created reports in Oracle Discoverer® and Integrated Review TM, both ad-hoc query and reporting tools, research staff have enhanced their ability to clean, analyze and report more accurate data captured within and among Case Report Forms (eCRFs) by individual study or across multiple studies. PMID:16779428

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections.

PubMed

Khashab, Mohammed M; Xiang, Jim; Kahn, James B

2006-10-01

To compare safety data with levofloxacin 500 mg and 750 mg from clinical trials for the treatment of respiratory infections. We compared adverse event data for levofloxacin 500 mg and 750 mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy. Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500 mg and in 45.5% (519/1141) of those treated with 750 mg (p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) (p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in > or = 2% of patients. Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750 mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.

Bridging the gap in complementary and alternative medicine research: manualization as a means of promoting standardization and flexibility of treatment in clinical trials of acupuncture.

PubMed

Schnyer, Rosa N; Allen, John J B

2002-10-01

An important methodological challenge encountered in acupuncture clinical research involves the design of treatment protocols that help ensure standardization and replicability while allowing for the necessary flexibility to tailor treatments to each individual. Manualization of protocols used in clinical trials of acupuncture and other traditionally-based complementary and alternative medicine (CAM) systems facilitates the systematic delivery of replicable and standardized, yet individually-tailored treatments. To facilitate high-quality CAM acupuncture research by outlining a method for the systematic design and implementation of protocols used in CAM clinical trials based on the concept of treatment manualization. A series of treatment manuals was developed to systematically articulate the Chinese medical theoretical and clinical framework for a given Western-defined illness, to increase the quality and consistency of treatment, and to standardize the technical aspects of the protocol. In all, three manuals were developed for National Institutes of Health (NIH)-funded clinical trials of acupuncture for depression, spasticity in cerebral palsy, and repetitive stress injury. In Part I, the rationale underlying these manuals and the challenges encountered in creating them are discussed, and qualitative assessments of their utility are provided. In Part II, a methodology to develop treatment manuals for use in clinical trials is detailed, and examples are given. A treatment manual provides a precise way to train and supervise practitioners, enable evaluation of conformity and competence, facilitate the training process, and increase the ability to identify the active therapeutic ingredients in clinical trials of acupuncture.

Measures that identify prescription medication misuse, abuse, and related events in clinical trials: ACTTION critique and recommended considerations

PubMed Central

Smith, Shannon M.; Jones, Judith K.; Katz, Nathaniel P.; Roland, Carl L.; Setnik, Beatrice; Trudeau, Jeremiah J.; Wright, Stephen; Burke, Laurie B.; Comer, Sandra D.; Dart, Richard C.; Dionne, Raymond; Haddox, J. David; Jaffe, Jerome H.; Kopecky, Ernest A.; Martell, Bridget A.; Montoya, Ivan D.; Stanton, Marsha; Wasan, Ajay D.; Turk, Dennis C.; Dworkin, Robert H.

2017-01-01

Accurate assessment of inappropriate medication use events (i.e., misuse, abuse, and related events [MAREs]) occurring in clinical trials is an important component in evaluating a medication’s abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions [27]. Only 2 approaches have been reported that are specifically designed to identify and classify MAREs occurring in clinical trials, rather than to measure an individual’s risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion [SR-MAD] instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System [MADDERS]. The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively in order to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of both MADDERS and SR-MAD. PMID:28479207

Voice recognition software for clinical use.

PubMed

Korn, K

1998-11-01

The current generation voice recognition products truly offer the promise of voice recognition systems, that are financially and operationally acceptable for use in a health care facility. Although the initial capital outlay for the purchase of such equipment may be substantial, the long-term benefit is felt to outweigh the expense. The ability to utilize computer equipment for educational purposes and information management alone helps to rationalize the cost. In addition, it is important to remember that the Internet has become a substantial source of information which provides another functional use for this equipment. Although one can readily see the implication for such a program in clinical practice, other uses for the program should not be overlooked. Uses far beyond the writing of clinic notes and correspondence can be easily envisioned. Utilization of voice recognition software offers clinical practices the ability to produce quality printed records in a timely and cost-effective manner. After learning procedures for the selected product and appropriately formatting word processing software and printers, printed progress notes should be able to be produced in less time than traditional dictation and transcription methods. Although certain procedures and practices may need to be altered, or may preclude optimal utilization of this type of system, many advantages are apparent. It is recommended that facilities consider utilization of Voice Recognition products such as Dragon Systems Naturally Speaking Software, or at least consider a trial of this method with one of the limited-feature products, if current dictation practices are unsatisfactory or excessively costly. Free downloadable trial software or single user software can provide a reduced-cost method for trial evaluation of such products if a major commitment is not felt to be desired. A list of voice recognition software manufacturer web sites may be accessed through the following: http://www.dragonsys.com/ http://www.software.ibm/com/is/voicetype/ http://www.lhs.com/

Study design of the CLOSURE I Trial: a prospective, multicenter, randomized, controlled trial to evaluate the safety and efficacy of the STARFlex septal closure system versus best medical therapy in patients with stroke or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale.

PubMed

Furlan, Anthony J; Reisman, Mark; Massaro, Joseph; Mauri, Laura; Adams, Harold; Albers, Gregory W; Felberg, Robert; Herrmann, Howard; Kar, Saibal; Landzberg, Michael; Raizner, Albert; Wechsler, Lawrence

2010-12-01

Some strokes of unknown etiology may be the result of a paradoxical embolism traversing through a nonfused foramen ovale (patent foramen ovale [PFO]). The utility of percutaneously placed devices for treatment of patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO is unknown. In addition, there are no clear data about the utility of medical interventions or other surgical procedures in this situation. Despite limited data, many patients are being treated with PFO closure devices. Thus, there is a strong need for clinical trials that test the potential efficacy of PFO occlusive devices in this situation. To address this gap in medical knowledge, we designed the CLOSURE I trial, a randomized, clinical trial comparing the use of a percutaneously placed PFO occlusive device and best medical therapy versus best medical therapy alone for prevention of recurrent ischemic neurologic symptoms among persons with TIA or ischemic stroke. This prospective, multicenter, randomized, controlled trial has finished enrollment. Two-year follow-up for all 910 patients is required. The primary end point is the 2-year incidence of stroke or TIA, all-cause mortality for the first 30 days, and neurologic mortality from ≥ 31 days of follow-up, as adjudicated by a panel of physicians who are unaware of treatment allocation. This article describes the rationale and study design of CLOSURE I. This trial should provide information as to whether the STARFlex septal closure system is safe and more effective than best medical therapy alone in preventing recurrent stroke/TIA and mortality in patients with PFO and whether the STARFlex septal closure device can demonstrate superiority compared with best medical therapy alone. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00201461.

Breast Cancer Screening in a Low Income Managed Care Population

DTIC Science & Technology

1998-10-01

is the only screening test to be demonstrated by prospective clinical trial to decrease cancer mortality (11-13). Its efficiency and relative safety...increase in the utilization of mammography in conjunction with clinical breast exam, the technology continues to be underutilized, especially among certain...Using familiar sites for special program activities e.g. churches, clinic sites; Developing culturally-sensitive information at the appropriate literacy

Assessing the challenges of multi-scope clinical research sites: an example from NIH HIV/AIDS clinical trials networks.

PubMed

Rosas, Scott R; Cope, Marie T; Villa, Christie; Motevalli, Mahnaz; Utech, Jill; Schouten, Jeffrey T

2014-04-01

Large-scale, multi-network clinical trials are seen as a means for efficient and effective utilization of resources with greater responsiveness to new discoveries. Formal structures instituted within the National Institutes of Health (NIH) HIV/AIDS Clinical Trials facilitate collaboration and coordination across networks and emphasize an integrated approach to HIV/AIDS vaccine, prevention and therapeutics clinical trials. This study examines the joint usage of clinical research sites as means of gaining efficiency, extending capacity, and adding scientific value to the networks. A semi-structured questionnaire covering eight clinical management domains was administered to 74 (62% of sites) clinical site coordinators at single- and multi-network sites to identify challenges and efficiencies related to clinical trials management activities and coordination with multi-network units. Overall, respondents at multi-network sites did not report more challenges than single-network sites, but did report unique challenges to overcome including in the areas of study prioritization, community engagement, staff education and training, and policies and procedures. The majority of multi-network sites reported that such affiliations do allow for the consolidation and cost-sharing of research functions. Suggestions for increasing the efficiency or performance of multi-network sites included streamlining standards and requirements, consolidating protocol activation methods, using a single cross-network coordinating centre, and creating common budget and payment mechanisms. The results of this assessment provide important information to consider in the design and management of multi-network configurations for the NIH HIV/AIDS Clinical Trials Networks, as well as others contemplating and promoting the concept of multi-network settings. © 2013 John Wiley & Sons Ltd.

Global Health Innovation Technology Models.

PubMed

Harding, Kimberly

2016-01-01

Chronic technology and business process disparities between High Income, Low Middle Income and Low Income (HIC, LMIC, LIC) research collaborators directly prevent the growth of sustainable Global Health innovation for infectious and rare diseases. There is a need for an Open Source-Open Science Architecture Framework to bridge this divide. We are proposing such a framework for consideration by the Global Health community, by utilizing a hybrid approach of integrating agnostic Open Source technology and healthcare interoperability standards and Total Quality Management principles. We will validate this architecture framework through our programme called Project Orchid. Project Orchid is a conceptual Clinical Intelligence Exchange and Virtual Innovation platform utilizing this approach to support clinical innovation efforts for multi-national collaboration that can be locally sustainable for LIC and LMIC research cohorts. The goal is to enable LIC and LMIC research organizations to accelerate their clinical trial process maturity in the field of drug discovery, population health innovation initiatives and public domain knowledge networks. When sponsored, this concept will be tested by 12 confirmed clinical research and public health organizations in six countries. The potential impact of this platform is reduced drug discovery and public health innovation lag time and improved clinical trial interventions, due to reliable clinical intelligence and bio-surveillance across all phases of the clinical innovation process.

Global Health Innovation Technology Models

PubMed Central

Harding, Kimberly

2016-01-01

Chronic technology and business process disparities between High Income, Low Middle Income and Low Income (HIC, LMIC, LIC) research collaborators directly prevent the growth of sustainable Global Health innovation for infectious and rare diseases. There is a need for an Open Source-Open Science Architecture Framework to bridge this divide. We are proposing such a framework for consideration by the Global Health community, by utilizing a hybrid approach of integrating agnostic Open Source technology and healthcare interoperability standards and Total Quality Management principles. We will validate this architecture framework through our programme called Project Orchid. Project Orchid is a conceptual Clinical Intelligence Exchange and Virtual Innovation platform utilizing this approach to support clinical innovation efforts for multi-national collaboration that can be locally sustainable for LIC and LMIC research cohorts. The goal is to enable LIC and LMIC research organizations to accelerate their clinical trial process maturity in the field of drug discovery, population health innovation initiatives and public domain knowledge networks. When sponsored, this concept will be tested by 12 confirmed clinical research and public health organizations in six countries. The potential impact of this platform is reduced drug discovery and public health innovation lag time and improved clinical trial interventions, due to reliable clinical intelligence and bio-surveillance across all phases of the clinical innovation process.

Clinical utility of lenalidomide in the treatment of myelodysplastic syndromes

PubMed Central

Abou Zahr, Abdallah; Saad Aldin, Ehab; Komrokji, Rami S; Zeidan, Amer M

2015-01-01

Myelodysplastic syndromes (MDS) represent a heterogeneous group of acquired clonal hematopoietic disorders characterized by peripheral blood cytopenias, paradoxical BM hypercellularity, ineffective hematopoiesis, and increased risk of leukemic transformation. Risk stratification, using different prognostic scores and markers, is at the core of MDS management. Deletion 5q [del(5q)] MDS is a distinct class of MDS characterized by the haploinsufficiency of specific genes, microRNAs, and proteins, which has been linked to increased sensitivity to the drug lenalidomide. Phase II and III clinical trials have demonstrated the efficacy of lenalidomide in improving clinical outcomes of patients with del(5q) MDS, including reduction in red blood cell transfusion requirements and improvements in quality of life. Lenalidomide has also demonstrated some activity in non-del(5q) lower-risk MDS as well as higher-risk MDS, especially in combination with other agents. In this paper, we review the pathogenesis of del(5q) MDS, the proposed mechanisms of action of lenalidomide, the major clinical trials that documented the activity of lenalidomide in different MDS populations, potential predictors of benefit from the drug and suggested mechanisms of resistance, and the use of combination strategies to expand the clinical utility of lenalidomide in MDS. PMID:25565910

Medicine Based Evidence for Individualized Decision Making: Case Study of Systemic Lupus Erythematosus.

PubMed

Wivel, Ashley E; Lapane, Kate; Kleoudis, Christi; Singer, Burton H; Horwitz, Ralph I

2017-11-01

To guide management decisions for an index patient, evidence is required from comparisons between approximate matches to the profile of the index case, where some matches contain responses to treatment and others act as controls. We describe a method for constructing clinically relevant histories/profiles using data collected but unreported from 2 recent phase 3 randomized controlled trials assessing belimumab in subjects with clinically active and serologically positive systemic lupus erythematosus. Outcome was the Systemic lupus erythematosus Responder Index (SRI) measured at 52 weeks. Among 1175 subjects, we constructed an algorithm utilizing 11 trajectory variables including 4 biological, 2 clinical, and 5 social/behavioral. Across all biological and social/behavioral variables, the proportion of responders based on the SRI whose value indicated clinical worsening or no improvement ranged from 27.5% to 42.3%. Kappa values suggested poor agreement, indicating that each biological and patient-reported outcome provides different information than gleaned from the SRI. The richly detailed patient profiles needed to guide decision-making in clinical practice are sharply at odds with the limited information utilized in conventional randomized controlled trial analyses. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel joint selection methods can reduce sample size for rheumatoid arthritis clinical trials with ultrasound endpoints.

PubMed

Allen, John C; Thumboo, Julian; Lye, Weng Kit; Conaghan, Philip G; Chew, Li-Ching; Tan, York Kiat

2018-03-01

To determine whether novel methods of selecting joints through (i) ultrasonography (individualized-ultrasound [IUS] method), or (ii) ultrasonography and clinical examination (individualized-composite-ultrasound [ICUS] method) translate into smaller rheumatoid arthritis (RA) clinical trial sample sizes when compared to existing methods utilizing predetermined joint sites for ultrasonography. Cohen's effect size (ES) was estimated (ES^) and a 95% CI (ES^L, ES^U) calculated on a mean change in 3-month total inflammatory score for each method. Corresponding 95% CIs [nL(ES^U), nU(ES^L)] were obtained on a post hoc sample size reflecting the uncertainty in ES^. Sample size calculations were based on a one-sample t-test as the patient numbers needed to provide 80% power at α = 0.05 to reject a null hypothesis H 0 : ES = 0 versus alternative hypotheses H 1 : ES = ES^, ES = ES^L and ES = ES^U. We aimed to provide point and interval estimates on projected sample sizes for future studies reflecting the uncertainty in our study ES^S. Twenty-four treated RA patients were followed up for 3 months. Utilizing the 12-joint approach and existing methods, the post hoc sample size (95% CI) was 22 (10-245). Corresponding sample sizes using ICUS and IUS were 11 (7-40) and 11 (6-38), respectively. Utilizing a seven-joint approach, the corresponding sample sizes using ICUS and IUS methods were nine (6-24) and 11 (6-35), respectively. Our pilot study suggests that sample size for RA clinical trials with ultrasound endpoints may be reduced using the novel methods, providing justification for larger studies to confirm these observations. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Postapproval Development Options in COPD: A Case Study in Value-Based Healthcare Systems.

PubMed

Murphy, Michael F; Antonini, Paola; Lai, Zhihong Vicki

2011-01-01

Research and development activities in an era of globalization encounter a mosaic of providers, products, services, and intermediaries; regulatory and other government institutions; and consumers. The introduction of novel therapeutics into this environment mandates research programs that are relevant to the registration process, payers and purchasers, transparent pricing, and rule-driven business practices, while providing data relevant to marketing initiatives internationally. To outline an example for clinical development programs that incorporate the perspective of multiple stakeholders into a portfolio of study designs to provide optimal data platforms that can resonate with diverse recipients. A contract research organization directly involved in the design, execution, and analysis of clinical trials for new drugs and devices across pharmaceutical and biotechnology companies provides a unique perspective regarding opportunities and challenges within the international clinical research environment. Drs Murphy, Antonini, and Lai, representing Worldwide Clinical Trials, utilize chronic obstructive pulmonary disease as a demonstration project exploiting its prevalence, direct and indirect costs, and the rapid infusion/diffusion of innovative therapy into practice as a rationale for focus, and illustrate methods of informing registration and technology assessments during a prototypical development process. By virtue of its chronicity, prevalence, and pattern of healthcare utilization, chronic obstructive pulmonary disease provides an ideal case for illustrating the application of clinical trial methodology that can facilitate data evaluation through the prism of multiple stakeholders. Adding an international dimension exacerbates system complexity and serves to illustrate the breadth of issues that can be addressed within this therapeutic area.

Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2.

PubMed

Jack, Clifford R; Barnes, Josephine; Bernstein, Matt A; Borowski, Bret J; Brewer, James; Clegg, Shona; Dale, Anders M; Carmichael, Owen; Ching, Christopher; DeCarli, Charles; Desikan, Rahul S; Fennema-Notestine, Christine; Fjell, Anders M; Fletcher, Evan; Fox, Nick C; Gunter, Jeff; Gutman, Boris A; Holland, Dominic; Hua, Xue; Insel, Philip; Kantarci, Kejal; Killiany, Ron J; Krueger, Gunnar; Leung, Kelvin K; Mackin, Scott; Maillard, Pauline; Malone, Ian B; Mattsson, Niklas; McEvoy, Linda; Modat, Marc; Mueller, Susanne; Nosheny, Rachel; Ourselin, Sebastien; Schuff, Norbert; Senjem, Matthew L; Simonson, Alix; Thompson, Paul M; Rettmann, Dan; Vemuri, Prashanthi; Walhovd, Kristine; Zhao, Yansong; Zuk, Samantha; Weiner, Michael

2015-07-01

Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Medicare Long-Term CPAP Coverage Policy: A Cost-Utility Analysis

PubMed Central

Billings, Martha E.; Kapur, Vishesh K.

2013-01-01

Study Objectives: CPAP is an effective treatment for OSA that may reduce health care utilization and costs. Medicare currently reimburses the costs of long-term CPAP therapy only if the patient is adherent during a 90-day trial. If not, Medicare requires a repeat polysomnogram (PSG) and another trial which seems empirically not cost-effective. We modeled the cost-effectiveness of current Medicare policy compared to an alternative policy (clinic-only) without the adherence criterion and repeat PSG. Design: Cost-utility and cost-effectiveness analysis. Setting: U.S. Medicare Population. Patients or Participants: N/A. Interventions: N/A. Measurements and Results: We created a decision tree modeling (1) clinic only follow-up vs. (2) current Medicare policy. Costs were assigned based on Medicare reimbursement rates in 2012. Sensitivity analyses were conducted to test our assumptions. We estimated cumulative costs, overall adherence, and QALY gained for a 5-year time horizon from the perspective of Medicare as the payer. Current Medicare policy is more costly than the clinic-only policy but has higher net adherence and improved utility. Current Medicare policy compared to clinic-only policy costs $30,544 more per QALY. Conclusions: Current CMS policy promotes early identification of those more likely to adhere to CPAP therapy by requiring strict adherence standards. The policy effect is to deny coverage to those unlikely to use CPAP long-term and prevent wasted resources. Future studies are needed to measure long-term adherence in an elderly population with and without current adherence requirements to verify the cost-effectiveness of a policy change. Citation: Billings ME; Kapur VK. Medicare long-term CPAP coverage policy: a cost-utility analysis. J Clin Sleep Med 2013;9(10):1023-1029. PMID:24127146

Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group

PubMed Central

Scher, Howard I.; Halabi, Susan; Tannock, Ian; Morris, Michael; Sternberg, Cora N.; Carducci, Michael A.; Eisenberger, Mario A.; Higano, Celestia; Bubley, Glenn J.; Dreicer, Robert; Petrylak, Daniel; Kantoff, Philip; Basch, Ethan; Kelly, William Kevin; Figg, William D.; Small, Eric J.; Beer, Tomasz M.; Wilding, George; Martin, Alison; Hussain, Maha

2014-01-01

Purpose To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone. Methods A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data. Results The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group. Conclusion PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit. PMID:18309951

Clinical trials bureaucracy: unintended consequences of well-intentioned policy.

PubMed

Califf, Robert M

2006-01-01

As randomized controlled trials have become the 'gold standard' for medical research, a complex regulatory structure for the conduct of clinical trials has emerged. However, this structure has not been adequately assessed to ensure that regulations governing human subjects research actually produce the desired effects. Our purpose is to identify some of the major shortcomings in the current regulatory system of human clinical trials oversight, and to propose some potential solutions to these problems. We discuss the evolution of the current US regulatory environment and its application in the context of several widely-used drug therapies. Despite numerous randomized controlled trials, performed within a structure of extensive documentation and data collection, serious shortcomings in a number of pharmaceutical therapies were not detected until after the drugs were approved and widely adopted by clinicians. The current system of regulatory bureaucracy in clinical trials has led to an extremely expensive research paradigm that, in spite of complex systems of oversight and exhaustive data collection, cannot be shown to adequately ensure the integrity of the research process and the protection of human research subjects. Some parts of the system, including Research Ethics Review Boards, may not be well-suited to carrying out their core mission of overseeing research conduct, and other aspects of clinical trials regulatory structure, such as monitoring/auditing review and adverse event reporting, may constitute a waste of money and resources. Misdirected data collection and adverse events reporting divert valuable resources and hamper development of large, simple clinical trials powered to definitively answer important research questions. Careful scrutiny of the utility of current or proposed regulatory schemes is required to ensure the integrity of human subjects research and to enhance the effectiveness of research dollars.

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.

A data-driven approach to quality risk management

PubMed Central

Alemayehu, Demissie; Alvir, Jose; Levenstein, Marcia; Nickerson, David

2013-01-01

Aim: An effective clinical trial strategy to ensure patient safety as well as trial quality and efficiency involves an integrated approach, including prospective identification of risk factors, mitigation of the risks through proper study design and execution, and assessment of quality metrics in real-time. Such an integrated quality management plan may also be enhanced by using data-driven techniques to identify risk factors that are most relevant in predicting quality issues associated with a trial. In this paper, we illustrate such an approach using data collected from actual clinical trials. Materials and Methods: Several statistical methods were employed, including the Wilcoxon rank-sum test and logistic regression, to identify the presence of association between risk factors and the occurrence of quality issues, applied to data on quality of clinical trials sponsored by Pfizer. Results: Only a subset of the risk factors had a significant association with quality issues, and included: Whether study used Placebo, whether an agent was a biologic, unusual packaging label, complex dosing, and over 25 planned procedures. Conclusion: Proper implementation of the strategy can help to optimize resource utilization without compromising trial integrity and patient safety. PMID:24312890

Early initiation of beta blockade in heart failure: issues and evidence.

PubMed

Williams, Randall E

2005-09-01

Despite clinical trials demonstrating that inhibitors of the renin-angiotensin and sympathetic nervous systems can reduce the mortality and morbidity risk associated with heart failure, these drugs have remained underutilized in general clinical practice. In particular, many patients with heart failure due to left ventricular systolic dysfunction fail to receive beta blockers, although this class of drugs, as well as other antihypertensive agents such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, are recommended as part of routine heart failure therapy by national expert consensus guidelines. In-hospital initiation of beta-blocker therapy may improve long-term utilization by physicians and compliance by patients through obviating many of the misperceived dangers associated with beta blockade. The following review of the clinical trial data from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, the Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, and the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial on the efficacy, safety, and tolerability of beta blockers indicates that early initiation can be safely achieved and can improve patient outcomes.

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use.

PubMed

Nayak, Satyaprakash; Sander, Oliver; Al-Huniti, Nidal; de Alwis, Dinesh; Chain, Anne; Chenel, Marylore; Sunkaraneni, Soujanya; Agrawal, Shruti; Gupta, Neeraj; Visser, Sandra A G

2018-03-01

Quantitative pharmacology (QP) applications in translational medicine, drug-development, and therapeutic use were crowd-sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial-burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model-informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy. © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Early ART initiation among HIV-positive pregnant women in central Mozambique: a stepped wedge randomized controlled trial of an optimized Option B+ approach.

PubMed

Cowan, James F; Micek, Mark; Cowan, Jessica F Greenberg; Napúa, Manuel; Hoek, Roxanne; Gimbel, Sarah; Gloyd, Stephen; Sherr, Kenneth; Pfeiffer, James T; Chapman, Rachel R

2015-04-30

Despite effective prevention strategies and increasing investments in global health, maternal to child transmission (MTCT) of HIV remains a significant problem globally, especially in sub-Saharan Africa. In 2012, there were 94,000 HIV-positive pregnant women in Mozambique. Approximately 15% of these women transmitted HIV to their newborn infants, resulting in nearly 14,000 new pediatric HIV infections that year. To address this issue, in 2013, the Mozambican Ministry of Health implemented the World Health Organization-recommended "Option B+" strategy in which all newly diagnosed HIV-positive pregnant women are counseled to initiate combination anti-retroviral therapy (ART) immediately upon diagnosis regardless of CD4 count and to continue treatment for life. Given the limited experience with Option B+ in sub-Saharan Africa, few rigorous pragmatic trials have studied this new treatment strategy. This study utilizes an initial formative research process involving patient and health care provider interviews and focus groups, workforce assessments, value stream mapping, and commodity utilization assessments to understand the strengths and weaknesses in the current Option B+ care cascade. The formative research is intended to guide identification and prioritization of key workflow modifications and the development of an enhanced adherence and retention package. These two components are bundled into a defined intervention implemented and evaluated across six health facilities utilizing a stepped wedge randomized controlled trial study design. The overall objective of this trial is to develop and test a pilot intervention in central Mozambique to implement the new Option B+ guidelines with high fidelity and increase the proportion of HIV-positive pregnant women in target antenatal clinics (ANC) who start ART prior to delivery and are retained in care. This pragmatic study utilizes research strategies that have the potential to meaningfully improve the Option B+ care cascade in central Mozambique and to decrease the MTCT of HIV. This trial is designed to identify critical low-cost improvement strategies that can be bundled into a defined intervention. If this intervention has a measurable impact, it can be rapidly scaled up to other ANC in Mozambique and sub-Saharan Africa. ClinicalTrials.gov: NCT02371265.

Cost-effectiveness and cost-utility of cognitive therapy, rational emotive behavioral therapy, and fluoxetine (Prozac) in treating depression: a randomized clinical trial.

PubMed

Sava, Florin A; Yates, Brian T; Lupu, Viorel; Szentagotai, Aurora; David, Daniel

2009-01-01

Cost-effectiveness and cost-utility of cognitive therapy (CT), rational emotive behavioral therapy (REBT), and fluoxetine (Prozac) for major depressive disorder (MDD) were compared in a randomized clinical trial with a Romanian sample of 170 clients. Each intervention was offered for 14 weeks, plus three booster sessions. Beck Depression Inventory (BDI) scores were obtained prior to intervention, 7 and 14 weeks following the start of intervention, and 6 months following completion of intervention. CT, REBT, and fluoxetine did not differ significantly in changes in the BDI, depression-free days (DFDs), or Quality-Adjusted Life Years (QALYs). Average BDI scores decreased from 31.1 before treatment to 9.7 six months following completion of treatment. Due to lower costs, both psychotherapies were more cost-effective, and had better cost-utility, than pharmacotherapy: median $26.44/DFD gained/month for CT and $23.77/DFD gained/month for REBT versus $34.93/DFD gained/month for pharmacotherapy, median $/QALYs=$1,638, $1,734, and $2,287 for CT, REBT, and fluoxetine (Prozac), respectively. (c) 2008 Wiley Periodicals, Inc.

[Health services research the example of atopic dermatitis].

PubMed

Schmitt, J

2011-03-01

Within the past years, health services research projects have analyzed critically the management of atopic eczema (AE) in routine care, quantified the utility of controlling severe AE, and introduced an international standardization of core outcome measures for AE. With a prevalence of 16%, AE is the most frequent chronic condition at all among children and adolescents seeking medical care. Despite lower prevalence in adults, about 60% of patients with AE in routine care are adults. There is a clinically relevant comorbidity of AE and psychiatric conditions. Independent of patient's age and physician's medical discipline topical corticosteroids dominate outpatient treatment of AE. However, there is considerable heterogeneity in the management of AE between treating physicians. Despite a lack of clinical trials, systemic corticosteroids are most frequently prescribed for severe AE. In contrast, cyclosporine only plays a minor role in routine care of severe AE although its efficacy is well-documented in trials. This observation stimulated a head-to-head trial that indicated superiority of cyclosporine over prednisolone for severe adult AE. The control of severe AE has high priority from the perspective of the general population and from the patients' perspective. Competence of the treating physician, disease severity and patient's competence to adjust treatment to disease activity are the main determinants of patient satisfaction. Aiming for a better comparability of clinical trials and better translation of trial evidence into clinical practice, we conducted a Delphi exercise including clinical experts from 11 countries, editors of international dermatological journals, regulatory agencies, and patient representatives. The preliminary core set of outcome domains for eczema trials as defined by the panel included symptoms, physician-assessed clinical signs, and a measurement for long-term control of flares. Symptoms such as itching should be regularly assessed in clinical practice. The presented studies indicate that health services research not only describes and critically analyzes the effectiveness of routine clinical care, but is also translational research in that it may stimulate clinical trials and generate new, clinically relevant hypotheses for experimental studies.

Clinical utility of level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1.

PubMed

Schmitt, Manfred; Mengele, Karin; Napieralski, Rudolf; Magdolen, Viktor; Reuning, Ute; Gkazepis, Apostolos; Sweep, Fred; Brünner, Nils; Foekens, John; Harbeck, Nadia

2010-11-01

The prognostic and/or predictive value of the cancer biomarkers, urokinase-type plasminogen activator (uPA) and its inhibitor (plasminogen activator inhibitor [PAI]-1), determined by ELISA in tumor-tissue extracts, was demonstrated for several cancer types in numerous clinically relevant retrospective or prospective studies, including a multicenter breast cancer therapy trial (Chemo-N0). Consequently, for the first time ever for any cancer biomarker for breast cancer, uPA and PAI-1 have reached the highest level of evidence, level-of-evidence-1. At present, two other breast cancer therapy trials, NNBC-3 and Plan B, also incorporating uPA and PAI-1 as treatment-assignment tools are in effect. Furthermore, small synthetic molecules targeting uPA are currently in Phase II clinical trials in patients afflicted with advanced cancer of the ovary, breast or pancreas.

Individual and Composite Study Endpoints: Separating the Wheat from the Chaff

PubMed Central

Goldberg, Robert; Gore, Joel M.; Barton, Bruce; Gurwitz, Jerry

2014-01-01

We provide an overview of the individual and combined clinical endpoints and patient reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes. PMID:24486289

Evolving early (pre-dementia) Alzheimer's disease trials: suit the outcomes to the population and study design.

PubMed

Doody, R S

2010-04-01

Assuming that some cases of Alzheimer's disease (AD) could be prevented or delayed, prevention trials will be developed for this neurodegenerative condition. Initially, stakeholders will have to agree about the definition of prevention-true primary prevention, meaning the prevention of AD neuropathological changes; the prevention of clinical signs and symptoms that often augur AD; or preventing the progression of signs and symptoms to full-blown dementia. True primary prevention trials will have to rely completely upon neuroimaging or biomarker outcomes that reflect AD pathology. On the other hand, trials designed to prevent signs and symptoms of dementia will require researchers to agree on the phenomenology that would constitute an unequivocal endpoint: cognitive worsening on one or more measure compared to a normative group; development of Mild cognitive impairment (MCI); or development of Alzheimer's dementia. Prevention trials utilizing any of these outcomes in the general public will be large, will have to utilize low risk public health interventions, and might therefore have only a small impact (treatment effect size), especially if the studies are too short or the study populations are too diverse. An alternative to interventions aimed at the general public would be any attempt to prevent signs and symptoms of dementia in individuals thought to be at an increased risk for clinical dementia. These trials could try to reduce the development of signs and symptoms of dementia in cognitively normal subjects, or they could try to prevent progression from some form of Mild Cognitive Impairment to AD, or they could have the more subtle goal of reducing the accumulation of subclinical deficits in MCI subjects. If the populations for these trials are limited to individuals who have abnormal laboratory and neuroimaging studies associated with AD neuropathology, the results will not generalize to biomarker-negative, at risk individuals, who are likely to constitute the majority of any clinically relevant study population. Outcome measures for each study design will depend upon the characteristics of the study.

A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

DTIC Science & Technology

2014-09-01

antibody (J591) against the external portion of PSMA that binds to viable PSMA-expressing cells and is internalized. Studies utilizing J591...metastatic CRPC to bone (Rad223, Xofigo ®) leading to excitement within the field. A more tumor-targeted approach utilizing J591 is of increased...has generated renewed scientific and clinical interest. In addition, recent studies utilizing J591-based immuno- PET imaging providing additional

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.

Cost-effectiveness of post-diagnosis treatment in dementia coordinated by Multidisciplinary Memory Clinics in comparison to treatment coordinated by general practitioners: an example of a pragmatic trial.

PubMed

Meeuwsen, E J; German, P; Melis, R J F; Adang, E M; Golüke-Willemse, G A; Krabbe, P F; de Leest, B J; van Raak, F H J M; Schölzel-Dorenbos, C J M; Visser, M C; Wolfs, C A; Vliek, S; Rikkert, M G M Olde

2009-03-01

With the rising number of dementia patients with associated costs and the recognition that there is room for improvement in the provision of dementia care, the question arises on how to efficiently provide high quality dementia care. To describe the design of a study to determine multidisciplinary memory clinics' (MMC) effectiveness and cost-effectiveness in post-diagnosis treatment and care-coordination of dementia patients and their caregivers compared to the post-diagnosis treatment and care-coordination by general practitioners (GP). Next, this article provides the theoretical background of pragmatic trials, often needed in complex interventions, with the AD- Euro study as an example of such a pragmatic approach in a clinical trial. The study is a pragmatic multicentre, randomised clinical trial with an economic evaluation alongside, which aims to recruit 220 independently living patients with a new dementia diagnosis and their informal caregivers. After baseline measurements, patient and caregiver are allocated to the treatment arm MMC or GP and are visited for follow up measurements at 6 and 12 months. Primary outcome measures are Health Related Quality of Life of the patient as rated by the caregiver using the Quality of Life in Alzheimer's Disease instrument (Qol-AD) and self-perceived caregiving burden of the informal caregiver measured using the Sense of Competence Questionnaire (SCQ). To establish cost-effectiveness a cost-utility analysis using utilities generated by the EuroQol instrument (EQ-5D) will be conducted from a societal perspective. Analyses will be done in an intention-to-treat fashion. The inclusion period started in January 2008 and will commence until at least December 2008. After finalising follow up the results of the study are expected to be available halfway through 2010. The study will provide an answer to whether follow-up of dementia patients can best be done in specialised outpatient memory clinics or in primary care settings with regard to quality and costs. It will enable decision making on how to provide good and efficient health care services in dementia. ClinicalTrials.gov Identifier NCT00554047.

From the RNA world to the clinic.

PubMed

Sullenger, Bruce A; Nair, Smita

2016-06-17

The study of RNA has continually emphasized the structural and functional versatility of RNA molecules. This versatility has inspired translational and clinical researchers to explore the utility of RNA-based therapeutic agents for a wide variety of medical applications. Several RNA therapeutics, with diverse modes of action, are being evaluated in large late-stage clinical trials, and many more are in early clinical development. Hundreds of patients are enrolled in large trials testing messenger RNAs to combat cancer, small interfering RNAs to treat renal and hepatic disorders, and aptamers to combat ocular and cardiovascular disease. Results from these studies are generating considerable interest among the biomedical community and the public and will be important for the future development of this emerging class of therapeutic agents. Copyright © 2016, American Association for the Advancement of Science.

Using e-technologies in clinical trials

PubMed Central

Rosa, Carmen; Campbell, Aimee N. C.; Miele, Gloria M.; Brunner, Meg; Winstanley, Erin L.

2015-01-01

Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices or the Internet) into the design and execution of studies. In the meantime, individuals and corporations are relying more on electronic platforms and most have incorporated such technology into their daily lives. This paper provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for treatment of substance use disorders is presented. Using e-technologies to design and implement clinical trials has the potential to reach a wide audience, making trials more efficient while also reducing costs; however, researchers should be cautious when adopting these tools given the many challenges in using new technologies, as well as threats to participant privacy/confidentiality. Challenges of using e-technologies can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored. PMID:26176884

A Recommended Scale for Cognitive Screening in Clinical Trials of Parkinson’s Disease

PubMed Central

Chou, Kelvin L.; Amick, Melissa M.; Brandt, Jason; Camicioli, Richard; Frei, Karen; Gitelman, Darren; Goldman, Jennifer; Growdon, John; Hurtig, Howard I.; Levin, Bonnie; Litvan, Irene; Marsh, Laura; Simuni, Tanya; Tröster, Alexander I.; Uc, Ergun Y.

2010-01-01

Background Cognitive impairment is common in Parkinson’s disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. Methods The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Results Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force’s evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. Conclusions This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD. PMID:20878991

Using e-technologies in clinical trials.

PubMed

Rosa, Carmen; Campbell, Aimee N C; Miele, Gloria M; Brunner, Meg; Winstanley, Erin L

2015-11-01

Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices or the Internet) into the design and execution of studies. In the meantime, individuals and corporations are relying more on electronic platforms and most have incorporated such technology into their daily lives. This paper provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for treatment of substance use disorders is presented. Using e-technologies to design and implement clinical trials has the potential to reach a wide audience, making trials more efficient while also reducing costs; however, researchers should be cautious when adopting these tools given the many challenges in using new technologies, as well as threats to participant privacy/confidentiality. Challenges of using e-technologies can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored. Published by Elsevier Inc.

Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL study): study protocol for a randomized controlled trial.

PubMed

Muscedere, John; Maslove, David; Boyd, John Gordon; O'Callaghan, Nicole; Lamontagne, Francois; Reynolds, Steven; Albert, Martin; Hall, Rick; McGolrick, Danielle; Jiang, Xuran; Day, Andrew G

2016-09-29

Nosocomial infections remain an important source of morbidity, mortality, and increased health care costs in hospitalized patients. This is particularly problematic in intensive care units (ICUs) because of increased patient vulnerability due to the underlying severity of illness and increased susceptibility from utilization of invasive therapeutic and monitoring devices. Lactoferrin (LF) and the products of its breakdown have multiple biological effects, which make its utilization of interest for the prevention of nosocomial infections in the critically ill. This is a phase II randomized, multicenter, double-blinded trial to determine the effect of LF on antibiotic-free days in mechanically ventilated, critically ill, adult patients in the ICU. Eligible, consenting patients will be randomized to receive either LF or placebo. The treating clinician will remain blinded to allocation during the study; blinding will be maintained by using opaque syringes and containers. The primary outcome will be antibiotic-free days, defined as the number of days alive and free of antibiotics 28 days after randomization. Secondary outcomes will include: antibiotic utilization, adjudicated diagnosis of nosocomial infection (longer than 72 h of admission to ICU), hospital and ICU length of stay, change in organ function after randomization, hospital and 90-day mortality, incidence of tracheal colonization, changes in gastrointestinal permeability, and immune function. Outcomes to inform the conduct of a larger definitive trial will also be evaluated, including feasibility as determined by recruitment rates and protocol adherence. The results from this study are expected to provide insight into a potential novel therapeutic use for LF in critically ill adult patients. Further, analysis of study outcomes will inform a future, large-scale phase III randomized controlled trial powered on clinically important outcomes related to the use of LF. The trial was registered at www.ClinicalTrials.gov on 18 November 2013. NCT01996579 .

Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD-'Assessing QbTest Utility in ADHD' (AQUA): a randomised controlled trial.

PubMed

Hall, Charlotte L; Walker, Gemma M; Valentine, Althea Z; Guo, Boliang; Kaylor-Hughes, Catherine; James, Marilyn; Daley, David; Sayal, Kapil; Hollis, Chris

2014-12-01

The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current 'gold standard' ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. This multisite randomised controlled trial will recruit young people (aged 6-17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. NCT02209116. 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.

Statistical inference on censored data for targeted clinical trials under enrichment design.

PubMed

Chen, Chen-Fang; Lin, Jr-Rung; Liu, Jen-Pei

2013-01-01

For the traditional clinical trials, inclusion and exclusion criteria are usually based on some clinical endpoints; the genetic or genomic variability of the trial participants are not totally utilized in the criteria. After completion of the human genome project, the disease targets at the molecular level can be identified and can be utilized for the treatment of diseases. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Some of the patients enrolled in targeted clinical trials with a positive result for the molecular target might not have the specific molecular targets. As a result, the treatment effect may be underestimated in the patient population truly with the molecular target. To resolve this issue, under the exponential distribution, we develop inferential procedures for the treatment effects of the targeted drug based on the censored endpoints in the patients truly with the molecular targets. Under an enrichment design, we propose using the expectation-maximization algorithm in conjunction with the bootstrap technique to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed methods. Simulation results demonstrate that under the exponential distribution, the proposed estimator is nearly unbiased with adequate precision, and the confidence interval can provide adequate coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. On the other hand, when the proportional hazard assumption is violated, additional simulation studies show that the type I error rate is not controlled at the nominal level and is an increasing function of the positive predictive value. A numerical example illustrates the proposed procedures. Copyright © 2013 John Wiley & Sons, Ltd.

Neurocognitive outcomes in neurofibromatosis clinical trials: Recommendations for the domain of attention.

PubMed

Walsh, Karin S; Janusz, Jennifer; Wolters, Pamela L; Martin, Staci; Klein-Tasman, Bonita P; Toledo-Tamula, Mary Anne; Thompson, Heather L; Payne, Jonathan M; Hardy, Kristina K; de Blank, Peter; Semerjian, Claire; Gray, Laura Schaffner; Solomon, Sondra E; Ullrich, Nicole

2016-08-16

Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials. © 2016 American Academy of Neurology.

Mortality in two recent reports of clinical trials on patients with congestive heart failure compared with mortality in three previous clinical trials.

PubMed

Singer, R B

2000-01-01

Several clinical trials of drug treatment of patients with congestive heart failure (CHF) have previously been reported as Mortality Abstracts in the Journal of Insurance Medicine. Results are presented here for two similar clinical trials reported in September 1999 and compared with the previous results. In a recent international multicenter clinical trial, excess mortality in terms of excess death rates (EDRs) was reduced from 195 per 1000 per year in the placebo group to 139 in the group treated with Spironolactone. There was no significant reduction in the Danish multicenter study of Dofetilide to convert the atrial fibrillation (AF) to a normal rhythm in the 25% of the CHF patients who had AF (EDR was 224 in the placebo group and 216 in the Dofetilide group). In both of these studies, there were more patients with severe CHF than in the previous studies and the EDR values were higher. Results from the Danish study by severity according to the New York Heart Association (NYHA) classification show a progressive increase in EDR from 173 in class 2 to 237 in class 3 to 392 in class 4. Excess mortality in symptomatic CHF is far outside the issue limits for individual life insurance, but these results are of potential utility for the underwriting of such cases for structured settlement annuities.

Improving outcomes in adults with epilepsy and intellectual disability (EpAID) using a nurse-led intervention: study protocol for a cluster randomised controlled trial.

PubMed

Ring, Howard; Gilbert, Nakita; Hook, Roxanne; Platt, Adam; Smith, Christopher; Irvine, Fiona; Donaldson, Cam; Jones, Elizabeth; Kelly, Joanna; Mander, Adrian; Murphy, Caroline; Pennington, Mark; Pullen, Angela; Redley, Marcus; Rowe, Simon; Wason, James

2016-06-24

In adults with intellectual disability (ID) and epilepsy there are suggestions that improvements in management may follow introduction of epilepsy nurse-led care. However, this has not been tested in a definitive clinical trial and results cannot be generalised from general population studies as epilepsy tends to be more severe and to involve additional clinical comorbidities in adults with ID. This trial investigates whether nurses with expertise in epilepsy and ID, working proactively to a clinically defined role, can improve clinical and quality of life outcomes in the management of epilepsy within this population, compared to treatment as usual. The trial also aims to establish whether any perceived benefits represent good value for money. The EpAID clinical trial is a two-arm cluster randomised controlled trial of nurse-led epilepsy management versus treatment as usual. This trial aims to obtain follow-up data from 320 participants with ID and drug-resistant epilepsy. Participants are randomly assigned either to a 'treatment as usual' control or a 'defined epilepsy nurse role' active arm, according to the cluster site at which they are treated. The active intervention utilises the recently developed Learning Disability Epilepsy Specialist Nurse Competency Framework for adults with ID. Participants undergo 4 weeks of baseline data collection, followed by a minimum of 20 weeks intervention (novel treatment or treatment as usual), followed by 4 weeks of follow-up data collection. The primary outcome is seizure severity, including associated injuries and the level of distress manifest by the patient in the preceding 4 weeks. Secondary outcomes include cost-utility analysis, carer strain, seizure frequency and side effects. Descriptive measures include demographic and clinical descriptors of participants and clinical services in which they receive their epilepsy management. Qualitative study of clinical interactions and semi-structured interviews with clinicians and participants' carers are also undertaken. The EpAID clinical trial is the first cluster randomised controlled trial to test possible benefits of a nurse-led intervention in adults with epilepsy and ID. This research will have important implications for ID and epilepsy services. The challenges of undertaking such a trial in this population, and the approaches to meeting these are discussed. International Standard Randomised Controlled Trial Number: ISRCTN96895428 version 1.1. Registered on 26 March 2013.

Childhood asthma clusters and response to therapy in clinical trials.

PubMed

Chang, Timothy S; Lemanske, Robert F; Mauger, David T; Fitzpatrick, Anne M; Sorkness, Christine A; Szefler, Stanley J; Gangnon, Ronald E; Page, C David; Jackson, Daniel J

2014-02-01

Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility. To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials. A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial. CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial). In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Estimation of utilities in attention-deficit hyperactivity disorder for economic evaluations.

PubMed

Lloyd, Andrew; Hodgkins, Paul; Sasane, Rahul; Akehurst, Ron; Sonuga-Barke, Edmund J S; Fitzgerald, Patrick; Nixon, Annabel; Erder, Haim; Brazier, John

2011-01-01

Attempts to estimate the cost effectiveness of attention-deficit hyperactivity disorder (ADHD) treatments in the past have relied on classifying ADHD patients as responders or non-responders to treatment. Responder status has been associated with a small gain in health-related quality of life (HR-QOL) [or utility, as measured using the generic QOL measure EQ-5D] of 0.06 (on a scale from 0 being dead to 1.0 being full health). The goal of the present study was to develop and validate several ADHD-related health states, and to estimate utility values measured amongst the general public for those states and to re-estimate utility values associated with responder status. Detailed qualitative interview data were collected from 20 young ADHD patients to characterize their HR-QOL. In addition, item-by-item clinical and HR-QOL data from a clinical trial were used to define and describe four health states (normal; borderline to mildly ill; moderately to markedly ill; and severely ill). ADHD experts assessed the content validity of the descriptions. The states were rated by 100 members of the UK general public using the time trade-off (TTO) interview and visual analog scale. Statistical mapping was also undertaken to estimate Clinical Global Impression-Improvement (CGI-I) utilities (i.e. response status) from Clinical Global Impression-Severity (CGI-S) defined states. The mapping work estimated changes in utilities from study baseline to last visit for patients with a CGI-I score of ≤ 2 or ≤ 3. The validity of the four health states developed in this study was supported by in-depth interviews with ADHD experts and patients, and clinical trial data. TTO-derived utilities for the four health states ranged from 0.839 (CGI-S state 'normal') to 0.444 (CGI-S state 'severely ill'). From the mapping work, the change in utility for treatment responders was 0.19 for patients with a CGI-I score of ≤ 2 and 0.15 for patients with a CGI-I score of ≤ 3. The present study provides utilities for different severity levels of ADHD estimated in a TTO study. This approach provides a more granular assessment of the impact of ADHD on HR-QOL than binary approaches employed in previous economic analyses. Change in utility for responders and non-responders at different levels of CGI-I was estimated, and thus these utilities may be used to compare health gains of different ADHD interventions.

Innovation at the Intersection of Clinical Trials and Real-World Data Science to Advance Patient Care.

PubMed

Swift, Brandon; Jain, Lokesh; White, Craig; Chandrasekaran, Vasu; Bhandari, Aman; Hughes, Dyfrig A; Jadhav, Pravin R

2018-05-16

While efficacy and safety data collected from randomized clinical trials are the evidentiary standard for determining market authorization, this alone may no longer be sufficient to address the needs of key stakeholders (regulators, providers, and payers) and guarantee long-term success of pharmaceutical products. There is a heightened interest from stakeholders on understanding the use of real-world evidence (RWE) to substantiate benefit-risk assessment and support the value of a new drug. This review provides an overview of real-world data (RWD) and related advances in the regulatory framework, and discusses their impact on clinical research and development. A framework for linking drug development decisions with the value proposition of the drug, utilizing pharmacokinetic-pharmacodynamic-pharmacoeconomic models, is introduced. The summary presented here is based on the presentations and discussion at the symposium entitled Innovation at the Intersection of Clinical Trials and Real-World Data to Advance Patient Care at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) 2017 Annual Meeting. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

TU-C-9A-01: IROC Organization and Clinical Trial Credentialing

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

Followill, D; Molineu, A; Xiao, Y

2014-06-15

As a response to recommendations from a report from the Institute of Medicine, NCI is reorganizing it clinical trial groups into a National Clinical Trial Network (NCTN) that consists of four adult groups (Alliance, ECOGACRIN, NRG, and SWOG) and one children’s group (COG). NRG will house CIRO, a center to promote innovative radiation therapy research and intergroup collaboration in radiation. The quality assurance groups that support clinical trials have also been restructured. ITC, OSU Imaging corelab, Philadelphia Imaging core-lab, QARC, RPC, and RTOGQA have joined together to create the Imaging and Radiation Oncology Core (IROC) Group. IROC’s mission is tomore » provide integrated radiation oncology and diagnostic imaging quality control programs in support of the NCI’s NCTN thereby assuring high quality data for clinical trials designed to improve the clinical outcomes for cancer patients worldwide. This will be accomplished through five core services: site qualification, trial design support, credentialing, data management, case review.These changes are important for physicist participating in NCI clinical trials to understand. We will describe in detail the IROC’s activities and five core services so that as a user, the medical physicist can learn how to efficiently utilize this group. We will describe common pitfalls encountered in credentialing for current protocols and present methods to avoid them. These may include the which benchmarks are required for NSABP B-51/RTOG 1304 and how to plan them as well as tips for phantom planning. We will explain how to submit patient and phantom cases in the TRIAD system used by IROC. Learning Objectives: To understand the basic organization of IROC, its mission and five core services To learn how to use TRIAD for patient and phantom data submission To learn how to avoid common pitfalls in credentialing for current trials.« less

Development of the Lymphoma Enterprise Architecture Database: A caBIG(tm) Silver level compliant System

PubMed Central

Huang, Taoying; Shenoy, Pareen J.; Sinha, Rajni; Graiser, Michael; Bumpers, Kevin W.; Flowers, Christopher R.

2009-01-01

Lymphomas are the fifth most common cancer in United States with numerous histological subtypes. Integrating existing clinical information on lymphoma patients provides a platform for understanding biological variability in presentation and treatment response and aids development of novel therapies. We developed a cancer Biomedical Informatics Grid™ (caBIG™) Silver level compliant lymphoma database, called the Lymphoma Enterprise Architecture Data-system™ (LEAD™), which integrates the pathology, pharmacy, laboratory, cancer registry, clinical trials, and clinical data from institutional databases. We utilized the Cancer Common Ontological Representation Environment Software Development Kit (caCORE SDK) provided by National Cancer Institute’s Center for Bioinformatics to establish the LEAD™ platform for data management. The caCORE SDK generated system utilizes an n-tier architecture with open Application Programming Interfaces, controlled vocabularies, and registered metadata to achieve semantic integration across multiple cancer databases. We demonstrated that the data elements and structures within LEAD™ could be used to manage clinical research data from phase 1 clinical trials, cohort studies, and registry data from the Surveillance Epidemiology and End Results database. This work provides a clear example of how semantic technologies from caBIG™ can be applied to support a wide range of clinical and research tasks, and integrate data from disparate systems into a single architecture. This illustrates the central importance of caBIG™ to the management of clinical and biological data. PMID:19492074

Development of the Lymphoma Enterprise Architecture Database: a caBIG Silver level compliant system.

PubMed

Huang, Taoying; Shenoy, Pareen J; Sinha, Rajni; Graiser, Michael; Bumpers, Kevin W; Flowers, Christopher R

2009-04-03

Lymphomas are the fifth most common cancer in United States with numerous histological subtypes. Integrating existing clinical information on lymphoma patients provides a platform for understanding biological variability in presentation and treatment response and aids development of novel therapies. We developed a cancer Biomedical Informatics Grid (caBIG) Silver level compliant lymphoma database, called the Lymphoma Enterprise Architecture Data-system (LEAD), which integrates the pathology, pharmacy, laboratory, cancer registry, clinical trials, and clinical data from institutional databases. We utilized the Cancer Common Ontological Representation Environment Software Development Kit (caCORE SDK) provided by National Cancer Institute's Center for Bioinformatics to establish the LEAD platform for data management. The caCORE SDK generated system utilizes an n-tier architecture with open Application Programming Interfaces, controlled vocabularies, and registered metadata to achieve semantic integration across multiple cancer databases. We demonstrated that the data elements and structures within LEAD could be used to manage clinical research data from phase 1 clinical trials, cohort studies, and registry data from the Surveillance Epidemiology and End Results database. This work provides a clear example of how semantic technologies from caBIG can be applied to support a wide range of clinical and research tasks, and integrate data from disparate systems into a single architecture. This illustrates the central importance of caBIG to the management of clinical and biological data.

Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment.

PubMed

Schmidt, Keith T; Chau, Cindy H; Price, Douglas K; Figg, William D

2016-12-01

Precision medicine in oncology is the result of an increasing awareness of patient-specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (eg, HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to an FDA-approved targeted therapy (eg, trastuzumab, erlotinib). Clinically relevant germline mutations in drug-metabolizing enzymes and transporters (eg, TPMT, DPYD) have been shown to impact drug response, providing a rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers has been shown to help direct treatment decisions, especially in breast cancer (eg, Oncotype DX). More recently, the use of next-generation sequencing to detect many potential "actionable" cancer molecular alterations is further shifting the 1 gene-1 drug paradigm toward a more comprehensive, multigene approach. Currently, many clinical trials (eg, NCI-MATCH, NCI-MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials such as the NCI-MATCH will help determine the clinical utility and future development of the precision-medicine approach. © 2016, The American College of Clinical Pharmacology.

Leveraging Digital Health Technologies and Outpatient Sampling in Clinical Drug Development: A Phase 1 Exploratory Study.

PubMed

Dockendorf, Marissa F; Murthy, Gowri; Bateman, Kevin P; Kothare, Prajakti A; Anderson, Melanie; Xie, Iris; Sachs, Jeff R; Burlage, Rubi; Goldman, Andra; Moyer, Matthew; Shah, Jyoti; Ruba, Rachel; Shipley, Lisa; Harrelson, Jane

2018-06-09

Merck & Co., Inc. (Kenilworth, New Jersey) is investing in approaches to enrich clinical trial data and augment decision-making through utilization of digital health technologies, outpatient sampling, and real-time data access. As part of this strategy, a Phase 1 study was conducted to explore a few technologies of interest. In this fixed-sequence, two-period trial, 16 healthy subjects were administered 50-mg once-daily sitagliptin packaged in a bottle that electronically captured the date and time study medication was dispensed (Period 1) and in a traditional pharmacy bottle (Period 2). Dried blood spot (DBS) samples were collected for sitagliptin concentration analysis on select study days, both in-clinic and at-home, with collection time recorded using an electronic diary in Period 1 and by clinic staff in Period 2. Study results demonstrated the feasibility and subject acceptance of collecting digital adherence data and outpatient DBS samples in clinical trials and highlighted areas for future improvements. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A Brief Chronicle of CD4 as a Biomarker for HIV/AIDS: A Tribute to the Memory of John L. Fahey.

PubMed

Kagan, Jonathan M; Sanchez, Ana M; Landay, Alan; Denny, Thomas N

Foundational cellular immunology research of the 1960s and 1970s, together with the advent of monoclonal antibodies and flow cytometry, provided the knowledge base and the technological capability that enabled the elucidation of the role of CD4 T cells in HIV infection. Research identifying the sources and magnitude of variation in CD4 measurements, standardized reagents and protocols, and the development of clinical flow cytometers all contributed to the feasibility of widespread CD4 testing. Cohort studies and clinical trials provided the context for establishing the utility of CD4 for prognosis in HIV-infected persons, initial assessment of in vivo antiretroviral drug activity, and as a surrogate marker for clinical outcome in antiretroviral therapeutic trials. Even with sensitive HIV viral load measurement, CD4 cell counting is still utilized in determining antiretroviral therapy eligibility and time to initiate therapy. New point of care technologies are helping both to lower the cost of CD4 testing and enable its use in HIV test and treat programs around the world.

Use of FEV1 in Cystic Fibrosis Epidemiologic Studies and Clinical Trials: A Statistical Perspective for the Clinical Researcher

PubMed Central

Szczesniak, Rhonda; Heltshe, Sonya L.; Stanojevic, Sanja; Mayer-Hamblett, Nicole

2017-01-01

Background Forced expiratory volume in 1 second (FEV1) is an established marker of cystic fibrosis (CF) disease progression that is used to capture clinical course and evaluate therapeutic efficacy. The research community has established FEV1 surveillance data through a variety of observational data sources such as patient registries, and there is a growing pipeline of new CF therapies demonstrated to be efficacious in clinical trials by establishing improvements in FEV1. Results In this review, we summarize from a statistical perspective the clinical relevance of FEV1 based on its association with morbidity and mortality in CF, its role in epidemiologic studies of disease progression and comparative effectiveness, and its utility in clinical trials. In addition, we identify opportunities to advance epidemiologic research and the clinical development pipeline through further statistical considerations. Conclusions Our understanding of CF disease course, therapeutics, and clinical care has evolved immensely in the past decades, in large part due to the thoughtful application of rigorous research methods and meaningful clinical endpoints such as FEV1. A continued commitment to conduct research that minimizes the potential for bias, maximizes the limited patient population, and harmonizes approaches to FEV1 analysis while maintaining clinical relevance, will facilitate further opportunities to advance CF care. PMID:28117136

Barriers to investigator-initiated deep brain stimulation and device research

PubMed Central

Malone, Donald; Okun, Michael S.; Booth, Joan; Machado, Andre G.

2014-01-01

The success of device-based research in the clinical neurosciences has overshadowed a critical and emerging problem in the biomedical research environment in the United States. Neuroprosthetic devices, such as deep brain stimulation (DBS), have been shown in humans to be promising technologies for scientific exploration of neural pathways and as powerful treatments. Large device companies have, over the past several decades, funded and developed major research programs. However, both the structure of clinical trial funding and the current regulation of device research threaten investigator-initiated efforts in neurologic disorders. The current atmosphere dissuades clinical investigators from pursuing formal and prospective research with novel devices or novel indications. We review our experience in conducting a federally funded, investigator-initiated, device-based clinical trial that utilized DBS for thalamic pain syndrome. We also explore barriers that clinical investigators face in conducting device-based clinical trials, particularly in early-stage studies or small disease populations. We discuss 5 specific areas for potential reform and integration: (1) alternative pathways for device approval; (2) eliminating right of reference requirements; (3) combining federal grant awards with regulatory approval; (4) consolidation of oversight for human subjects research; and (5) private insurance coverage for clinical trials. Careful reformulation of regulatory policy and funding mechanisms is critical for expanding investigator-initiated device research, which has great potential to benefit science, industry, and, most importantly, patients. PMID:24670888

Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review.

PubMed

Maze, Mervyn

2016-02-01

The purpose of this report is to facilitate an understanding of the possible application of xenon for neuroprotection in critical care settings. This narrative review appraises the literature assessing the efficacy and safety of xenon in preclinical models of acute ongoing neurologic injury. Databases of the published literature (MEDLINE® and EMBASE™) were appraised for peer-reviewed manuscripts addressing the use of xenon in both preclinical models and disease states of acute ongoing neurologic injury. For randomized clinical trials not yet reported, the investigators' declarations in the National Institutes of Health clinical trials website were considered. While not a primary focus of this review, to date, xenon cannot be distinguished as superior for surgical anesthesia over existing alternatives in adults. Nevertheless, studies in a variety of preclinical disease models from multiple laboratories have consistently shown xenon's neuroprotective properties. These properties are enhanced in settings where xenon is combined with hypothermia. Small randomized clinical trials are underway to explore xenon's efficacy and safety in clinical settings of acute neurologic injury where hypothermia is the current standard of care. According to the evidence to date, the neuroprotective efficacy of xenon in preclinical models and its safety in clinical anesthesia set the stage for the launch of randomized clinical trials to determine whether these encouraging neuroprotective findings can be translated into clinical utility.

Adaptive designs in clinical trials: why use them, and how to run and report them.

PubMed

Pallmann, Philip; Bedding, Alun W; Choodari-Oskooei, Babak; Dimairo, Munyaradzi; Flight, Laura; Hampson, Lisa V; Holmes, Jane; Mander, Adrian P; Odondi, Lang'o; Sydes, Matthew R; Villar, Sofía S; Wason, James M S; Weir, Christopher J; Wheeler, Graham M; Yap, Christina; Jaki, Thomas

2018-02-28

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial's course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

Increasing the quantity and quality of searching for current best evidence to answer clinical questions: protocol and intervention design of the MacPLUS FS Factorial Randomized Controlled Trials.

PubMed

Agoritsas, Thomas; Iserman, Emma; Hobson, Nicholas; Cohen, Natasha; Cohen, Adam; Roshanov, Pavel S; Perez, Miguel; Cotoi, Chris; Parrish, Rick; Pullenayegum, Eleanor; Wilczynski, Nancy L; Iorio, Alfonso; Haynes, R Brian

2014-09-20

Finding current best evidence for clinical decisions remains challenging. With 3,000 new studies published every day, no single evidence-based resource provides all answers or is sufficiently updated. McMaster Premium LiteratUre Service--Federated Search (MacPLUS FS) addresses this issue by looking in multiple high quality resources simultaneously and displaying results in a one-page pyramid with the most clinically useful at the top. Yet, additional logistical and educational barriers need to be addressed to enhance point-of-care evidence retrieval. This trial seeks to test three innovative interventions, among clinicians registered to MacPLUS FS, to increase the quantity and quality of searching for current best evidence to answer clinical questions. In a user-centered approach, we designed three interventions embedded in MacPLUS FS: (A) a web-based Clinical Question Recorder; (B) an Evidence Retrieval Coach composed of eight short educational videos; (C) an Audit, Feedback and Gamification approach to evidence retrieval, based on the allocation of 'badges' and 'reputation scores.' We will conduct a randomized factorial controlled trial among all the 904 eligible medical doctors currently registered to MacPLUS FS at the hospitals affiliated with McMaster University, Canada. Postgraduate trainees (n=429) and clinical faculty/staff (n=475) will be randomized to each of the three following interventions in a factorial design (AxBxC). Utilization will be continuously recorded through clinicians’ accounts that track logins and usage, down to the level of individual keystrokes. The primary outcome is the rate of searches per month per user during the six months of follow-up. Secondary outcomes, measured through the validated Impact Assessment Method questionnaire, include: utility of answers found (meeting clinicians’ information needs), use (application in practice), and perceived usefulness on patient outcomes. Built on effective models for the point-of-care teaching, these interventions approach evidence retrieval as a clinical skill. If effective, they may offer the opportunity to enhance it for a large audience, at low cost, providing better access to relevant evidence across many top EBM resources in parallel. ClinicalTrials.Gov NCT02038439.

Estimating individual benefits of medical or behavioral treatments in severely ill patients.

PubMed

Diaz, Francisco J

2017-01-01

There is a need for statistical methods appropriate for the analysis of clinical trials from a personalized-medicine viewpoint as opposed to the common statistical practice that simply examines average treatment effects. This article proposes an approach to quantifying, reporting and analyzing individual benefits of medical or behavioral treatments to severely ill patients with chronic conditions, using data from clinical trials. The approach is a new development of a published framework for measuring the severity of a chronic disease and the benefits treatments provide to individuals, which utilizes regression models with random coefficients. Here, a patient is considered to be severely ill if the patient's basal severity is close to one. This allows the derivation of a very flexible family of probability distributions of individual benefits that depend on treatment duration and the covariates included in the regression model. Our approach may enrich the statistical analysis of clinical trials of severely ill patients because it allows investigating the probability distribution of individual benefits in the patient population and the variables that influence it, and we can also measure the benefits achieved in specific patients including new patients. We illustrate our approach using data from a clinical trial of the anti-depressant imipramine.

Prevention of infectious complications after elective colorectal surgery in children: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee comprehensive review.

PubMed

Rangel, Shawn J; Islam, Saleem; St Peter, Shawn D; Goldin, Adam B; Abdullah, Fizan; Downard, Cynthia D; Saito, Jacqueline M; Blakely, Martin L; Puligandla, Pramod S; Dasgupta, Roshni; Austin, Mary; Chen, Li Ern; Renaud, Elizabeth; Arca, Marjorie J; Calkins, Casey M

2015-01-01

This goal of this review was to examine the clinical evidence in support of commonly utilized measures intended to reduce complications following elective colorectal surgery. Literature searches were performed to identify relevant studies from Medline, PubMed, and Cochrane databases. The American Pediatric Surgery Association Outcomes and Clinical Trials Committee selected eight questions to address this topic systematically in the context of three management areas: 1) appropriate utilization of systemic antibiotics for colorectal procedures, 2) reduction of stool burden through mechanical bowel preparation, and 3) intraluminal gut decontamination through use of enteral nonabsorbable antibiotics. Primary outcomes of interest included the occurrence of infectious and mechanical complications related to stool burden and intraluminal bacterial concentration (incisional surgical site infection, anastomotic leakage, and intraabdominal abscess). The evidence in support of each management category was systematically reviewed, graded, and summarized in the context of the review's primary outcomes. Practice recommendations were made as deemed appropriate by the committee. Clinical evidence in support of interventions to reduce infectious complications following colorectal surgery is derived almost exclusively from the adult literature. High-quality evidence to guide clinical practice in children is sorely needed, as the available data may have only limited relevance to pediatric colorectal diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal.

PubMed

Ivanova, Anastasia; Tamura, Roy N

2015-12-01

A new clinical trial design, designated the two-way enriched design (TED), is introduced, which augments the standard randomized placebo-controlled trial with second-stage enrichment designs in placebo non-responders and drug responders. The trial is run in two stages. In the first stage, patients are randomized between drug and placebo. In the second stage, placebo non-responders are re-randomized between drug and placebo and drug responders are re-randomized between drug and placebo. All first-stage data, and second-stage data from first-stage placebo non-responders and first-stage drug responders, are utilized in the efficacy analysis. The authors developed one, two and three degrees of freedom score tests for treatment effect in the TED and give formulae for asymptotic power and for sample size computations. The authors compute the optimal allocation ratio between drug and placebo in the first stage for the TED and compare the operating characteristics of the design to the standard parallel clinical trial, placebo lead-in and randomized withdrawal designs. Two motivating examples from different disease areas are presented to illustrate the possible design considerations. © The Author(s) 2011.

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

Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good Research Practices Task Force report.

PubMed

Ramsey, Scott D; Willke, Richard J; Glick, Henry; Reed, Shelby D; Augustovski, Federico; Jonsson, Bengt; Briggs, Andrew; Sullivan, Sean D

2015-03-01

Clinical trials evaluating medicines, medical devices, and procedures now commonly assess the economic value of these interventions. The growing number of prospective clinical/economic trials reflects both widespread interest in economic information for new technologies and the regulatory and reimbursement requirements of many countries that now consider evidence of economic value along with clinical efficacy. As decision makers increasingly demand evidence of economic value for health care interventions, conducting high-quality economic analyses alongside clinical studies is desirable because they broaden the scope of information available on a particular intervention, and can efficiently provide timely information with high internal and, when designed and analyzed properly, reasonable external validity. In 2005, ISPOR published the Good Research Practices for Cost-Effectiveness Analysis Alongside Clinical Trials: The ISPOR RCT-CEA Task Force report. ISPOR initiated an update of the report in 2014 to include the methodological developments over the last 9 years. This report provides updated recommendations reflecting advances in several areas related to trial design, selecting data elements, database design and management, analysis, and reporting of results. Task force members note that trials should be designed to evaluate effectiveness (rather than efficacy) when possible, should include clinical outcome measures, and should obtain health resource use and health state utilities directly from study subjects. Collection of economic data should be fully integrated into the study. An incremental analysis should be conducted with an intention-to-treat approach, complemented by relevant subgroup analyses. Uncertainty should be characterized. Articles should adhere to established standards for reporting results of cost-effectiveness analyses. Economic studies alongside trials are complementary to other evaluations (e.g., modeling studies) as information for decision makers who consider evidence of economic value along with clinical efficacy when making resource allocation decisions. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Cost-effectiveness of multidisciplinary management of Tinnitus at a specialized Tinnitus centre

PubMed Central

Cima, Rilana; Joore, Manuela; Maes, Iris; Scheyen, Dyon; Refaie, Amr El; Baguley, David M; Vlaeyen, Johan WS; Anteunis, Lucien

2009-01-01

Background Tinnitus is a common chronic health condition that affects 10% to 20% of the general population. Among severe sufferers it causes disability in various areas. As a result of the tinnitus, quality of life is often impaired. At present there is no cure or uniformly effective treatment, leading to fragmentized and costly tinnitus care. Evidence suggests that a comprehensive multidisciplinary approach in treating tinnitus is effective. The main objective of this study is to examine the effectiveness, costs, and cost-effectiveness of a comprehensive treatment provided by a specialized tinnitus center versus usual care. This paper describes the study protocol. Methods/Design In a randomized controlled clinical trial 198 tinnitus patients will be randomly assigned to a specialized tinnitus care group or a usual care group. Adult tinnitus sufferers referred to the audiological centre are eligible. Included patients will be followed for 12 months. Primary outcome measure is generic quality of life (measured with the Health Utilities Index Mark III). Secondary outcomes are severity of tinnitus, general distress, tinnitus cognitions, tinnitus specific fear, and costs. Based on health state utility outcome data the number of patients to include is 198. Economic evaluation will be performed from a societal perspective. Discussion This is, to our knowledge, the first randomized controlled trial that evaluates a comprehensive treatment of tinnitus and includes a full economic evaluation from a societal perspective. If this intervention proves to be effective and cost-effective, implementation of this intervention is considered and anticipated. Trial Registration The trial has been registered at ClinicalTrial.gov. The trial registration number is NCT00733044 PMID:19210767

Effectiveness of the head CT choice decision aid in parents of children with minor head trauma: study protocol for a multicenter randomized trial

PubMed Central

2014-01-01

Background Blunt head trauma is a common cause of death and disability in children worldwide. Cranial computed tomography (CT), the reference standard for the diagnosis of traumatic brain injury (TBI), exposes children to ionizing radiation which has been linked to the development of brain tumors, leukemia, and other cancers. We describe the methods used to develop and test the effectiveness of a decision aid to facilitate shared decision-making with parents regarding whether to obtain a head CT scan or to further observe their child at home. Methods/Design This is a protocol for a multicenter clinician-level parallel randomized trial to compare an intervention group receiving a decision aid, ‘Head CT Choice’, to a control group receiving usual care. The trial will be conducted at five diverse emergency departments (EDs) in Minnesota and California. Clinicians will be randomized to decision aid or usual care. Parents visiting the ED with children who are less than 18-years-old, have experienced blunt head trauma within 24 hours, and have one or two risk factors for clinically-important TBI (ciTBI) from the Pediatric Emergency Care Applied Research Network head injury clinical prediction rules will be eligible for enrollment. We will measure the effect of Head CT Choice on: (1) parent knowledge regarding their child’s risk of ciTBI, the available diagnostic options, and the risks of radiation exposure associated with a cranial CT scan (primary outcome); (2) parent engagement in the decision-making process; (3) the degree of conflict parents experience related to feeling uninformed; (4) patient and clinician satisfaction with the decision made; (5) the rate of ciTBI at seven days; (6) the proportion of patients in whom a cranial CT scan is obtained; and (7) seven-day healthcare utilization. To capture these outcomes, we will administer parent and clinician surveys immediately after each clinical encounter, obtain video recordings of parent-clinician discussions, administer parent healthcare utilization diaries, analyze hospital billing records, review the electronic medical record, and conduct telephone follow-up. Discussion This multicenter trial will robustly assess the effectiveness of a decision aid on patient-centered outcomes, safety, and healthcare utilization in parents of children with minor head trauma in five diverse EDs. Trial registration ClinicalTrials.gov registration number: NCT02063087. Registration date February 13, 2014. PMID:24965659

Analysis of longitudinal laboratory data in the presence of common selection mechanisms: a view toward greater emphasis on pre-marketing pharmaceutical safety.

PubMed

Schildcrout, Jonathan S; Jenkins, Cathy A; Ostroff, Jack H; Gillen, Daniel L; Harrell, Frank E; Trost, Donald C

2008-05-30

Pharmaceutical safety has received substantial attention in the recent past; however, longitudinal clinical laboratory data routinely collected during clinical trials to derive safety profiles are often used ineffectively. For example, these data are frequently summarized by comparing proportions (between treatment arms) of participants who cross pre-specified threshold values at some time during follow-up. This research is intended, in part, to encourage more effective utilization of these data by avoiding unnecessary dichotomization of continuous data, acknowledging and making use of the longitudinal follow-up, and combining data from multiple clinical trials. However, appropriate analyses require careful consideration of a number of challenges (e.g. selection, comparability of study populations, etc.). We discuss estimation strategies based on estimating equations and maximum likelihood for analyses in the presence of three response history-dependent selection mechanisms: dropout, follow-up frequency, and treatment discontinuation. In addition, because clinical trials' participants usually represent non-random samples from target populations, we describe two sensitivity analysis approaches. All discussions are motivated by an analysis that aims to characterize the dynamic relationship between concentrations of a liver enzyme (alanine aminotransferase) and three distinct doses (no drug, low dose, and high dose) of an nk-1 antagonist across four Phase II clinical trials.

New Paradigm for Translational Modeling to Predict Long‐term Tuberculosis Treatment Response

PubMed Central

Bartelink, IH; Zhang, N; Keizer, RJ; Strydom, N; Converse, PJ; Dooley, KE; Nuermberger, EL

2017-01-01

Abstract Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse‐to‐human translational pharmacokinetics (PKs) – pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species‐specific protein binding, drug‐drug interactions, and patient‐specific pathology. Simulations of recent trials testing 4‐month regimens predicted 65% (95% confidence interval [CI], 55–74) relapse‐free patients vs. 80% observed in the REMox‐TB trial, and 79% (95% CI, 72–87) vs. 82% observed in the Rifaquin trial. Simulation of 6‐month regimens predicted 97% (95% CI, 93–99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials. PMID:28561946

High-intensity focused ultrasound: advances in technology and experimental trials support enhanced utility of focused ultrasound surgery in oncology

PubMed Central

Malietzis, G; Monzon, L; Hand, J; Wasan, H; Leen, E; Abel, M; Muhammad, A; Abel, P

2013-01-01

High-intensity focused ultrasound (HIFU) is a rapidly maturing technology with diverse clinical applications. In the field of oncology, the use of HIFU to non-invasively cause tissue necrosis in a defined target, a technique known as focused ultrasound surgery (FUS), has considerable potential for tumour ablation. In this article, we outline the development and underlying principles of HIFU, overview the limitations and commercially available equipment for FUS, then summarise some of the recent technological advances and experimental clinical trials that we predict will have a positive impact on extending the role of FUS in cancer therapy. PMID:23403455

Two-sample statistics for testing the equality of survival functions against improper semi-parametric accelerated failure time alternatives: an application to the analysis of a breast cancer clinical trial.

PubMed

Broët, Philippe; Tsodikov, Alexander; De Rycke, Yann; Moreau, Thierry

2004-06-01

This paper presents two-sample statistics suited for testing equality of survival functions against improper semi-parametric accelerated failure time alternatives. These tests are designed for comparing either the short- or the long-term effect of a prognostic factor, or both. These statistics are obtained as partial likelihood score statistics from a time-dependent Cox model. As a consequence, the proposed tests can be very easily implemented using widely available software. A breast cancer clinical trial is presented as an example to demonstrate the utility of the proposed tests.

An approach for utilizing clinical statements in HL7 RIM to evaluate eligibility criteria.

PubMed

Bache, Richard; Daniel, Christel; James, Julie; Hussain, Sajjad; McGilchrist, Mark; Delaney, Brendan; Taweel, Adel

2014-01-01

The HL7 RIM (Reference Information Model) is a commonly used standard for the exchange of clinical data and can be employed for integrating the patient care and clinical research domains. Yet it is not sufficiently well specified to ensure a canonical representation of structured clinical data when used for the automated evaluation of eligibility criteria from a clinical trial protocol. We present an approach to further constrain the RIM to create a common information model to hold clinical data. In order to demonstrate our approach, we identified 132 distinct data elements from 10 rich clinical trails. We then defined a taxonomy to (i) identify the types of data elements that would need to be stored and (ii) define the types of predicate that would be used to evaluate them. This informed the definition of a pattern used to represent the data, which was shown to be sufficient for storing and evaluating the clinical statements required by the trials.

The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials

PubMed Central

Foong, Rachel E.; Harper, Alana J.; King, Louise; Turkovic, Lidija; Davis, Miriam; Clem, Charles C.; Davis, Stephanie D.; Ranganathan, Sarath; Hall, Graham L.

2018-01-01

The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3–6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible. PMID:29707562

Improving the CellSearch® system.

PubMed

Swennenhuis, J F; van Dalum, G; Zeune, L L; Terstappen, L W M M

2016-12-01

The CellSearch® CTC test enumerates tumor cells present in 7.5 ml blood of cancer patients. improvements, extensions and different utilities of the cellsearch system are discussed in this paper. Areas covered: This paper describes work performed with the CellSearch system, which go beyond the normal scope of the test. All results from searches with the search term 'CellSearch' from Web of Science and PubMed were categorized and discussed. Expert commentary: The CellSearch Circulating Tumor Cell test captures and identifies tumor cells in blood that are associated with poor clinical outcome. How to best use CTC in clinical practice is being explored in many clinical trials. The ability to extract information from the CTC to guide therapy will expand the potential clinical utility of CTC.

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma.

PubMed

Joseph, Jocelyn; Zobniw, Chrystia; Davis, Jennifer; Anderson, Jaime; Trinh, Van Anh

2018-04-01

To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). An English-language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T-cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab's place in therapy. Avelumab is the first Food and Drug Administration-approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings.

Evidence-based medicine and big genomic data.

PubMed

Ioannidis, John P A; Khoury, Muin J

2018-05-01

Genomic and other related big data (Big Genomic Data, BGD for short) are ushering a new era of precision medicine. This overview discusses whether principles of evidence-based medicine hold true for BGD and how they should be operationalized in the current era. Major evidence-based medicine principles include the systematic identification, description and analysis of the validity and utility of BGD, the combination of individual clinical expertise with individual patient needs and preferences, and the focus on obtaining experimental evidence, whenever possible. BGD emphasize information of single patients with an overemphasis on N-of-1 trials to personalize treatment. However, large-scale comparative population data remain indispensable for meaningful translation of BGD personalized information. The impact of BGD on population health depends on its ability to affect large segments of the population. While several frameworks have been proposed to facilitate and standardize decision making for use of genomic tests, there are new caveats that arise from BGD that extend beyond the limitations that were applicable for more simple genetic tests. Non-evidence-based use of BGD may be harmful and result in major waste of healthcare resources. Randomized controlled trials will continue to be the strongest arbitrator for the clinical utility of genomic technologies, including BGD. Research on BGD needs to focus not only on finding robust predictive associations (clinical validity) but also more importantly on evaluating the balance of health benefits and potential harms (clinical utility), as well as implementation challenges. Appropriate features of such useful research on BGD are discussed.

Hepatitis C Virus Resistance Testing in Genotype 1: The Changing Role in Clinical Utility.

PubMed

Molino, Suzanne; Martin, Michelle T

2017-09-01

To review the role and utility of baseline resistance testing with currently available and pipeline genotype 1 hepatitis C virus (HCV) treatment. Authors reviewed liver meeting abstracts for data on currently-available and pipeline genotype 1 retreatment regimens from January 1, 2015, to March 23, 2017. Additional trials were identified from a review of clinicaltrials.gov using the pipeline medication names. Authors identified reports of current and pipeline genotype 1 retreatment regimens. Seven references were clinical study results presented at the meetings of the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, and 2 studies were from clinicaltrials.gov . Retreatment trial data of currently available salvage regimens indicate that baseline NS5A resistance-associated substitutions (RASs) may decrease sustained virological response (SVR) rates when retreating with ledipasvir/sofosbuvir but are not affected when using elbasvir/grazoprevir + sofosbuvir + ribavirin, paritaprevir/ritonavir/ombitasvir + dasabuvir + sofosbuvir, or sofosbuvir/velpatasvir + ribavirin. Pipeline data indicate that baseline NS5A RASs do not affect SVR rates when retreating with sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir. Baseline resistance testing was used for decisional support for 3 clinical scenarios in patients with HCV genotype 1 infection at the time of manuscript submission. Pending the approval of 2 new direct-acting antiviral regimens in the third quarter of 2017, the rapidly evolving HCV treatment guidelines will likely reflect a decreased clinical utility for resistance testing.

A review of the clinical utility of duloxetine in the treatment of diabetic peripheral neuropathic pain

PubMed Central

King, Jordan B; Schauerhamer, Marisa B; Bellows, Brandon K

2015-01-01

Diabetes mellitus is a world-wide epidemic with many long-term complications, with neuropathy being the most common. In particular, diabetic peripheral neuropathic pain (DPNP), can be one of the most distressing complications associated with diabetes, leading to decreases in physical and mental quality of life. Despite the availability of many efficient medications, DPNP remains a challenge to treat, and the optimal sequencing of pharmacotherapy remains unknown. Currently, there are only three medications approved by the US Food and Drug Administration specifically for the management of DPNP. Duloxetine (DUL), a selective serotonin-norepinephrine reuptake inhibitor, is one of these. With the goal of optimizing pharmacotherapy use in DPNP population, a review of current literature was conducted, and the clinical utility of DUL described. Along with early clinical trials, recently published observational studies and pharmacoeconomic models may be useful in guiding decision making by clinicians and managed care organizations. In real-world practice settings, DUL is associated with decreased or similar opioid utilization, increased medication adherence, and similar health care costs compared with current standard of care. DUL has consistently been found to be a cost-effective option over short time-horizons. Currently, the long-term cost-effectiveness of DUL is unknown. Evidence derived from randomized clinical trials, real-world observations, and economic models support the use of DUL as a first-line treatment option from the perspective of the patient, clinician, and managed care payer. PMID:26309404

A review of the clinical utility of duloxetine in the treatment of diabetic peripheral neuropathic pain.

PubMed

King, Jordan B; Schauerhamer, Marisa B; Bellows, Brandon K

2015-01-01

Diabetes mellitus is a world-wide epidemic with many long-term complications, with neuropathy being the most common. In particular, diabetic peripheral neuropathic pain (DPNP), can be one of the most distressing complications associated with diabetes, leading to decreases in physical and mental quality of life. Despite the availability of many efficient medications, DPNP remains a challenge to treat, and the optimal sequencing of pharmacotherapy remains unknown. Currently, there are only three medications approved by the US Food and Drug Administration specifically for the management of DPNP. Duloxetine (DUL), a selective serotonin-norepinephrine reuptake inhibitor, is one of these. With the goal of optimizing pharmacotherapy use in DPNP population, a review of current literature was conducted, and the clinical utility of DUL described. Along with early clinical trials, recently published observational studies and pharmacoeconomic models may be useful in guiding decision making by clinicians and managed care organizations. In real-world practice settings, DUL is associated with decreased or similar opioid utilization, increased medication adherence, and similar health care costs compared with current standard of care. DUL has consistently been found to be a cost-effective option over short time-horizons. Currently, the long-term cost-effectiveness of DUL is unknown. Evidence derived from randomized clinical trials, real-world observations, and economic models support the use of DUL as a first-line treatment option from the perspective of the patient, clinician, and managed care payer.

Cervical auscultation in the diagnosis of oropharyngeal aspiration in children: a study protocol for a randomised controlled trial.

PubMed

Frakking, Thuy T; Chang, Anne B; O'Grady, Kerry-Ann F; Walker-Smith, Katie; Weir, Kelly A

2013-11-07

Oropharyngeal aspiration (OPA) can lead to recurrent respiratory illnesses and chronic lung disease in children. Current clinical feeding evaluations performed by speech pathologists have poor reliability in detecting OPA when compared to radiological procedures such as the modified barium swallow (MBS). Improved ability to diagnose OPA accurately via clinical evaluation potentially reduces reliance on expensive, less readily available radiological procedures. Our study investigates the utility of adding cervical auscultation (CA), a technique of listening to swallowing sounds, in improving the diagnostic accuracy of a clinical evaluation for the detection of OPA. We plan an open, unblinded, randomised controlled trial at a paediatric tertiary teaching hospital. Two hundred and sixteen children fulfilling the inclusion criteria will be randomised to one of the two clinical assessment techniques for the clinical detection of OPA: (1) clinical feeding evaluation only (CFE) group or (2) clinical feeding evaluation with cervical auscultation (CFE + CA) group. All children will then undergo an MBS to determine radiologically assessed OPA. The primary outcome is the presence or absence of OPA, as determined on MBS using the Penetration-Aspiration Scale. Our main objective is to determine the sensitivity, specificity, negative and positive predictive values of 'CFE + CA' versus 'CFE' only compared to MBS-identified OPA. Early detection and appropriate management of OPA is important to prevent chronic pulmonary disease and poor growth in children. As the reliability of CFE to detect OPA is low, a technique that can improve the diagnostic accuracy of the CFE will help minimise consequences to the paediatric respiratory system. Cervical auscultation is a technique that has previously been documented as a clinical adjunct to the CFE; however, no published RCTs addressing the reliability of this technique in children exist. Our study will be the first to establish the utility of CA in assessing and diagnosing OPA risk in young children. Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12613000589785.

Conditionally replicative adenovirus for gastrointestinal cancers.

PubMed

Yamamoto, Masato

2004-08-01

The clinical outcome of advanced gastrointestinal (GI) cancers (especially pancreatic and oesophageal cancers) is dismal, despite the advance of conventional therapeutic strategies. Cancer gene therapy is a category of new therapeutics, among which conditionally replicative adenovirus (CRAd) is one promising strategy to overcome existing obstacles of cancer gene therapy. Various CRAds have been developed for GI cancer treatment by taking advantage of the replication biology of adenovirus. Some CRAds have already been tested in clinical trials, but have fallen short of initial expectations. Concerns for clinical applicability include therapeutic potency, replication selectivity and interval end points in clinical trials. In addition, improvement of experimental animal models is needed for a deeper understanding of CRAd biology. Despite these obstacles, CRAds continue to be an exciting area of investigation with great potential for clinical utility. Further virological and oncological research will eventually lead to full realisation of the therapeutic potential of CRAds in the field of GI cancers.

Guidelines on Good Clinical Laboratory Practice

PubMed Central

Ezzelle, J.; Rodriguez-Chavez, I. R.; Darden, J. M.; Stirewalt, M.; Kunwar, N.; Hitchcock, R.; Walter, T.; D’Souza, M. P.

2008-01-01

A set of Good Clinical Laboratory Practice (GCLP) standards that embraces both the research and clinical aspects of GLP were developed utilizing a variety of collected regulatory and guidance material. We describe eleven core elements that constitute the GCLP standards with the objective of filling a gap for laboratory guidance, based on IND sponsor requirements, for conducting laboratory testing using specimens from human clinical trials. These GCLP standards provide guidance on implementing GLP requirements that are critical for laboratory operations, such as performance of protocol-mandated safety assays, peripheral blood mononuclear cell processing and immunological or endpoint assays from biological interventions on IND-registered clinical trials. The expectation is that compliance with the GCLP standards, monitored annually by external audits, will allow research and development laboratories to maintain data integrity and to provide immunogenicity, safety, and product efficacy data that is repeatable, reliable, auditable and that can be easily reconstructed in a research setting. PMID:18037599

Population Based Analysis of Hematologic Malignancy Referrals to a Comprehensive Cancer Center, Referrals for Blood and Marrow Transplantation, and Participation in Clinical Trials, Survey and Biospecimen Research by Race

PubMed Central

Clay, Alyssa; Peoples, Brittany; Zhang, Yali; Moysich, Kirsten; Ross, Levi; McCarthy, Philip; Hahn, Theresa

2017-01-01

Racial and ethnic disparities have been reported in clinical trial/research participation, utilization of autologous and allogeneic BMT and availability of allogeneic donors. We performed a population-based cohort study to investigate adult hematologic malignancy referrals to a U.S tertiary cancer center, utilization of BMT and participation in clinical trials, survey and biospecimen research, by race. U.S. Census Data and the New York State Public Access Cancer Epidemiology Database identified the racial distribution of the general population and new hematologic malignancy cases in the primary catchment area. From 2005–2011, 1,106 patients aged 18–75 years were referred for BMT consultation; while the rate of BMT among hematologic malignancy referrals did not differ by race, the reasons for not receiving a BMT did. Participation in biospecimen research did not vary by race, however African-Americans and other minorities were significantly less likely to participate in survey research than European-Americans. While rates of hematologic malignancy referrals and use of BMT for minorities appear low (<10%), they closely reflect the race distribution of all hematologic malignancy cases and the Western New York population. African-Americans are equally likely as other races to participate in biospecimen banking, but further study is needed to understand reasons for lower participation in survey research. PMID:25899454

Predictive probability methods for interim monitoring in clinical trials with longitudinal outcomes.

PubMed

Zhou, Ming; Tang, Qi; Lang, Lixin; Xing, Jun; Tatsuoka, Kay

2018-04-17

In clinical research and development, interim monitoring is critical for better decision-making and minimizing the risk of exposing patients to possible ineffective therapies. For interim futility or efficacy monitoring, predictive probability methods are widely adopted in practice. Those methods have been well studied for univariate variables. However, for longitudinal studies, predictive probability methods using univariate information from only completers may not be most efficient, and data from on-going subjects can be utilized to improve efficiency. On the other hand, leveraging information from on-going subjects could allow an interim analysis to be potentially conducted once a sufficient number of subjects reach an earlier time point. For longitudinal outcomes, we derive closed-form formulas for predictive probabilities, including Bayesian predictive probability, predictive power, and conditional power and also give closed-form solutions for predictive probability of success in a future trial and the predictive probability of success of the best dose. When predictive probabilities are used for interim monitoring, we study their distributions and discuss their analytical cutoff values or stopping boundaries that have desired operating characteristics. We show that predictive probabilities utilizing all longitudinal information are more efficient for interim monitoring than that using information from completers only. To illustrate their practical application for longitudinal data, we analyze 2 real data examples from clinical trials. Copyright © 2018 John Wiley & Sons, Ltd.

A Mechanomodulatory Device to Minimize Incisional Scar Formation

PubMed Central

Wong, Victor W.; Beasley, Bill; Zepeda, John; Dauskardt, Reinhold H.; Yock, Paul G.; Longaker, Michael T.; Gurtner, Geoffrey C.

2013-01-01

Objective To mechanically control the wound environment and prevent cutaneous scar formation. Approach We subjected various material substrates to biomechanical testing to investigate their ability to modulate skin behavior. Combinations of elastomeric materials, adhesives, and strain applicators were evaluated to develop topical stress-shielding devices. Noninvasive imaging modalities were utilized to characterize anatomic site-specific differences in skin biomechanical properties in humans. The devices were tested in a validated large animal model of hypertrophic scarring. Phase I within-patient controlled clinical trials were conducted to confirm their safety and efficacy in scar reduction in patients undergoing abdominoplasty surgery. Results Among the tested materials and device applicators, a polymer device was developed that effectively off-loaded high tension wounds and blocked pro-fibrotic pathways and excess scar formation in red Duroc swine. In humans, different anatomic sites exhibit unique biomechanical properties that may correlate with the propensity to form scars. In the clinical trial, utilization of this device significantly reduced incisional scar formation and improved scar appearance for up to 12 months compared with control incisions that underwent routine postoperative care. Innovation This is the first device that is able to precisely control the mechanical environment of incisional wounds and has been demonstrated in multiple clinical trials to significantly reduce scar formation after surgery. Conclusion Mechanomodulatory strategies to control the incisional wound environment can significantly reduce pathologic scarring and fibrosis after surgery. PMID:24527342

The Methodology of Clinical Studies Used by the FDA for Approval of High-Risk Orthopaedic Devices.

PubMed

Barker, Jordan P; Simon, Stephen D; Dubin, Jonathan

2017-05-03

The purpose of this investigation was to examine the methodology of clinical trials used by the U.S. Food and Drug Administration (FDA) to determine the safety and effectiveness of high-risk orthopaedic devices approved between 2001 and 2015. Utilizing the FDA's online public database, this systematic review audited study design and methodological variables intended to minimize bias and confounding. An additional analysis of blinding as well as the Checklist to Evaluate a Report of a Nonpharmacological Trial (CLEAR NPT) was applied to the randomized controlled trials (RCTs). Of the 49 studies, 46 (94%) were prospective and 37 (76%) were randomized. Forty-seven (96%) of the studies were controlled in some form. Of 35 studies that reported it, blinding was utilized in 21 (60%), of which 8 (38%) were reported as single-blinded and 13 (62%) were reported as double-blinded. Of the 37 RCTs, outcome assessors were clearly blinded in 6 (16%), whereas 15 (41%) were deemed impossible to blind as implants could be readily discerned on imaging. When the CLEAR NPT was applied to the 37 RCTs, >70% of studies were deemed "unclear" in describing generation of allocation sequences, treatment allocation concealment, and adequate blinding of participants and outcome assessors. This study manifests the highly variable reporting and strength of clinical research methodology accepted by the FDA to approve high-risk orthopaedic devices.

Value of information methods to design a clinical trial in a small population to optimise a health economic utility function.

PubMed

Pearce, Michael; Hee, Siew Wan; Madan, Jason; Posch, Martin; Day, Simon; Miller, Frank; Zohar, Sarah; Stallard, Nigel

2018-02-08

Most confirmatory randomised controlled clinical trials (RCTs) are designed with specified power, usually 80% or 90%, for a hypothesis test conducted at a given significance level, usually 2.5% for a one-sided test. Approval of the experimental treatment by regulatory agencies is then based on the result of such a significance test with other information to balance the risk of adverse events against the benefit of the treatment to future patients. In the setting of a rare disease, recruiting sufficient patients to achieve conventional error rates for clinically reasonable effect sizes may be infeasible, suggesting that the decision-making process should reflect the size of the target population. We considered the use of a decision-theoretic value of information (VOI) method to obtain the optimal sample size and significance level for confirmatory RCTs in a range of settings. We assume the decision maker represents society. For simplicity we assume the primary endpoint to be normally distributed with unknown mean following some normal prior distribution representing information on the anticipated effectiveness of the therapy available before the trial. The method is illustrated by an application in an RCT in haemophilia A. We explicitly specify the utility in terms of improvement in primary outcome and compare this with the costs of treating patients, both financial and in terms of potential harm, during the trial and in the future. The optimal sample size for the clinical trial decreases as the size of the population decreases. For non-zero cost of treating future patients, either monetary or in terms of potential harmful effects, stronger evidence is required for approval as the population size increases, though this is not the case if the costs of treating future patients are ignored. Decision-theoretic VOI methods offer a flexible approach with both type I error rate and power (or equivalently trial sample size) depending on the size of the future population for whom the treatment under investigation is intended. This might be particularly suitable for small populations when there is considerable information about the patient population.

Utilizing Social Media for Community Consultation and Public Disclosure in Exception from Informed Consent Trials

PubMed Central

Stephens, Shannon W.; Williams, Carolyn; Gray, Randal; Kerby, Jeffrey D.; Wang, Henry E.; Bosarge, Patrick L.

2016-01-01

Background The U.S. Food and Drug Administration and Department of Health and Human Services outline regulations allowing an Exception From Informed Consent (EFIC) for research conducted in an emergency settings. Acute care clinical trials utilizing EFIC must include community consultation and public disclosure (CC/PD) activities. We describe our experience using social media to facilitate the CC/PD process in two trauma resuscitation clinical trials. Methods We conducted local CC/PD activities for two multicenter trauma clinical trials, Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) and Prehospital Tranexamic Acid Use for Traumatic Brain Injury (ROC TXA). As part of the CC/PD process, we developed research study advertisements using the social media website Facebook. The Facebook advertisements directed users to a regional study website that contained trial information. We targeted the advertisements to specific demographic users, in specific geographic areas. We analyzed the data using descriptive statistics. Results During the study periods, the PROPPR Facebook advertisement was displayed 5,001,520 times, (12 displays per target population) with 374 individuals selected the advertisement. The ROC-TXA Facebook advertisement was displayed 3,806,448 times (8 per target population) with 790 individuals selecting the advertisement. Respondents to both Facebook advertisements were mostly male (52.6%), with the highest proportion between the ages 15-24 (28.2%). Collectively, 26.9% of individuals that clicked on the Facebook advertisement, spent > 3 minutes on the study website [3min – 49 min]. Commonly accessed webpages were “Contact Us” (PROPPR 5.5%, TXA 7.7%), “Study-specific FAQs” (PROPPR 2.4%), ROC-TXA 6.7%) and “Opt-Out of Research” (PROPPR 2.5%, ROC-TXA 3.8%). Of 51 total individuals viewing the opt-out of research information (PROPPR 19, ROC-TXA 32), Time spent on that specific page was modest (PROPPR 62 seconds, ROC-TXA 55 seconds), with no individuals requesting to opt-out of either study participation. Conclusion In clinical trauma trials, using EFIC, social media may provide a viable option for facilitating the CC/PD process. Level Of Evidence Descriptive Study, Level IV. PMID:26998781

Clinical utility of curcumin extract.

PubMed

Asher, Gary N; Spelman, Kevin

2013-01-01

Turmeric root has been used medicinally in China and India for thousands of years. The active components are thought to be the curcuminoids, primarily curcumin, which is commonly available worldwide as a standardized extract. This article reviews the pharmacology of curcuminoids, their use and efficacy, potential adverse effects, and dosage and standardization. Preclinical studies point to mechanisms of action that are predominantly anti-inflammatory and antineoplastic, while early human clinical trials suggest beneficial effects for dyspepsia, peptic ulcer, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, uveitis, orbital pseudotumor, and pancreatic cancer. Curcumin is well-tolerated; the most common side effects are nausea and diarrhea. Theoretical interactions exist due to purported effects on metabolic enzymes and transport proteins, but clinical reports do not support any meaningful interactions. Nonetheless, caution, especially with chemotherapy agents, is advised. Late-phase clinical trials are still needed to confirm most beneficial effects.

Application of Balanced Scorecard in the Evaluation of a Complex Health System Intervention: 12 Months Post Intervention Findings from the BHOMA Intervention: A Cluster Randomised Trial in Zambia

PubMed Central

Mutale, Wilbroad; Stringer, Jeffrey; Chintu, Namwinga; Chilengi, Roma; Mwanamwenge, Margaret Tembo; Kasese, Nkatya; Balabanova, Dina; Spicer, Neil; Lewis, James; Ayles, Helen

2014-01-01

Introduction In many low income countries, the delivery of quality health services is hampered by health system-wide barriers which are often interlinked, however empirical evidence on how to assess the level and scope of these barriers is scarce. A balanced scorecard is a tool that allows for wider analysis of domains that are deemed important in achieving the overall vision of the health system. We present the quantitative results of the 12 months follow-up study applying the balanced scorecard approach in the BHOMA intervention with the aim of demonstrating the utility of the balanced scorecard in evaluating multiple building blocks in a trial setting. Methods The BHOMA is a cluster randomised trial that aims to strengthen the health system in three rural districts in Zambia. The intervention aims to improve clinical care quality by implementing practical tools that establish clear clinical care standards through intensive clinic implementations. This paper reports the findings of the follow-up health facility survey that was conducted after 12 months of intervention implementation. Comparisons were made between those facilities in the intervention and control sites. STATA version 12 was used for analysis. Results The study found significant mean differences between intervention(I) and control (C) sites in the following domains: Training domain (Mean I:C; 87.5.vs 61.1, mean difference 23.3, p = 0.031), adult clinical observation domain (mean I:C; 73.3 vs.58.0, mean difference 10.9, p = 0.02 ) and health information domain (mean I:C; 63.6 vs.56.1, mean difference 6.8, p = 0.01. There was no gender differences in adult service satisfaction. Governance and motivation scores did not differ between control and intervention sites. Conclusion This study demonstrates the utility of the balanced scorecard in assessing multiple elements of the health system. Using system wide approaches and triangulating data collection methods seems to be key to successful evaluation of such complex health intervention. Trial number ClinicalTrials.gov NCT01942278 PMID:24751780

Associations among visual acuity and vision- and health-related quality of life among patients in the multicenter uveitis steroid treatment trial.

PubMed

Frick, Kevin D; Drye, Lea T; Kempen, John H; Dunn, James P; Holland, Gary N; Latkany, Paul; Rao, Narsing A; Sen, H Nida; Sugar, Elizabeth A; Thorne, Jennifer E; Wang, Robert C; Holbrook, Janet T

2012-03-01

To evaluate the associations between visual acuity and self-reported visual function; visual acuity and health-related quality of life (QoL) metrics; a summary measure of self-reported visual function and health-related QoL; and individual domains of self-reported visual function and health-related QoL in patients with uveitis. Best-corrected visual acuity, vision-related functioning as assessed by the NEI VFQ-25, and health-related QoL as assessed by the SF-36 and EuroQoL EQ-5D questionnaires were obtained at enrollment in a clinical trial of uveitis treatments. Multivariate regression and Spearman correlations were used to evaluate associations between visual acuity, vision-related function, and health-related QoL. Among the 255 patients, median visual acuity in the better-seeing eyes was 20/25, the vision-related function score indicated impairment (median, 60), and health-related QoL scores were within the normal population range. Better visual acuity was predictive of higher visual function scores (P ≤ 0.001), a higher SF-36 physical component score, and a higher EQ-5D health utility score (P < 0.001). The vision-specific function score was predictive of all general health-related QoL (P < 0.001). The correlations between visual function score and general quality of life measures were moderate (ρ = 0.29-0.52). The vision-related function score correlated positively with visual acuity and moderately positively with general QoL measures. Cost-utility analyses relying on changes in generic healthy utility measures will be more likely to detect changes when there are clinically meaningful changes in vision-related function, rather than when there are only changes in visual acuity. (ClinicalTrials.gov number, NCT00132691.).

McMaster PLUS: a cluster randomized clinical trial of an intervention to accelerate clinical use of evidence-based information from digital libraries.

PubMed

Haynes, R Brian; Holland, Jennifer; Cotoi, Chris; McKinlay, R James; Wilczynski, Nancy L; Walters, Leslie A; Jedras, Dawn; Parrish, Rick; McKibbon, K Ann; Garg, Amit; Walter, Stephen D

2006-01-01

Physicians have difficulty keeping up with new evidence from medical research. We developed the McMaster Premium LiteratUre Service (PLUS), an internet-based addition to an existing digital library, which delivered quality- and relevance-rated medical literature to physicians, matched to their clinical disciplines. We evaluated PLUS in a cluster-randomized trial of 203 participating physicians in Northern Ontario, comparing a Full-Serve version (that included alerts to new articles and a cumulative database of alerts) with a Self-Serve version (that included a passive guide to evidence-based literature). Utilization of the service was the primary trial end-point. Mean logins to the library rose by 0.77 logins/month/user (95% CI 0.43, 1.11) in the Full-Serve group compared with the Self-Serve group. The proportion of Full-Serve participants who utilized the service during each month of the study period showed a sustained increase during the intervention period, with a relative increase of 57% (95% CI 12, 123) compared with the Self-Serve group. There were no differences in these proportions during the baseline period, and following the crossover of the Self-Serve group to Full-Serve, the Self-Serve group's usage became indistinguishable from that of the Full-Serve group (relative difference 4.4 (95% CI -23.7, 43.0). Also during the intervention and crossover periods, measures of self-reported usefulness did not show a difference between the 2 groups. A quality- and relevance-rated online literature service increased the utilization of evidence-based information from a digital library by practicing physicians.

McMaster PLUS: A Cluster Randomized Clinical Trial of an Intervention to Accelerate Clinical Use of Evidence-based Information from Digital Libraries

PubMed Central

Haynes, R. Brian; Holland, Jennifer; Cotoi, Chris; McKinlay, R. James; Wilczynski, Nancy L.; Walters, Leslie A.; Jedras, Dawn; Parrish, Rick; McKibbon, K. Ann; Garg, Amit; Walter, Stephen D.

2006-01-01

Background Physicians have difficulty keeping up with new evidence from medical research. Methods We developed the McMaster Premium LiteratUre Service (PLUS), an internet-based addition to an existing digital library, which delivered quality- and relevance-rated medical literature to physicians, matched to their clinical disciplines. We evaluated PLUS in a cluster-randomized trial of 203 participating physicians in Northern Ontario, comparing a Full-Serve version (that included alerts to new articles and a cumulative database of alerts) with a Self-Serve version (that included a passive guide to evidence-based literature). Utilization of the service was the primary trial end-point. Results Mean logins to the library rose by 0.77 logins/month/user (95% CI 0.43, 1.11) in the Full-Serve group compared with the Self-Serve group. The proportion of Full-Serve participants who utilized the service during each month of the study period showed a sustained increase during the intervention period, with a relative increase of 57% (95% CI 12, 123) compared with the Self-Serve group. There were no differences in these proportions during the baseline period, and following the crossover of the Self-Serve group to Full-Serve, the Self-Serve group’s usage became indistinguishable from that of the Full-Serve group (relative difference 4.4 (95% CI −23.7, 43.0). Also during the intervention and crossover periods, measures of self-reported usefulness did not show a difference between the 2 groups. Conclusion A quality- and relevance-rated online literature service increased the utilization of evidence-based information from a digital library by practicing physicians. PMID:16929034

A mixed methods study to assess the feasibility of a randomised controlled trial of invasive urodynamic testing versus clinical assessment and non-invasive tests prior to surgery for stress urinary incontinence in women: the INVESTIGATE-I study.

PubMed

Hilton, Paul; Armstrong, Natalie; Brennand, Catherine; Howel, Denise; Shen, Jing; Bryant, Andrew; Tincello, Douglas G; Lucas, Malcolm G; Buckley, Brian S; Chapple, Christopher R; Homer, Tara; Vale, Luke; McColl, Elaine

2015-09-08

The position of invasive urodynamic testing (IUT) in diagnostic pathways for urinary incontinence is unclear, and systematic reviews have called for further trials evaluating clinical utility. The objective of this study was to inform the decision whether to proceed to a definitive randomised trial of IUT compared to clinical assessment with non-invasive tests, prior to surgery in women with stress urinary incontinence (SUI) or stress-predominant mixed urinary incontinence (MUI). A mixed methods study comprising a pragmatic multicentre randomised pilot trial, a qualitative face-to face interview study with patients eligible for the trial, an exploratory economic evaluation including value of information study, a survey of clinicians' views about IUT, and qualitative telephone interviews with purposively sampled survey respondents. Only the first and second of these elements are reported here. Trial participants were randomised to either clinical assessment with non-invasive tests (control arm) or clinical assessment with non-invasive tests plus IUT (intervention arm). The main outcome measures of these feasibility studies were confirmation that units can identify and recruit eligible women, acceptability of investigation strategies and data collection tools, and acquisition of outcome data to determine the sample size for a definitive trial. The primary outcome proposed for a definitive trial was ICIQ-FLUTS (total score) 6 months after surgery or the start of nonsurgical treatment. Of 284 eligible women, 222 (78%) were recruited, 165/219 (75%) returned questionnaires at baseline, and 125/200 returned them (63%) at follow-up. Most women underwent surgery; management plans were changed in 19 (19%) participants following IUT. Participants interviewed were positive about the trial and the associated documentation. All elements of a definitive trial were rehearsed. Such a trial would require between 232 and 922 participants, depending on the target difference in the primary outcome. We identified possible modifications to our protocol for application in a definitive trial including clarity over inclusion/exclusions, screening processes, reduction in secondary outcomes, and modification to patient questionnaire booklets and bladder diaries. A definitive trial of IUT versus clinical assessment prior to surgery for SUI or stress predominant MUI is feasible and remains relevant. Current Controlled Trials: ISRCTN 71327395, registered 7 June 2010.

Efficacy and safety of Lian-Ju-Gan-Mao capsules for treating the common cold with wind-heat syndrome: study protocol for a randomized controlled trial.

PubMed

Wang, Shengjun; Jiang, Hongli; Yu, Qin; She, Bin; Mao, Bing

2017-01-05

The common cold is a common and frequent respiratory disease mainly caused by viral infection of the upper respiratory tract. Chinese herbal medicine has been increasingly prescribed to treat the common cold; however, there is a lack of evidence to support the wide utility of this regimen. This protocol describes an ongoing phase II randomized controlled clinical trial, based on the theory of traditional Chinese medicine (TCM), with the objective of evaluating the efficacy and safety of Lian-Ju-Gan-Mao capsules (LJGMC), a Chinese patent medicine, compared with placebo in patients suffering from the common cold with wind-heat syndrome (CCWHS). This is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. A total of 240 patients will be recruited and randomly assigned to a high-dose group, medium-dose group, low-dose group, and placebo-matched group in a 1:1:1:1 ratio. The treatment course is 3 consecutive days, with a 5-day follow-up. The primary outcome is time to all symptoms' clearance. Secondary outcomes include time to the disappearance of primary symptoms and each secondary symptom, time to fever relief, time to fever clearance, and change in TCM symptom and sign scores. This trial is a well-designed study according to principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high-quality evidence on the efficacy and safety of LJGMC in treating CCWHS and help to optimize the dose for the next phase III clinical trial. Moreover, the protocol presents a detailed and practical methodology for future clinical trials of drugs developed based on TCM. Chinese Clinical Trial Registry, ChiCTR-IPR-15006504 . Registered on 4 June 2015.

Adaptive semantic tag mining from heterogeneous clinical research texts.

PubMed

Hao, T; Weng, C

2015-01-01

To develop an adaptive approach to mine frequent semantic tags (FSTs) from heterogeneous clinical research texts. We develop a "plug-n-play" framework that integrates replaceable unsupervised kernel algorithms with formatting, functional, and utility wrappers for FST mining. Temporal information identification and semantic equivalence detection were two example functional wrappers. We first compared this approach's recall and efficiency for mining FSTs from ClinicalTrials.gov to that of a recently published tag-mining algorithm. Then we assessed this approach's adaptability to two other types of clinical research texts: clinical data requests and clinical trial protocols, by comparing the prevalence trends of FSTs across three texts. Our approach increased the average recall and speed by 12.8% and 47.02% respectively upon the baseline when mining FSTs from ClinicalTrials.gov, and maintained an overlap in relevant FSTs with the base- line ranging between 76.9% and 100% for varying FST frequency thresholds. The FSTs saturated when the data size reached 200 documents. Consistent trends in the prevalence of FST were observed across the three texts as the data size or frequency threshold changed. This paper contributes an adaptive tag-mining framework that is scalable and adaptable without sacrificing its recall. This component-based architectural design can be potentially generalizable to improve the adaptability of other clinical text mining methods.

Measures That Identify Prescription Medication Misuse, Abuse, and Related Events in Clinical Trials: ACTTION Critique and Recommended Considerations.

PubMed

Smith, Shannon M; Jones, Judith K; Katz, Nathaniel P; Roland, Carl L; Setnik, Beatrice; Trudeau, Jeremiah J; Wright, Stephen; Burke, Laurie B; Comer, Sandra D; Dart, Richard C; Dionne, Raymond; Haddox, J David; Jaffe, Jerome H; Kopecky, Ernest A; Martell, Bridget A; Montoya, Ivan D; Stanton, Marsha; Wasan, Ajay D; Turk, Dennis C; Dworkin, Robert H

2017-11-01

Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD. Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

Utility-Weighted Modified Rankin Scale as Primary Outcome in Stroke Trials

PubMed Central

Voormolen, Daphne C.; Venema, Esmee; Roozenbeek, Bob; Polinder, Suzanne; Haagsma, Juanita A.; Nieboer, Daan; Chalos, Vicky; Yoo, Albert J.; Schreuders, Jennifer; van der Lugt, Aad; Majoie, Charles B.L.M.; Roos, Yvo B.W.E.M.; van Zwam, Wim H.; van Oostenbrugge, Robert J.; Steyerberg, Ewout W.; Dippel, Diederik W.J.; Lingsma, Hester F.

2018-01-01

Background and Purpose— The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a new patient-centered primary outcome in stroke trials. We aimed to describe utility weights for the mRS health states and to evaluate the statistical efficiency of the UW-mRS to detect treatment effects in stroke intervention trials. Methods— We used data of the 500 patients enrolled in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Utility values were elicited from the EuroQol Group 5-Dimension Self-Report Questionnaire assessed at 90 days after inclusion, simultaneously with the mRS. Utility weights were determined by averaging the utilities of all patients within each mRS category. We performed simulations to evaluate statistical efficiency. The simulated treatment effect was an odds ratio of 1.65 in favor of the treatment arm, similar for all mRS cutoffs. This treatment effect was analyzed using 3 approaches: linear regression with the UW-mRS as outcome, binary logistic regression with a dichotomized mRS (0–1/2–6, 0–2/3–6, and 0–4/5–6), and proportional odds logistic regression with the ordinal mRS. The statistical power of the 3 approaches was expressed as the proportion of 10 000 simulations that resulted in a statistically significant treatment effect (P≤0.05). Results— The mean utility values (SD) for mRS categories 0 to 6 were: 0.95 (0.08), 0.93 (0.13), 0.83 (0.21), 0.62 (0.27), 0.42 (0.28), 0.11 (0.28), and 0 (0), respectively, but varied substantially between individual patients within each category. The UW-mRS approach was more efficient than the dichotomous approach (power 85% versus 71%) but less efficient than the ordinal approach (power 85% versus 87%). Conclusions— The UW-mRS as primary outcome does not capture individual variation in utility values and may reduce the statistical power of a randomized trial. PMID:29535271

Review of patient-reported outcome measures in chronic hepatitis C

PubMed Central

2012-01-01

Background Chronic hepatitis C (CHC) and its treatment are associated with a variety of patient-reported symptoms and impacts. Some CHC symptoms and impacts may be difficult to evaluate through objective clinical testing, and more easily measured through patient self-report. This literature review identified concepts raised by CHC patients related to symptoms, impacts, and treatment effects, and evaluated integration of these concepts within patient-reported outcome (PRO) measures. The goal of this work was to provide recommendations for incorporation of PRO measurement of concepts that are relevant to the CHC experience into CHC clinical trial design. Methods A three-tiered literature search was conducted. This included searches on concepts of importance, PRO measures used in clinical trials, and existing PRO measures. The PRO Concept Search focused on reviewing issues raised by CHC patients about CHC symptoms, disease impact, and treatment effects. The CHC Trials with PRO Endpoints Search reviewed clinical trials with PRO endpoints to assess differences between treatments over time. The PRO Measure Search reviewed existing PRO measures associated with the concepts of interest. Results This multi-tiered approach identified five key concepts of interest: depression/anxiety, fatigue, flu-like symptoms, cognitive function, insomnia. Comparing these five concepts of interest to the PRO measures in published CHC clinical trials showed that, while treatment of CHC may decrease health-related quality of life in a number of mental and physical domains, the PRO measures that were utilized in published clinical trials inadequately covered the concepts of interest. Further review of 18 existing PRO measures of the concepts of interest showed only four of the 18 were validated in CHC populations. Conclusions This review identified several gaps in the literature regarding assessment of symptoms and outcomes reported as important by CHC patients. Further research is needed to ensure that CHC clinical trials evaluate concepts that are important to patients and include measures that have evidence supporting content validity, reliability, construct validity, and responsiveness. PMID:22871087

Adolescent decision making about participation in a hypothetical HIV vaccine trial.

PubMed

Alexander, Andreia B; Ott, Mary A; Lally, Michelle A; Sniecinski, Kevin; Baker, Alyne; Zimet, Gregory D

2015-03-10

The purpose of this study was to examine the process of adolescent decision-making about participation in an HIV vaccine clinical trial, comparing it to adult models of informed consent with attention to developmental differences. As part of a larger study of preventive misconception in adolescent HIV vaccine trials, we interviewed 33 male and female 16-19-year-olds who have sex with men. Participants underwent a simulated HIV vaccine trial consent process, and then completed a semistructured interview about their decision making process when deciding whether or not to enroll in and HIV vaccine trial. An ethnographic content analysis approach was utilized. Twelve concepts related to adolescents' decision-making about participation in an HIV vaccine trial were identified and mapped onto Appelbaum and Grisso's four components of decision making capacity including understanding of vaccines and how they work, the purpose of the study, trial procedures, and perceived trial risks and benefits, an appreciation of their own situation, the discussion and weighing of risks and benefits, discussing the need to consult with others about participation, motivations for participation, and their choice to participate. The results of this study suggest that most adolescents at high risk for HIV demonstrate the key abilities needed to make meaningful decisions about HIV vaccine clinical trial participation. Published by Elsevier Ltd.

Open-Label Randomized Trial of Titrated Disease Management for Patients with Hypertension: Study Design and Baseline Sample Characteristics

PubMed Central

Jackson, George L.; Weinberger, Morris; Kirshner, Miriam A.; Stechuchak, Karen M.; Melnyk, Stephanie D.; Bosworth, Hayden B.; Coffman, Cynthia J.; Neelon, Brian; Van Houtven, Courtney; Gentry, Pamela W.; Morris, Isis J.; Rose, Cynthia M.; Taylor, Jennifer P.; May, Carrie L.; Han, Byungjoo; Wainwright, Christi; Alkon, Aviel; Powell, Lesa; Edelman, David

2016-01-01

Despite the availability of efficacious treatments, only half of patients with hypertension achieve adequate blood pressure (BP) control. This paper describes the protocol and baseline subject characteristics of a 2-arm, 18-month randomized clinical trial of titrated disease management (TDM) for patients with pharmaceutically-treated hypertension for whom systolic blood pressure (SBP) is not controlled (≥140mmHg for non-diabetic or ≥130mmHg for diabetic patients). The trial is being conducted among patients of four clinic locations associated with a Veterans Affairs Medical Center. An intervention arm has a TDM strategy in which patients' hypertension control at baseline, 6, and 12 months determines the resource intensity of disease management. Intensity levels include: a low-intensity strategy utilizing a licensed practical nurse to provide bi-monthly, non-tailored behavioral support calls to patients whose SBP comes under control; medium-intensity strategy utilizing a registered nurse to provide monthly tailored behavioral support telephone calls plus home BP monitoring; and high-intensity strategy utilizing a pharmacist to provide monthly tailored behavioral support telephone calls, home BP monitoring, and pharmacist-directed medication management. Control arm patients receive the low-intensity strategy regardless of BP control. The primary outcome is SBP. There are 385 randomized (192 intervention; 193 control) veterans that are predominately older (mean age 63.5 years) men (92.5%). 61.8% are African American, and the mean baseline SBP for all subjects is 143.6mmHg. This trial will determine if a disease management program that is titrated by matching the intensity of resources to patients' BP control leads to superior outcomes compared to a low-intensity management strategy. PMID:27417982

Open-label randomized trial of titrated disease management for patients with hypertension: Study design and baseline sample characteristics.

PubMed

Jackson, George L; Weinberger, Morris; Kirshner, Miriam A; Stechuchak, Karen M; Melnyk, Stephanie D; Bosworth, Hayden B; Coffman, Cynthia J; Neelon, Brian; Van Houtven, Courtney; Gentry, Pamela W; Morris, Isis J; Rose, Cynthia M; Taylor, Jennifer P; May, Carrie L; Han, Byungjoo; Wainwright, Christi; Alkon, Aviel; Powell, Lesa; Edelman, David

2016-09-01

Despite the availability of efficacious treatments, only half of patients with hypertension achieve adequate blood pressure (BP) control. This paper describes the protocol and baseline subject characteristics of a 2-arm, 18-month randomized clinical trial of titrated disease management (TDM) for patients with pharmaceutically-treated hypertension for whom systolic blood pressure (SBP) is not controlled (≥140mmHg for non-diabetic or ≥130mmHg for diabetic patients). The trial is being conducted among patients of four clinic locations associated with a Veterans Affairs Medical Center. An intervention arm has a TDM strategy in which patients' hypertension control at baseline, 6, and 12months determines the resource intensity of disease management. Intensity levels include: a low-intensity strategy utilizing a licensed practical nurse to provide bi-monthly, non-tailored behavioral support calls to patients whose SBP comes under control; medium-intensity strategy utilizing a registered nurse to provide monthly tailored behavioral support telephone calls plus home BP monitoring; and high-intensity strategy utilizing a pharmacist to provide monthly tailored behavioral support telephone calls, home BP monitoring, and pharmacist-directed medication management. Control arm patients receive the low-intensity strategy regardless of BP control. The primary outcome is SBP. There are 385 randomized (192 intervention; 193 control) veterans that are predominately older (mean age 63.5years) men (92.5%). 61.8% are African American, and the mean baseline SBP for all subjects is 143.6mmHg. This trial will determine if a disease management program that is titrated by matching the intensity of resources to patients' BP control leads to superior outcomes compared to a low-intensity management strategy. Published by Elsevier Inc.

Evaluating Protocol Lifecycle Time Intervals in HIV/AIDS Clinical Trials

PubMed Central

Schouten, Jeffrey T.; Dixon, Dennis; Varghese, Suresh; Cope, Marie T.; Marci, Joe; Kagan, Jonathan M.

2014-01-01

Background Identifying efficacious interventions for the prevention and treatment of human diseases depends on the efficient development and implementation of controlled clinical trials. Essential to reducing the time and burden of completing the clinical trial lifecycle is determining which aspects take the longest, delay other stages, and may lead to better resource utilization without diminishing scientific quality, safety, or the protection of human subjects. Purpose In this study we modeled time-to-event data to explore relationships between clinical trial protocol development and implementation times, as well as identify potential correlates of prolonged development and implementation. Methods We obtained time interval and participant accrual data from 111 interventional clinical trials initiated between 2006 and 2011 by NIH’s HIV/AIDS Clinical Trials Networks. We determined the time (in days) required to complete defined phases of clinical trial protocol development and implementation. Kaplan-Meier estimates were used to assess the rates at which protocols reached specified terminal events, stratified by study purpose (therapeutic, prevention) and phase group (pilot/phase I, phase II, and phase III/ IV). We also examined several potential correlates to prolonged development and implementation intervals. Results Even though phase grouping did not determine development or implementation times of either therapeutic or prevention studies, overall we observed wide variation in protocol development times. Moreover, we detected a trend toward phase III/IV therapeutic protocols exhibiting longer developmental (median 2 ½ years) and implementation times (>3years). We also found that protocols exceeding the median number of days for completing the development interval had significantly longer implementation. Limitations The use of a relatively small set of protocols may have limited our ability to detect differences across phase groupings. Some timing effects present for a specific study phase may have been masked by combining protocols into phase groupings. Presence of informative censoring, such as withdrawal of some protocols from development if they began showing signs of lost interest among investigators, complicates interpretation of Kaplan-Meier estimates. Because this study constitutes a retrospective examination over an extended period of time, it does not allow for the precise identification of relative factors impacting timing. Conclusions Delays not only increase the time and cost to complete clinical trials, but they also diminish their usefulness by failing to answer research questions in time. We believe that research analyzing the time spent traversing defined intervals across the clinical trial protocol development and implementation continuum can stimulate business process analyses and reengineering efforts that could lead to reductions in the time from clinical trial concept to results, thereby accelerating progress in clinical research. PMID:24980279

Utility of colposcopy in a phase 2 portion of a microbicide clinical trial of BufferGel and 0.5% PRO 2000 Gel

PubMed Central

Chirenje, Zvavahera M; Mâsse, Benoît R; Maslankowski, Lisa A; Ramjee, Gita; Coletti, Anne S; Tembo, Tchangani N; Magure, Tsitsi M; Soto-Torres, Lydia; Kelly, Cliff; Hillier, Sharon; Karim, Abdool

2012-01-01

Background The majority of new HIV infections are acquired through heterosexual transmission. There is urgent need for prevention methods to compliment behavior change and condom use. Topical microbicide represent a potential strategy for reduction of HIV transmission in women. Methods Monthly Colposcopy evaluations were performed during pelvic examinations among 299 women enrolled in the Phase 2 portion of HPTN 035 study at four sites (1 in USA, 3 in Southern Africa). This was a phase 2/2b, multisite, randomized, and controlled clinical trial with four arms: BufferGel, 0.5% PRO2000 Gel, placebo gel and no gel. At two of the sites, pelvic examinations were conducted by the use of naked eye without colposcopy. Results A colposcopy finding of any kind was detected in 48% of participants at baseline compared to 40% at 3 months (p =0.04). The lower rates were also observed in vaginal discharge (22% at baseline, 16% at 3 months, p=0.06), erythema (15% at baseline, 8% at 3 months, p=0.004). The trend towards significance at p=0.05 disappear when utilizing stringent statistical significance levels. A pelvic finding of any kind was detected in 71% of colposcopy participants compared to 41% of participants who had naked eye examination only conducted at two sites that performed both colposcopy and naked eye without colposcopy. Use of colposcopy yielded significantly higher rates of participants with deep epithelial disruption, erythema and ecchymosis. We observed no cases of incident Chlamydia, Gonorrhea, or Syphilis during the three month follow up. There were 2 cases of incident HIV during 3-month study period neither of which was associated with any abnormal colposcopy evaluation findings. Conclusion No safety signals were observed in the 4 study arms, allowing seamless transition from phase 2 to 2b. Colposcopy utility in microbicide clinical trials has minimal value given high rates of background noise findings of no relevant clinical significance. PMID:22944480

Utility of colposcopy in a phase 2 portion of a microbicide clinical trial of BufferGel and 0.5% PRO 2000 Gel.

PubMed

Chirenje, Zvavahera M; Mâsse, Benoît R; Maslankowski, Lisa A; Ramjee, Gita; Coletti, Anne S; Tembo, Tchangani N; Magure, Tsitsi M; Soto-Torres, Lydia; Kelly, Cliff; Hillier, Sharon; Karim, Abdool

2012-08-27

The majority of new HIV infections are acquired through heterosexual transmission. There is urgent need for prevention methods to compliment behavior change and condom use. Topical microbicide represent a potential strategy for reduction of HIV transmission in women. Monthly Colposcopy evaluations were performed during pelvic examinations among 299 women enrolled in the Phase 2 portion of HPTN 035 study at four sites (1 in USA, 3 in Southern Africa). This was a phase 2/2b, multisite, randomized, and controlled clinical trial with four arms: BufferGel, 0.5% PRO2000 Gel, placebo gel and no gel. At two of the sites, pelvic examinations were conducted by the use of naked eye without colposcopy. A colposcopy finding of any kind was detected in 48% of participants at baseline compared to 40% at 3 months (p =0.04). The lower rates were also observed in vaginal discharge (22% at baseline, 16% at 3 months, p=0.06), erythema (15% at baseline, 8% at 3 months, p=0.004). The trend towards significance at p=0.05 disappear when utilizing stringent statistical significance levels. A pelvic finding of any kind was detected in 71% of colposcopy participants compared to 41% of participants who had naked eye examination only conducted at two sites that performed both colposcopy and naked eye without colposcopy. Use of colposcopy yielded significantly higher rates of participants with deep epithelial disruption, erythema and ecchymosis. We observed no cases of incident Chlamydia, Gonorrhea, or Syphilis during the three month follow up. There were 2 cases of incident HIV during 3-month study period neither of which was associated with any abnormal colposcopy evaluation findings. No safety signals were observed in the 4 study arms, allowing seamless transition from phase 2 to 2b. Colposcopy utility in microbicide clinical trials has minimal value given high rates of background noise findings of no relevant clinical significance.

Considerations in reporting palliative care clinical trials: Standardizing information reported and authorship practices

PubMed Central

LeBlanc, Thomas W.; Abernethy, Amy P.; Currow, David C.; Kutner, Jean S.

2014-01-01

Purpose of Review The nature of palliative care practice, especially the reliance on referrals and differing models of service delivery, poses unique challenges for the creation and interpretation of an evidence base, frequently limiting the applicability of data to patient care. Here we discuss two core aspects of clinical trials reporting in palliative medicine: 1) proposed standards governing the collection and reporting of data, and 2) rules governing authorship and publication. Recent Findings Existing literature often inadequately describes the characteristics of patients, caregivers, clinicians, systems, and interventions included in studies, thereby limiting the utility of results. Summary A generalizability framework is needed to ensure a robust evidence base that advances practice. Lessons learned through the development of research cooperative groups in palliative care reinforce the importance of an authorship protocol for large trials and working groups. PMID:23080306

The Quality of Registration of Clinical Trials: Still a Problem

PubMed Central

Viergever, Roderik F.; Karam, Ghassan; Reis, Andreas; Ghersi, Davina

2014-01-01

Introduction The benefits of clinical trials registration include improved transparency on clinical trials for healthcare workers and patients, increased accountability of trialists, the potential to address publication bias and selective reporting, and possibilities for research collaboration and prioritization. However, poor quality of information in registered records of trials has been found to undermine these benefits in the past. Trialists' increasing experience with trial registration and recent developments in registration systems may have positively affected data quality. This study was conducted to investigate whether the quality of registration has improved. Methods We repeated a study from 2009, using the same methods and the same research team. A random sample of 400 records of clinical trials that were registered between 01/01/2012 and 01/01/2013 was taken from the International Clinical Trials Registry Platform (ICTRP) and assessed for the quality of information on 1) contact details, 2) interventions and 3) primary outcomes. Results were compared to the equivalent assessments from our previous study. Results There was a small and not statistically significant increase from 81.0% to 85.5% in the percentage of records that provided a name of a contact person. There was a significant increase from 68.7% to 74.9% in the number of records that provided either an email address or a telephone number. There was a significant increase from 44.2% to 51.9% in the number of intervention arms that were complete in registering intervention specifics. There was a significant increase from 38.2% to 57.6% in the number of primary outcomes that were specific measures with a meaningful timeframe. Approximately half of all trials continued to be retrospectively registered. Discussion There have been small but significant improvements in the quality of registration since 2009. Important problems with quality remain and continue to constitute an impediment to the meaningful utilization of registered trial information. PMID:24427293

Biomarkers as drug development tools: discovery, validation, qualification and use.

PubMed

Kraus, Virginia B

2018-06-01

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.

A randomised controlled trial evaluating the utility of a patient Decision Aid to improve clinical trial (RAVES 08.03) related decision-making.

PubMed

Sundaresan, Puma; Ager, Brittany; Turner, Sandra; Costa, Dan; Kneebone, Andrew; Pearse, Maria; Woo, Henry; Tesson, Stephanie; Juraskova, Ilona; Butow, Phyllis

2017-10-01

Randomised controlled trials (RCTs) are considered the 'gold-standard' for evaluating medical treatments. However, patients and clinicians report difficulties with informed consent and recruitment. We evaluated the utility of a Decision Aid (DA) in reducing RCT-related decisional conflict, and improving RCT knowledge and recruitment. Potential participants for a radiotherapy RCT were invited to participate in the current study. Participants were randomised to receive the RCT's participant information sheet with or without a DA. Questionnaires were administered at baseline, one and six months. The primary outcome measure was decisional conflict. Secondary outcome measures included knowledge regarding and recruitment to the RCT. 129 men were randomised to the DA (63) and control (66) arms. Decisional conflict was significantly lower over 6-months (p=0.048) in the DA arm. Knowledge regarding the RCT was significantly higher at 6months (p=0.033) in the DA arm. 20.6% of the DA arm (13 of 63) and 9% of the control arm (6 of 66) entered the RCT. This study demonstrates the utility of a DA in reducing decisional conflict and improving trial knowledge in men with cancer who are making decisions regarding RCT participation. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review.

PubMed

Merker, Jason D; Oxnard, Geoffrey R; Compton, Carolyn; Diehn, Maximilian; Hurley, Patricia; Lazar, Alexander J; Lindeman, Neal; Lockwood, Christina M; Rai, Alex J; Schilsky, Richard L; Tsimberidou, Apostolia M; Vasalos, Patricia; Billman, Brooke L; Oliver, Thomas K; Bruinooge, Suanna S; Hayes, Daniel F; Turner, Nicholas C

2018-06-01

Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

Self-System Therapy for Distress Associated with Persistent Low Back Pain: A Randomized Clinical Trial

PubMed Central

Waters, Sandra J.; McKee, Daphne C.; Campbell, Lisa C.; Shelby, Rebecca A.; Dixon, Kim E.; Fras, Anne Marie; Keefe, Francis J.

2015-01-01

Objective Persistent low back pain (PLBP) is associated with vulnerability to depression. PLBP frequently requires major changes in occupation and lifestyle, which can lead to a sense of failing to attain one’s personal goals (self-discrepancy). Method We conducted a clinical trial to examine the efficacy of self-system therapy (SST), a brief structured therapy for depression based on self-discrepancy theory. A total of 101 patients with PLBP and clinically significant depressive symptoms were randomized either to SST, pain education, or standard care. Results Patients receiving SST showed significantly greater improvement in depressive symptoms. Reduction in self-discrepancy predicted reduction in depressive symptoms only within the SST condition. Conclusions Findings support the utility of SST for individuals facing persistent pain and associated depression. PMID:26079438

The continuing search for antitumor agents from higher plants

PubMed Central

Pan, Li; Chai, Heebyung; Kinghorn, A. Douglas

2009-01-01

Plant secondary metabolites and their semi-synthetic derivatives continue to play an important role in anticancer drug therapy. In this short review, selected single chemical entity antineoplastic agents from higher plants that are currently in clinical trials as cancer chemotherapy drug candidates are described. These compounds are representative of a wide structural diversity. In addition, the approaches taken toward the discovery of anticancer agents from tropical plants in the laboratory of the authors are summarized. The successful clinical utilization of cancer chemotherapeutic agents from higher plants has been evident for about half a century, and, when considered with the promising pipeline of new plant-derived compounds now in clinical trials, this augurs well for the continuation of drug discovery research efforts to elucidate additional candidate substances of this type. PMID:20228943

What's hot, what's new: Report from the American Transplant Congress 2017.

PubMed

Cooper, Matthew; Li, Xian C; Adams, Andrew B

2018-02-01

Significant advances in clinical practice as well as basic and translational science were presented at the American Transplant Congress this year. Topics included innovative clinical trials to recent advances in our basic understanding of the scientific underpinnings of transplant immunology. Key areas of interest included the following: clinical trials utilizing hepatitis C virus-positive (HCV + ) donors for HCV - recipients, the impact of the new allocation policies, normothermic perfusion, novel treatments for desensitization, attempts at precision medicine, advances in xenotransplantation, the role of mitochondria and exosomes in rejection, nanomedicine, and the impact of the microbiota on transplant outcomes. This review highlights some of the most interesting and noteworthy presentations from the meeting. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Host-dependent variables: The missing link to personalized medicine.

PubMed

Demlova, Regina; Zdrazilova-Dubska, Lenka; Sterba, Jaroslav; Stanta, Giorgio; Valik, Dalibor

2018-04-26

Individualized medicine has the potential to tailor anticancer therapy with the best response and highest safety margin to provide better patient care. However, modern targeted therapies are still being tested through clinical trials comparing preselected patient cohorts and assessed upon behaviour of group averages. Clinically manifesting malignant disease requires identification of host- and tumour-dependent variables such as biological characteristics of the tumour and its microenvironment including immune response features, and overall capacity of the host to receive, tolerate and efficiently utilize treatment. Contemporary medical oncology including clinical trial design need to refocus from assessing group averages to individuality taking into consideration time dependent host-associated characteristics and reinventing outliers to be appreciated as naturally occurring variables collectively determining the ultimate outcome of malignant disease. Copyright © 2018. Published by Elsevier Ltd.

Surgical management of stress urinary incontinence in women: safety, effectiveness and cost-utility of trans-obturator tape (TOT) versus tension-free vaginal tape (TVT) five years after a randomized surgical trial

PubMed Central

2011-01-01

Background We recently completed a randomized clinical trial of two minimally invasive surgical procedures for stress urinary incontinence, the retropubic tension-free vaginal tape (TVT) versus the trans-obturator tape (TOT) procedure. At one year postoperatively, we were concerned to find that a significant number of women had tape that was palpable when a vaginal examination was undertaken. Because the risk factors for adverse outcomes of tape surgery are not clearly understood, we are unable to say whether palpable tapes will lead to vaginal erosions or whether they merge into vaginal tissue. We do not know whether patients go on to have further adverse consequences of surgery, leading to additional cost to patients and healthcare system. Our current study is a 5 year follow-up of the women who took part in our original trial. Methods/Design All 199 women who participated in our original trial will be contacted and invited to take part in the follow-up study. Consenting women will attend a clinic visit where they will have a physical examination to identify vaginal erosion or other serious adverse outcomes of surgery, undertake a standardized pad test for urinary incontinence, and complete several health-related quality of life questionnaires (15D, UDI-6, IIQ-7). Analyses will compare the outcomes for women in the TOT versus TVT groups. The cost-effectiveness of TOT versus TVT over the 5 years after surgery, will be assessed with the use of disease-specific health service administrative data and an objective health outcome measure. A cost-utility analysis may also be undertaken, based on economic modeling, data from the clinical trial and inputs obtained from published literature. Discussion This study is needed now, because TOT and TVT are among the most frequently conducted surgical procedures for stress urinary incontinence in Canada. Because stress urinary incontinence is so common, the impact of selecting an approach that causes more adverse events, or is less effective, will have a significant impact on individual quality of life, and societal and health care costs. Trial registration ClinicalTrials.gov NCT00234754. Registered October 2005. PMID:21781314

Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice?

PubMed Central

Shahin, Mohamed H.A.; Johnson, Julie A.

2013-01-01

Purpose of review To review the most promising genetic markers associated with the variability in the safety or efficacy of warfarin and clopidogrel and highlight the verification and validation initiatives for translating clopidogrel and warfarin pharmacogenetic tests to clinical practice. Recent findings Rapid advances in pharmacogenetics, continuous decrease in genotyping cost, development of point-of-care devices and the newly established clinical genotyping programs at several institutions hold the promise of individualizing clopidogrel and warfarin based on genotype. Guidelines have been established to assist clinicians in prescribing clopidogrel or warfarin dose based on genotype. However, the clinical utility of clopidogrel and warfarin is still limited. Accordingly, large randomized clinical trials are underway to define the role of clopidogrel and warfarin pharmacogenetics in clinical practice. Summary Pharmacogenetics has offered compelling evidence toward the individualization of clopidogrel and warfarin therapies. The rapid advances in technology make the clinical implementation of clopidogrel and warfarin pharmacogenetics possible. The clinical genotyping programs and the ongoing clinical trials will help in overcoming some of the barriers facing the clinical implementation of clopidogrel and warfarin pharmacogenetics. PMID:23478884

Trial-Based Cost-Utility Analysis of Icotinib versus Gefitinib as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer in China.

PubMed

Zhang, Chunxiang; Zhang, Hongmei; Shi, Jinning; Wang, Dong; Zhang, Xiuwei; Yang, Jian; Zhai, Qizhi; Ma, Aixia

2016-01-01

Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed. Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy. The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market.

Latin American Clinical Epidemiology Network Series - Paper 4: Economic evaluation of Kangaroo Mother Care: cost utility analysis of results from a randomized controlled trial conducted in Bogotá.

PubMed

Ruiz, Juan Gabriel; Charpak, Nathalie; Castillo, Mario; Bernal, Astrid; Ríos, John; Trujillo, Tammy; Córdoba, María Adelaida

2017-06-01

Although kangaroo mother care (KMC) has been shown to be safe and effective in randomized controlled trials (RCTs), there are no published complete economic evaluations including the three components of the full intervention. A cost utility analysis performed on the results of an RCT conducted in Bogotá, Colombia between 1993 and 1996. Hospital and ambulatory costs were estimated by microcosting in a sample of preterm infants from a University Hospital in Bogotá in 2011 and at a KMC clinic in the same period. Utility scores were assigned by experts by means of (1) direct ordering and scoring discrete health states and (2) constructing a multi-attribute utility function. Ninety-five percent confidence intervals (CIs) for the incremental cost-utility ratios (ICURs) were computed by the Fiellers theorem method. One-way sensitivity analysis on price estimates for valuing costs was performed. ICUR at 1 year of corrected age was $ -1,546 per extra quality-adjusted life year gained using the KMC method (95% CI $ -7,963 to $ 4,910). In Bogotá, the use of KMC is dominant: more effective and cost-saving. Although results from an economic analysis should not be extrapolated to different systems and communities, this dominant result suggests that KMC could be cost-effective in similar low and middle income countries settings. Copyright © 2016 Elsevier Inc. All rights reserved.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY 2016 OUTPATIENT GLUCOSE MONITORING CONSENSUS STATEMENT.

PubMed

Bailey, Timothy S; Grunberger, George; Bode, Bruce W; Handelsman, Yehuda; Hirsch, Irl B; Jovanovič, Lois; Roberts, Victor Lawrence; Rodbard, David; Tamborlane, William V; Walsh, John

2016-02-01

This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

Biomarkers for Early Detection of Clinically Relvant Prostate Cancer: A Multi-Institutional Validation Trial - Genomic Health, Inc. — EDRN Public Portal

Cancer.gov

Validate a panel of tissue-based biomarkers to determine the presence of or progression to clinically relevant prostate cancer at the time of diagnosis. Utilize a novel, biopsy based multi-gene quantitative RT-PCR assay developed by Genomic Health, Oncotype DX Prostate Cancer Assay, which discriminates aggressive from indolent cancer on multivariate modeling of PCa patients.

Does the Cultural Formulation Interview for the fifth revision of the diagnostic and statistical manual of mental disorders (DSM-5) affect medical communication? A qualitative exploratory study from the New York site.

PubMed

Aggarwal, Neil K; Desilva, Ravi; Nicasio, Andel V; Boiler, Marit; Lewis-Fernández, Roberto

2015-01-01

Cross-cultural mental health researchers often analyze patient explanatory models of illness to optimize service provision. The Cultural Formulation Interview (CFI) is a cross-cultural assessment tool released in May 2013 with DSM-5 to revise shortcomings from the DSM-IV Outline for Cultural Formulation (OCF). The CFI field trial took place in 6 countries, 14 sites, and with 321 patients to explore its feasibility, acceptability, and clinical utility with patients and clinicians. We sought to analyze if and how CFI feasibility, acceptability, and clinical utility were related to patient-clinician communication. We report data from the New York site which enrolled 7 clinicians and 32 patients in 32 patient-clinician dyads. We undertook a data analysis independent of the parent field trial by conducting content analyses of debriefing interviews with all participants (n = 64) based on codebooks derived from frameworks for medical communication and implementation outcomes. Three coders created codebooks, coded independently, established inter-rater coding reliability, and analyzed if the CFI affects medical communication with respect to feasibility, acceptability, and clinical utility. Despite racial, ethnical, cultural, and professional differences within our group of patients and clinicians, we found that promoting satisfaction through the interview, eliciting data, eliciting the patient's perspective, and perceiving data at multiple levels were common codes that explained how the CFI affected medical communication. We also found that all but two codes fell under the implementation outcome of clinical utility, two fell under acceptability, and none fell under feasibility. Our study offers new directions for research on how a cultural interview affects patient-clinician communication. Future research can analyze how the CFI and other cultural interviews impact medical communication in clinical settings with subsequent effects on outcomes such as medication adherence, appointment retention, and health condition.

Does the Cultural Formulation Interview (CFI) for the Fifth Revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) affect medical communication? A qualitative exploratory study from the New York site

PubMed Central

Aggarwal, Neil K.; DeSilva, Ravi; Nicasio, Andel V.; Boiler, Marit; Lewis-Fernández, Roberto

2014-01-01

Objectives Cross-cultural mental health researchers often analyze patient explanatory models of illness to optimize service provision. The Cultural Formulation Interview (CFI) is a cross-cultural assessment tool released in May 2013 with DSM-5 to revise shortcomings from the DSM-IV Outline for Cultural Formulation (OCF). The CFI field trial took place in 6 countries, 14 sites, and with 321 patients to explore its feasibility, acceptability, and clinical utility with patients and clinicians. We sought to analyze if and how CFI feasibility, acceptability, and clinical utility were related to patient-clinician communication. Design We report data from the New York site which enrolled 7 clinicians and 32 patients in 32 patient-clinician dyads. We undertook a data analysis independent of the parent field trial by conducting content analyses of debriefing interviews with all participants (n=64) based on codebooks derived from frameworks for medical communication and implementation outcomes. Three coders created codebooks, coded independently, established inter-rater coding reliability, and analyzed if the CFI affects medical communication with respect to feasibility, acceptability, and clinical utility. Results Despite racial, ethnic, cultural, and professional differences within our group of patients and clinicians, we found that promoting satisfaction through the interview, eliciting data, eliciting the patient’s perspective, and perceiving data at multiple levels were common codes that explained how the CFI affected medical communication. We also found that all but 2 codes fell under the implementation outcome of clinical utility, 2 fell under acceptability, and none fell under feasibility. Conclusion Our study offers new directions for research on how a cultural interview affects patient-clinician communication. Future research can analyze how the CFI and other cultural interviews impact medical communication in clinical settings with subsequent effects on outcomes such as medication adherence, appointment retention, and health condition. PMID:25372242

Pharmacokinetic evaluation and clinical utility of azilsartan medoxomil for the treatment of hypertension.

PubMed

Angeli, Fabio; Verdecchia, Paolo; Pascucci, Chiara; Poltronieri, Cristina; Reboldi, Gianpaolo

2013-03-01

Azilsartan medoxomil is a newly approved angiotensin-receptor blocker for the management of hypertension. It is a prodrug that is quickly hydrolyzed to the active moiety azilsartan, a potent and highly selective angiotensin-receptor blocker with estimated bioavailability of ∼ 60%. This new agent induces a potent and long-lasting antihypertensive effect. The effective therapeutic antihypertensive dosages of azilsartan medoxomil in humans vary from 40 to 80 mg/day. The authors review the results of clinical trials published in journals indexed in Medline, Scopus and Google Scholar. Primarily the authors discuss articles that analyze the safety and efficacy of azilsartan in lowering blood pressure. Clinical trials have demonstrated that azilsartan is superior to other angiotensin-receptor blockers in lowering blood pressure. However, the clinical blood pressure trials of azilsartan published to date have been mainly conducted in patients without serious comorbidities and it is not clear if azilsartan has advantages over other angiotensin-receptor blockers in the treatment of these types of hypertensive patients. In addition, it remains to be determined whether the specific pharmacologic and pharmacokinetic characteristics of azilsartan will have a clinically significant impact on long-term cardiovascular outcomes.

Microdose clinical trial: quantitative determination of nicardipine and prediction of metabolites in human plasma.

PubMed

Yamane, Naoe; Takami, Tomonori; Tozuka, Zenzaburo; Sugiyama, Yuichi; Yamazaki, Akira; Kumagai, Yuji

2009-01-01

A sample treatment procedure and high-sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantitative determination of nicardipine in human plasma were developed for a microdose clinical trial with nicardipine, a non-radioisotope labeled drug. The calibration curve was linear in the range of 1-500 pg/mL using 1 mL of plasma. Analytical method validation for the clinical dose, for which the calibration curve was linear in the range of 0.2-100 ng/mL using 20 microL of plasma, was also conducted. Each method was successfully applied to making determinations in plasma using LC/MS/MS after administration of a microdose (100 microg) and clinical dose (20 mg) to each of six healthy volunteers. We tested new approaches in the search for metabolites in plasma after microdosing. In vitro metabolites of nicardipine were characterized using linear ion trap-fourier transform ion cyclotron resonance mass spectrometry (LIT-FTICRMS) and the nine metabolites predicted to be in plasma were analyzed using LC/MS/MS. There is a strong possibility that analysis of metabolites by LC/MS/MS may advance to utilization in microdose clinical trials with non-radioisotope labeled drugs.

Design of a community-based intergenerational oral health study: "Baby Smiles".

PubMed

Milgrom, Peter; Riedy, Christine A; Weinstein, Philip; Mancl, Lloyd A; Garson, Gayle; Huebner, Colleen E; Smolen, Darlene; Sutherland, Marilynn

2013-08-06

Rural, low-income pregnant women and their children are at high risk for poor oral health and have low utilization rates of dental care. The Baby Smiles study was designed to increase low-income pregnant women's utilization of dental care, increase young children's dental care utilization, and improve home oral health care practices. Baby Smiles was a five-year, four-site randomized intervention trial with a 2 × 2 factorial design. Four hundred participants were randomly assigned to one of four treatment arms in which they received either brief Motivational Interviewing (MI) or health education (HE) delivered during pregnancy and after the baby was born. In the prenatal study phase, the interventions were designed to encourage dental utilization during pregnancy. After childbirth, the focus was to utilize dental care for the infant by age one. The two primary outcome measures were dental utilization during pregnancy or up to two months postpartum for the mother, and preventive dental utilization by 18 months of age for the child. Medicaid claims data will be used to assess the primary outcomes. Questionnaires were administered at enrollment and 3, 9 and 18 months postpartum (study end) to assess mediating and moderating factors. This trial can help define the most effective way to provide one-on-one counseling to pregnant women and new mothers regarding visits to the dentist during pregnancy and after the child is born. It supports previous work demonstrating the potential of reducing mother-to-child transmission of Streptococcus mutans and the initiation of dental caries prevention in early childhood. ClinicalTrials.gov Identifier NCT01120041.

Soluble biomarkers development in osteoarthritis: from discovery to personalized medicine

PubMed Central

Henrotin, Yves; Sanchez, Christelle; Cornet, Anne; Van de Put, Joachim; Douette, Pierre; Gharbi, Myriam

2015-01-01

Abstract Context: Specific soluble biomarkers could be a precious tool for diagnosis, prognosis and personalized management of osteoarthritic (OA) patients. Objective: To describe the path of soluble biomarker development from discovery to clinical qualification and regulatory adoption toward OA-related biomarker qualification. Methods and results: This review summarizes current guidance on the use of biomarkers in OA in clinical trials and their utility at five stages, including preclinical development and phase 1 to phase 4 trials. It also presents all the available regulatory requirements. Conclusions: The path through the adoption of a specific soluble biomarker for OA is steep but is worth the challenge due to the benefit that it can provide. PMID:26954785

Two-Sample Statistics for Testing the Equality of Survival Functions Against Improper Semi-parametric Accelerated Failure Time Alternatives: An Application to the Analysis of a Breast Cancer Clinical Trial

PubMed Central

BROËT, PHILIPPE; TSODIKOV, ALEXANDER; DE RYCKE, YANN; MOREAU, THIERRY

2010-01-01

This paper presents two-sample statistics suited for testing equality of survival functions against improper semi-parametric accelerated failure time alternatives. These tests are designed for comparing either the short- or the long-term effect of a prognostic factor, or both. These statistics are obtained as partial likelihood score statistics from a time-dependent Cox model. As a consequence, the proposed tests can be very easily implemented using widely available software. A breast cancer clinical trial is presented as an example to demonstrate the utility of the proposed tests. PMID:15293627

Consolidative autologous hematopoietic stem-cell transplantation in first remission for non-Hodgkin lymphoma: current indications and future perspective.

PubMed

Iams, Wade; Reddy, Nishitha M

2014-10-01

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data.

Feasibility and acceptability of the DSM-5 Field Trial procedures in the Johns Hopkins Community Psychiatry Programs†

PubMed Central

Clarke, Diana E.; Wilcox, Holly C.; Miller, Leslie; Cullen, Bernadette; Gerring, Joan; Greiner, Lisa H.; Newcomer, Alison; Mckitty, Mellisha V.; Regier, Darrel A.; Narrow, William E.

2014-01-01

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) contains criteria for psychiatric diagnoses that reflect advances in the science and conceptualization of mental disorders and address the needs of clinicians. DSM-5 also recommends research on dimensional measures of cross-cutting symptoms and diagnostic severity, which are expected to better capture patients’ experiences with mental disorders. Prior to its May 2013 release, the American Psychiatric Association (APA) conducted field trials to examine the feasibility, clinical utility, reliability, and where possible, the validity of proposed DSM-5 diagnostic criteria and dimensional measures. The methods and measures proposed for the DSM-5 field trials were pilot tested in adult and child/adolescent clinical samples, with the goal to identify and correct design and procedural problems with the proposed methods before resources were expended for the larger DSM-5 Field Trials. Results allowed for the refinement of the protocols, procedures, and measures, which facilitated recruitment, implementation, and completion of the DSM-5 Field Trials. These results highlight the benefits of pilot studies in planning large multisite studies. PMID:24615761

[Generalization of the results of clinical studies through the analysis of subgroups].

PubMed

Costa, João; Fareleira, Filipa; Ascensão, Raquel; Vaz Carneiro, António

2012-01-01

Subgroup analysis in clinical trials are usually performed to define the potential heterogeneity of treatment effect in relation with the baseline risk, physiopathology, practical application of therapy or the under-utilization in clinical practice of effective interventions due to uncertainties of its benefit/risk ratio. When appropriately planned, subgroup analysis are a valid methodology the define benefits in subgroups of patients, thus providing good quality evidence to support clinical decision making. However, in order to be correct, subgroup analysis should be defined a priori, done in small numbers, should be fully reported and, most important, must endure statistical tests for interaction. In this paper we present an example of the treatment of post-menopausal osteoporosis, in which the benefits of an intervention (the higher the fracture risk is, the better the benefit is) with a specific agent (bazedoxifene) was only disclosed after a post-hoc analysis of the initial global trial sample.

Comparative effectiveness research and its utility in In-clinic practice

PubMed Central

Dang, Amit; Kaur, Kirandeep

2016-01-01

One of the important components of patient-centered healthcare is comparative effectiveness research (CER), which aims at generating evidence from the real-life setting. The primary purpose of CER is to provide comparative information to the healthcare providers, patients, and policy makers about the standard of care available. This involves research on clinical questions unanswered by the explanatory trials during the regulatory approval process. Main methods of CER involve randomized controlled trials and observational methods. The limitations of these two methods have been overcome with the help of new statistical methods. After the evidence generation, it is equally important to communicate the results to all the interested organizations. CER is beginning to have its impact in the clinical practice as its results become part of the clinical practice guidelines. CER will have far-reaching scientific and financial impact. CER will make both the treating physician and the patient equally responsible for the treatment offered. PMID:26955571

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis.

PubMed

Veale, Douglas J; McGonagle, Dennis; McInnes, Iain B; Krueger, James G; Ritchlin, Christopher T; Elewaut, Dirk; Kanik, Keith S; Hendrikx, Thijs; Berstein, Gabriel; Hodge, Jennifer; Telliez, Jean-Baptiste

2018-04-03

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.

Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

PubMed Central

Blumberg, Jeffrey B.; Vita, Joseph A.; Chen, C. -Y. Oliver

2015-01-01

Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

The Emerging Role of Mindfulness Meditation as Effective Self-Management Strategy, Part 2: Clinical Implications for Chronic Pain, Substance Misuse, and Insomnia.

PubMed

Khusid, Marina A; Vythilingam, Meena

2016-09-01

Mindfulness-based interventions have been increasingly utilized in the management of chronic pain since 1982. This second review of a two-part series evaluates the efficacy, mechanism, and safety of mindfulness meditation for chronic pain, substance use disorder, tobacco use disorder, and insomnia frequently co-occurring after return from deployment. Standard databases were searched until August 4, 2015. 72 relevant systematic reviews and clinical trials met the inclusion criteria. The Strength of Recommendation Taxonomy was used to assess the quality of individual studies and to rate the strength of recommendation (SOR) for each clinical condition. Mindfulness-based interventions effectively and durably reduce pain intensity, improve functional status, pain-related psychological consequences, quality of life (SOR B). They can also be utilized as an adjunctive intervention aimed at improving health-related quality of life in individuals with substance use disorders interested in self-management strategies (SOR B). Mindfulness training for smokers used adjunctively with pharmacotherapy shows efficacy in maintaining abstinence comparable to that of the current standard of care (SOR B). Future large, well-designed randomized clinical trials using active controls in service members and veterans with co-occurring pain and psychological health conditions are necessary to provide more precise clinical guidance. Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

Recommendations for research priorities in breast cancer by the Coalition of Cancer Cooperative Groups Scientific Leadership Council: systemic therapy and therapeutic individualization.

PubMed

Sparano, Joseph A; Hortobagyi, Gabriel N; Gralow, Julie R; Perez, Edith A; Comis, Robert L

2010-02-01

Over 9,000 women with breast cancer are enrolled annually on clinical trials sponsored by the National Cancer Institute (NCI), accounting for about one-third of all patients enrolled on NCI-sponsored trials. Thousands are also enrolled on pharmaceutical-sponsored studies. Although breast cancer mortality rates have recently declined for the first time in part due to systemic therapeutic advances, coordinated efforts will be necessary to maintain this trend. The Coalition of Cancer Cooperative Groups convened the Scientific Leadership Council in breast cancer (BC), an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for chemoprevention, development and application of molecular markers for predicting therapeutic benefit and toxicity, intermediate markers predictive of therapeutic effect, pathogenesis-based therapeutic approaches, utilization of adaptive designs requiring fewer patients to achieve objectives, special and minority populations, and effects of BC and treatment on patients and families. Panelists identified 13 ongoing studies as High Priority and identified gaps in the current trial portfolio. We propose priorities for current and future clinical breast cancer research evaluating systemic therapies that may serve to improve the efficiency of clinical trials, identify individuals most likely to derive therapeutic benefit, and prioritize therapeutic strategies.

Targeting IL-2: an unexpected effect in treating immunological diseases.

PubMed

Ye, Congxiu; Brand, David; Zheng, Song G

2018-01-01

Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis since Treg dysfunction in both animals and humans is associated with multi-organ autoimmune and inflammatory disease. While IL-2 is generally considered to promote T-cell proliferation and enhance effector T-cell function, recent studies have demonstrated that treatments that utilize low-dose IL-2 unexpectedly induce immune tolerance and promote Treg development resulting in the suppression of unwanted immune responses and eventually leading to treatment of some autoimmune disorders. In the present review, we discuss the biology of IL-2 and its signaling to help define the key role played by IL-2 in the development and function of Treg cells. We also summarize proof-of-concept clinical trials which have shown that low-dose IL-2 can control autoimmune diseases safely and effectively by specifically expanding and activating Treg. However, future studies will be needed to validate a better and safer dosing strategy for low-dose IL-2 treatments utilizing well-controlled clinical trials. More studies will also be needed to validate the appropriate dose of IL-2/anti-cytokine or IL-2/anti-IL-2 complex in the experimental animal models before moving to the clinic.

An automated system for assessing cognitive function in any environment

NASA Astrophysics Data System (ADS)

Wesnes, Keith A.

2005-05-01

The Cognitive Drug Research (CDR) computerized assessment system has been in use in worldwide clinical trials for over 20 years. It is a computer based system which assesses core aspects of human cognitive function including attention, information, working memory and long-term memory. It has been extensively validated and can be performed by a wide range of clinical populations including patients with various types of dementia. It is currently in worldwide use in clinical trials to evaluate new medicines, as well as a variety of programs involving the effects of age, stressors illnesses and trauma upon human cognitive function. Besides being highly sensitive to drugs which will impair or improve function, its utility has been maintained over the last two decades by constantly increasing the number of platforms upon which it can operate. Besides notebook versions, the system can be used on a wrist worn device, PDA, via tht telephone and over the internet. It is the most widely used automated cognitive function assessment system in worldwide clinical research. It has dozens of parallel forms and requires little training to use or administer. The basic development of the system wil be identified, and the huge databases (normative, patient population, drug effects) which have been built up from hundreds of clinical trials will be described. The system is available for use in virtually any environment or type of trial.

Cost-effectiveness of prize-based incentives for stimulant abusers in outpatient psychosocial treatment programs.

PubMed

Olmstead, Todd A; Sindelar, Jody L; Petry, Nancy M

2007-03-16

To evaluate the cost-effectiveness of a prize-based intervention as an addition to usual care for stimulant abusers. This cost-effectiveness analysis is based on a randomized clinical trial implemented within the National Drug Abuse Treatment Clinical Trials Network. The trial was conducted at eight community-based outpatient psychosocial drug abuse treatment clinics. Four hundred and fifteen stimulant abusers were assigned to usual care (N=206) or usual care plus abstinence-based incentives (N=209) for 12 weeks. Participants randomized to the incentive condition earned the chance to draw for prizes for submitting substance negative samples; the number of draws earned increased with continuous abstinence time. Incremental cost-effectiveness ratios were estimated to compare prize-based incentives relative to usual care. The primary patient outcome was longest duration of confirmed stimulant abstinence (LDA). Unit costs were obtained via surveys administered at the eight participating clinics. Resource utilizations and patient outcomes were obtained from the clinical trial. Acceptability curves are presented to illustrate the uncertainty due to the sample and to provide policy relevant information. The incremental cost to lengthen the LDA by 1 week was 258 US dollars (95% confidence interval, 191-401 US dollars). Sensitivity analyses on several key parameters show that this value ranges from 163 to 269 US dollars. Compared with the usual care group, the incentive group had significantly longer LDAs and significantly higher costs.

Patient Recruitment into a Multicenter Randomized Clinical Trial 
for Kidney Disease: Report of the Focal Segmental Glomerulosclerosis Clinical Trial (FSGS CT)

PubMed Central

Ferris, Maria; Norwood, Victoria; Radeva, Milena; Gassman, Jennifer J.; Al‐Uzri, Amira; Askenazi, David; Matoo, Tej; Pinsk, Maury; Sharma, Amita; Smoyer, William; Stults, Jenna; Vyas, Shefali; Weiss, Robert; Gipson, Debbie; Kaskel, Frederick; Friedman, Aaron; Moxey‐Mims, Marva

2012-01-01

Abstract We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open‐label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web‐based anonymous survey of site investigators revealed site‐related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start‐up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. Clin Trans Sci 2013; Volume 6: 13–20 PMID:23399084

Patient recruitment into a multicenter randomized clinical trial for kidney disease: report of the focal segmental glomerulosclerosis clinical trial (FSGS CT).

PubMed

Ferris, Maria; Norwood, Victoria; Radeva, Milena; Gassman, Jennifer J; Al-Uzri, Amira; Askenazi, David; Matoo, Tej; Pinsk, Maury; Sharma, Amita; Smoyer, William; Stults, Jenna; Vyas, Shefali; Weiss, Robert; Gipson, Debbie; Kaskel, Frederick; Friedman, Aaron; Moxey-Mims, Marva; Trachtman, Howard

2013-02-01

We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open-label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web-based anonymous survey of site investigators revealed site-related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start-up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. © 2013 Wiley Periodicals, Inc.

Clinical utility and validity of the Functional Disability Inventory (FDI) among a multicenter sample of youth with chronic pain

PubMed Central

Kashikar-Zuck, Susmita; Flowers, Stacy R.; Claar, Robyn Lewis; Guite, Jessica W.; Logan, Deirdre E.; Lynch-Jordan, Anne M; Palermo, Tonya M.; Wilson, Anna C.

2011-01-01

The Functional Disability Inventory (FDI) is a well-established and commonly used measure of physical functioning and disability in youth with chronic pain. Further validation of the measure has been called for, in particular, examination of the clinical utility and factor structure of the measure. To address this need, we utilized a large multicenter dataset of pediatric patients with chronic pain who had completed the FDI and other measures assessing pain and emotional functioning. Clinical reference points to allow for interpretation of raw scores were developed to enhance clinical utility of the measure and exploratory factor analysis was performed to examine its factor structure. Participants included 1300 youth ages 8 to 18 years (M=14.2 years; 76% female) with chronic pain. Examination of the distribution of FDI scores and validation with measures of depressive symptoms and pain intensity yielded three distinct categories of disability: No/Minimal Disability, Moderate Disability and Severe Disability. Factor analysis of FDI scores revealed a two-factor solution representing vigorous Physical Activities and non-physically strenuous Daily Activities. The three-level classification system and factor structure were further explored via comparison across the four most commonly encountered pain conditions in clinical settings (head, back, abdominal and widespread pain). Our findings provide important new information regarding the clinical utility and validity of the FDI. This will greatly enhance the interpretability of scores for research and clinical use in a wide range of pediatric pain conditions. In particular these findings will facilitate use of the FDI as an outcome measure in future clinical trials. PMID:21458162

Recruitment of black and Latina women to a randomized controlled trial.

PubMed

Martin, Anika; Negron, Rennie; Balbierz, Amy; Bickell, Nina; Howell, Elizabeth A

2013-08-01

Minority women are often not adequately represented in randomized controlled trials, limiting the generalizability of research trial results. We implemented a recruitment strategy for a postpartum depression prevention trial that utilized patient feedback to identify and understand the recruitment barriers of black and Latina postpartum women. Feedback on patients' reasons for trial refusal informed adaptations to the recruitment process. We calculated weekly recruitment rates and analyzed qualitative and quantitative data from patient refusals. Of the 668 women who were approached and completed the consent process, 540 enrolled in the trial and 128 declined participation. Over 52-weeks of recruitment, refusal rates decreased from 40% to 19%. A taxonomy of eight reasons for refusal derived from patient responses identified barriers to recruitment and generated targeted revisions to the recruitment message. A recruitment strategy designed to incorporate and respond to patient feedback improved recruitment of Black and Latina women to a clinical trial.

Statewide Trends in Utilization and Outcomes of Endovascular Treatment of Acute Ischemic Stroke: Analysis of Minnesota Hospital Association Data (2014 and 2015).

PubMed

Hussein, Haitham M; Saleem, Muhammad A; Qureshi, Adnan I

2018-03-01

The study aims at examining the changes in endovascular procedures utilization after the publication of the clinical trials showing their benefit in patients with acute ischemic stroke (AIS). Minnesota Hospital Association database from 137 member hospitals was used to calculate the statewide utilization rates for 2 periods: prior to (calendar year 2014) and after (calendar year 2015) the publication of multiple randomized clinical trials showing the efficacy of endovascular therapy. Patients were identified using International Classification of Disease, Clinical Modification, 9th revision (ICD-9) or ICD-10 codes (ICD-10 started October 2015). Utilization rates for endovascular treatment were calculated monthly, quarterly, and annually. Of the 13,043 patients admitted with AIS, 434 patients (mean age 68.5 ± 15.5 years; 51.2% women) received endovascular treatment. The number of procedures increased from 194 in 2014 to 240 in 2015. Utilization rate was 3.4% in the first quarter of 2014, gradually declined to reach its lowest value (2.6%) the last quarter of 2014, then steadily increased to reach its peak (4%) in the last quarter of 2015. Procedures performed at comprehensive stroke centers increased from 52% of total procedures in 2014 to 57.5% in 2015, whereas those performed at primary stroke centers decreased from 22.6% to 19.5%. In 2015, fewer patients had hypertension (50.4% versus 60.3%; P = .039) and more patients had chronic kidney disease (28.3% versus 15.5%; P = .001) compared with 2014. Intracranial hemorrhage, mortality rate, and rate of home discharge were similar between the 2 years. Utilization of endovascular procedures for treatment of AIS has been rapidly influenced by medical literature. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Texas Medication Algorithm Project: development and feasibility testing of a treatment algorithm for patients with bipolar disorder.

PubMed

Suppes, T; Swann, A C; Dennehy, E B; Habermacher, E D; Mason, M; Crismon, M L; Toprac, M G; Rush, A J; Shon, S P; Altshuler, K Z

2001-06-01

Use of treatment guidelines for treatment of major psychiatric illnesses has increased in recent years. The Texas Medication Algorithm Project (TMAP) was developed to study the feasibility and process of developing and implementing guidelines for bipolar disorder, major depressive disorder, and schizophrenia in the public mental health system of Texas. This article describes the consensus process used to develop the first set of TMAP algorithms for the Bipolar Disorder Module (Phase 1) and the trial testing the feasibility of their implementation in inpatient and outpatient psychiatric settings across Texas (Phase 2). The feasibility trial answered core questions regarding implementation of treatment guidelines for bipolar disorder. A total of 69 patients were treated with the original algorithms for bipolar disorder developed in Phase 1 of TMAP. Results support that physicians accepted the guidelines, followed recommendations to see patients at certain intervals, and utilized sequenced treatment steps differentially over the course of treatment. While improvements in clinical symptoms (24-item Brief Psychiatric Rating Scale) were observed over the course of enrollment in the trial, these conclusions are limited by the fact that physician volunteers were utilized for both treatment and ratings. and there was no control group. Results from Phases 1 and 2 indicate that it is possible to develop and implement a treatment guideline for patients with a history of mania in public mental health clinics in Texas. TMAP Phase 3, a recently completed larger and controlled trial assessing the clinical and economic impact of treatment guidelines and patient and family education in the public mental health system of Texas, improves upon this methodology.

APRN Usability Testing of a Tailored Computer-Mediated Health Communication Program

PubMed Central

Lin, Carolyn A.; Neafsey, Patricia J.; Anderson, Elizabeth

2010-01-01

This study tested the usability of a touch-screen enabled “Personal Education Program” (PEP) with Advanced Practice Registered Nurses (APRN). The PEP is designed to enhance medication adherence and reduce adverse self-medication behaviors in older adults with hypertension. An iterative research process was employed, which involved the use of: (1) pre-trial focus groups to guide the design of system information architecture, (2) two different cycles of think-aloud trials to test the software interface, and (3) post-trial focus groups to gather feedback on the think-aloud studies. Results from this iterative usability testing process were utilized to systematically modify and improve the three PEP prototype versions—the pilot, Prototype-1 and Prototype-2. Findings contrasting the two separate think-aloud trials showed that APRN users rated the PEP system usability, system information and system-use satisfaction at a moderately high level between trials. In addition, errors using the interface were reduced by 76 percent and the interface time was reduced by 18.5 percent between the two trials. The usability testing processes employed in this study ensured an interface design adapted to APRNs' needs and preferences to allow them to effectively utilize the computer-mediated health-communication technology in a clinical setting. PMID:19940619

Impact of the National Institutes of Health Focal Segmental Glomerulosclerosis (NIH FSGS) clinical trial on the treatment of steroid-resistant FSGS.

PubMed

Canetta, Pietro A; Radhakrishnan, Jai

2013-03-01

Idiopathic focal segmental glomerulosclerosis (FSGS) is among the most common, morbid and treatment-resistant conditions faced by nephrologists. While glucocorticoids have traditionally been the mainstay of initial treatment, they induce remission in only a minority of patients. A variety of other immunosuppressants have been utilized against steroid-resistant FSGS, but few have been rigorously examined in well-controlled trials. Recently, the results were published from a National Institutes of Health (NIH)-sponsored multicenter randomized trial comparing cyclosporine (CSA) with a combination of mycophenolate mofetil (MMF) and pulse dexamethasone (DEX) for the treatment of steroid-resistant FSGS. No difference in treatment effectiveness was shown between the two groups, and adverse effects were comparable. This was the largest randomized trial ever undertaken in FSGS, but it was unfortunately underpowered to show clinically relevant differences in response rates. This shortcoming, along with particularities of the study population and outcome measures, makes it challenging to draw definitive conclusions from the trial results. Despite these limitations, the trial does provide valuable insights into treatment strategies for FSGS and offers important lessons for planning future research.

Integrating utilization-focused evaluation with business process modeling for clinical research improvement.

PubMed

Kagan, Jonathan M; Rosas, Scott; Trochim, William M K

2010-10-01

New discoveries in basic science are creating extraordinary opportunities to design novel biomedical preventions and therapeutics for human disease. But the clinical evaluation of these new interventions is, in many instances, being hindered by a variety of legal, regulatory, policy and operational factors, few of which enhance research quality, the safety of study participants or research ethics. With the goal of helping increase the efficiency and effectiveness of clinical research, we have examined how the integration of utilization-focused evaluation with elements of business process modeling can reveal opportunities for systematic improvements in clinical research. Using data from the NIH global HIV/AIDS clinical trials networks, we analyzed the absolute and relative times required to traverse defined phases associated with specific activities within the clinical protocol lifecycle. Using simple median duration and Kaplan-Meyer survival analysis, we show how such time-based analyses can provide a rationale for the prioritization of research process analysis and re-engineering, as well as a means for statistically assessing the impact of policy modifications, resource utilization, re-engineered processes and best practices. Successfully applied, this approach can help researchers be more efficient in capitalizing on new science to speed the development of improved interventions for human disease.

Pressure ulcer risk assessment and prevention: a systematic comparative effectiveness review.

PubMed

Chou, Roger; Dana, Tracy; Bougatsos, Christina; Blazina, Ian; Starmer, Amy J; Reitel, Katie; Buckley, David I

2013-07-02

Pressure ulcers are associated with substantial health burdens but may be preventable. To review the clinical utility of pressure ulcer risk assessment instruments and the comparative effectiveness of preventive interventions in persons at higher risk. MEDLINE (1946 through November 2012), CINAHL, the Cochrane Library, grant databases, clinical trial registries, and reference lists. Randomized trials and observational studies on effects of using risk assessment on clinical outcomes and randomized trials of preventive interventions on clinical outcomes. Multiple investigators abstracted and checked study details and quality using predefined criteria. One good-quality trial found no evidence that use of a pressure ulcer risk assessment instrument, with or without a protocolized intervention strategy based on assessed risk, reduces risk for incident pressure ulcers compared with less standardized risk assessment based on nurses' clinical judgment. In higher-risk populations, 1 good-quality and 4 fair-quality randomized trials found that more advanced static support surfaces were associated with lower risk for pressure ulcers compared with standard mattresses (relative risk range, 0.20 to 0.60). Evidence on the effectiveness of low-air-loss and alternating-air mattresses was limited, with some trials showing no clear differences from advanced static support surfaces. Evidence on the effectiveness of nutritional supplementation, repositioning, and skin care interventions versus usual care was limited and had methodological shortcomings, precluding strong conclusions. Only English-language articles were included, publication bias could not be formally assessed, and most studies had methodological shortcomings. More advanced static support surfaces are more effective than standard mattresses for preventing ulcers in higher-risk populations. The effectiveness of formal risk assessment instruments and associated intervention protocols compared with less standardized assessment methods and the effectiveness of other preventive interventions compared with usual care have not been clearly established.

The potential impact of recruitment method on sample characteristics and treatment outcomes in a psychosocial trial for women with co-occurring substance use disorder and PTSD.

PubMed

Winhusen, Theresa; Winstanley, Erin L; Somoza, Eugene; Brigham, Gregory

2012-01-01

Recruitment method can impact the sample composition of a clinical trial and, thus, the generalizability of the results, but the importance of recruitment method in substance use disorder trials has received little attention. The present paper sought to address this research gap by evaluating the association between recruitment method and sample characteristics and treatment outcomes in a substance use disorder trial. In a multi-site trial evaluating Seeking Safety (SS), relative to Women's Health Education (WHE), for women with co-occurring PTSD (either sub-threshold or full PTSD) and substance use disorders, one site assessed the method by which each participant was recruited. Data from this site (n=106), which recruited participants from newspaper advertising and clinic intakes, were analyzed. Participants recruited through advertising, relative to those from the clinic, had significantly higher levels of baseline drug use and higher rates of meeting DSM-IV-TR criteria for full PTSD. Results suggest that the effectiveness of SS in decreasing PTSD symptoms was greater for participants recruited through advertising relative to those recruited from the clinic. Conversely, the results revealed a significant treatment effect in the clinic-recruited participants, not seen in the advertising-recruited participants, with SS, relative to WHE, participants being more likely to report past week drug use during the follow-up phase. Recruitment method may impact sample composition and treatment effects. Replication of this finding would have important implications for substance use disorder efficacy trials which often utilize advertising to recruit participants. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Attention Training for School-Aged Children with ADHD: Results of an Open Trial

ERIC Educational Resources Information Center

Tamm, Leanne; Hughes, Carroll; Ames, Laure; Pickering, Joyce; Silver, Cheryl H.; Stavinoha, Peter; Castillo, Christine L.; Rintelmann, Jeanne; Moore, Jarrette; Foxwell, Aleksandra; Bolanos, S. Gina; Hines, Tabatha; Nakonezny, Paul A.; Emslie, Graham

2010-01-01

Objective: The article discusses a feasibility study conducted to examine whether Pay Attention!, an intervention training sustained, selective, alternating, and divided attention, could be utilized in a clinical setting with children diagnosed with ADHD, and whether children who received the intervention made attention and executive functioning…

A systematic review of natural health product treatment for vitiligo

PubMed Central

Szczurko, Orest; Boon, Heather S

2008-01-01

Background Vitiligo is a hypopigmentation disorder affecting 1 to 4% of the world population. Fifty percent of cases appear before the age of 20 years old, and the disfigurement results in psychiatric morbidity in 16 to 35% of those affected. Methods Our objective was to complete a comprehensive, systematic review of the published scientific literature to identify natural health products (NHP) such as vitamins, herbs and other supplements that may have efficacy in the treatment of vitiligo. We searched eight databases including MEDLINE and EMBASE for vitiligo, leucoderma, and various NHP terms. Prospective controlled clinical human trials were identified and assessed for quality. Results Fifteen clinical trials were identified, and organized into four categories based on the NHP used for treatment. 1) L-phenylalanine monotherapy was assessed in one trial, and as an adjuvant to phototherapy in three trials. All reported beneficial effects. 2) Three clinical trials utilized different traditional Chinese medicine products. Although each traditional Chinese medicine trial reported benefit in the active groups, the quality of the trials was poor. 3) Six trials investigated the use of plants in the treatment of vitiligo, four using plants as photosensitizing agents. The studies provide weak evidence that photosensitizing plants can be effective in conjunction with phototherapy, and moderate evidence that Ginkgo biloba monotherapy can be useful for vitiligo. 4) Two clinical trials investigated the use of vitamins in the therapy of vitiligo. One tested oral cobalamin with folic acid, and found no significant improvement over control. Another trial combined vitamin E with phototherapy and reported significantly better repigmentation over phototherapy only. It was not possible to pool the data from any studies for meta-analytic purposes due to the wide difference in outcome measures and poor quality ofreporting. Conclusion Reports investigating the efficacy of NHPs for vitiligo exist, but are of poor methodological quality and contain significant reporting flaws. L-phenylalanine used with phototherapy, and oral Ginkgo biloba as monotherapy show promise and warrant further investigation. PMID:18498646

Modeling and validating Bayesian accrual models on clinical data and simulations using adaptive priors.

PubMed

Jiang, Yu; Simon, Steve; Mayo, Matthew S; Gajewski, Byron J

2015-02-20

Slow recruitment in clinical trials leads to increased costs and resource utilization, which includes both the clinic staff and patient volunteers. Careful planning and monitoring of the accrual process can prevent the unnecessary loss of these resources. We propose two hierarchical extensions to the existing Bayesian constant accrual model: the accelerated prior and the hedging prior. The new proposed priors are able to adaptively utilize the researcher's previous experience and current accrual data to produce the estimation of trial completion time. The performance of these models, including prediction precision, coverage probability, and correct decision-making ability, is evaluated using actual studies from our cancer center and simulation. The results showed that a constant accrual model with strongly informative priors is very accurate when accrual is on target or slightly off, producing smaller mean squared error, high percentage of coverage, and a high number of correct decisions as to whether or not continue the trial, but it is strongly biased when off target. Flat or weakly informative priors provide protection against an off target prior but are less efficient when the accrual is on target. The accelerated prior performs similar to a strong prior. The hedging prior performs much like the weak priors when the accrual is extremely off target but closer to the strong priors when the accrual is on target or only slightly off target. We suggest improvements in these models and propose new models for future research. Copyright © 2014 John Wiley & Sons, Ltd.

Population-Based Analysis of Hematologic Malignancy Referrals to a Comprehensive Cancer Center, Referrals for Blood and Marrow Transplantation, and Participation in Clinical Trial, Survey, and Biospecimen Research by Race.

PubMed

Clay, Alyssa; Peoples, Brittany; Zhang, Yali; Moysich, Kirsten; Ross, Levi; McCarthy, Philip; Hahn, Theresa

2015-08-01

Racial and ethnic disparities have been reported in clinical trial/research participation, utilization of autologous and allogeneic blood and marrow transplantation (BMT), and availability of allogeneic donors. We performed a population-based cohort study to investigate adult hematologic malignancy referrals to a US tertiary cancer center, utilization of BMT, and participation in clinical trial, survey, and biospecimen research by race. US Census Data and the New York State Public Access Cancer Epidemiology Database identified the racial distribution of the general population and new hematologic malignancy cases in the primary catchment area. From 2005 to 2011, 1106 patients aged 18 to 75 years were referred for BMT consultation; although the rate of BMT among hematologic malignancy referrals did not differ by race, the reasons for not receiving a BMT did. Participation in biospecimen research did not vary by race; however, African Americans and other minorities were significantly less likely to participate in survey research than European Americans. Although rates of hematologic malignancy referrals and use of BMT for minorities appear to be low (<10%), they closely reflect the race distribution of all hematologic malignancy cases and the western New York population. African Americans are equally likely as other races to participate in biospecimen banking, but further study is needed to understand reasons for lower participation in survey research. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

PubMed Central

Jones, Melissa K.; Lu, Bin; Girman, Sergey; Wang, Shaomei

2017-01-01

Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments. PMID:28111323

The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine.

PubMed

Vassy, Jason L; Lautenbach, Denise M; McLaughlin, Heather M; Kong, Sek Won; Christensen, Kurt D; Krier, Joel; Kohane, Isaac S; Feuerman, Lindsay Z; Blumenthal-Barby, Jennifer; Roberts, J Scott; Lehmann, Lisa Soleymani; Ho, Carolyn Y; Ubel, Peter A; MacRae, Calum A; Seidman, Christine E; Murray, Michael F; McGuire, Amy L; Rehm, Heidi L; Green, Robert C

2014-03-20

Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care. This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients' genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results. The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies. ClinicalTrials.gov identifier NCT01736566.

Cost-effectiveness of Tofacitinib in the Treatment of Moderate to Severe Rheumatoid Arthritis in South Korea.

PubMed

Lee, Min-Young; Park, Sun-Kyeong; Park, Sun-Young; Byun, Ji-Hye; Lee, Sang-Min; Ko, Su-Kyoung; Lee, Eui-Kyung

2015-08-01

This study evaluated the cost-effectiveness of introducing tofacitinib, an oral Janus kinase inhibitor, to the treatment of Korean patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs. In this cost-utility analysis model, patients transitioned through treatment sequences based on Korean guidelines for RA patients with inadequate response to conventional disease-modifying antirheumatic drugs. Lifetime health-related quality of life and costs were evaluated. Characteristics of the model cohort were based on those reported by the Oral Rheumatoid Arthritis phase 3 triaL (ORAL) Standard randomized Controlled trial of tofacitinib or adalimumab versus placebo. Efficacy was assessed using American College of Rheumatology response rates, converted to the changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, based on tofacitinib clinical trials data. Published clinical trial data on discontinuation rates of the indicated drugs were incorporated in the model. The HAQ-DI scores were mapped onto utility values to calculate outcomes in terms of quality-adjusted life-years (QALYs); HAQ-DI-to-utility (EuroQoL 5D) mapping was based on data from 5 tofacitinib clinical trials. Costs were analyzed from a societal perspective, with values expressed in 2013 Korean won (KRW). Cost-effectiveness is presented in terms of incremental cost-effectiveness ratios (ICERs). One-way sensitivity analyses were performed to assess the robustness of the model. First-line tofacitinib used before the standard of care (base-case analysis) increased both treatment costs and QALYs gained versus the standard-of-care treatment sequence, resulting in an ICER of KRW 13,228,910 per QALY. Tofacitinib also increased costs and QALYs gained when incorporated as a second-, third-, or fourth-line therapy. The inclusion of first-line tofacitinib increased the duration of active immunomodulatory therapy from 9.4 to 13.2 years. Tofacitinib-associated increases in costs were attributable to the increased lifetime drug costs. In sensitivity analyses, variations in input parameters and assumptions yielded ICERs in the range of KRW 6,995,719 per QALY to KRW 37,450,109 per QALY. From a societal perspective, the inclusion of tofacitinib as a treatment strategy for moderate to severe RA is cost-effective; this conclusion was considered robust based on multiple sensitivity analyses. The study was limited by the lack of clinical data on follow-up therapy after tofacitinib administration and a lack of long-term data on discontinuation of drug use. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Evolution of Biomarker Guided Therapy for Heart Failure: Current Concepts and Trial Evidence

PubMed Central

Pruett, Amanda E; Lee, Amanda K; Patterson, Herbert; Schwartz, Todd A; Glotzer, Jana M; Adams, Jr, Kirkwood F

2015-01-01

Optimizing management of patients with heart failure remains quite challenging despite many significant advances in drug and device therapy for this syndrome. Although a large body of evidence from robust clinical trials supports multiple thera-pies, utilization of these well-established treatments remains inconsistent and outcomes suboptimal in “real-world” patients with heart failure. Disease management programs may be effective, but are difficult to implement due to cost and logistical issues. Another approach to optimizing therapy is to utilize biomarkers to guide therapeutic choices. Natriuretic peptides pro-vide additional information of significant clinical value in the diagnosis and estimation of risk inpatients with heart failure. Ongoing research suggests a potential important added role for natriuretic peptides in heart failure. Guiding therapy based on serial changes in these biomarkers may be an effective strategy to optimize treatment and achieve better outcomes in this syn-drome. Initial, innovative, proof-of-concept studies have provided encouraging results and important insights into key as-pects of this strategy, but well designed, large-scale, multicenter, randomized, outcome trials are needed to definitively estab-lish this novel approach to management. Given the immense and growing public health burden of heart failure, identification of cost-effective ways to decrease the morbidity and mortality due to this syndrome is critical. PMID:24251462

Virtual reality for acute pain reduction in adolescents undergoing burn wound care: a prospective randomized controlled trial.

PubMed

Kipping, Belinda; Rodger, Sylvia; Miller, Kate; Kimble, Roy M

2012-08-01

Effective pain management remains a challenge for adolescents during conscious burn wound care procedures. Virtual reality (VR) shows promise as a non-pharmacological adjunct in reducing pain. This study assessed off-the-shelf VR for (1) its effect on reducing acute pain intensity during adolescent burn wound care, and (2) its clinical utility in a busy hospital setting. Forty-one adolescents (11-17 years) participated in this prospective randomized controlled trial. Acute pain outcomes including adolescent self-report, nursing staff behavioral observation, caregiver observation and physiological measures were collected. Length of procedure times and adolescent reactions were also recorded to inform clinical utility. Nursing staff reported a statistically significant reduction in pain scores during dressing removal, and significantly less rescue doses of Entonox given to those receiving VR, compared to those receiving standard distraction. For all other pain outcomes and length of treatment, there was a trend for lower pain scores and treatment times for those receiving VR, but these differences were not statistically significant. Despite only minimal pain reduction achieved using off-the-shelf VR, other results from this trial and previous research on younger children with burns suggest a customized, adolescent and hospital friendly device may be more effective in pain reduction. Copyright © 2012. Published by Elsevier Ltd.

Integration of the work-related online aftercare intervention 'GSA-online plus' (healthy and without stress at the workplace) into clinical practice: study protocol for an implementation study.

PubMed

Zwerenz, Rüdiger; Böhme, Katja; Wirth, Astrid; Labitzke, Nicole; Pachtchenko, Sergei; Beutel, Manfred E

2018-05-02

In a previous RCT we established the efficacy of the psychodynamic online aftercare programme 'GSA-Online' ('Health Training Stress Management at the Workplace') for rehabilitants with work-related stress facing return to work after long-term sickness absence. The purpose of this trial is to implement it into routine care. The study is performed in rehabilitation clinics with patients of different medical indications (psychosomatic, orthopedic and cardiological diseases). Rehabilitants get access to the study platform during inpatient medical rehabilitation. 'GSA-Online plus' integrates exploratory and motivational videos on the web application to familiarize potential participants and motivate them to follow through with it. In the 12-week writing intervention, patients write weekly online diary entries, answered by anonymous online therapists within 24 h. Primary outcome measures are the recommendation rate of 'GSA-Online plus' and participation rates of the rehabilitants. As secondary outcomes, psychological symptoms, overall satisfaction, helpfulness of the therapeutic feedback and utilization of 'GSA-Online plus' will be analysed exploratory along with the course of weekly ratings of well-being and work ability. Meanwhile many clinical trials and meta-analysis prove that internet-based interventions are effective. This study will add insights on the dissemination and implementation of efficacious, evidence-based online treatments into medical practice. We expect a successful implementation of 'GSA-Online plus' in the clinical routine of the rehabilitation clinics. The focus of evaluation is on acceptance of the programme, both by the physicians in charge and the patients. In the future 'GSA-Online plus' could be implemented as a routine aftercare programme for rehabilitation inpatients with occupational stress. The trial was retrospectively registered on 6th January 2017 at ClinicalTrials.gov (Trial Registration number: ClinicalTrials Gov ID NCT03019718 ).

Cost effectiveness of a telephone intervention to promote dilated fundus examination in adults with diabetes mellitus

PubMed Central

Schechter, Clyde B; Basch, Charles E; Caban, Arlene; Walker, Elizabeth A

2008-01-01

In a clinical trial, we have previously shown that a telephone intervention can significantly increase participation in dilated fundus examination (DFE) screening among low-income adults with diabetes. Here the costs and cost-effectiveness ratio of this intervention are calculated. Intervention effectiveness was estimated as the difference in DFE utilization between the telephone intervention and print groups from the clinical trial multiplied by the size of the telephone intervention group. A micro-costing approach was used. Personnel time was aggregated from logs kept during the clinical trial of the intervention. Wage rates were taken from a commercial compensation database. Telephone charges were estimated based on prevailing fees. The cost-effectiveness ratio was calculated as the ratio of total costs of the intervention to the number of DFEs gained by the intervention. A sensitivity analysis estimated the cost-effectiveness of a more limited telephone intervention. A probabilistic sensitivity analysis using bootstrap samples from the clinical trial results quantified the uncertainties in resource utilization and intervention effectiveness. Net intervention costs were US$18,676.06, with an associated gain of 43.7 DFEs and 16.4 new diagnoses of diabetic retinopathy. The cost-effectiveness ratio is US$427.37 per DFE gained. A restricted intervention limiting the number of calls to 5, as opposed to 7, would achieve the same results, but would cost approximately 17% less. In the probabilistic sensitivity analysis, the 5th and 95th percentiles of the cost-effectiveness ratio were US$304.05 and US$692.52 per DFE gained, respectively. Our telephone intervention is more expensive than simple mail or telephone reminders used in other settings to promote preventive care; it is, however, also considerably more effective, and is effective in a low-income minority population at greater risk for diabetes complications. The costs are dominated by labor costs, and may be substantially defrayed, without loss of effectiveness, by restricting the number of telephone calls to 5 per patient. PMID:19668428

Evidence-Base Update of Psychosocial Treatments for Child and Adolescent Depression

PubMed Central

Weersing, V. Robin; Jeffreys, Megan; Do, Minh-Chau T.; Schwartz, Karen T. G.; Bolano, Carl

2017-01-01

Depression in youth is prevalent and disabling and tends to presage a chronic and recurrent course of illness and impairment in adulthood. Clinical trial research in youth depression has a 30 year history, and evidence-based treatment reviews appeared in 1998 and 2008. The current review of 42 randomized controlled trials (RCTs) updates these reviews to include RCTs published between 2008 and 2014 (N = 14) and re-evaluates previously reviewed literature. Given the growing maturity of the field, this review utilized a stringent set of methodological criteria for trial inclusion, most notable for excluding trials based in sub-clinical samples of youth that had been included in previous reviews (N = 12) and including well-designed RCTs with null and negative findings (N = 8). Findings from the current review suggest that evidence for child treatments is notably weaker than for adolescent interventions, with no child treatments achieving well-established status and the evidentiary basis of treatments downgraded from previous reports. Cognitive behavioral therapy (CBT) for clinically depressed children appears to be possibly efficacious, with mixed findings across trials. For depressed adolescents, both CBT and Interpersonal Psychotherapy (IPT) are well-established interventions, with evidence of efficacy in multiple trials by independent investigative teams. This positive conclusion is tempered by the small size of the IPT literature (N = 6) and concern that CBT effects may be attenuated in clinically complicated samples and when compared against active control conditions. In conclusion, data on predictors, moderators, and mediators are examined and priorities for future research discussed. PMID:27870579

Feasibility of Economic Analysis of Radiation Therapy Oncology Group (RTOG) 91-11 Using Medicare Data

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

Konski, Andre, E-mail: akonski@med.wayne.ed; Bhargavan, Mythreyi; Owen, Jean

Purpose: The specific aim of this analysis was to evaluate the feasibility of performing a cost-effectiveness analysis using Medicare data from patients treated on a randomized Phase III clinical trial. Methods and Materials: Cost data included Medicare Part A and Part B costs from all providers-inpatient, outpatient, skilled nursing facility, home health, hospice, and physicians-and were obtained from the Centers for Medicare and Medicaid Services for patients eligible for Medicare, treated on Radiation Therapy Oncology Group (RTOG) 9111 between 1992 and 1996. The 47-month expected discounted (annual discount rate of 3%) cost for each arm of the trial was calculatedmore » in 1996 dollars, with Kaplan-Meier sampling average estimates of survival probabilities for each month and mean monthly costs. Overall and disease-free survival was also discounted 3%/year. The analysis was performed from a payer's perspective. Incremental cost-effectiveness ratios were calculated comparing the chemotherapy arms to the radiation alone arm. Results: Of the 547 patients entered, Medicare cost data and clinical outcomes were available for 66 patients. Reasons for exclusion included no RTOG follow-up, Medicare HMO enrollment, no Medicare claims since trial entry, and trial entry after 1996. Differences existed between groups in tumor characteristics, toxicity, and survival, all which could affect resource utilization. Conclusions: Although we were able to test the methodology of economic analysis alongside a clinical trial using Medicare data, the results may be difficult to translate to the entire trial population because of non-random missing data. Methods to improve Medicare data capture and matching to clinical trial samples are required.« less

Powered robotic exoskeletons in post-stroke rehabilitation of gait: a scoping review.

PubMed

Louie, Dennis R; Eng, Janice J

2016-06-08

Powered robotic exoskeletons are a potential intervention for gait rehabilitation in stroke to enable repetitive walking practice to maximize neural recovery. As this is a relatively new technology for stroke, a scoping review can help guide current research and propose recommendations for advancing the research development. The aim of this scoping review was to map the current literature surrounding the use of robotic exoskeletons for gait rehabilitation in adults post-stroke. Five databases (Pubmed, OVID MEDLINE, CINAHL, Embase, Cochrane Central Register of Clinical Trials) were searched for articles from inception to October 2015. Reference lists of included articles were reviewed to identify additional studies. Articles were included if they utilized a robotic exoskeleton as a gait training intervention for adult stroke survivors and reported walking outcome measures. Of 441 records identified, 11 studies, all published within the last five years, involving 216 participants met the inclusion criteria. The study designs ranged from pre-post clinical studies (n = 7) to controlled trials (n = 4); five of the studies utilized a robotic exoskeleton device unilaterally, while six used a bilateral design. Participants ranged from sub-acute (<7 weeks) to chronic (>6 months) stroke. Training periods ranged from single-session to 8-week interventions. Main walking outcome measures were gait speed, Timed Up and Go, 6-min Walk Test, and the Functional Ambulation Category. Meaningful improvement with exoskeleton-based gait training was more apparent in sub-acute stroke compared to chronic stroke. Two of the four controlled trials showed no greater improvement in any walking outcomes compared to a control group in chronic stroke. In conclusion, clinical trials demonstrate that powered robotic exoskeletons can be used safely as a gait training intervention for stroke. Preliminary findings suggest that exoskeletal gait training is equivalent to traditional therapy for chronic stroke patients, while sub-acute patients may experience added benefit from exoskeletal gait training. Efforts should be invested in designing rigorous, appropriately powered controlled trials before powered exoskeletons can be translated into a clinical tool for gait rehabilitation post-stroke.

Progression of Ebola Therapeutics During the 2014-2015 Outbreak.

PubMed

Mendoza, Emelissa J; Qiu, Xiangguo; Kobinger, Gary P

2016-02-01

The recent Ebola virus (EBOV) outbreak in West Africa was the deadliest EBOV epidemic in history, highlighting the need for a safe and efficacious treatment against EBOV disease (EVD). In the absence of an approved treatment, experimental drugs were utilized under compassionate grounds hoping to diminish EVD-associated morbidity and mortality. As more data were collected from safety studies, Phase II/III clinical trials were introduced in Guinea, Sierra Leone, and Liberia to test promising candidates, including small-molecule drugs, RNA-based treatments, and antibody-based therapies. In this review, we summarize the use of, and preliminary observations from, current clinical trials with EVD therapeutics, shedding light on experimental drug selection, emergency clinical evaluation, and the impact these factors may have on future infectious disease outbreaks. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Aggregated N-of-1 randomized controlled trials: modern data analytics applied to a clinically valid method of intervention effectiveness.

PubMed

Cushing, Christopher C; Walters, Ryan W; Hoffman, Lesa

2014-03-01

Aggregated N-of-1 randomized controlled trials (RCTs) combined with multilevel modeling represent a methodological advancement that may help bridge science and practice in pediatric psychology. The purpose of this article is to offer a primer for pediatric psychologists interested in conducting aggregated N-of-1 RCTs. An overview of N-of-1 RCT methodology is provided and 2 simulated data sets are analyzed to demonstrate the clinical and research potential of the methodology. The simulated data example demonstrates the utility of aggregated N-of-1 RCTs for understanding the clinical impact of an intervention for a given individual and the modeling of covariates to explain why an intervention worked for one patient and not another. Aggregated N-of-1 RCTs hold potential for improving the science and practice of pediatric psychology.

Interconnecting smartphone, image analysis server, and case report forms in clinical trials for automatic skin lesion tracking in clinical trials

NASA Astrophysics Data System (ADS)

Haak, Daniel; Doma, Aliaa; Gombert, Alexander; Deserno, Thomas M.

2016-03-01

Today, subject's medical data in controlled clinical trials is captured digitally in electronic case report forms (eCRFs). However, eCRFs only insufficiently support integration of subject's image data, although medical imaging is looming large in studies today. For bed-side image integration, we present a mobile application (App) that utilizes the smartphone-integrated camera. To ensure high image quality with this inexpensive consumer hardware, color reference cards are placed in the camera's field of view next to the lesion. The cards are used for automatic calibration of geometry, color, and contrast. In addition, a personalized code is read from the cards that allows subject identification. For data integration, the App is connected to an communication and image analysis server that also holds the code-study-subject relation. In a second system interconnection, web services are used to connect the smartphone with OpenClinica, an open-source, Food and Drug Administration (FDA)-approved electronic data capture (EDC) system in clinical trials. Once the photographs have been securely stored on the server, they are released automatically from the mobile device. The workflow of the system is demonstrated by an ongoing clinical trial, in which photographic documentation is frequently performed to measure the effect of wound incision management systems. All 205 images, which have been collected in the study so far, have been correctly identified and successfully integrated into the corresponding subject's eCRF. Using this system, manual steps for the study personnel are reduced, and, therefore, errors, latency and costs decreased. Our approach also increases data security and privacy.

Prophylaxis of migraine headaches with riboflavin: A systematic review.

PubMed

Thompson, D F; Saluja, H S

2017-08-01

Migraine headache is a relatively common, debilitating condition that costs our healthcare system over 78 billion dollars per year. Riboflavin has been advocated as a safe, effective prophylactic therapy for the prevention of migraines. The purpose of this study was to provide a systematic review of the current role of riboflavin in the prophylaxis of migraine headache. A MEDLINE literature search inclusive of the dates 1966-2016 was performed using the search terms: riboflavin and migraine disorders. Excerpta Medica was searched from 1980 to 2016 using the search terms: riboflavin and migraine. Additionally, Web of Science was searched using the terms riboflavin and migraine inclusive of 1945-2016. Bibliographies of all relevant papers were reviewed for additional citations. We utilized the PRISMA guidelines to select English language, human, clinical trials of riboflavin as a single entity or in combination, review articles, and supporting pharmacokinetic and pharmacogenomic data assessing the efficacy and mechanism of riboflavin therapy in the prophylactic treatment of migraine headache. A total of 11 clinical trials reveal a mixed effect of riboflavin in the prophylaxis of migraine headache. Five clinical trials show a consistent positive therapeutic effect in adults; four clinical trials show a mixed effect in paediatric and adolescent patients, and two clinical trials of combination therapy have not shown benefit. Adverse reactions with riboflavin have generally been mild. Riboflavin is well tolerated, inexpensive and has demonstrated efficacy in the reduction of adult patient's migraine headache frequency. Additional data are needed, however, to resolve questions involving pharmacokinetic issues and pharmacogenomic implications of therapy. © 2017 John Wiley & Sons Ltd.

Tobacco dependence counseling in a randomized multisite clinical trial

PubMed Central

Croghan, Ivana T.; Trautman, Judith A.; Winhusen, Theresa; Ebbert, Jon O.; Kropp, Frankie; Schroeder, Darrell R.; Hurt, Richard D.

2012-01-01

Pharmacotherapy trials for treating tobacco dependence would benefit from behavioral interventions providing treatment consistent with clinical practice guidelines but not directing participants to treatments not evaluated in the trial. The Smoke Free and Living It© behavioral intervention manual includes participant and interventionist guides and is designed to provide both practical counseling and intra-treatment support. We utilized this intervention manual in a multicenter, randomized clinical trial of smokers with attention deficit hyperactivity disorder. In this study, we evaluated how the interventional manual performed in a “train-the-trainer” model requiring uniform counseling across 6 sites and 15 interventionists. We analyzed the skill-adherence of the interventionists and the intervention-adherence of the participants. The 255 randomized participants completed 9.3 ± 2.8 sessions (mean ± SD), with 157 participants (61.6%) completing all 11 of the sessions and 221 (86.7%) completing at least 6 of the 11 sessions. Of the 163 sessions for which the study interventionists were evaluated, 156 (95.7%) were rated as adherent to protocol and “meeting expectations” on at least 6 of 7 established criteria, illustrating that fidelity can be maintained with minimal supervision. The self-help and interventionists guides of the Smoke Free and Living It manual can thus be used to provide behavioral intervention with a high rate of adherence by both the interventionists and the participants. This manual meets the requirements of the United States Public Health Service Clinical Practice Guideline, can be adapted to specific research protocols, and provides a useful option for behavioral intervention during clinical trials for smoking cessation. PMID:22406192

Tobacco dependence counseling in a randomized multisite clinical trial.

PubMed

Croghan, Ivana T; Trautman, Judith A; Winhusen, Theresa; Ebbert, Jon O; Kropp, Frankie B; Schroeder, Darrell R; Hurt, Richard D

2012-07-01

Pharmacotherapy trials for treating tobacco dependence would benefit from behavioral interventions providing treatment consistent with clinical practice guidelines but not directing participants to treatments not evaluated in the trial. The Smoke Free and Living It© behavioral intervention manual includes participant and interventionist guides and is designed to provide both practical counseling and intra-treatment support. We utilized this intervention manual in a multicenter, randomized clinical trial of smokers with attention deficit hyperactivity disorder. In this study, we evaluated how the interventional manual performed in a "train-the-trainer" model requiring uniform counseling across 6 sites and 15 interventionists. We analyzed the skill-adherence of the interventionists and the intervention-adherence of the participants. The 255 randomized participants completed 9.3±2.8 sessions (mean±SD), with 157 participants (61.6%) completing all 11 of the sessions and 221 (86.7%) completing at least 6 of the 11 sessions. Of the 163 sessions for which the study interventionists were evaluated, 156 (95.7%) were rated as adherent to protocol and "meeting expectations" on at least 6 of 7 established criteria, illustrating that fidelity can be maintained with minimal supervision. The self-help and interventionists guides of the Smoke Free and Living It manual can thus be used to provide behavioral intervention with a high rate of adherence by both the interventionists and the participants. This manual meets the requirements of the United States Public Health Service Clinical Practice Guideline, can be adapted to specific research protocols, and provides a useful option for behavioral intervention during clinical trials for smoking cessation. Copyright © 2012 Elsevier Inc. All rights reserved.

Counterbalancing patient demands with evidence: results from a pan-Canadian randomized clinical trial of brief supportive-expressive group psychotherapy for women with systemic lupus erythematosus.

PubMed

Dobkin, Patricia L; Da Costa, Deborah; Joseph, Lawrence; Fortin, Paul R; Edworthy, Steven; Barr, Susan; Ensworth, Stephanie; Esdaile, John M; Beaulieu, André; Zummer, Michel; Senécal, Jean-Luc; Goulet, Jean-Richard; Choquette, Denis; Rich, Eric; Smith, Doug; Cividino, Alfred; Gladman, Dafna; St-Pierre, Yvan; Clarke, Ann E

2002-01-01

To evaluate the effect of Brief Supportive-Expressive Group Psychotherapy as an adjunct to standard medical care in reducing psychological distress, medical symptoms, and health care costs and improving quality of life in women with systemic lupus erythematosus (SLE). A randomized clinical trial was conducted with 133 SLE female patients from 9 clinics across Canada. Clinical and psychosocial measures were taken at baseline, posttreatment, and 6 and 12 months posttreatment. Outcomes assessed were psychological distress, quality of life, disease activity, health service utilization, and diminished productivity. Intention-to-treat analyses revealed that there were no clinically important group differences on any of the outcome measures. Although both groups improved over time on several measures (e.g., decreases in psychological distress, stress, and emotion-oriented coping), these changes could not be attributed to the psychotherapeutic intervention. Thus, evidence does not support the referral of these patients to this type of intervention.

Nanoparticle-Delivered Chemotherapy: Old Drugs in New Packages.

PubMed

Lee, Michael S; Dees, E Claire; Wang, Andrew Z

2017-03-15

Cytotoxic chemotherapies have a narrow therapeutic window, with high peaks and troughs of plasma concentration. Novel nanoparticle formulations of cytotoxic chemotherapy drugs can enhance pharmacokinetic characteristics and facilitate passive targeting of drugs to tumors via the enhanced permeability and retention effect, thus mitigating toxicity. Nanoparticle vehicles currently in clinical use or undergoing clinical investigation for anticancer therapies include liposomes, polymeric micelles, protein-drug nanoparticles, and dendrimers. Multiple nanoparticle formulations of existing cytotoxic chemotherapies are approved for use in several indications, with clinical data indeed showing optimization of pharmacokinetics and different toxicity profiles compared with their parent drugs. There are also many new nanoparticle drug formulations in development and undergoing early- and late-phase clinical trials, including several that utilize active targeting or triggered release based on environmental stimuli. Here, we review the rationale for nanoparticle formulations of existing or previously investigated cytotoxic drugs, describe currently approved nanoparticle formulations of drugs, and discuss some of the most promising clinical trials currently underway.

Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

PubMed Central

Scheiermann, Julia; Klinman, Dennis M.

2014-01-01

Synthetic oligonucleotides (ODN) that express unmethylated “CpG motifs” trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer. PMID:24975812

Development and Preliminary Feasibility Study of a Brief Behavioral Activation Mobile Application (Behavioral Apptivation) to Be Used in Conjunction With Ongoing Therapy.

PubMed

Dahne, Jennifer; Kustanowitz, Jacob; Lejuez, C W

2018-02-01

Depressive symptoms are the most frequently treated psychiatric condition in the United States. Brief behavioral activation treatment for depression (BATD) is a popular, evidence-based psychotherapy with strong research support for the treatment of depression. In this paper, we describe the development and initial pilot feasibility testing of a BATD mobile application (Behavioral Apptivation) to be used by patients and therapists in conjunction with BATD therapy. We present information regarding the app development process as well as results from a small open-label feasibility trial of the app utilized in conjunction with individual BATD. We include a case series from the open-label trial highlighting how Behavioral Apptivation can be utilized in clinical practice.

Second generation photodynamic agents: a review.

PubMed

Sternberg, E D; Dolphin, D

1993-10-01

Over the last decade, laser treatment of neoplastic diseases has become routine. The ability of these light-induced therapies to effect positive results is increased with the utilization of photosensitizing dyes. The approval of Photofrin in Canada as a first generation photodynamic therapeutic agent for the treatment of some forms of bladder cancer is being followed by the development of other agents with improved properties. At this time a number of second generation photosensitizing dyes are under study in phase I/II clinical trials. A review of the status of these trials along with mechanistic aspects is reviewed in this article. In addition, a review of the status of lasers to be utilized for photodynamic therapy gives some indication of which instruments could be considered for this therapy in the future.

Development of an automated analysis system for data from flow cytometric intracellular cytokine staining assays from clinical vaccine trials

PubMed Central

Shulman, Nick; Bellew, Matthew; Snelling, George; Carter, Donald; Huang, Yunda; Li, Hongli; Self, Steven G.; McElrath, M. Juliana; De Rosa, Stephen C.

2008-01-01

Background Intracellular cytokine staining (ICS) by multiparameter flow cytometry is one of the primary methods for determining T cell immunogenicity in HIV-1 clinical vaccine trials. Data analysis requires considerable expertise and time. The amount of data is quickly increasing as more and larger trials are performed, and thus there is a critical need for high throughput methods of data analysis. Methods A web based flow cytometric analysis system, LabKey Flow, was developed for analyses of data from standardized ICS assays. A gating template was created manually in commercially-available flow cytometric analysis software. Using this template, the system automatically compensated and analyzed all data sets. Quality control queries were designed to identify potentially incorrect sample collections. Results Comparison of the semi-automated analysis performed by LabKey Flow and the manual analysis performed using FlowJo software demonstrated excellent concordance (concordance correlation coefficient >0.990). Manual inspection of the analyses performed by LabKey Flow for 8-color ICS data files from several clinical vaccine trials indicates that template gates can appropriately be used for most data sets. Conclusions The semi-automated LabKey Flow analysis system can analyze accurately large ICS data files. Routine use of the system does not require specialized expertise. This high-throughput analysis will provide great utility for rapid evaluation of complex multiparameter flow cytometric measurements collected from large clinical trials. PMID:18615598

RPMIS: The Roswell Park Management Information System

PubMed Central

Priore, R.L.; Lane, W.W.; Edgerton, F.T.; Naeher, C.H.; Reese, P.A.

1978-01-01

This paper presents a generalized approach to data entry and editing utilizing formatted video computer terminals. The purpose of the system developed is to facilitate the creation of many small data bases, with a minimum of implementation time, while maintaining extensive editing capability and preserving ease of use by data entry personnel. RPMIS has demonstrated its utility in shortening the time between research activities and clinical application of results. The system allows entry and retrieval of overlapping subsets of the patient's record in an order and format most appropriate to the individual application. It is used for production of synoptic presentations of information from the labs, the ward and the clinic. RPMIS was designed for the clinical trials setting and has been well received and implemented for numerous such studies. Additional uses have included several registries, screening clinics, retrospective studies, and epidemiologic investigations. The system has found fortuitous use in maintaining curriculum vitae, publications lists and continuing medical education credits.

Do Circulating Tumor Cells, Exosomes, and Circulating Tumor Nucleic Acids Have Clinical Utility?

PubMed Central

Gold, Bert; Cankovic, Milena; Furtado, Larissa V.; Meier, Frederick; Gocke, Christopher D.

2016-01-01

Diagnosing and screening for tumors through noninvasive means represent an important paradigm shift in precision medicine. In contrast to tissue biopsy, detection of circulating tumor cells (CTCs) and circulating tumor nucleic acids provides a minimally invasive method for predictive and prognostic marker detection. This allows early and serial assessment of metastatic disease, including follow-up during remission, characterization of treatment effects, and clonal evolution. Isolation and characterization of CTCs and circulating tumor DNA (ctDNA) are likely to improve cancer diagnosis, treatment, and minimal residual disease monitoring. However, more trials are required to validate the clinical utility of precise molecular markers for a variety of tumor types. This review focuses on the clinical utility of CTCs and ctDNA testing in patients with solid tumors, including somatic and epigenetic alterations that can be detected. A comparison of methods used to isolate and detect CTCs and some of the intricacies of the characterization of the ctDNA are also provided. PMID:25908243

Randomized controlled trial of a cognitive-behavioral intervention for HIV-positive persons: an investigation of treatment effects on psychosocial adjustment.

PubMed

Carrico, Adam W; Chesney, Margaret A; Johnson, Mallory O; Morin, Stephen F; Neilands, Torsten B; Remien, Robert H; Rotheram-Borus, Mary Jane; Lennie Wong, F

2009-06-01

Questions remain regarding the clinical utility of psychological interventions for HIV-positive persons because randomized controlled trials have utilized stringent inclusion criteria and focused extensively on gay men. The present randomized controlled trial examined the efficacy of a 15-session, individually delivered cognitive-behavioral intervention (n = 467) compared to a wait-list control (n = 469) in a diverse sample of HIV-positive persons who reported HIV transmission risk behavior. Five intervention sessions that dealt with executing effective coping responses were delivered between baseline and the 5 months post-randomization. Additional assessments were completed through 25 months post-randomization. Despite previously documented reductions in HIV transmission risk, no intervention-related changes in psychosocial adjustment were observed across the 25-month investigation period. In addition, there were no intervention effects on psychosocial adjustment among individuals who presented with mild to moderate depressive symptoms. More intensive mental health interventions may be necessary to improve psychosocial adjustment among HIV-positive individuals.

Trial-Based Cost-Utility Analysis of Icotinib versus Gefitinib as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer in China

PubMed Central

Zhang, Chunxiang; Zhang, Hongmei; Shi, Jinning; Wang, Dong; Zhang, Xiuwei; Yang, Jian; Zhai, Qizhi; Ma, Aixia

2016-01-01

Background Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed. Results Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy. Conclusions The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market. PMID:27015267

From Controlled Trial to Community Adoption: The Multisite Translational Community Trial

PubMed Central

Murimi, Mary; Gonzalez, Anjelica; Njike, Valentine; Green, Lawrence W.

2011-01-01

Methods for translating the findings of controlled trials, such as the Diabetes Prevention Program, into real-world community application have not been clearly defined. A standardized research methodology for making and evaluating such a transition is needed. We introduce the multisite translational community trial (mTCT) as the research analog to the multisite randomized controlled trial. The mTCT is adapted to incorporate the principles and practices of community-based participatory research and the increased relevance and generalizability gained from diverse community settings. The mTCT is a tool designed to bridge the gap between what a clinical trial demonstrates can work in principle and what is needed to make it workable and effective in real-world settings. Its utility could be put to the test, in particular with practice-based research networks such as the Prevention Research Centers. PMID:21680935

Laser in Glaucoma and Ocular Hypertension (LiGHT) trial. A multicentre, randomised controlled trial: design and methodology.

PubMed

Gazzard, Gus; Konstantakopoulou, Evgenia; Garway-Heath, David; Barton, Keith; Wormald, Richard; Morris, Stephen; Hunter, Rachael; Rubin, Gary; Buszewicz, Marta; Ambler, Gareth; Bunce, Catey

2018-05-01

The Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial aims to establish whether initial treatment with selective laser trabeculoplasty (SLT) is superior to initial treatment with topical medication for primary open-angle glaucoma (POAG) or ocular hypertension (OHT). The LiGHT Trial is a prospective, unmasked, multicentre, pragmatic, randomised controlled trial. 718 previously untreated patients with POAG or OHT were recruited at six collaborating centres in the UK between 2012 and 2014. The trial comprises two treatment arms: initial SLT followed by conventional medical therapy as required, and medical therapy without laser therapy. Randomisation was provided online by a web-based randomisation service. Participants will be monitored for 3 years, according to routine clinical practice. The target intraocular pressure (IOP) was set at baseline according to an algorithm, based on disease severity and lifetime risk of loss of vision at recruitment, and subsequently adjusted on the basis of IOP control, optic disc and visual field. The primary outcome measure is health-related quality of life (HRQL) (EQ-5D five-level). Secondary outcomes are treatment pathway cost and cost-effectiveness, Glaucoma Utility Index, Glaucoma Symptom Scale, Glaucoma Quality of Life, objective measures of pathway effectiveness, visual function and safety profiles and concordance. A single main analysis will be performed at the end of the trial on an intention-to-treat basis. The LiGHT Trial is a multicentre, pragmatic, randomised clinical trial that will provide valuable data on the relative HRQL, clinical effectiveness and cost-effectiveness of SLT and topical IOP-lowering medication. ISRCTN32038223, Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

O8.10A MODEL FOR RESEARCH INITIATIVES FOR RARE CANCERS: THE COLLABORATIVE EPENDYMOMA RESEARCH NETWORK (CERN)

PubMed Central

Armstrong, T.S.; Aldape, K.; Gajjar, A.; Haynes, C.; Hirakawa, D.; Gilbertson, R.; Gilbert, M.R.

2014-01-01

Ependymoma represents less than 5% of adult central nervous system (CNS) tumors and a higher percentage of pediatric CNS tumors, but it remains an orphan disease. The majority of the laboratory-based research and clinical trials have been conducted in the pediatric setting, a reflection of the relative incidence and funding opportunities. CERN, created in 2006, was designed to establish a collaborative effort between laboratory and clinical research and pediatric and adult investigators. The organization of CERN is based on integration and collaboration among five projects. Project 1 contains the clinical trials network encompassing both adult and pediatric centers. This group has completed 2 clinical trials with more underway. Project 2 is focused on molecular classification of human ependymoma tumor tissues and also contains the tumor repository which has now collected over 600 fully clinically annotated CNS ependymomas from adults and children. Project 3 is focused on drug discovery utilizing robust laboratory models of ependymoma to perform high throughput screening of drug libraries, then taking promising agents through extensive preclinical testing including monitoring of drug delivery to tumor using state of the art microdialysis. Project 4 contains the basic research efforts evaluating the molecular pathogenesis of ependymoma and has successfully translated these findings by generating the first mouse models of ependymoma that are employed in preclinical drug development in Project 3. Project 5 studies patient outcomes, including the incorporation of these measures in the clinical trials. This project also contains an online Ependymoma Outcomes survey, collecting data on the consequences of the disease and its treatment. These projects have been highly successful and collaborative. For example, the serial measurement of symptom burden (Project 5) has greatly contributed to the evaluation of treatment efficacy of a clinical trial (Project 1) and investigators from Project 2 are evaluating potential predictive markers from tumor tissue from the same clinical trial. Results from genomic and molecular discoveries generated by Project 4 were evaluated using the clinical material from the Tumor Registry (Project 2). Agents identified from the high throughput screening in Project 3 are being used to create novel clinical trials (Project 1). As a complimentary effort, CERN's community outreach efforts provide a major gateway to patients, families, caregivers and healthcare providers, contributing to greater awareness of ependymoma, and supporting clinical trial accrual in Project 1. In summary, CERN has successfully created a collaborative, multi-national integrated effort combining pediatric- and adult-focused investigators spanning from basic science to patient outcomes measures. This research paradigm may be an effective approach for other rare cancers.

CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2015 EXECUTIVE SUMMARY.

PubMed

Garber, Alan J; Abrahamson, Martin Julian; Barzilay, Joshua I; Blonde, Lawrence; Bloomgarden, Zachary T; Bush, Michael A; Dagogo-Jack, Samuel; Davidson, Michael B; Einhorn, Daniel; Garber, Jeffrey R; Garvey, W Timothy; Grunberger, George; Handelsman, Yehuda; Hirsch, Irl B; Jellinger, Paul S; McGill, Janet B; Mechanick, Jeffrey I; Rosenblit, Paul David; Umpierrez, Guillermo E

2015-12-01

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON TESTING FOR AUTONOMIC AND SOMATIC NERVE DYSFUNCTION.

PubMed

Vinik, Aaron I; Camacho, Pauline M; Davidson, Jaime A; Handelsman, Yehuda; Lando, Howard M; Leddy, Anne L; Reddy, Sethu K; Cook, Richard; Spallone, Vicenza; Tesfaye, Solomon; Ziegler, Dan

2017-12-01

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR RISK.

PubMed

Goodman, Neil; Guay, Andre; Dandona, Paresh; Dhindsa, Sandeep; Faiman, Charles; Cunningham, Glenn R

2015-09-01

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

[Therapeutic impact of screening for myocardial ischemia among asymptomatic type 2 diabetic subjects].

PubMed

Wallemacq, Caroline M; Scheen, André J

2008-08-27

Coronary artery disease is the major cause of mortality of type 2 diabetic subjects. Its early diagnosis to prevent progression and clinical events has intuitive appeal. Somehow, rationale for screening has not been clearly established. Screening should not modify the medical therapy because diabetic subjects have to be treated in a secondary prevention strategy. We have no data from randomized trials concerning a better outcome after revascularization in this specific population. The question how to select the high risk population to be screened has no response by now. SPECT and stress echocardiography seem valuable for screening but not for risk stratification. A large randomized clinical trial is required to confirm the cost-utility ratio of such a screening.

Costs of care in a mild-to-moderate Alzheimer clinical trial sample: key resources and their determinants.

PubMed

Gustavsson, Anders; Cattelin, Francoise; Jönsson, Linus

2011-07-01

Costs of care are frequently included as secondary endpoint in Alzheimer clinical trials because payers demand evidence of the budgetary effects of novel therapies. Future clinical trial protocols can be optimized on the basis of the currently available data, including what are the key resources and how are they correlated to disease severity measures. Primary patient-level data from two 18 months clinical trials of a putative disease modifier in mild-to-moderate Alzheimer's disease (n = 2,744) were analyzed to identify key components of costs of care and their determinants in a clinical trial setting. Costs of care were assessed with the resource utilization in dementia Lite (RUD) instrument, which includes patient accommodation, informal care, community care, and hospitalizations. The contribution of each component to total costs of care and their correlation with one another and key disease severity measures (Alzheimer's Disease Assessment Scale--Cognitive Subscale, Mini-Mental State Examination, Clinical Dementia Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory, and Neuropsychiatric Inventory Questionnaire) was explored. Informal care constituted 82% to 86% of the total costs of care over the 18-months trial and community care services and patient accommodation contributed 6% to 8% each. Informal care was positively correlated with hospitalizations but negatively to patient accommodation, indicating that these services are supplements. Informal care also had the strongest pair-wise correlation with key disease severity measures, suggesting a higher chance of identifying a treatment effect on this component. ADL-ability (Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory) was the strongest predictor of costs of care of all disease severity measures. Informal care is the most important component of costs of care in a mild-to-moderate Alzheimer clinical trial sample, and it is primarily driven by the ADL-ability of the patient. Investigators should focus on the assessment of this economic endpoint because a significant treatment effect on this resource is likely to also affect total costs of care. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Adapting Social Neuroscience Measures for Schizophrenia Clinical Trials, Part 2: Trolling the Depths of Psychometric Properties

PubMed Central

Kern, Robert S.

2013-01-01

The psychometric properties of 4 paradigms adapted from the social neuroscience literature were evaluated to determine their suitability for use in clinical trials of schizophrenia. This 2-site study (University of California, Los Angeles and University of North Carolina) included 173 clinically stable schizophrenia outpatients and 88 healthy controls. The social cognition battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others’ mental states (self-referential memory and empathic accuracy). Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure, and (4) tolerability. Of the 4 paradigms, empathic accuracy demonstrated the strongest characteristics, including large between-group differences, adequate test-retest reliability (.72), negligible practice effects, and good tolerability ratings. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting social neuroscience paradigms for use in clinical trials. PMID:24072805

Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug.

PubMed

Ding, Xuan; Day, Jeffrey S; Sperry, David C

2016-11-01

Absorption modeling has demonstrated its great value in modern drug product development due to its utility in understanding and predicting in vivo performance. In this case, we integrated physiologically based modeling in the development processes to effectively design extended-release (ER) clinical products for an ester prodrug LY545694. By simulating the trial results of immediate-release products, we delineated complex pharmacokinetics due to prodrug conversion and established an absorption model to describe the clinical observations. This model suggested the prodrug has optimal biopharmaceutical properties to warrant developing an ER product. Subsequently, we incorporated release profiles of prototype ER tablets into the absorption model to simulate the in vivo performance of these products observed in an exploratory trial. The models suggested that the absorption of these ER tablets was lower than the IR products because the extended release from the formulations prevented the drug from taking advantage of the optimal absorption window. Using these models, we formed a strategy to optimize the ER product to minimize the impact of the absorption window limitation. Accurate prediction of the performance of these optimized products by modeling was confirmed in a third clinical trial.

Attributes of Successful Leaders in Research

ERIC Educational Resources Information Center

Willenberg, Kelly M.

2014-01-01

What makes a leader successful? As the Director of Research at the Vanderbilt-Ingram Cancer Center's (VICC) Clinical Trials Office, the author had to think of new ways to engage employees when becoming the director nearly 15 years ago. The staff started a GLUE (Greater Loyalty Utilizing Empowerment) Committee. The committee was established to help…

RCT of a Psychological Intervention for Patients with Cancer: I. Mechanisms of Change

ERIC Educational Resources Information Center

Andersen, Barbara L.; Shelby, Rebecca A.; Golden-Kreutz, Deanna M.

2007-01-01

Little is known about the therapeutic processes contributing to efficacy of psychological interventions for patients with cancer. Data from a randomized clinical trial yielding robust biobehavioral and health effects (B. L. Andersen et al., 2004, 2007) were used to examine associations between process variables, treatment utilization, and…

Application of balanced scorecard in the evaluation of a complex health system intervention: 12 months post intervention findings from the BHOMA intervention: a cluster randomised trial in Zambia.

PubMed

Mutale, Wilbroad; Stringer, Jeffrey; Chintu, Namwinga; Chilengi, Roma; Mwanamwenge, Margaret Tembo; Kasese, Nkatya; Balabanova, Dina; Spicer, Neil; Lewis, James; Ayles, Helen

2014-01-01

In many low income countries, the delivery of quality health services is hampered by health system-wide barriers which are often interlinked, however empirical evidence on how to assess the level and scope of these barriers is scarce. A balanced scorecard is a tool that allows for wider analysis of domains that are deemed important in achieving the overall vision of the health system. We present the quantitative results of the 12 months follow-up study applying the balanced scorecard approach in the BHOMA intervention with the aim of demonstrating the utility of the balanced scorecard in evaluating multiple building blocks in a trial setting. The BHOMA is a cluster randomised trial that aims to strengthen the health system in three rural districts in Zambia. The intervention aims to improve clinical care quality by implementing practical tools that establish clear clinical care standards through intensive clinic implementations. This paper reports the findings of the follow-up health facility survey that was conducted after 12 months of intervention implementation. Comparisons were made between those facilities in the intervention and control sites. STATA version 12 was used for analysis. The study found significant mean differences between intervention(I) and control (C) sites in the following domains: Training domain (Mean I:C; 87.5.vs 61.1, mean difference 23.3, p = 0.031), adult clinical observation domain (mean I:C; 73.3 vs.58.0, mean difference 10.9, p = 0.02 ) and health information domain (mean I:C; 63.6 vs.56.1, mean difference 6.8, p = 0.01. There was no gender differences in adult service satisfaction. Governance and motivation scores did not differ between control and intervention sites. This study demonstrates the utility of the balanced scorecard in assessing multiple elements of the health system. Using system wide approaches and triangulating data collection methods seems to be key to successful evaluation of such complex health intervention. ClinicalTrials.gov NCT01942278.

An Item Response Theory Modeling of Alcohol and Marijuana Dependences: A National Drug Abuse Treatment Clinical Trials Network Study*

PubMed Central

Wu, Li-Tzy; Pan, Jeng-Jong; Blazer, Dan G.; Tai, Betty; Stitzer, Maxine L.; Brooner, Robert K.; Woody, George E.; Patkar, Ashwin A.; Blaine, Jack D.

2009-01-01

Objective: The aim of this study was to examine psychometric properties of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostics criteria for alcohol and marijuana dependences among 462 alcohol users and 311 marijuana users enrolled in two multisite trials of the National Drug Abuse Treatment Clinical Trials Network. Method: Diagnostic questions were assessed by the DSM-IV checklist. Data were analyzed by the item response theory and the multiple indicators–multiple causes method procedures. Results: Criterion symptoms of alcohol and marijuana dependences exhibited a high level of internal consistency. All individual symptoms showed good discrimination in distinguishing alcohol or marijuana users between high and low severity levels of the continuum. In both groups, “withdrawal” appeared to measure the most severe symptom of the dependence continuum. There was little evidence of measurement nonequivalence in assessing symptoms of dependence by gender, age, race/ethnicity, and educational level. Conclusions: These findings highlight the clinical utility of the DSM-IV checklist in assessing alcohol- and marijuana-dependence syndromes among treatment-seeking substance users. PMID:19371493

A Bayesian Hybrid Adaptive Randomisation Design for Clinical Trials with Survival Outcomes.

PubMed

Moatti, M; Chevret, S; Zohar, S; Rosenberger, W F

2016-01-01

Response-adaptive randomisation designs have been proposed to improve the efficiency of phase III randomised clinical trials and improve the outcomes of the clinical trial population. In the setting of failure time outcomes, Zhang and Rosenberger (2007) developed a response-adaptive randomisation approach that targets an optimal allocation, based on a fixed sample size. The aim of this research is to propose a response-adaptive randomisation procedure for survival trials with an interim monitoring plan, based on the following optimal criterion: for fixed variance of the estimated log hazard ratio, what allocation minimizes the expected hazard of failure? We demonstrate the utility of the design by redesigning a clinical trial on multiple myeloma. To handle continuous monitoring of data, we propose a Bayesian response-adaptive randomisation procedure, where the log hazard ratio is the effect measure of interest. Combining the prior with the normal likelihood, the mean posterior estimate of the log hazard ratio allows derivation of the optimal target allocation. We perform a simulation study to assess and compare the performance of this proposed Bayesian hybrid adaptive design to those of fixed, sequential or adaptive - either frequentist or fully Bayesian - designs. Non informative normal priors of the log hazard ratio were used, as well as mixture of enthusiastic and skeptical priors. Stopping rules based on the posterior distribution of the log hazard ratio were computed. The method is then illustrated by redesigning a phase III randomised clinical trial of chemotherapy in patients with multiple myeloma, with mixture of normal priors elicited from experts. As expected, there was a reduction in the proportion of observed deaths in the adaptive vs. non-adaptive designs; this reduction was maximized using a Bayes mixture prior, with no clear-cut improvement by using a fully Bayesian procedure. The use of stopping rules allows a slight decrease in the observed proportion of deaths under the alternate hypothesis compared with the adaptive designs with no stopping rules. Such Bayesian hybrid adaptive survival trials may be promising alternatives to traditional designs, reducing the duration of survival trials, as well as optimizing the ethical concerns for patients enrolled in the trial.

Cost Utility Analysis of Cervical Therapeutic Medial Branch Blocks in Managing Chronic Neck Pain

PubMed Central

Manchikanti, Laxmaiah; Pampati, Vidyasagar; Kaye, Alan D.; Hirsch, Joshua A.

2017-01-01

Background:Controlled diagnostic studies have established the prevalence of cervical facet joint pain to range from 36% to 67% based on the criterion standard of ≥ 80% pain relief. Treatment of cervical facet joint pain has been described with Level II evidence of effectiveness for therapeutic facet joint nerve blocks and radiofrequency neurotomy and with no significant evidence for intraarticular injections. However, there have not been any cost effectiveness or cost utility analysis studies performed in managing chronic neck pain with or without headaches with cervical facet joint interventions. Study Design:Cost utility analysis based on the results of a double-blind, randomized, controlled trial of cervical therapeutic medial branch blocks in managing chronic neck pain. Objectives:To assess cost utility of therapeutic cervical medial branch blocks in managing chronic neck pain. Methods: A randomized trial was conducted in a specialty referral private practice interventional pain management center in the United States. This trial assessed the clinical effectiveness of therapeutic cervical medial branch blocks with or without steroids for an established diagnosis of cervical facet joint pain by means of controlled diagnostic blocks. Cost utility analysis was performed with direct payment data for the procedures for a total of 120 patients over a period of 2 years from this trial based on reimbursement rates of 2016. The payment data provided direct procedural costs without inclusion of drug treatments. An additional 40% was added to procedural costs with multiplication of a factor of 1.67 to provide estimated total costs including direct and indirect costs, based on highly regarded surgical literature. Outcome measures included significant improvement defined as at least a 50% improvement with reduction in pain and disability status with a combined 50% or more reduction in pain in Neck Disability Index (NDI) scores. Results:The results showed direct procedural costs per one-year improvement in quality adjusted life year (QALY) of United States Dollar (USD) of $2,552, and overall costs of USD $4,261. Overall, each patient on average received 5.7 ± 2.2 procedures over a period of 2 years. Average significant improvement per procedure was 15.6 ± 12.3 weeks and average significant improvement in 2 years per patient was 86.0 ± 24.6 weeks. Limitations:The limitations of this cost utility analysis are that data are based on a single center evaluation. Only costs of therapeutic interventional procedures and physician visits were included, with extrapolation of indirect costs. Conclusion:The cost utility analysis of therapeutic cervical medial branch blocks in the treatment of chronic neck pain non-responsive to conservative management demonstrated clinical effectiveness and cost utility at USD $4,261 per one year of QALY. PMID:29200944

Cost Utility Analysis of Cervical Therapeutic Medial Branch Blocks in Managing Chronic Neck Pain.

PubMed

Manchikanti, Laxmaiah; Pampati, Vidyasagar; Kaye, Alan D; Hirsch, Joshua A

2017-01-01

Background: Controlled diagnostic studies have established the prevalence of cervical facet joint pain to range from 36% to 67% based on the criterion standard of ≥ 80% pain relief. Treatment of cervical facet joint pain has been described with Level II evidence of effectiveness for therapeutic facet joint nerve blocks and radiofrequency neurotomy and with no significant evidence for intraarticular injections. However, there have not been any cost effectiveness or cost utility analysis studies performed in managing chronic neck pain with or without headaches with cervical facet joint interventions. Study Design: Cost utility analysis based on the results of a double-blind, randomized, controlled trial of cervical therapeutic medial branch blocks in managing chronic neck pain. Objectives: To assess cost utility of therapeutic cervical medial branch blocks in managing chronic neck pain. Methods: A randomized trial was conducted in a specialty referral private practice interventional pain management center in the United States. This trial assessed the clinical effectiveness of therapeutic cervical medial branch blocks with or without steroids for an established diagnosis of cervical facet joint pain by means of controlled diagnostic blocks. Cost utility analysis was performed with direct payment data for the procedures for a total of 120 patients over a period of 2 years from this trial based on reimbursement rates of 2016. The payment data provided direct procedural costs without inclusion of drug treatments. An additional 40% was added to procedural costs with multiplication of a factor of 1.67 to provide estimated total costs including direct and indirect costs, based on highly regarded surgical literature. Outcome measures included significant improvement defined as at least a 50% improvement with reduction in pain and disability status with a combined 50% or more reduction in pain in Neck Disability Index (NDI) scores. Results: The results showed direct procedural costs per one-year improvement in quality adjusted life year (QALY) of United States Dollar (USD) of $2,552, and overall costs of USD $4,261. Overall, each patient on average received 5.7 ± 2.2 procedures over a period of 2 years. Average significant improvement per procedure was 15.6 ± 12.3 weeks and average significant improvement in 2 years per patient was 86.0 ± 24.6 weeks. Limitations: The limitations of this cost utility analysis are that data are based on a single center evaluation. Only costs of therapeutic interventional procedures and physician visits were included, with extrapolation of indirect costs. Conclusion: The cost utility analysis of therapeutic cervical medial branch blocks in the treatment of chronic neck pain non-responsive to conservative management demonstrated clinical effectiveness and cost utility at USD $4,261 per one year of QALY.

Biomarkers for Early Detection of Clinically Relevant Prostate Cancer. A Multi-Institutional Validation Trial

DTIC Science & Technology

2016-10-01

Study (PASS). We are in the process of evaluating these three biomarker panels in tissue, blood, and urine samples with well annotated clinical and...impacting both the initial choice of therapy and decision-making during AS. The objective of the study is to utilize analytically validated assays that...predict reclassification from Gleason 6 cancer to Gleason 7 or greater. The analysis plan was determined before specimens were selected for the study

Biomarkers for Early Detection of Clinically Relevant Prostate Cancer. A Multi-Institutional Validation Trial

DTIC Science & Technology

2016-10-01

Study (PASS). We are in the process of evaluating these three biomarker panels in tissue, blood, and urine samples with well annotated clinical and...choice of therapy and decision-making during AS. The objective of the study is to utilize analytically validated assays that take into account tumor...Gleason 6 cancer to Gleason 7 or greater. The analysis plan was determined before specimens were selected for the study , and included 7 breaking

Review of the influence of pigment dispersion and exfoliation glaucoma diagnosis on intraocular pressure in clinical trials evaluating primary open-angle glaucoma and ocular hypertension.

PubMed

Stewart, William C; DeMill, D L; Wirostko, Barbara M; Nelson, Lindsay A; Stewart, Jeanette A

2013-08-01

To evaluate published, randomized, prospective, parallel clinical trials utilizing currently approved glaucoma medications to determine what influence, if any, pigment dispersion (PD) or exfoliation glaucoma (XFG) patients had on the intraocular pressure. A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and April 2011. If the articles met the inclusion/exclusion criteria, they were analyzed for PD and XFG. Twenty-four articles were included, containing 49 treatment arms that included PD or XFG patients. The range of PD patients was 0% to 4.5%, with a mean of 1.5±0.9%, and for XFG patients 0% to 6.3%, with a mean of 2.2±2.1%. The treatment arms with PD showed a difference in the intraocular pressures (IOPs), for all studies analyzed together, for the baseline IOPs between clinical trials that did and did not include PD patients (8 AM IOPs: with PD 26.5±0.9 mm Hg and without PD 25.8±1.3 mm Hg, P=0.024; and diurnal curve mean IOPs: with PD 25.3±1.1 mm Hg and without PD 24.5±1.3 mm Hg, P=0.024). The XFG treatment arms showed that there was a difference in the IOPs for all studies analyzed together for diurnal baseline IOPs between clinical trials that did and did not include XFG patients (with XFG 25.2±1.2 mm Hg and without XFG 24.3±1.0 mm Hg, P=0.016). Trial designs for prospective, parallel, glaucoma clinical studies that are performed in the United States generally can include PD and XFG patients with only a small impact on the IOP and a low number of such subjects enrolled.

Effectiveness and cost-effectiveness of a health coaching intervention to improve the lifestyle of patients with knee osteoarthritis: cluster randomized clinical trial.

PubMed

Carmona-Terés, Victoria; Lumillo-Gutiérrez, Iris; Jodar-Fernández, Lina; Rodriguez-Blanco, Teresa; Moix-Queraltó, Joanna; Pujol-Ribera, Enriqueta; Mas, Xavier; Batlle-Gualda, Enrique; Gobbo-Montoya, Milena; Berenguera, Anna

2015-02-25

The prevalence of osteoarthritis and knee osteoarthritis in the Spanish population is estimated at 17% and 10.2%, respectively. The clinical guidelines concur that the first line treatment for knee osteoarthritis should be non-pharmacological and include weight loss, physical activity and self-management of pain. Health Coaching has been defined as an intervention that facilitates the achievement of health improvement goals, the reduction of unhealthy lifestyles, the improvement of self-management for chronic conditions and quality of life enhancement. The aim of this study is to analyze the effectiveness, cost-effectiveness and cost-utility of a health coaching intervention on quality of life, pain, overweight and physical activity in patients from 18 primary care centres of Barcelona with knee osteoarthritis. Methodology from the Medical Research Council on developing complex interventions. Phase 1: Intervention modelling and operationalization through a qualitative, socioconstructivist study using theoretical sampling with 10 in-depth interviews to patients with knee osteoarthritis and 4 discussion groups of 8-12 primary care professionals, evaluated using a sociological discourse analysis. Phase 2: Effectiveness, cost-effectiveness and cost-utility study with a community-based randomized clinical trial. 360 patients with knee osteoarthritis (180 in each group). Randomization unit: Primary Care Centre. Intervention Group: will receive standard care plus 20-hour health coaching and follow-up sessions. will receive standard care. quality of life as measured by the WOMAC index. Data Analyses: will include standardized response mean and multilevel analysis of repeated measures. Economic analysis: based on cost-effectiveness and cost-utility measures. Phase 3: Evaluation of the intervention programme with a qualitative study. Methodology as in Phase 1. If the analyses show the cost-effectiveness and cost-utility of the intervention the results can be incorporated into the clinical guidelines for the management of knee osteoarthritis in primary care. ISRCTN57405925. Registred 20 June 2014.

Design of the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study to assess the ability of remote monitoring to treat and triage patients more effectively

PubMed Central

Marzegalli, Maurizio; Landolina, Maurizio; Lunati, Maurizio; Perego, Giovanni B; Pappone, Alessia; Guenzati, Giuseppe; Campana, Carlo; Frigerio, Maria; Parati, Gianfranco; Curnis, Antonio; Colangelo, Irene; Valsecchi, Sergio

2009-01-01

Background Heart failure patients with implantable defibrillators (ICD) frequently visit the clinic for routine device monitoring. Moreover, in the case of clinical events, such as ICD shocks or alert notifications for changes in cardiac status or safety issues, they often visit the emergency department or the clinic for an unscheduled visit. These planned and unplanned visits place a great burden on healthcare providers. Internet-based remote device interrogation systems, which give physicians remote access to patients' data, are being proposed in order to reduce routine and interim visits and to detect and notify alert conditions earlier. Methods The EVOLVO study is a prospective, randomized, parallel, unblinded, multicenter clinical trial designed to compare remote ICD management with the current standard of care, in order to assess its ability to treat and triage patients more effectively. Two-hundred patients implanted with wireless-transmission-enabled ICD will be enrolled and randomized to receive either the Medtronic CareLink® monitor for remote transmission or the conventional method of in-person evaluations. The purpose of this manuscript is to describe the design of the trial. The results, which are to be presented separately, will characterize healthcare utilizations as a result of ICD follow-up by means of remote monitoring instead of conventional in-person evaluations. Trial registration ClinicalTrials.gov: NCT00873899 PMID:19538734

Rethinking the therapeutic misconception: social justice, patient advocacy, and cancer clinical trial recruitment in the US safety net.

PubMed

Burke, Nancy J

2014-09-20

Approximately 20% of adult cancer patients are eligible to participate in a clinical trial, but only 2.5-9% do so. Accrual is even less for minority and medically underserved populations. As a result, critical life-saving treatments and quality of life services developed from research studies may not address their needs. This study questions the utility of the bioethical concern with therapeutic misconception (TM), a misconception that occurs when research subjects fail to distinguish between clinical research and ordinary treatment, and therefore attribute therapeutic intent to research procedures in the safety net setting. This paper provides ethnographic insight into the ways in which research is discussed and related to standard treatment. In the course of two years of ethnographic fieldwork in a safety net hospital, I conducted clinic observations (n=150 clinic days) and in-depth in-person qualitative interviews with patients (n=37) and providers (n=15). I used standard qualitative methods to organize and code resulting fieldnote and interview data. Findings suggest that TM is limited in relevance for the interdisciplinary context of cancer clinical trial recruitment in the safety net setting. Ethnographic data show the value of the discussions that happen prior to the informed consent, those that introduce the idea of participation in research. These preliminary discussions are elemental especially when recruiting underserved and vulnerable patients for clinical trial participation who are often unfamiliar with medical research and how it relates to medical care. Data also highlight the multiple actors involved in research discussions and the ethics of social justice and patient advocacy they mobilize, suggesting that class, inequality, and dependency influence the forms of ethical engagements in public hospital settings. On the ground ethics of social justice and patient advocacy are more relevant than TM as guiding ethical principles in the context of ongoing cancer disparities and efforts to diversify clinical trial participation.

Safety Studies for Use of Adipose Tissue‐Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial

PubMed Central

Riester, Scott M.; Denbeigh, Janet M.; Lin, Yang; Jones, Dakota L.; de Mooij, Tristan; Lewallen, Eric A.; Nie, Hai; Paradise, Christopher R.; Radel, Darcie J.; Dudakovic, Amel; Camilleri, Emily T.; Larson, Dirk R.; Qu, Wenchun; Krych, Aaron J.; Frick, Matthew A.; Im, Hee‐Jeong; Dietz, Allan B.; Smith, Jay

2016-01-01

Abstract Adipose‐derived mesenchymal stem cells (AMSCs) offer potential as a therapeutic option for clinical applications in musculoskeletal regenerative medicine because of their immunomodulatory functions and capacity for trilineage differentiation. In preparation for a phase I clinical trial using AMSCs to treat patients with osteoarthritis, we carried out preclinical studies to assess the safety of human AMSCs within the intra‐articular joint space. Culture‐expanded human AMSCs grown in human platelet‐lysate were delivered via intra‐articular injections into normal healthy rabbit knees and knees at risk for the development of osteoarthritis after bilateral medial anterior hemimeniscectomy. Treatment outcomes and safety were evaluated by assessing the general health, function, and behavior of the animals. Joint tissues were analyzed by x‐ray, magnetic resonance imaging, and histopathology. Intra‐articular AMSC therapy was well tolerated in this study. We did not observe adverse systemic reactions, nor did we find evidence of damage to intra‐articular joint tissues. Thus, the data generated in this study show a favorable safety profile for AMSCs within the joint space in support of a phase I clinical trial evaluating the clinical utility of AMSCs to treat osteoarthritis. Stem Cells Translational Medicine 2017;6:910–922 PMID:28297568

Head Tilt Posturography to Enhance Balance Control Assessment for Astronauts: A Case Study

NASA Technical Reports Server (NTRS)

Hwang, E. Y.; Paloski, W. H.

2006-01-01

For many years, we have used a standard clinical computerized dynamic posturography (CDP) protocol to assess recovery of integrated sensory-motor function in astronauts returning from space flight. The most reliable indications of postflight crew performance capabilities have been obtained from the sensory organization tests (SOTs) within the CDP protocol, particularly SOTs 5 (eyes closed, surface support sway referenced) and 6 (eyes open, surface support and visual surround sway referenced), which are sensitive to changes in availability and/or utilization of vestibular cues. We have observed, however, that some astronauts exhibiting visible signs of incomplete sensory-motor recovery are able to score within clinical norms on standard SOTs 5 and 6 trials, perhaps as a result of cognitive strategies driven by their naturally competitive natures. To improve the sensitivity of the CDP protocol for assessing recovery of integrated sensory-motor function and fitness to return to duties and/or activities of daily living, we have introduced pitch plane head tilt SOT trials to our protocol. In a preliminary study of 5 short duration (11day missions) astronauts, we showed that they were unable to maintain balance on landing day when performing dynamic head tilt trials, despite scoring within the clinically normal range on the standard SOT trials. The present case report illustrates the advantages of including head tilt trials for assessing sensory-motor recovery in long duration crewmembers.

Coordinating resources for prospective medication risk management of older home care clients in primary care: procedure development and RCT study design for demonstrating its effectiveness.

PubMed

Toivo, Terhi; Dimitrow, Maarit; Puustinen, Juha; Savela, Eeva; Pelkonen, Katariina; Kiuru, Valtteri; Suominen, Tuula; Kinnunen, Sirkka; Uunimäki, Mira; Kivelä, Sirkka-Liisa; Leikola, Saija; Airaksinen, Marja

2018-03-16

The magnitude of safety risks related to medications of the older adults has been evidenced by numerous studies, but less is known of how to manage and prevent these risks in different health care settings. The aim of this study was to coordinate resources for prospective medication risk management of home care clients ≥ 65 years in primary care and to develop a study design for demonstrating effectiveness of the procedure. Health care units involved in the study are from primary care in Lohja, Southern Finland: home care (191 consented clients), the public healthcare center, and a private community pharmacy. System based risk management theory and action research method was applied to construct the collaborative procedure utilizing each profession's existing resources in medication risk management of older home care clients. An inventory of clinical measures in usual clinical practice and systematic review of rigorous study designs was utilized in effectiveness study design. The new coordinated medication management model (CoMM) has the following 5 stages: 1) practical nurses are trained to identify clinically significant drug-related problems (DRPs) during home visits and report those to the clinical pharmacist. Clinical pharmacist prepares the cases for 2) an interprofessional triage meeting (50-70 cases/meeting of 2 h) where decisions are made on further action, e.g., more detailed medication reviews, 3) community pharmacists conduct necessary medication reviews and each patients' physician makes final decisions on medication changes needed. The final stages concern 4) implementation and 5) follow-up of medication changes. Randomized controlled trial (RCT) was developed to demonstrate the effectiveness of the procedure. The developed procedure is feasible for screening and reviewing medications of a high number of older home care clients to identify clients with severe DRPs and provide interventions to solve them utilizing existing primary care resources. The study is registered in the Clinical Trials.gov ( NCT02545257 ). Registration date September 9 2015.

A value-based medicine analysis of ranibizumab for the treatment of subfoveal neovascular macular degeneration.

PubMed

Brown, Melissa M; Brown, Gary C; Brown, Heidi C; Peet, Jonathan

2008-06-01

To assess the conferred value and average cost-utility (cost-effectiveness) for intravitreal ranibizumab used to treat occult/minimally classic subfoveal choroidal neovascularization associated with age-related macular degeneration (AMD). Value-based medicine cost-utility analysis. MARINA (Minimally Classic/Occult Trial of the Anti-Vascular Endothelial Growth Factor Antibody Ranibizumab in the Treatment of Neovascular AMD) Study patients utilizing published primary data. Reference case, third-party insurer perspective, cost-utility analysis using 2006 United States dollars. Conferred value in the forms of (1) quality-adjusted life-years (QALYs) and (2) percent improvement in health-related quality of life. Cost-utility is expressed in terms of dollars expended per QALY gained. All outcomes are discounted at a 3% annual rate, as recommended by the Panel on Cost-effectiveness in Health and Medicine. Data are presented for the second-eye model, first-eye model, and combined model. Twenty-two intravitreal injections of 0.5 mg of ranibizumab administered over a 2-year period confer 1.039 QALYs, or a 15.8% improvement in quality of life for the 12-year period of the second-eye model reference case of occult/minimally classic age-related subfoveal choroidal neovascularization. The reference case treatment cost is $52652, and the cost-utility for the second-eye model is $50691/QALY. The quality-of-life gain from the first-eye model is 6.4% and the cost-utility is $123887, whereas the most clinically simulating combined model yields a quality-of-life gain of 10.4% and cost-utility of $74169. By conventional standards and the most commonly used second-eye and combined models, intravitreal ranibizumab administered for occult/minimally classic subfoveal choroidal neovascularization is a cost-effective therapy. Ranibizumab treatment confers considerably greater value than other neovascular macular degeneration pharmaceutical therapies that have been studied in randomized clinical trials.

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

Feasibility and acceptability of the DSM-5 Field Trial procedures in the Johns Hopkins Community Psychiatry Programs.

PubMed

Clarke, Diana E; Wilcox, Holly C; Miller, Leslie; Cullen, Bernadette; Gerring, Joan; Greiner, Lisa H; Newcomer, Alison; McKitty, Mellisha V; Regier, Darrel A; Narrow, William E

2014-06-01

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) contains criteria for psychiatric diagnoses that reflect advances in the science and conceptualization of mental disorders and address the needs of clinicians. DSM-5 also recommends research on dimensional measures of cross-cutting symptoms and diagnostic severity, which are expected to better capture patients' experiences with mental disorders. Prior to its May 2013 release, the American Psychiatric Association (APA) conducted field trials to examine the feasibility, clinical utility, reliability, and where possible, the validity of proposed DSM-5 diagnostic criteria and dimensional measures. The methods and measures proposed for the DSM-5 field trials were pilot tested in adult and child/adolescent clinical samples, with the goal to identify and correct design and procedural problems with the proposed methods before resources were expended for the larger DSM-5 Field Trials. Results allowed for the refinement of the protocols, procedures, and measures, which facilitated recruitment, implementation, and completion of the DSM-5 Field Trials. These results highlight the benefits of pilot studies in planning large multisite studies. Copyright © 2013, American Psychiatric Association. All rights reserved.

Osteoporosis therapies: evidence from health-care databases and observational population studies.

PubMed

Silverman, Stuart L

2010-11-01

Osteoporosis is a well-recognized disease with severe consequences if left untreated. Randomized controlled trials are the most rigorous method for determining the efficacy and safety of therapies. Nevertheless, randomized controlled trials underrepresent the real-world patient population and are costly in both time and money. Modern technology has enabled researchers to use information gathered from large health-care or medical-claims databases to assess the practical utilization of available therapies in appropriate patients. Observational database studies lack randomization but, if carefully designed and successfully completed, can provide valuable information that complements results obtained from randomized controlled trials and extends our knowledge to real-world clinical patients. Randomized controlled trials comparing fracture outcomes among osteoporosis therapies are difficult to perform. In this regard, large observational database studies could be useful in identifying clinically important differences among therapeutic options. Database studies can also provide important information with regard to osteoporosis prevalence, health economics, and compliance and persistence with treatment. This article describes the strengths and limitations of both randomized controlled trials and observational database studies, discusses considerations for observational study design, and reviews a wealth of information generated by database studies in the field of osteoporosis.

Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer.

PubMed

Nagasaka, Misako; Gadgeel, Shirish M

2018-01-01

Adjuvant platinum based chemotherapy is accepted as standard of care in stage II and III non-small cell lung cancer (NSCLC) patients and is often considered in patients with stage IB disease who have tumors ≥ 4 cm. The survival advantage is modest with approximately 5% at 5 years. Areas covered: This review article presents relevant data regarding chemotherapy use in the perioperative setting for early stage NSCLC. A literature search was performed utilizing PubMed as well as clinical trial.gov. Randomized phase III studies in this setting including adjuvant and neoadjuvant use of chemotherapy as well as ongoing trials on targeted therapy and immunotherapy are also discussed. Expert commentary: With increasing utilization of screening computed tomography scans, it is possible that the percentage of early stage NSCLC patients will increase in the coming years. Benefits of adjuvant chemotherapy in early stage NSCLC patients remain modest. There is a need to better define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy. Trials for adjuvant targeted therapy, including adjuvant EGFR-TKI trials and trials of immunotherapy drugs are ongoing and will define the role of these agents as adjuvant therapy.

INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): a mixed-methods study to assess the feasibility of a future randomised controlled trial of invasive urodynamic testing prior to surgery for stress urinary incontinence in women.

PubMed

Hilton, Paul; Armstrong, Natalie; Brennand, Catherine; Howel, Denise; Shen, Jing; Bryant, Andrew; Tincello, Douglas G; Lucas, Malcolm G; Buckley, Brian S; Chapple, Christopher R; Homer, Tara; Vale, Luke; McColl, Elaine

2015-02-01

The position of invasive urodynamic testing in the diagnostic pathway for urinary incontinence (UI) is unclear. Systematic reviews have called for further trials evaluating clinical utility, although a preliminary feasibility study was considered appropriate. To inform the decision whether or not to proceed to a definitive randomised trial of invasive urodynamic testing compared with clinical assessment with non-invasive tests, prior to surgery in women with stress UI (SUI) or stress predominant mixed UI (MUI). A mixed-methods study comprising a pragmatic multicentre randomised pilot trial; economic evaluation; survey of clinicians' views about invasive urodynamic testing; qualitative interviews with clinicians and trial participants. Urogynaecology, female urology and general gynaecology units in Newcastle, Leicester, Swansea, Sheffield, Northumberland, Gateshead and South Tees. Trial recruits were women with SUI or stress predominant MUI who were considering surgery after unsuccessful conservative treatment. Relevant clinicians completed two online surveys. Subsets of survey respondents and trial participants took part in separate qualitative interview studies. Pilot trial participants were randomised to undergo clinical assessment with non-invasive tests (control arm); or assessment as controls, plus invasive urodynamic testing (intervention arm). Confirmation that units can identify and recruit eligible women; acceptability of investigation strategies and data collection tools; acquisition of outcome data to determine the sample size for a definitive trial. The proposed primary outcome for the definitive trial was International Consultation on Incontinence Modular Questionnaire (ICIQ) Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) (total score) 6 months after surgery or the start of non-surgical treatment; secondary outcomes included: ICIQ-FLUTS (subscales); ICIQ Urinary Incontinence Short Form; ICIQ Lower Urinary Tract Symptoms Quality of Life; Urogenital Distress Inventory; EuroQol-5D; costs, quality-adjusted life-years (QALYs) and incremental cost per QALY, Short Form 12; 3-day bladder diary. Of 284 eligible women, 222 (78%) were recruited; 165/219 (75%) returned questionnaires at baseline and 125/200 (63%) who were sent questionnaires at follow-up. There were few missing data items in returned questionnaires, with individual outcome scales calculable for 81%-94%. Most women underwent surgery; management plans were changed in 19 (19%) participants following invasive urodynamic testing. Participant Costs Questionnaires were returned by 53% 6 months after treatment; complete data to undertake cost-utility analysis were available in 27% (intervention) and 47% (control). While insufficient to recommend changes in practice, the results suggest further research would be valuable. All clinicians responding to the survey had access to invasive urodynamic testing, and most saw it as essential prior to surgery in women with SUI with or without other symptoms; nevertheless, 70% considered the research question underlying INVESTIGATE important and most were willing to randomise patients in a definitive trial. Participants interviewed were positive about the trial and associated documentation; the desire of some women to avoid invasive urodynamic testing contrasted with opinions expressed by clinicians through both survey and interview responses. All elements of a definitive trial and economic evaluation were rehearsed; several areas for protocol modification were identified. Such a trial would require to 400-900 participants, depending on the difference in primary outcome sought. A definitive trial of invasive urodynamic testing versus clinical assessment prior to surgery for SUI or stress predominant MUI should be undertaken. Current Controlled Trials ISRCTN71327395. The National Institute for Health Research Health Technology Assessment programme.

Building the Evidence Base for Decision-making in Cancer Genomic Medicine Using Comparative Effectiveness Research

PubMed Central

Goddard, Katrina A.B.; Knaus, William A.; Whitlock, Evelyn; Lyman, Gary H.; Feigelson, Heather Spencer; Schully, Sheri D.; Ramsey, Scott; Tunis, Sean; Freedman, Andrew N.; Khoury, Muin J.; Veenstra, David L.

2013-01-01

Background The clinical utility is uncertain for many cancer genomic applications. Comparative effectiveness research (CER) can provide evidence to clarify this uncertainty. Objectives To identify approaches to help stakeholders make evidence-based decisions, and to describe potential challenges and opportunities using CER to produce evidence-based guidance. Methods We identified general CER approaches for genomic applications through literature review, the authors’ experiences, and lessons learned from a recent, seven-site CER initiative in cancer genomic medicine. Case studies illustrate the use of CER approaches. Results Evidence generation and synthesis approaches include comparative observational and randomized trials, patient reported outcomes, decision modeling, and economic analysis. We identified significant challenges to conducting CER in cancer genomics: the rapid pace of innovation, the lack of regulation, the limited evidence for clinical utility, and the beliefs that genomic tests could have personal utility without having clinical utility. Opportunities to capitalize on CER methods in cancer genomics include improvements in the conduct of evidence synthesis, stakeholder engagement, increasing the number of comparative studies, and developing approaches to inform clinical guidelines and research prioritization. Conclusions CER offers a variety of methodological approaches to address stakeholders’ needs. Innovative approaches are needed to ensure an effective translation of genomic discoveries. PMID:22516979

From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials.

PubMed

Lam, Thomas; Hetherington, John W; Greenman, John; Maraveyas, Anthony

2006-02-01

'Metronomic chemotherapy' represents a novel anti-angiogenic strategy whereby low-dose chemotherapy is utilized in a continuous fashion in order to target tumor endothelium. There are many potential advantages of this strategy and clinical trials are already underway. However, although the scheduling of metronomic chemotherapy is relatively unequivocal, metronomic dosing principles are at present poorly defined. Arbitrarily, 10-33% of the maximum tolerated dose comprises 'the dose range'. We argue that this is too empirical and propose a set of phase I metronomic chemotherapy dosing strategies based on a principled approach which may help to reduce the problem of empiricism in dosing for metronomic chemotherapy trials.

Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

PubMed Central

Ramos, Nestor R.; Mo, Clifton C.; Karp, Judith E.; Hourigan, Christopher S.

2015-01-01

The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the current criteria for “complete” remission. Nevertheless, most AML patients ultimately die from their disease, most commonly as clinically evident relapsed AML. Despite a variety of available salvage therapy options, prognosis in patients with relapsed or refractory AML is generally poor. In this review, we outline the commonly utilized salvage cytotoxic therapy interventions and then highlight novel investigational efforts currently in clinical trials using both pathway-targeted agents and immunotherapy based approaches. We conclude that there is no current standard of care for adult relapsed or refractory AML other than offering referral to an appropriate clinical trial. PMID:25932335

Pharmacogenomics in early-phase clinical development

PubMed Central

Burt, Tal; Dhillon, Savita

2015-01-01

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs. PMID:23837482

Partnerships and Pathways of Dissemination: The NIDA-SAMHSA Blending Initiative in the Clinical Trials Network

PubMed Central

Martino, Steve; Brigham, Gregory S.; Higgins, Christine; Gallon, Steve; Freese, Thomas E.; Albright, Lonnetta M.; Hulsey, Eric G.; Krom, Laurie; Storti, Susan A.; Perl, Harold; Nugent, Cathrine D.; Pintello, Denise; Condon, Timothy P.

2010-01-01

Since 2001, the National Drug Abuse Treatment Clinical Trials Network (CTN) has worked to put the results of its trials into the hands of community treatment programs, in large part through its participation in the National Institute on Drug Abuse - Substance Abuse and Mental Health Services Administration Blending Initiative and its close involvement with the Center for Substance Abuse Treatment’s Addiction Technology Transfer Centers. This article describes 1) the CTN’s integral role in the Blending Initiative, 2) key partnerships and dissemination pathways through which the results of CTN trials are developed into blending products and then transferred to community treatment programs, and 3) three blending initiatives involving buprenorphine, motivational incentives, and motivational interviewing. The Blending Initiative has resulted in high utilization of its products, preparation of over 200 regional trainers, widespread training of service providers in most U.S. States, Puerto Rico, and the U.S. Virgin Islands, and movement toward the development of web-based implementation supports and technical assistance. Implications for future directions of the Blending Initiative and opportunities for research are discussed. PMID:20307793

NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer?

PubMed

Friberg, Sten; Nyström, Andreas M

2016-03-09

This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream.

Novel pharmacotherapy for the treatment of hospital-acquired and ventilator-associated pneumonia caused by resistant gram-negative bacteria.

PubMed

Kidd, James M; Kuti, Joseph L; Nicolau, David P

2018-03-01

Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP. Areas covered: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed. Expert opinion: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated.

Clinical validation of the CHRONIOUS wearable system in patients with chronic disease.

PubMed

Bellos, Christos; Papadopoulos, Athanassios; Rosso, Roberto; Fotiadis, Dimitrios I

2013-01-01

The CHRONIOUS system defines a powerful and easy to use framework which has been designed to provide services to clinicians and their patients suffering from chronic diseases. The system is composed of a wearable shirt that integrate several body sensors, a portable smart device and a central sub-system that is responsible for the long term storage of the collected patient's data. A multi-parametric expert system is developed for the analysis of the collected data using intelligent algorithms and complex techniques. Apart for the vital signals, dietary habits, drug intake, activity data, environmental and biochemical parameters are recorded. The CHRONIOUS platform is validated through clinical trials in several medical centers and patient's home environments recruiting patients suffering from Chronic Obstructive pulmonary disease (COPD) and Chronic Kidney Disease (CKD) diseases. The clinical trials contribute in improving the system's accuracy, while Pulmonologists and Nephrologists experts utilized the CHRONIOUS platform to evaluate its efficiency and performance. The results of the utilization of the system were very encouraging. The CHRONIOUS system has been proven to be a well-validated real-time patient monitoring and supervision platform, providing a useful tool for the clinician and the patient that would contribute to the more effective management of chronic diseases.

Structured patient handoff on an internal medicine ward: A cluster randomized control trial.

PubMed

Tam, Penny; Nijjar, Aman P; Fok, Mark; Little, Chris; Shingina, Alexandra; Bittman, Jesse; Raghavan, Rashmi; Khan, Nadia A

2018-01-01

The effect of a multi-faceted handoff strategy in a high volume internal medicine inpatient setting on process and patient outcomes has not been clearly established. We set out to determine if a multi-faceted handoff intervention consisting of education, standardized handoff procedures, including fixed time and location for face-to-face handoff would result in improved rates of handoff compared with usual practice. We also evaluated resident satisfaction, health resource utilization and clinical outcomes. This was a cluster randomized controlled trial in a large academic tertiary care center with 18 inpatient internal medicine ward teams from January-April 2013. We randomized nine inpatient teams to an intervention where they received an education session standardizing who and how to handoff patients, with practice and feedback from facilitators. The control group of 9 teams continued usual non-standardized handoffs. The primary process outcome was the rate of patients handed over per 1000 patient nights. Other process outcomes included perceptions of inadequate handoff by overnight physicians, resource utilization overnight and hospital length of stay. Clinical outcomes included medical errors, frequency of patients requiring higher level of care overnight, and in-hospital mortality. The intervention group demonstrated a significant increase in the rate of patients handed over to the overnight physician (62.90/1000 person-nights vs. 46.86/1000 person-nights, p = 0.002). There was no significant difference in other process outcomes except resource utilization was increased in the intervention group (26.35/1000 person-days vs. 17.57/1000 person-days, p-value = 0.01). There was no significant difference between groups in medical errors (4.8% vs. 4.1%), need for higher level of care or in hospital mortality. Limitations include a dependence of accurate record keeping by the overnight physician, the possibility of cross-contamination in the handoff process, analysis at the cluster level and an overall low number of clinical events. Implementation of a multi-faceted resident handoff intervention did not result in a significant improvement in patient safety although did improve number of patients handed off. Novel methods to improve handoff need to be explored. Registered at ClinicalTrials.gov: NCT01796756.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

PubMed Central

Krasowski, Matthew D.

2010-01-01

In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy. PMID:20640233

Hypertension with unsatisfactory sleep health (HUSH): study protocol for a randomized controlled trial.

PubMed

Levenson, Jessica C; Rollman, Bruce L; Ritterband, Lee M; Strollo, Patrick J; Smith, Kenneth J; Yabes, Jonathan G; Moore, Charity G; Harvey, Allison G; Buysse, Daniel J

2017-06-06

Insomnia is common in primary care medical practices. Although behavioral treatments for insomnia are safe, efficacious, and recommended in practice guidelines, they are not widely-available, and their effects on comorbid medical conditions remain uncertain. We are conducting a pragmatic clinical trial to test the efficacy of two cognitive behavioral treatments for insomnia (Brief Behavioral Treatment for Insomnia (BBTI) and Sleep Healthy Using the Internet (SHUTi)) versus an enhanced usual care condition (EUC). The study is a three-arm, parallel group, randomized controlled trial. Participants include 625 adults with hypertension and insomnia, recruited via electronic health records from primary care practices affiliated with a large academic medical center. After screening and baseline assessments, participants are randomized to treatment. BBTI is delivered individually with a live therapist via web-interface/telehealth sessions, while SHUTi is a self-guided, automated, interactive, web-based form of cognitive behavioral therapy for insomnia. Participants in EUC receive an individualized sleep report, educational resources, and an online educational video. Treatment outcomes are measured at 9 weeks, 6 months, and 12 months. The primary outcome is patient-reported sleep disturbances. Secondary outcomes include other self-reported sleep measures, home blood pressure, body mass index, quality of life, health functioning, healthcare utilization, and side effects. This randomized clinical trial compares two efficacious insomnia interventions to EUC, and provides a cost-effective and efficient examination of their similarities and differences. The pragmatic orientation of this trial may impact sleep treatment delivery in real world clinical settings and advance the dissemination and implementation of behavioral sleep interventions. ClinicalTrials.gov (Identifier: NCT02508129 ; Date Registered: July 21, 2015).

Update to the study protocol, including statistical analysis plan for a randomized clinical trial comparing comprehensive cardiac rehabilitation after heart valve surgery with control: the CopenHeartVR trial.

PubMed

Sibilitz, Kirstine Laerum; Berg, Selina Kikkenborg; Hansen, Tina Birgitte; Risom, Signe Stelling; Rasmussen, Trine Bernholdt; Hassager, Christian; Køber, Lars; Gluud, Christian; Thygesen, Lau Caspar; Lindschou, Jane; Schmid, Jean Paul; Taylor, Rod S; Zwisler, Ann-Dorthe

2015-02-05

Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising because of an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post-surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesize that a comprehensive cardiac rehabilitation program can improve physical capacity and self-assessed mental health and reduce hospitalization and healthcare costs after heart valve surgery. This randomized clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients 1:1 to an intervention or a control group, using central randomization, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise and a psycho-educational intervention comprising five consultations. The primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. The secondary outcome is self-assessed mental health measured by the standardized questionnaire Short Form-36. Long-term healthcare utilization and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design will be used to evaluate qualitative and quantitative findings, encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study. This randomized clinical trial will contribute with evidence of whether cardiac rehabilitation should be provided after heart valve surgery. The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015). Trial registered 16 March 2012; ClinicalTrials.gov ( NCT01558765 ).

Comparison of smartphone application-based vital sign monitors without external hardware versus those used in clinical practice: a prospective trial.

PubMed

Alexander, John C; Minhajuddin, Abu; Joshi, Girish P

2017-08-01

Use of healthcare-related smartphone applications is common. However, there is concern that inaccurate information from these applications may lead patients to make erroneous healthcare decisions. The objective of this study is to study smartphone applications purporting to measure vital sign data using only onboard technology compared with monitors used routinely in clinical practice. This is a prospective trial comparing correlation between a clinically utilized vital sign monitor (Propaq CS, WelchAllyn, Skaneateles Falls, NY, USA) and four smartphone application-based monitors Instant Blood Pressure, Instant Blood Pressure Pro, Pulse Oximeter, and Pulse Oximeter Pro. We performed measurements of heart rate (HR), systolic blood pressures (SBP), diastolic blood pressure (DBP), and oxygen saturation (SpO 2 ) using standard monitor and four smartphone applications. Analysis of variance was used to compare measurements from the applications to the routine monitor. The study was completed on 100 healthy volunteers. Comparison of routine monitor with the smartphone applications shows significant differences in terms of HR, SpO 2 and DBP. The SBP values from the applications were not significantly different from those from the routine monitor, but had wide limits of agreement signifying a large degree of variation in the compared values. The degree of correlation between monitors routinely used in clinical practice and the smartphone-based applications studied is insufficient to recommend clinical utilization. This lack of correlation suggests that the applications evaluated do not provide clinically meaningful data. The inaccurate data provided by these applications can potentially contribute to patient harm.

Herbal medicine for low back pain: a Cochrane review.

PubMed

Gagnier, Joel J; van Tulder, Maurits W; Berman, Brian; Bombardier, Claire

2007-01-01

A systematic review of randomized controlled trials. To determine the effectiveness of herbal medicine compared with placebo, no intervention, or "standard/accepted/conventional treatments" for nonspecific low back pain. Low back pain is a common condition and a substantial economic burden in industrialized societies. A large proportion of patients with chronic low back pain use complementary and alternative medicine (CAM) and/or visit CAM practitioners. Several herbal medicines have been purported for use in low back pain. The following databases were searched: Medline (1966 to April 2003), Embase (1980 to April 2003), Cochrane Controlled Trials Register (Issue 1, 2003), and Cochrane Complementary Medicine (CM) field Trials Register. Additionally, reference lists in review articles, guidelines, and in the retrieved trials were checked. Randomized controlled trials (RCTs), using adults (>18 years of age) suffering from acute, subacute, or chronic nonspecific low back pain. Types of interventions included herbal medicines defined as a plant that is used for medicinal purposes in any form. Primary outcome measures were pain and function. Two reviewers (J.J.G. and M.W.T.) conducted electronic searches in all databases. One reviewer (J.J.G.) contacted content experts and acquired relevant citations. Authors, title, subject headings, publication type, and abstract of the isolated studies were downloaded or a hard copy was retrieved. Methodologic quality and clinical relevance were assessed separately by two individuals (J.J.G. and M.W.T.). Disagreements were resolved by consensus. Ten trials were included in this review. Two high-quality trials utilizing Harpagophytum procumbens (Devil's claw) found strong evidence for short-term improvements in pain and rescue medication for daily doses standardized to 50 mg or 100 mg harpagoside with another high-quality trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib. Two moderate-quality trials utilizing Salix alba (White willow bark) found moderate evidence for short-term improvements in pain and rescue medication for daily doses standardized to 120 mg or 240 mg salicin with an additional trial demonstrating relative equivalence to 12.5 mg per day of rofecoxib. Three low-quality trials using Capsicum frutescens (Cayenne) using various topical preparations found moderate evidence for favorable results against placebo and one trial found equivalence to a homeopathic ointment. Harpagophytum procumbens, Salix alba, and Capsicum frutescens seem to reduce pain more than placebo. Additional trials testing these herbal medicines against standard treatments will clarify their equivalence in terms of efficacy. The quality of reporting in these trials was generally poor; thus, trialists should refer to the CONSORT statement in reporting clinical trials of herbal medicines.

Guidelines for the Reporting of Treatment Trials for Alcohol Use Disorders

PubMed Central

Witkiewitz, Katie; Finney, John W.; Harris, Alex H.S; Kivlahan, Daniel R.; Kranzler, Henry R.

2015-01-01

Background The primary goals in conducting clinical trials of treatments for alcohol use disorders (AUDs) is to identify efficacious treatments and determine which treatments are most efficacious for which patients. Accurate reporting of study design features and results is imperative to enable readers of research reports to evaluate to what extent a study has achieved these goals. Guidance on quality of clinical trial reporting has evolved substantially over the past two decades, primarily through the publication and widespread adoption of the Consolidated Standards of Reporting Trials (CONSORT) statement. However, there is room to improve the adoption of those standards in reporting the design and findings of treatment trials for AUD. Methods Narrative review of guidance on reporting quality in AUD treatment trials. Results Despite improvements in the reporting of results of treatment trials for AUD over the past two decades, many published reports provide insufficient information on design or methods. Conclusions The reporting of alcohol treatment trial design, analysis, and results requires improvement in four primary areas: (1) trial registration, (2) procedures for recruitment and retention, (3) procedures for randomization and intervention design considerations, and (4) statistical methods used to assess treatment efficacy. Improvements in these areas and the adoption of reporting standards by authors, reviewers, and editors are critical to an accurate assessment of the reliability and validity of treatment effects. Continued developments in this area are needed to move AUD treatment research forward via systematic reviews and meta-analyses that maximize the utility of completed studies. PMID:26259958

The Gene Therapy Resource Program: A Decade of Dedication to Translational Research by the National Heart, Lung, and Blood Institute.

PubMed

Flotte, Terence R; Daniels, Eric; Benson, Janet; Bevett-Rose, Jeneé M; Cornetta, Kenneth; Diggins, Margaret; Johnston, Julie; Sepelak, Susan; van der Loo, Johannes C M; Wilson, James M; McDonald, Cheryl L

2017-12-01

Over a 10-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice clinical-grade vector cores for recombinant adeno-associated virus and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early-phase clinical trials. In addition, the GTRP has utilized a Steering Committee and a Scientific Review Board to guide overall progress and effectiveness and to evaluate individual proposals. These resources have been deployed to assist 82 investigators with 172 approved service proposals. These efforts have assisted in clinical trial implementation across a wide range of genetic, cardiac, pulmonary, and blood diseases. Program outcomes and potential future directions of the program are discussed.

Illustrating idiographic methods for translation research: moderation effects, natural clinical experiments, and complex treatment-by-subgroup interactions.

PubMed

Ridenour, Ty A; Wittenborn, Andrea K; Raiff, Bethany R; Benedict, Neal; Kane-Gill, Sandra

2016-03-01

A critical juncture in translation research involves the preliminary studies of intervention tools, provider training programs, policies, and other mechanisms used to leverage knowledge garnered at one translation stage into another stage. Potentially useful for such studies are rigorous techniques for conducting within-subject clinical trials, which have advanced incrementally over the last decade. However, these methods have largely not been utilized within prevention or translation contexts. The purpose of this manuscript is to demonstrate the flexibility, wide applicability, and rigor of idiographic clinical trials for preliminary testing of intervention mechanisms. Specifically demonstrated are novel uses of state-space modeling for testing intervention mechanisms of short-term outcomes, identifying heterogeneity in and moderation of within-person treatment mechanisms, a horizontal line plot to refine sampling design during the course of a clinic-based experimental study, and the need to test a treatment's efficacy as treatment is administered along with (e.g., traditional 12-month outcomes).

Neurofeedback and networks of depression

PubMed Central

Linden, David E. J.

2014-01-01

Recent advances in imaging technology and in the understanding of neural circuits relevant to emotion, motivation, and depression have boosted interest and experimental work in neuromodulation for affective disorders. Real-time functional magnetic resonance imaging (fMRI) can be used to train patients in the self regulation of these circuits, and thus complement existing neurofeedback technologies based on electroencephalography (EEG). EEG neurofeedback for depression has mainly been based on models of altered hemispheric asymmetry. fMRI-based neurofeedback (fMRI-NF) can utilize functional localizer scans that allow the dynamic adjustment of the target areas or networks for self-regulation training to individual patterns of emotion processing. An initial application of fMRI-NF in depression has produced promising clinical results, and further clinical trials are under way. Challenges lie in the design of appropriate control conditions for rigorous clinical trials, and in the transfer of neurofeedback protocols from the laboratory to mobile devices to enhance the sustainability of any clinical benefits. PMID:24733975

Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy.

PubMed

Chen, Yamei; Liu, Delong

2014-01-01

As a result of the recent advances in molecular immunology, virology, genetics, and cell processing, chimeric antigen receptor (CAR)-directed cancer therapy has finally arrived for clinical application. CAR-directed adoptive immunotherapy represents a novel form of gene therapy, cellular therapy, and immunotherapy, a combination of three in one. Early phase clinical trial was reported in patients with refractory chronic lymphoid leukemia with 17p deletion. Accompanying the cytokine storm and tumor lysis syndrome was the shocking disappearance of the leukemia cells refractory to chemotherapy and monoclonal antibodies. CAR therapy was reproduced in both children and adults with refractory acute lymphoid leukemia. The CAR technology is being explored for solid tumor therapy, such as glioma. Close to 30 clinical trials are underway in the related fields (www.clinicaltrials.gov). Further improvement in gene targeting, cell expansion, delivery constructs (such as using Sleeping Beauty or Piggyback transposons) will undoubtedly enhance clinical utility. It is foreseeable that CAR-engineered T cell therapy will bring targeted cancer therapy into a new era.

The Globalization of Cooperative Groups.

PubMed

Valdivieso, Manuel; Corn, Benjamin W; Dancey, Janet E; Wickerham, D Lawrence; Horvath, L Elise; Perez, Edith A; Urton, Alison; Cronin, Walter M; Field, Erica; Lackey, Evonne; Blanke, Charles D

2015-10-01

The National Cancer Institute (NCI)-supported adult cooperative oncology research groups (now officially Network groups) have a longstanding history of participating in international collaborations throughout the world. Most frequently, the US-based cooperative groups work reciprocally with the Canadian national adult cancer clinical trial group, NCIC CTG (previously the National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the largest contributor to cooperative groups based in the United States, and vice versa. Although international collaborations have many benefits, they are most frequently utilized to enhance patient accrual to large phase III trials originating in the United States or Canada. Within the cooperative group setting, adequate attention has not been given to the study of cancers that are unique to countries outside the United States and Canada, such as those frequently associated with infections in Latin America, Asia, and Africa. Global collaborations are limited by a number of barriers, some of which are unique to the countries involved, while others are related to financial support and to US policies that restrict drug distribution outside the United States. This article serves to detail the cooperative group experience in international research and describe how international collaboration in cancer clinical trials is a promising and important area that requires greater consideration in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

The Globalization of Cooperative Groups

PubMed Central

Valdivieso, Manuel; Corn, Benjamin W.; Dancey, Janet E.; Wickerham, D. Lawrence; Horvath, L. Elise; Perez, Edith A.; Urton, Alison; Cronin, Walter M.; Field, Erica; Lackey, Evonne; Blanke, Charles D.

2015-01-01

The National Cancer Institute-supported adult cooperative oncology research groups (now officially Network groups) have a long-standing history of participating in international collaborations throughout the world. Most frequently, the U.S. based cooperative groups work reciprocally with the Canadian national adult cancer clinical trial group, NCIC CTG (previously the National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the largest contributor to cooperative groups based in the U.S., and vice versa. Although international collaborations have many benefits, they are most frequently utilized to enhance patient accrual to large phase III trials originating in the U.S. or Canada. Within the cooperative group setting, adequate attention has not been given to the study of cancers that are unique to countries outside the U.S. and Canada, such as those frequently associated with infections in Latin America, Asia and Africa. Global collaborations are limited by a number of barriers, some of which are unique to the countries involved, while others are related to financial support and to U.S. policies that restrict drug distribution outside the U.S. This manuscript serves to detail the cooperative group experience in international research and describe how international collaboration in cancer clinical trials is a promising and important area that requires greater consideration in the future. PMID:26433551

Real-time optimized biofeedback utilizing sport techniques (ROBUST): a study protocol for a randomized controlled trial.

PubMed

Taylor, Jeffrey B; Nguyen, Anh-Dung; Paterno, Mark V; Huang, Bin; Ford, Kevin R

2017-02-07

Anterior cruciate ligament (ACL) injuries in female athletes lead to a variety of short- and long-term physical, financial, and psychosocial ramifications. While dedicated injury prevention training programs have shown promise, ACL injury rates remain high as implementation has not become widespread. Conventional prevention programs use a combination of resistance, plyometric, balance and agility training to improve high-risk biomechanics and reduce the risk of injury. While many of these programs focus on reducing knee abduction load and posture during dynamic activity, targeting hip extensor strength and utilization may be more efficacious, as it is theorized to be an underlying mechanism of injury in adolescent female athletes. Biofeedback training may complement traditional preventive training, but has not been widely studied in connection with ACL injuries. We hypothesize that biofeedback may be needed to maximize the effectiveness of neuromuscular prophylactic interventions, and that hip-focused biofeedback will improve lower extremity biomechanics to a larger extent than knee-focused biofeedback during dynamic sport-specific tasks and long-term movement strategies. This is an assessor-blind, randomized control trial of 150 adolescent competitive female (9-19 years) soccer players. Each participant receives 3x/week neuromuscular preventive training and 1x/week biofeedback, the mode depending on their randomization to one of 3 biofeedback groups (hip-focused, knee-focused, sham). The primary aim is to assess the impact of biofeedback training on knee abduction moments (the primary biomechanical predictor of future ACL injury) during double-leg landings, single-leg landings, and unplanned cutting. Testing will occur immediately before the training intervention, immediately after the training intervention, and 6 months after the training intervention to assess the long-term retention of modified biomechanics. Secondary aims will assess performance changes, including hip and core strength, power, and agility, and the extent to which maturation effects biofeedback efficacy. The results of the Real-time Optimized Biofeedback Utilizing Sport Techniques (ROBUST) trial will help complement current preventive training and may lead to clinician-friendly methods of biofeedback to incorporate into widespread training practices. Date of publication in ClinicalTrials.gov: 20/04/2016. ClinicalTrials.gov Identifier: NCT02754700 .

The NIAID Division of AIDS enterprise information system: integrated decision support for global clinical research programs

PubMed Central

Gupta, Nitin; Varghese, Suresh; Virkar, Hemant

2011-01-01

The National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) Enterprise Information System (DAIDS-ES) is a web-based system that supports NIAID in the scientific, strategic, and tactical management of its global clinical research programs for HIV/AIDS vaccines, prevention, and therapeutics. Different from most commercial clinical trials information systems, which are typically protocol-driven, the DAIDS-ES was built to exchange information with those types of systems and integrate it in ways that help scientific program directors lead the research effort and keep pace with the complex and ever-changing global HIV/AIDS pandemic. Whereas commercially available clinical trials support systems are not usually disease-focused, DAIDS-ES was specifically designed to capture and incorporate unique scientific, demographic, and logistical aspects of HIV/AIDS treatment, prevention, and vaccine research in order to provide a rich source of information to guide informed decision-making. Sharing data across its internal components and with external systems, using defined vocabularies, open standards and flexible interfaces, the DAIDS-ES enables NIAID, its global collaborators and stakeholders, access to timely, quality information about NIAID-supported clinical trials which is utilized to: (1) analyze the research portfolio, assess capacity, identify opportunities, and avoid redundancies; (2) help support study safety, quality, ethics, and regulatory compliance; (3) conduct evidence-based policy analysis and business process re-engineering for improved efficiency. This report summarizes how the DAIDS-ES was conceptualized, how it differs from typical clinical trial support systems, the rationale for key design choices, and examples of how it is being used to advance the efficiency and effectiveness of NIAID's HIV/AIDS clinical research programs. PMID:21816958

Charting a Roadmap for Heart Failure Biomarker Studies

PubMed Central

Ahmad, Tariq; Fiuzat, Mona; Pencina, Michael J.; Geller, Nancy L.; Zannad, Faiez; Cleland, John G. F.; Snider, James V.; Blankenberg, Stephan; Adams, Kirkwood F.; Redberg, Rita F.; Kim, Jae B.; Mascette, Alice; Mentz, Robert J.; O'Connor, Christopher M.; Felker, G. Michael; Januzzi, James L.

2014-01-01

Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta- analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers. PMID:24929535

Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols.

PubMed

Charvet, Leigh E; Kasschau, Margaret; Datta, Abhishek; Knotkova, Helena; Stevens, Michael C; Alonzo, Angelo; Loo, Colleen; Krull, Kevin R; Bikson, Marom

2015-01-01

The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: (1) training of staff in tDCS treatment and supervision; (2) assessment of the user's capability to participate in tDCS remotely; (3) ongoing training procedures and materials including assessments of the user and/or caregiver; (4) simple and fail-safe electrode preparation techniques and tDCS headgear; (5) strict dose control for each session; (6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required; (7) monitoring for treatment-emergent adverse effects; (8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population's level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations.

The NIAID Division of AIDS enterprise information system: integrated decision support for global clinical research programs.

PubMed

Kagan, Jonathan M; Gupta, Nitin; Varghese, Suresh; Virkar, Hemant

2011-12-01

The National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) Enterprise Information System (DAIDS-ES) is a web-based system that supports NIAID in the scientific, strategic, and tactical management of its global clinical research programs for HIV/AIDS vaccines, prevention, and therapeutics. Different from most commercial clinical trials information systems, which are typically protocol-driven, the DAIDS-ES was built to exchange information with those types of systems and integrate it in ways that help scientific program directors lead the research effort and keep pace with the complex and ever-changing global HIV/AIDS pandemic. Whereas commercially available clinical trials support systems are not usually disease-focused, DAIDS-ES was specifically designed to capture and incorporate unique scientific, demographic, and logistical aspects of HIV/AIDS treatment, prevention, and vaccine research in order to provide a rich source of information to guide informed decision-making. Sharing data across its internal components and with external systems, using defined vocabularies, open standards and flexible interfaces, the DAIDS-ES enables NIAID, its global collaborators and stakeholders, access to timely, quality information about NIAID-supported clinical trials which is utilized to: (1) analyze the research portfolio, assess capacity, identify opportunities, and avoid redundancies; (2) help support study safety, quality, ethics, and regulatory compliance; (3) conduct evidence-based policy analysis and business process re-engineering for improved efficiency. This report summarizes how the DAIDS-ES was conceptualized, how it differs from typical clinical trial support systems, the rationale for key design choices, and examples of how it is being used to advance the efficiency and effectiveness of NIAID's HIV/AIDS clinical research programs.

Recruitment methods in a clinical trial of provoked vulvodynia: Predictors of enrollment.

PubMed

Bachour, Candi C; Bachmann, Gloria A; Foster, David C; Wan, Jim Y; Rawlinson, Leslie A; Brown, Candace S

2017-02-01

Successful recruitment in clinical trials for chronic pain conditions is challenging, especially in women with provoked vulvodynia due to reluctance in discussing pain associated with sexual intercourse. The most successful recruitment methods and the characteristics of women reached with these methods are unknown. To compare the effectiveness and efficiency of four recruitment methods and to determine socioeconomic predictors for successful enrollment in a National Institutes of Health-sponsored multicenter clinical trial evaluating a gabapentin intervention in women with provoked vulvodynia. Recruitment methods utilized mass mailing, media, clinician referrals and community outreach. Effectiveness (number of participants enrolled) and efficiency (proportion screened who enrolled) were determined. Socioeconomic variables including race, educational level, annual household income, relationship status, age, menopausal status and employment status were also evaluated regarding which recruitment strategies were best at targeting specific cohorts. Of 868 potential study participants, 219 were enrolled. The most effective recruitment method in enrolling participants was mass mailing ( p < 0.001). There were no statistically significant differences in efficiency between recruitment methods ( p = 0.11). Relative to clinician referral, black women were 13 times as likely to be enrolled through mass mailing (adjusted odds ratio 12.5, 95% confidence interval, 3.6-43.1) as white women. There were no differences in enrollment according to educational level, annual income, relationship status, age, menopausal status, or employment status and recruitment method. In this clinical trial, mass mailing was the most effective recruitment method. Race of participants enrolled in a provoked vulvodynia trial was related to the recruitment method.

Determination of the optimal sample size for a clinical trial accounting for the population size.

PubMed

Stallard, Nigel; Miller, Frank; Day, Simon; Hee, Siew Wan; Madan, Jason; Zohar, Sarah; Posch, Martin

2017-07-01

The problem of choosing a sample size for a clinical trial is a very common one. In some settings, such as rare diseases or other small populations, the large sample sizes usually associated with the standard frequentist approach may be infeasible, suggesting that the sample size chosen should reflect the size of the population under consideration. Incorporation of the population size is possible in a decision-theoretic approach either explicitly by assuming that the population size is fixed and known, or implicitly through geometric discounting of the gain from future patients reflecting the expected population size. This paper develops such approaches. Building on previous work, an asymptotic expression is derived for the sample size for single and two-arm clinical trials in the general case of a clinical trial with a primary endpoint with a distribution of one parameter exponential family form that optimizes a utility function that quantifies the cost and gain per patient as a continuous function of this parameter. It is shown that as the size of the population, N, or expected size, N∗ in the case of geometric discounting, becomes large, the optimal trial size is O(N1/2) or O(N∗1/2). The sample size obtained from the asymptotic expression is also compared with the exact optimal sample size in examples with responses with Bernoulli and Poisson distributions, showing that the asymptotic approximations can also be reasonable in relatively small sample sizes. © 2016 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sensitivity and specificity of a digit symbol recognition trial in the identification of response bias.

PubMed

Kim, Nancy; Boone, Kyle B; Victor, Tara; Lu, Po; Keatinge, Carolyn; Mitchell, Cary

2010-08-01

Recently published practice standards recommend that multiple effort indicators be interspersed throughout neuropsychological evaluations to assess for response bias, which is most efficiently accomplished through use of effort indicators from standard cognitive tests already included in test batteries. The present study examined the utility of a timed recognition trial added to standard administration of the WAIS-III Digit Symbol subtest in a large sample of "real world" noncredible patients (n=82) as compared with credible neuropsychology clinic patients (n=89). Scores from the recognition trial were more sensitive in identifying poor effort than were standard Digit Symbol scores, and use of an equation incorporating Digit Symbol Age-Corrected Scaled Scores plus accuracy and time scores from the recognition trial was associated with nearly 80% sensitivity at 88.7% specificity. Thus, inclusion of a brief recognition trial to Digit Symbol administration has the potential to provide accurate assessment of response bias.

Ultrasound-assisted non-viral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion

PubMed Central

Wang, Z; Zourelias, L; Wu, C; Edwards, PC; Trombetta, M; Passineau, MJ

2015-01-01

Rationale Xerostomia is a common side effect of ionizing radiation used to treat head and neck cancer. A groundbreaking Phase I human clinical trial utilizing Adenoviral gene transfer of Aquaporin-1 (AQP1) to a single salivary gland of individuals suffering from radiation-induced xerostomia has recently been reported. Unfortunately, the limitations of the Adenoviral vector system utilized in this pioneering trial preclude its advancement to a Phase II trial and we have thus undertaken to evaluate the therapeutic potential of ultrasound-assisted non-viral gene transfer (UAGT) as an alternative means of delivering AQP1 gene therapy to the salivary gland by comparing head-to-head with the canonical Adenoviral vector in a swine model. Findings Swine irradiated unilaterally with a 10Gy electron beam targeted at the parotid gland suffered from significant, sustained hyposalivation that was bilateral, despite irradiation being confined to the targeted gland. Unilateral AQP1 gene therapy with UAGT resulted in bilateral restoration of stimulated salivary flow at 48 hours and one week post-treatment (1.62+/−0.48ml, 1.87+/−0.45ml) to pre-injury levels (1.34+/−0.14ml) in a manner comparable to Adenoviral delivery (2.32+/−0.6ml, 1.33+/−0.97ml). Conclusions UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy in the irradiated swine model and is a candidate for advancement to a Phase I human clinical trial. PMID:25871828

Evaluating the role of phase I expansion cohorts in oncologic drug development.

PubMed

Norris, Robin E; Behtaj, Mohadese; Fu, Pingfu; Dowlati, Afshin

2017-02-01

Importance Use of expansion cohorts (EC) in phase I trials is increasing. However, the utility of phase I EC in aiding drug development is unclear. We sought to determine factors associated with the inclusion of EC in phase I studies and the impact of EC on subsequent clinical development. Methods We performed a systematic review of all phase I trials published in the Journal of Clinical Oncology between June 2004 and May 2014. Presence of an EC, number of participants, funding source, class of agent, tumor type, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) were identified. Subsequent conduct of phase II studies and FDA approval of the study agent was also assessed. Results We identified 252 phase I studies. An EC was included in 105 studies. Average accrual on EC studies was 47 compared to 31 in studies without EC (p < 0.0001). There was no impact of time on the inclusion of EC. Only 4 % of phase I studies with an EC provided sample size justification. Source of funding had the only significant association with inclusion of EC. Addition of a phase I EC did not impact the phase I MTD/RP2D, subsequent phase II trial, or FDA approval. Conclusion The importance of including an EC in phase I trials is subject to ongoing debate. Our results demonstrated little benefit to including EC in phase I studies. These findings support that innovative design strategies are needed to optimize the utility of EC in phase I studies.

Structure to utilize interventionists' implementation experiences of a family-based behavioral weight management program to enhance the dissemination of the standardized intervention: The TODAY study.

PubMed

Chadwick, Jennifer Q; Van Buren, Dorothy J; Morales, Elisa; Timpson, Alexandra; Abrams, Ericka L; Syme, Amy; Preske, Jeff; Mireles, Gerardo; Anderson, Barbara; Grover, Nisha; Laffel, Lori

2017-08-01

Background For a 2- to 6-year period, interventionists for the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) randomized clinical trial delivered a family-based, behavioral weight-loss program (the TODAY Lifestyle Program) to 234 youth with type 2 diabetes. Interventionists held at least a bachelor's degree in psychology, social work, education, or health-related field and had experience working with children and families, especially from diverse ethnic and socioeconomic backgrounds. This article describes the administrative and organizational structure of the lifestyle program and how the structure facilitated collaboration among study leadership and lifestyle interventionists on the tailoring of the program to best suit the needs of the trial's diverse patient population. Methods During the pilot phase and throughout the duration of the trial, the interventionists' experiences in delivering the intervention were collected in a variety of ways including membership on study committees, survey responses, session audio recordings, and feedback during in-person trainings. Results The experiences of interventionists conveyed to study leadership through these channels resulted in decisions to tailor the lifestyle intervention's delivery location and ways to supplement the standardized educational materials to better address the needs of a diverse patient population. Conclusion The methods used within the TODAY study to encourage and utilize interventionists' experiences while implementing the lifestyle program may be useful to the design of future multi-site, clinical trials seeking to tailor behavioral interventions in a standardized, and culturally and developmentally sensitive manner.

Distance management of inflammatory bowel disease: Systematic review and meta-analysis

PubMed Central

Huang, Vivian W; Reich, Krista M; Fedorak, Richard N

2014-01-01

AIM: To review the effectiveness of distance management methods in the management of adult inflammatory bowel disease (IBD) patients. METHODS: A systematic review and meta-analysis of randomized controlled trials comparing distance management and standard clinic follow-up in the management of adult IBD patients. Distance management intervention was defined as any remote management method in which there is a patient self-management component whereby the patient interacts remotely via a self-guided management program, electronic interface, or self-directs open access to clinic follow up. The search strategy included electronic databases (Medline, PubMed, CINAHL, The Cochrane Central Register of Controlled Trials, EMBASE, KTPlus, Web of Science, and SCOPUS), conference proceedings, and internet search for web publications. The primary outcome was the mean difference in quality of life, and the secondary outcomes included mean difference in relapse rate, clinic visit rate, and hospital admission rate. Study selection, data extraction, and risk of bias assessment were completed by two independent reviewers. RESULTS: The search strategy identified a total of 4061 articles, but only 6 randomized controlled trials met the inclusion and exclusion criteria for the systematic review and meta-analysis. Three trials involved telemanagement, and three trials involved directed patient self-management and open access clinics. The total sample size was 1463 patients. There was a trend towards improved quality of life in distance management patients with an end IBDQ quality of life score being 7.28 (95%CI: -3.25-17.81) points higher than standard clinic follow-up. There was a significant decrease in the clinic visit rate among distance management patients mean difference -1.08 (95%CI: -1.60--0.55), but no significant change in relapse rate or hospital admission rate. CONCLUSION: Distance management of IBD significantly decreases clinic visit utilization, but does not significantly affect relapse rates or hospital admission rates. PMID:24574756

Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

DTIC Science & Technology

2017-10-01

mRNA and has been shown in many studies to improve predictive accuracy for cancer on initial biopsy,3,7-9 and to be correlated with more aggressive... Study (PASS). We are in the process of evaluating these three biomarker panels in tissue, blood, and urine samples with well annotated clinical and...during AS. The objective of the study is to utilize analytically validated assays that take into account tumor heterogeneity to measure biomarkers in

Repeat testing of low-level HIV-1 RNA: assay performance and implementation in clinical trials.

PubMed

White, Kirsten; Garner, Will; Wei, Lilian; Eron, Joseph J; Zhong, Lijie; Miller, Michael D; Martin, Hal; Plummer, Andrew; Tran-Muchowski, Cecilia; Lindstrom, Kim; Porter, James; Piontkowsky, David; Light, Angela; Reiske, Heinz; Quirk, Erin

2018-05-15

Assess the performance of HIV-1 RNA repeat testing of stored samples in cases of low-level viremia during clinical trials. Prospective and retrospective analysis of randomized clinical trial samples and reference standards. To evaluate assay variability of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, v2.0, three separate sources of samples were utilized: the World Health Organization (WHO) HIV reference standard (assayed using 50 independent measurements at six viral loads <200 copies/ml), retrospective analysis of four to six aliquots of plasma samples from four clinical trial participants, and prospective repeat testing of 120 samples from participants in randomized trials with low-level viremia. The TaqMan assay on the WHO HIV-1 RNA standards at viral loads <200 copies/ml performed within the expected variability according to assay specifications. However, standards with low viral loads of 36 and 18 copies/ml reported values of ≥ 50 copies/ml in 66 and 18% of tests, respectively. In participants treated with antiretrovirals who had unexpected viremia of 50-200 copies/ml after achieving <50 copies/ml, retesting of multiple aliquots of stored plasma found <50 copies/ml in nearly all cases upon retesting (14/15; 93%). Repeat testing was prospectively implemented in four clinical trials for all samples with virologic rebound of 50-200 copies/ml (n = 120 samples from 92 participants) from which 42% (50/120) had a retest result of less than 50 copies/ml and 58% (70/120) retested ≥ 50 copies/ml. The TaqMan HIV-1 RNA assay shows variability around 50 copies/ml that affects clinical trial results and may impact clinical practice. In participants with a history of viral load suppression, unexpected low-level viremia may be because of assay variability rather than low drug adherence or true virologic failure. Retesting a stored aliquot of the same sample may differentiate between assay variability and virologic failure as the source of viremia. This retesting strategy could save time, money, and anxiety for patients and their providers, as well as decrease follow-up clinic visits without increasing the risk of virologic failure and resistance development.

Cognitive Behavioral Treatment for Older Adults with Generalized Anxiety Disorder: A Therapist Manual for Primary Care Settings

ERIC Educational Resources Information Center

Stanley, Melinda A.; Diefenbach, Gretchen J.; Hopko, Derek R.

2004-01-01

At least four academic clinical trials have demonstrated the utility of cognitive behavior therapy (CBT) for older adults with generalized anxiety disorder (GAD). These data may not generalize, however, to more heterogeneous and functionally impaired patients and the medical settings in which they typically receive care. A recent pilot project…

Development and Preliminary Evaluation of a One-Week Summer Treatment Program for Separation Anxiety Disorder

ERIC Educational Resources Information Center

Santucci, Lauren C.; Ehrenreich, Jill T.; Trosper, Sarah E.; Bennett, Shannon M.; Pincus, Donna B.

2009-01-01

Numerous clinical trials have demonstrated the efficacy of cognitive behavior therapy (CBT) for the treatment of childhood Separation Anxiety Disorder (SAD) and other anxiety disorders yet additional research may still be needed to better access and engage anxious youth. In this study, we investigated the acceptability and preliminary utility of a…

The national drug abuse treatment clinical trials network data share project: website design, usage, challenges, and future directions.

PubMed

Shmueli-Blumberg, Dikla; Hu, Lian; Allen, Colleen; Frasketi, Michael; Wu, Li-Tzy; Vanveldhuisen, Paul

2013-01-01

There are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the 'gold standard' for establishing treatment effectiveness, but clinical trial research is very costly, and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. We describe the goals, developments, and usage of the Data Share website (http://www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the United States, including lessons learned, limitations, and major revisions, and considerations for future directions to improve data sharing. Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. The Data Share website offers researchers easy access to de-identified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, ongoing collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses.

The National Drug Abuse Treatment Clinical Trials Network Data Share Project: Website Design, Usage, Challenges and Future Directions

PubMed Central

Shmueli-Blumberg, Dikla; Hu, Lian; Allen, Colleen; Frasketi, Michael; Wu, Li-Tzy; VanVeldhuisen, Paul

2014-01-01

Background The are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the “gold standard” for establishing treatment effectiveness, but clinical trial research is very costly and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. Purpose We describe the goals, developments, and usage of the Data Share website (www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the US, including lessons learned, limitations and major revisions and considerations for future directions to improve data sharing. Methods Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Results Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Limitations Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. Conclusions The Data Share website offers researchers easy access to deidentified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, on-going collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses. PMID:24085772

Piloting the European Unified Patient Identity Management (EUPID) Concept to Facilitate Secondary Use of Neuroblastoma Data from Clinical Trials and Biobanking.

PubMed

Ebner, Hubert; Hayn, Dieter; Falgenhauer, Markus; Nitzlnader, Michael; Schleiermacher, Gudrun; Haupt, Riccardo; Erminio, Giovanni; Defferrari, Raffaella; Mazzocco, Katia; Kohler, Jan; Tonini, Gian Paolo; Ladenstein, Ruth; Schreier, Guenter

2016-01-01

Data from two contexts, i.e. the European Unresectable Neuroblastoma (EUNB) clinical trial and results from comparative genomic hybridisation (CGH) analyses from corresponding tumour samples shall be provided to existing repositories for secondary use. Utilizing the European Unified Patient IDentity Management (EUPID) as developed in the course of the ENCCA project, the following processes were applied to the data: standardization (providing interoperability), pseudonymization (generating distinct but linkable pseudonyms for both contexts), and linking both data sources. The applied procedures resulted in a joined dataset that did not contain any identifiers that would allow to backtrack the records to either data sources. This provided a high degree of privacy to the involved patients as required by data protection regulations, without preventing proper analysis.

Traditional and innovative experimental and clinical trial designs and their advantages and pitfalls.

PubMed

Weimer, Katja; Enck, Paul

2014-01-01

Many study designs and design variants have been developed in the past to either overcome or enhance drug-placebo differences in clinical trials or to identify and characterize placebo responders in experimental studies. They share many commonalities as well as differences that are discussed here: the role of deception and ethical restrictions, habituation effects and the control of the natural course of disease, assay sensitivity testing and effective blinding, acceptability and motivation of patients and volunteers, and the development of individualized medicine. These are fostered by two opposite strategies: utilizing the beneficial aspects of the placebo response-and avoiding its negative counterpart, the nocebo effect-in medical routine for the benefit of patients, and minimizing-by controlling-the negative aspects of the placebo effect during drug development.

Immunotherapy for drug abuse.

PubMed

Shen, Xiaoyun; Kosten, Thomas R

2011-12-01

Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use.

A Paradox-based data collection and management system for multi-center randomized clinical trials.

PubMed

Abdellatif, Mazen; Reda, Domenic J

2004-02-01

We have developed a Paradox-based data collection and management system for large-scale multi-site randomized clinical trials. The system runs under Windows operating system and integrates Symantec pcAnywhere32 telecommunications software for data transmission and remote control sessions, PKZIP utility for the compression/decompression of transmitted data, and Stat/Transfer for exporting the centralized Paradox database for analyses. We initially developed this system for VA Cooperative Study #399 'The Effect of Antiarrhythmic Therapy in Maintaining Stability of Sinus Rhythm in Atrial Fibrillation', which collects over 1000 variables on 706 patients at 20 sites. Patient intake for this 5-year study began in March of 1998. We have also developed an enhanced version of this system, which is being used in the NIH-funded 'Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)' that collects over 1200 variables on 1588 patients at 13 sites. Patient intake for this 4-year study began in October of 2000.

Advancing tuberculosis drug regimen development through innovative quantitative translational pharmacology methods and approaches.

PubMed

Hanna, Debra; Romero, Klaus; Schito, Marco

2017-03-01

The development of novel tuberculosis (TB) multi-drug regimens that are more efficacious and of shorter duration requires a robust drug development pipeline. Advances in quantitative modeling and simulation can be used to maximize the utility of patient-level data from prior and contemporary clinical trials, thus optimizing study design for anti-TB regimens. This perspective article highlights the work of seven project teams developing first-in-class translational and quantitative methodologies that aim to inform drug development decision-making, dose selection, trial design, and safety assessments, in order to achieve shorter and safer therapies for patients in need. These tools offer the opportunity to evaluate multiple hypotheses and provide a means to identify, quantify, and understand relevant sources of variability, to optimize translation and clinical trial design. When incorporated into the broader regulatory sciences framework, these efforts have the potential to transform the development paradigm for TB combination development, as well as other areas of global health. Copyright © 2016. Published by Elsevier Ltd.

Statistical analysis plan for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). A randomized controlled trial

PubMed Central

Damiani, Lucas Petri; Berwanger, Otavio; Paisani, Denise; Laranjeira, Ligia Nasi; Suzumura, Erica Aranha; Amato, Marcelo Britto Passos; Carvalho, Carlos Roberto Ribeiro; Cavalcanti, Alexandre Biasi

2017-01-01

Background The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) is an international multicenter randomized pragmatic controlled trial with allocation concealment involving 120 intensive care units in Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay. The primary objective of ART is to determine whether maximum stepwise alveolar recruitment associated with PEEP titration, adjusted according to the static compliance of the respiratory system (ART strategy), is able to increase 28-day survival in patients with acute respiratory distress syndrome compared to conventional treatment (ARDSNet strategy). Objective To describe the data management process and statistical analysis plan. Methods The statistical analysis plan was designed by the trial executive committee and reviewed and approved by the trial steering committee. We provide an overview of the trial design with a special focus on describing the primary (28-day survival) and secondary outcomes. We describe our data management process, data monitoring committee, interim analyses, and sample size calculation. We describe our planned statistical analyses for primary and secondary outcomes as well as pre-specified subgroup analyses. We also provide details for presenting results, including mock tables for baseline characteristics, adherence to the protocol and effect on clinical outcomes. Conclusion According to best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and beginning analyses. We anticipate that this document will prevent analysis bias and enhance the utility of the reported results. Trial registration ClinicalTrials.gov number, NCT01374022. PMID:28977255

Identifying components in consent information needed to support informed decision making about trial participation: An interview study with women managing cancer.

PubMed

Abhyankar, Purva; Velikova, Galina; Summers, Barbara; Bekker, Hilary L

2016-07-01

Research governance requires patients give informed consent to participate in clinical trials. However, there are concerns that consent information may not support patient participation decisions. This study investigates the utility of consent information in supporting women's trial participation decisions when receiving treatment for cancer. An interview study with women receiving cancer treatments at a medical oncology outpatient clinic in Yorkshire (UK). All women over 18 years, not admitted to a hospital ward and who had currently or previously been invited to take part in a trial were invited to take part in the study over a three month period. Interviews were audio-tape recorded, transcribed and analysed using thematic analysis. Of those eligible (n = 41), 21 women with breast (n = 11), ovarian (n = 8) and endometrial (n = 2) cancer participated (mean age = 57 years). Eighteen had made at least one trial decision and three were considering taking part in a trial. Findings are synthesised under two analytical themes: 1) Influence of the cancer and cancer treatment context on decision making for trial participation; and 2) Experiences of the consenting process and their influence on decision making. Designing trial information to represent explicitly the trial participation decision as being between standard care and study-related care options is more likely to effectively support patients in making informed decisions between standard care treatments and taking part in a trial. Copyright © 2016 Elsevier Ltd. All rights reserved.

Opioid Analgesics Administered for Pain in the Inpatient Pediatric Setting.

PubMed

Walco, Gary A; Gove, Nancy; Phillips, Jennifer; Weisman, Steven J

2017-10-01

This study aimed to describe utilization of opioid medications among infants, children, and adolescents on the inpatient setting. These data are needed to guide clinical trials and improve research methodologies, as well as to inform more about possible sources of opioid misuse in the United States. A retrospective chart review was conducted covering a span of 1 year, with a special focus on the prescription of opioids for long-term treatment of chronic pain. Opioid medications were prescribed for <5 days in most (75%) patients. Among those who were prescribed opioids for >14 days, the focus was often for reasons other than pain. These data indicate that models of chronic pain that may be utilized in clinical trials of longer-term opioid usage in pediatrics are exceedingly limited. In addition, the patterns of utilization indicate that opioid administration among pediatric inpatients is not a likely contributory factor to concerns about opioid misuse in the United States. This article presents data on the administration of opioids in a major children's hospital, with a special eye toward usage beyond treatment for short-term acute pain. These data are important to better inform discussions of research strategies for chronic pain, as well as concerns for misuse in the pediatric population. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke

PubMed Central

Shireman, Theresa I.; Wang, Kaijun; Saver, Jeffrey L.; Goyal, Mayank; Bonafé, Alain; Diener, Hans-Christoph; Levy, Elad I.; Pereira, Vitor M.; Albers, Gregory W.; Cognard, Christophe; Hacke, Werner; Jansen, Olav; Jovin, Tudor G.; Mattle, Heinrich P.; Nogueira, Raul G.; Siddiqui, Adnan H.; Yavagal, Dileep R.; Devlin, Thomas G.; Lopes, Demetrius K.; Reddy, Vivek K.; de Rochemont, Richard du Mesnil; Jahan, Reza; Vilain, Katherine A.; House, John; Lee, Jin-Moo; Cohen, David J.

2017-01-01

Background and Purpose Clinical trials have demonstrated improved 90-day outcomes for patients with acute ischemic stroke treated with stent retriever thrombectomy plus tissue-type plasminogen activator (SST+tPA) compared with tPA. Previous studies suggested that this strategy may be cost-effective, but models were derived from pooled data and older assumptions. Methods In this prospective economic substudy conducted alongside the SWIFT-PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), in-trial costs were measured for patients using detailed medical resource utilization and hospital billing data. Utility weights were assessed at 30 and 90 days using the EuroQol-5 dimension questionnaire. Post-trial costs and life-expectancy were estimated for each surviving patient using a model based on trial data and inputs derived from a contemporary cohort of ischemic stroke survivors. Results Index hospitalization costs were $17 183 per patient higher for SST+tPA than for tPA ($45 761 versus $28 578; P<0.001), driven by initial procedure costs. Between discharge and 90 days, costs were $4904 per patient lower for SST+tPA than for tPA ($11 270 versus $16 174; P=0.014); total 90-day costs remained higher with SST+tPA ($57 031 versus $44 752; P<0.001). Higher utility values for SST+tPA led to higher in-trial quality-adjusted life years (0.131 versus 0.105; P=0.005). In lifetime projections, SST+tPA was associated with substantial gains in quality-adjusted life years (6.79 versus 5.05), cost savings of $23 203 per patient and was economically dominant when compared with tPA in 90% of bootstrap replicates. Conclusions Among patients with acute ischemic stroke enrolled in the SWIFT-PRIME trial, SST increased initial treatment costs, but was projected to improve quality-adjusted life-expectancy and reduce healthcare costs over a lifetime horizon compared with tPA. PMID:28028150

Treatment of Post-Traumatic Stress Disorder Nightmares at a Veterans Affairs Medical Center

PubMed Central

Detweiler, Mark B.; Pagadala, Bhuvaneshwar; Candelario, Joseph; Boyle, Jennifer S.; Detweiler, Jonna G.; Lutgens, Brian W.

2016-01-01

The effectiveness of medications for PTSD in general has been well studied, but the effectiveness of medicatio.ns prescribed specifically for post-traumatic stress disorder (PTSD) nightmares is less well known. This retrospective chart review examined the efficacy of various medications used in actual treatment of PTSD nightmares at one Veteran Affairs Hospital. Records at the Salem, VA Veterans Affairs Medical Center (VAMC) were examined from 2009 to 2013 to check for the efficacy of actual treatments used in comparis.on with treatments suggested in three main review articles. The final sample consisted of 327 patients and 478 separate medication trials involving 21 individual medications plus 13 different medication combinations. The three most frequently utilized medications were prazosin (107 trials), risperidone (81 trials), and quetiapine (72 trials). Five medications had 20 or more trials with successful results (partial to full nightmare cessation) in >50% of trials: risperidone (77%, 1.0–6.0 mg), clonidine (63%, 0.1–2.0 mg), quetiapine (50%, 12.5–800.0 mg), mirtazapine (50%; 7.5–30.0 mg), and terazosin (64%, 50.0–300.0 mg). Notably, olanzapine (2.5–10.0) was successful (full remission) in all five prescription trials in five separate patients. Based on the clinical results, the use of risperidone, clonidine, terazosin, and olanzapine warrants additional investigation in clinically controlled trials as medications prescribed specifically for PTSD nightmares. PMID:27999253

Glucosamine for the Treatment of Osteoarthritis: The Time Has Come for Higher-Dose Trials.

PubMed

McCarty, Mark F; O'Keefe, James H; DiNicolantonio, James J

2018-04-18

Although clinical trials with glucosamine in osteoarthritis have yielded mixed results, leading to doubts about its efficacy, the utility of glucosamine for preventing joint destruction and inflammation is well documented in rodent models of arthritis, including models of spontaneous osteoarthritis. The benefit of oral glucosamine in adjuvant arthritis is markedly dose dependent, likely reflecting a modulation of tissue levels of UDP-N-acetylglucosamine that in turn influences mucopolysaccharide synthesis and the extent of protein O-GlcNAcylation. Importantly, the minimal oral dose of glucosamine that exerts a detectible benefit in adjuvant arthritis achieves plasma glucosamine levels similar to those achieved when the standard clinical dose of glucosamine, 1.5 g daily, is administered as a bolus. The response of plasma glucosamine levels to an increase in glucosamine intake is nearly linear. Remarkably, every published clinical trial with glucosamine has employed the same 1.5 g dose that Rottapharm recommended for its proprietary glucosamine sulfate product decades ago, yet there has never been any published evidence that this dose is optimal with respect to efficacy and side effects. If this dose is on the edge of demonstrable clinical efficacy when experimental design is ideal, then variations in the patient populations targeted, the assessment vehicles employed, and the potency of glucosamine preparations tested could be expected to yield some null results. Failure to employ bolus dosing may also be a factor in the null results observed in the GAIT study and other trials. Clinical studies evaluating the dose dependency of glucosamine's influence on osteoarthritis are long overdue.

Rare cancers: Challenges & issues.

PubMed

Pillai, Raveendran K; Jayasree, K

2017-01-01

Rare cancers account for about 22 per cent of all cancers diagnosed worldwide, disproportionately affecting some demographic groups, with an occurrence of less than 6 per 100,000 individuals annually. Many rare cancers in adults, adolescents and children are not curable, and patients and care providers have little option to take therapeutic decisions. The epidemiology of rare cancers is a challenging area of study but is inadequately addressed. Despite efforts mainly in some European nations, a few improvements have been observed in the management of rare cancers. Reasons for this obvious stagnation are multifactorial and are mainly inherent to logistical difficulties in carrying out clinical trials in very small patient populations, hesitation of the pharmaceutical industry to spend in small markets and complexity in creating adequate information for the development of cost-effective drugs. Rare cancers also face specific challenges that include late and incorrect diagnosis, lack of clinical expertise and lack of research interest and development of new therapies. The utilization of nationally representative study findings for the patients' evaluation may possibly offer chances to find out pathogenesis and prevalence, and this will eventually lead to control and prevention. Currently, advancing targeted therapies offer a great opportunity for the better management of rare cancers. Conducting clinical trials with small patient population, innovative clinical trial approach, prevailing controlling obstacles for international cooperation and financial support for research are the present challenges for rare cancers. The International Rare Cancers Initiative functions as a main platform for achieving new international clinical trials in rare tumours. This review delineates the current challenges and issues in the interpretation, management and research scenarios of rare cancers.

Rare cancers: Challenges & issues

PubMed Central

Pillai, Raveendran K.; Jayasree, K.

2017-01-01

Rare cancers account for about 22 per cent of all cancers diagnosed worldwide, disproportionately affecting some demographic groups, with an occurrence of less than 6 per 100,000 individuals annually. Many rare cancers in adults, adolescents and children are not curable, and patients and care providers have little option to take therapeutic decisions. The epidemiology of rare cancers is a challenging area of study but is inadequately addressed. Despite efforts mainly in some European nations, a few improvements have been observed in the management of rare cancers. Reasons for this obvious stagnation are multifactorial and are mainly inherent to logistical difficulties in carrying out clinical trials in very small patient populations, hesitation of the pharmaceutical industry to spend in small markets and complexity in creating adequate information for the development of cost-effective drugs. Rare cancers also face specific challenges that include late and incorrect diagnosis, lack of clinical expertise and lack of research interest and development of new therapies. The utilization of nationally representative study findings for the patients’ evaluation may possibly offer chances to find out pathogenesis and prevalence, and this will eventually lead to control and prevention. Currently, advancing targeted therapies offer a great opportunity for the better management of rare cancers. Conducting clinical trials with small patient population, innovative clinical trial approach, prevailing controlling obstacles for international cooperation and financial support for research are the present challenges for rare cancers. The International Rare Cancers Initiative functions as a main platform for achieving new international clinical trials in rare tumours. This review delineates the current challenges and issues in the interpretation, management and research scenarios of rare cancers. PMID:28574010

Guideline harmonization and implementation plan for the BETTER trial: Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice

PubMed Central

Rogers, Jess; Manca, Donna; Lang-Robertson, Kelly; Bell, Stephanie; Salvalaggio, Ginetta; Greiver, Michelle; Korownyk, Christina; Klein, Doug; Carroll, June C.; Kahan, Mel; Meuser, Jamie; Buchman, Sandy; Barrett, Rebekah M.; Grunfeld, Eva

2014-01-01

Background The aim of the Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice (BETTER) randomized controlled trial is to improve the primary prevention of and screening for multiple conditions (diabetes, cardiovascular disease, cancer) and some of the associated lifestyle factors (tobacco use, alcohol overuse, poor nutrition, physical inactivity). In this article, we describe how we harmonized the evidence-based clinical practice guideline recommendations and patient tools to determine the content for the BETTER trial. Methods We identified clinical practice guidelines and tools through a structured literature search; we included both indexed and grey literature. From these guidelines, recommendations were extracted and integrated into knowledge products and outcome measures for use in the BETTER trial. End-users (family physicians, nurse practitioners, nurses and dieticians) were engaged in reviewing the recommendations and tools, as well as tailoring the content to the needs of the BETTER trial and family practice. Results In total, 3–5 high-quality guidelines were identified for each condition; from these, we identified high-grade recommendations for the prevention of and screening for chronic disease. The guideline recommendations were limited by conflicting recommendations, vague wording and different taxonomies for strength of recommendation. There was a lack of quality evidence for manoeuvres to improve the uptake of guidelines among patients with depression. We developed the BETTER clinical algorithms for the implementation plan. Although it was difficult to identify high-quality tools, 180 tools of interest were identified. Interpretation The intervention for the BETTER trial was built by integrating existing guidelines and tools, and working with end-users throughout the process to increase the intervention’s utility for practice. Trial registration: ISRCTN07170460 PMID:25077119

Singapore Tele-technology Aided Rehabilitation in Stroke (STARS) trial: protocol of a randomized clinical trial on tele-rehabilitation for stroke patients.

PubMed

Koh, Gerald Choon-Huat; Yen, Shih Cheng; Tay, Arthur; Cheong, Angela; Ng, Yee Sien; De Silva, Deidre Anne; Png, Carolina; Caves, Kevin; Koh, Karen; Kumar, Yogaprakash; Phan, Shi Wen; Tai, Bee Choo; Chen, Cynthia; Chew, Effie; Chao, Zhaojin; Chua, Chun En; Koh, Yen Sin; Hoenig, Helen

2015-09-05

Most acute stroke patients with disabilities do not receive recommended rehabilitation following discharge to the community. Functional and social barriers are common reasons for non-adherence to post-discharge rehabilitation. Home rehabilitation is an alternative to centre-based rehabilitation but is costlier. Tele-rehabilitation is a possible solution, allowing for remote supervision of rehabilitation and eliminating access barriers. The objective of the Singapore Tele-technology Aided Rehabilitation in Stroke (STARS) trial is to determine if a novel tele-rehabilitation intervention for the first three months after stroke admission improves functional recovery compared to usual care. This is a single blind (evaluator blinded), parallel, two-arm randomised controlled trial study design involving 100 recent stroke patients. The inclusion criteria are age ≥40 years, having caregiver support and recent stroke defined as stroke diagnosis within 4 weeks. Consenting participants will be randomized with varying block size of 4 or 6 assuming a 1:1 treatment allocation with the participating centre as the stratification factor. The baseline assessment will be done within 4 weeks of stroke onset, followed by follow-up assessments at 3 and 6 months. The tele-rehabilitation intervention lasts for 3 months and includes exercise 5-days-a-week using an iPad-based system that allows recording of daily exercise with video and sensor data and weekly video-conferencing with tele-therapists after data review. Those allocated to the control group will receive usual care. The primary outcome measure is improvement in life task's social activity participation at three months as measured by the disability component of the Jette Late Life Functional and Disability Instrument (LLFDI). Secondary outcome variables consist of gait speed (Timed 5-Meter Walk Test) and endurance (Two-Minute Walk test), performance of basic activities of daily living (Shah-modified Barthel Index), balance confidence (Activities-Specific Balance Confidence Scale), patient self-reported health-related quality-of-life [Euro-QOL (EQ-5D)], health service utilization (Singapore Stroke Study Health Service Utilization Form) and caregiver reported stress (Zarit Caregiver Burden Inventory). The goal of this trial is to provide evidence on the potential benefit and cost-effectiveness of this novel tele-rehabilitation programme which will guide health care decision-making and potentially improve performance of post-stroke community-based rehabilitation. This trial protocol was registered under ClinicalTrials.gov on 18 July 2013 as study title "The Singapore Tele-technology Aided Rehabilitation in Stroke (STARS) Study" (ID: The STARS Study, ClinicalTrials.gov Identifier: NCT01905917 ).

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study

PubMed Central

2014-01-01

Background The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Methods Adults (n = 198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n = 101) or matching placebo lozenges (n = 97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Results Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P <0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P <0.01). There were no serious adverse events. Conclusions Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. Trial registration This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010. PMID:24988909

Oral administration of French maritime pine bark extract (Flavangenol(®)) improves clinical symptoms in photoaged facial skin.

PubMed

Furumura, Minao; Sato, Noriko; Kusaba, Nobutaka; Takagaki, Kinya; Nakayama, Juichiro

2012-01-01

French maritime pine bark extract (PBE) has gained popularity as a dietary supplement in the treatment of various diseases due to its polyphenol-rich ingredients. Oligometric proanthocyanidins (OPCs), a class of bioflavonoid complexes, are enriched in French maritime PBE and have antioxidant and anti-inflammatory activity. Previous studies have suggested that French maritime PBE helps reduce ultraviolet radiation damage to the skin and may protect human facial skin from symptoms of photoaging. To evaluate the clinical efficacy of French maritime PBE in the improvement of photodamaged facial skin, we conducted a randomized trial of oral supplementation with PBE. One hundred and twelve women with mild to moderate photoaging of the skin were randomized to either a 12-week open trial regimen of 100 mg PBE supplementation once daily or to a parallel-group trial regimen of 40 mg PBE supplementation once daily. A significant decrease in clinical grading of skin photoaging scores was observed in both time courses of 100 mg daily and 40 mg daily PBE supplementation regimens. A significant reduction in the pigmentation of age spots was also demonstrated utilizing skin color measurements. Clinically significant improvement in photodamaged skin could be achieved with PBE. Our findings confirm the efficacy and safety of PBE.

Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR).

PubMed

Evans, Scott R; Rubin, Daniel; Follmann, Dean; Pennello, Gene; Huskins, W Charles; Powers, John H; Schoenfeld, David; Chuang-Stein, Christy; Cosgrove, Sara E; Fowler, Vance G; Lautenbach, Ebbing; Chambers, Henry F

2015-09-01

Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The efficacy of low-level laser treatment in reducing pain and swelling after endodontic surgery: a systematic review

NASA Astrophysics Data System (ADS)

Moshari, Amirabbas; Vatanpour, Mehdi; Zakershahrak, Mehrsa

2016-03-01

Introduction: LLLT in oral cavity believed to reduce pain after endodontic surgery and wisdom tooth removal, to accelerate wound healing and to have an anti-inflammatory and regenerative effect. The aim of this systematic review therefore was to assess the proof available for the efficacy of low-level laser treatment in reducing pain and swelling after endodontic surgery. Methods: The PubMed service of the U.S. National Library of Medicine was searched with applicable search strategies. No language restriction was applied. The last electronic search was accomplished on August 31, 2015. All randomized clinical trials on the efficiency of low-level laser treatment in reducing pain and swelling after endodontic surgery was considered for the Meta-analysis. Quality consideration of the included randomized clinical trials was appraised according to CONSORT guidelines. Results: Only two randomized clinical trials were attained. These studies clarified that laser treatment could reduce pain and swelling, but the results were not significant. Conclusions: Low-level laser therapy can be advantageous for the reduction of postoperative pain but there is no strong confirmation for its efficiency. Its clinical utility and applicability relating to endodontic surgery, Along with the optimal energy dosage and the number of laser treatments needed after surgery, still, demand further research and experiment.

Design innovations and baseline findings in a long-term Parkinson’s trial: NET-PD LS-1

PubMed Central

2012-01-01

Background Based on the pre-clinical and the results of a phase 2 futility study, creatine was selected for an efficacy trial in Parkinson’s disease (PD). We present the design rationale and a description of the study cohort at baseline. Methods A randomized, multicenter, double-blind, parallel group, placebo controlled Phase 3 study of creatine (10 gm daily) in participants with early, treated PD, the Long-term Study – 1 (LS-1) is being conducted by the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network. The study utilizes a global statistical test (GST) encompassing multiple clinical rating scales to provide a multidimensional assessment of disease progression. Results A total of 1,741 PD participants from 45 sites in the U.S. and Canada were randomized 1:1 to either 10-gm creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS-1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. Conclusions LS-1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit against the background of dopaminergic therapy and best PD care. PMID:23079770

CARs in Chronic Lymphocytic Leukemia – Ready to Drive

PubMed Central

Wierda, William; Jena, Bipulendu; Cooper, Laurence J. N.; Shpall, Elizabeth

2013-01-01

Adoptive transfer of antigen-specific T cells has been adapted by investigators for treatment of chronic lymphocytic leukemia (CLL). To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens (TAAs), robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve potency. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, these early-phase trials are demonstrating impressive anti-tumor effects, particularly for CLL patients, paving the way for multi-center trials to establish the efficacy of CAR+ T cell therapy. PMID:23225251

Bayesian randomized clinical trials: From fixed to adaptive design.

PubMed

Yin, Guosheng; Lam, Chi Kin; Shi, Haolun

2017-08-01

Randomized controlled studies are the gold standard for phase III clinical trials. Using α-spending functions to control the overall type I error rate, group sequential methods are well established and have been dominating phase III studies. Bayesian randomized design, on the other hand, can be viewed as a complement instead of competitive approach to the frequentist methods. For the fixed Bayesian design, the hypothesis testing can be cast in the posterior probability or Bayes factor framework, which has a direct link to the frequentist type I error rate. Bayesian group sequential design relies upon Bayesian decision-theoretic approaches based on backward induction, which is often computationally intensive. Compared with the frequentist approaches, Bayesian methods have several advantages. The posterior predictive probability serves as a useful and convenient tool for trial monitoring, and can be updated at any time as the data accrue during the trial. The Bayesian decision-theoretic framework possesses a direct link to the decision making in the practical setting, and can be modeled more realistically to reflect the actual cost-benefit analysis during the drug development process. Other merits include the possibility of hierarchical modeling and the use of informative priors, which would lead to a more comprehensive utilization of information from both historical and longitudinal data. From fixed to adaptive design, we focus on Bayesian randomized controlled clinical trials and make extensive comparisons with frequentist counterparts through numerical studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Cost-Effectiveness of Internet-Based Cognitive-Behavioral Treatment for Bulimia Nervosa: Results of a Randomized Controlled Trial.

PubMed

Watson, Hunna J; McLagan, Nicole; Zerwas, Stephanie C; Crosby, Ross D; Levine, Michele D; Runfola, Cristin D; Peat, Christine M; Moessner, Markus; Zimmer, Benjamin; Hofmeier, Sara M; Hamer, Robert M; Marcus, Marsha D; Bulik, Cynthia M; Crow, Scott J

To evaluate the cost-effectiveness of Internet-based cognitive-behavioral therapy for bulimia nervosa (CBT-BN) compared to face-to-face delivery of CBT-BN. This study is a planned secondary analysis of data from a randomized clinical trial. Participants were 179 adults (98% female, mean age = 28 years) meeting DSM-IV criteria for bulimia nervosa who were randomized to group face-to-face or group Internet-based CBT-BN for 16 sessions during 20 weeks. The cost-effectiveness analysis was conducted from a third-party payor perspective, and a partial societal perspective analysis was conducted to investigate cost-utility (ie, cost per gain in quality-adjusted life-years) and patient out-of-pocket travel-related costs. Net health care costs were calculated from protocol and nonprotocol health care services using third-party payor cost estimates. The primary outcome measure in the clinical trial was abstinence from binge eating and purging, and the trial start and end dates were 2008 and 2016. The mean cost per abstinent patient at posttreatment was $7,757 (95% confidence limit [CL], $4,515, $13,361) for face-to-face and $11,870 (95% CL, $6,486, $22,188) for Internet-based CBT-BN, and at 1-year follow-up was $16,777 (95% CL, $10,298, $27,042) for face-to-face and $14,561 (95% CL, $10,165, $21,028) for Internet-based CBT-BN. There were no statistically significant differences between treatment arms in cost-effectiveness or cost-utility at posttreatment or 1-year follow-up. Out-of-pocket patient costs were significantly higher for face-to-face (mean [95% CL] = $178 [$127, $140]) than Internet-based ($50 [$50, $50]) therapy. Third-party payor cost-effectiveness of Internet-based CBT-BN is comparable with that of an accepted standard. Internet-based dissemination of CBT-BN may be a viable alternative for patients geographically distant from specialist eating disorder services who have an unmet need for treatment. ClinicalTrials.gov identifier: NCT00877786​. © Copyright 2017 Physicians Postgraduate Press, Inc.

Quality of life research in endometrial cancer: what is needed to advance progress in this disease site? Methodological considerations from the Gynecologic Cancer InterGroup Symptom Benefit Working Group brainstorming session, Leiden 2012.

PubMed

McAlpine, Jessica N; Greimel, Elfriede; Brotto, Lori A; Nout, Remy A; Shash, Emad; Avall-Lundqvist, Elisabeth; Friedlander, Michael L; Joly, Florence

2014-11-01

Quality of life (QoL) in endometrial cancer (EC) is understudied. Incorporation of QoL questionnaires and patient-reported outcomes in clinical trials has been inconsistent, and the tools and interpretation of these measures are unfamiliar to most practitioners. In 2012, the Gynecologic Cancer InterGroup Symptom Benefit Working Group convened for a brainstorming collaborative session to address deficiencies and work toward improving the quality and quantity of QoL research in women with EC. Through literature review and international expert contributions, we compiled a comprehensive appraisal of current generic and disease site-specific QoL assessment tools, strengths and weaknesses of these measures, assessment of sexual health, statistical considerations, and an exploration of the unique array of histopathologic and clinical factors that may influence QoL outcomes in women with EC. This collaborative composition is the first publication specific to EC that addresses methodology in QoL research and the components necessary to achieve high quality QoL data in clinical trials. Future recommendations regarding (1) the incorporation of patient-reported outcomes in all clinical trials in EC, (2) definition of an a priori hypothesis, (3) utilization of validated tools and consideration of new tools corresponding to new therapies or specific symptoms, (4) publication within the same time frame as clinical outcome data, and (5) attempt to correct for disease site-specific potential confounders are presented. Improved understanding of methodology in QoL research and an increased undertaking of EC-specific QoL research in clinical trials are imperative if we are to improve outcomes in women with EC.

Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design.

PubMed

Cho, Alex H; Killeya-Jones, Ley A; O'Daniel, Julianne M; Kawamoto, Kensaku; Gallagher, Patrick; Haga, Susanne; Lucas, Joseph E; Trujillo, Gloria M; Joy, Scott V; Ginsburg, Geoffrey S

2012-01-18

Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), or the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care. ClinicalTrials.gov: NCT00849563.

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.

Gene Therapy and Targeted Toxins for Glioma

PubMed Central

Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

2011-01-01

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

Subregional neuroanatomical change as a biomarker for Alzheimer's disease

PubMed Central

Holland, Dominic; Brewer, James B.; Hagler, Donald J.; Fennema-Notestine, Christine; Dale, Anders M.; Weiner, Michael; Thal, Leon; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Gamst, Anthony; Potter, William Z.; Montine, Tom; Anders, Dale; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Shaw, Les; Lee, Virginia M.-Y.; Korecka, Magdalena; Crawford, Karen; Neu, Scott; Harvey, Danielle; Kornak, John; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Vorobik, Remi; Quinn, Joseph; Schneider, Lon; Pawluczyk, Sonia; Spann, Bryan; Fleisher, Adam S.; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Badger, Beverly; Grossman, Hillel; Tang, Cheuk; Stern, Jessica; deToledo-Morrell, Leyla; Shah, Raj C.; Bach, Julie; Duara, Ranjan; Isaacson, Richard; Strauman, Silvia; Albert, Marilyn S.; Pedroso, Julia; Toroney, Jaimie; Rusinek, Henry; de Leon, Mony J.; De Santi, Susan M.; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Aiello, Marilyn; Clark, Christopher M.; Pham, Cassie; Nunez, Jessica; Smith, Charles D.; Given, Curtis A.; Hardy, Peter; DeKosky, Steven T.; Oakley, MaryAnn; Simpson, Donna M.; Ismail, M. Saleem; Porsteinsson, Anton; McCallum, Colleen; Cramer, Steven C.; Mulnard, Ruth A.; McAdams-Ortiz, Catherine; Diaz-Arrastia, Ramon; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Laubinger, Mary M.; Bartzokis, George; Silverman, Daniel H. S.; Lu, Po H.; Fletcher, Rita; Parfitt, Francine; Johnson, Heather; Farlow, Martin; Herring, Scott; Hake, Ann M.; van Dyck, Christopher H.; MacAvoy, Martha G.; Bifano, Laurel A.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Graham, Simon; Caldwell, Curtis; Feldman, Howard; Assaly, Michele; Hsiung, Ging-Yuek R.; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Gitelman, Darren; Johnson, Nancy; Mesulam, Marsel; Sadowsky, Carl; Villena, Teresa; Mesner, Scott; Aisen, Paul S.; Johnson, Kathleen B.; Behan, Kelly E.; Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.; Rosen, Allyson; Tinklenberg, Jared; Ashford, Wes; Sabbagh, Marwan; Connor, Donald; Obradov, Sanja; Killiany, Ron; Norbash, Alex; Obisesan, Thomas O.; Jayam-Trouth, Annapurni; Wang, Paul; Auchus, Alexander P.; Huang, Juebin; Friedland, Robert P.; DeCarli, Charles; Fletcher, Evan; Carmichael, Owen; Kittur, Smita; Mirje, Seema; Johnson, Sterling C.; Borrie, Michael; Lee, T.-Y.; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Highum, Diane; Preda, Adrian; Nguyen, Dana; Tariot, Pierre N.; Hendin, Barry A.; Scharre, Douglas W.; Kataki, Maria; Beversdorf, David Q.; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Gandy, Sam; Marenberg, Marjorie E.; Rovner, Barry W.; Pearlson, Godfrey; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Pare, Nadia; Williamson, Jeff D.; Sink, Kaycee M.; Potter, Huntington; Ashok Raj, B.; Giordano, Amy; Ott, Brian R.; Wu, Chuang-Kuo; Cohen, Ronald; Wilks, Kerri L.; Safirstein, Beth E.

2009-01-01

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease. PMID:19996185

Subregional neuroanatomical change as a biomarker for Alzheimer's disease.

PubMed

Holland, Dominic; Brewer, James B; Hagler, Donald J; Fennema-Notestine, Christine; Fenema-Notestine, Christine; Dale, Anders M

2009-12-08

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.

The normalization heuristic: an untested hypothesis that may misguide medical decisions.

PubMed

Aberegg, Scott K; O'Brien, James M

2009-06-01

Medical practice is increasingly informed by the evidence from randomized controlled trials. When such evidence is not available, clinical hypotheses based on pathophysiological reasoning and common sense guide clinical decision making. One commonly utilized general clinical hypothesis is the assumption that normalizing abnormal laboratory values and physiological parameters will lead to improved patient outcomes. We refer to the general use of this clinical hypothesis to guide medical therapeutics as the "normalization heuristic". In this paper, we operationally define this heuristic and discuss its limitations as a rule of thumb for clinical decision making. We review historical and contemporaneous examples of normalization practices as empirical evidence for the normalization heuristic and to highlight its frailty as a guide for clinical decision making.

Information mining over heterogeneous and high-dimensional time-series data in clinical trials databases.

PubMed

Altiparmak, Fatih; Ferhatosmanoglu, Hakan; Erdal, Selnur; Trost, Donald C

2006-04-01

An effective analysis of clinical trials data involves analyzing different types of data such as heterogeneous and high dimensional time series data. The current time series analysis methods generally assume that the series at hand have sufficient length to apply statistical techniques to them. Other ideal case assumptions are that data are collected in equal length intervals, and while comparing time series, the lengths are usually expected to be equal to each other. However, these assumptions are not valid for many real data sets, especially for the clinical trials data sets. An addition, the data sources are different from each other, the data are heterogeneous, and the sensitivity of the experiments varies by the source. Approaches for mining time series data need to be revisited, keeping the wide range of requirements in mind. In this paper, we propose a novel approach for information mining that involves two major steps: applying a data mining algorithm over homogeneous subsets of data, and identifying common or distinct patterns over the information gathered in the first step. Our approach is implemented specifically for heterogeneous and high dimensional time series clinical trials data. Using this framework, we propose a new way of utilizing frequent itemset mining, as well as clustering and declustering techniques with novel distance metrics for measuring similarity between time series data. By clustering the data, we find groups of analytes (substances in blood) that are most strongly correlated. Most of these relationships already known are verified by the clinical panels, and, in addition, we identify novel groups that need further biomedical analysis. A slight modification to our algorithm results an effective declustering of high dimensional time series data, which is then used for "feature selection." Using industry-sponsored clinical trials data sets, we are able to identify a small set of analytes that effectively models the state of normal health.

Clinical Trials and Tribulations: Lessons Learned from Recruiting Pregnant Ex-Smokers for Relapse Prevention

PubMed Central

Lopez, Elena N.; Simmons, Vani Nath; Quinn, Gwendolyn P.; Meade, Cathy D.; Chirikos, Thomas N.; Brandon, Thomas H.

2014-01-01

The development of smoking cessation and relapse-prevention interventions for pregnant and postpartum women is a public health priority. However, researchers have consistently reported substantial difficulty in accruing this population into clinical trials. The problem is particularly acute for relapse-prevention studies, which must recruit women who have already quit smoking because of their pregnancy. Although an important target for tobacco control efforts, these individuals represent an extremely small subgroup of the general population. This paper describes multiple recruitment strategies utilized for a clinical trial of a self-help relapse-prevention program for pregnant women. The effectiveness of the strategies and the direct expense per participant accrued are provided. A proactive recruitment strategy (telephoning women whose phone numbers were purchased from a marketing firm) was ultimately much more successful than a variety of reactive strategies (advertisement, press releases, direct mail, web placement, healthcare provider outreach). There were few differences between proactively and reactively recruited participants on baseline variables; the primary difference was that the former had smoked fewer cigarettes per day and reported lower nicotine dependence prior to quitting. Strengths and limitations of the recruitment strategies are discussed. PMID:18188749

The multimedia computer for office-based patient education: a systematic review.

PubMed

Wofford, James L; Smith, Edward D; Miller, David P

2005-11-01

Use of the multimedia computer for education is widespread in schools and businesses, and yet computer-assisted patient education is rare. In order to explore the potential use of computer-assisted patient education in the office setting, we performed a systematic review of randomized controlled trials (search date April 2004 using MEDLINE and Cochrane databases). Of the 26 trials identified, outcome measures included clinical indicators (12/26, 46.1%), knowledge retention (12/26, 46.1%), health attitudes (15/26, 57.7%), level of shared decision-making (5/26, 19.2%), health services utilization (4/26, 17.6%), and costs (5/26, 19.2%), respectively. Four trials targeted patients with breast cancer, but the clinical issues were otherwise diverse. Reporting of the testing of randomization (76.9%) and appropriate analysis of main effect variables (70.6%) were more common than reporting of a reliable randomization process (35.3%), blinding of outcomes assessment (17.6%), or sample size definition (29.4%). We concluded that the potential for improving the efficiency of the office through computer-assisted patient education has been demonstrated, but better proof of the impact on clinical outcomes is warranted before this strategy is accepted in the office setting.

Fecal Microbiota Transplantation Inhibits Multidrug-Resistant Gut Pathogens: Preliminary Report Performed in an Immunocompromised Host.

PubMed

Biliński, Jarosław; Grzesiowski, Paweł; Muszyński, Jacek; Wróblewska, Marta; Mądry, Krzysztof; Robak, Katarzyna; Dzieciątkowski, Tomasz; Wiktor-Jedrzejczak, Wiesław; Basak, Grzegorz W

2016-06-01

Colonization of the gastrointestinal tract with multidrug-resistant (MDR) bacteria is a consequence of gut dysbiosis. We describe the successful utilization of fecal microbiota transplantation to inhibit Klebsiella pneumoniae MBL(+) and Escherichia coli ESBL(+) gut colonization in the immunocompromised host as a novel tool in the battle against MDR microorganisms. ClinicalTrials.gov identifier NCT02461199.

Clinical Utility of the Modified Stroop Task as a Treatment Outcome Measure: Questions Raised

ERIC Educational Resources Information Center

Ball, Jillian R.; Mitchell, Philip B.; Touyz, Stephen W.; Griffiths, Rosalyn A.; Beumont, Pierre J. V.

2004-01-01

Data from an outpatient treatment trial for anorexia nervosa were examined to gain preliminary insights as to whether the modified Stroop colour-naming task might offer a useful measure of treatment outcome. It was hypothesised that interference for eating-, weight- and shape-related words on a modified version on the Stroop colour-naming task…

Arginine depletion by arginine deiminase does not affect whole protein metabolism or muscle fractional protein synthesis rate in mice

USDA-ARS?s Scientific Manuscript database

Due to the absolute need for arginine that certain cancer cells have, arginine depletion is a therapy in clinical trials to treat several types of cancers. Arginine is an amino acids utilized not only as a precursor for other important molecules, but also for protein synthesis. Because arginine depl...

Utility of Boron in Dermatology.

PubMed

Jackson, David G; Cardwell, Leah A; Oussedik, Elias; Feldman, Steven R

2017-08-09

Boron compounds are being investigated as therapies for dermatologic conditions. Several features of boron chemistry make this element an ideal component in dermatologic treatments. We review the published dermatologically-relevant clinical trials and case studies pertaining to boron compounds. PubMed was utilized to query terms boron, chemistry, drug, development, dermatology, atopic dermatitis, psoriasis, onychomycosis, tavaborole, AN 2690, crisaborole, and AN 2728. Clinical trials, case studies, animal studies and in vitro studies. pertaining to atopic dermatitis, psoriasis and onychomycosis were included. Crisaborole 2% topical solution reduced atopic dermatitis lesions by approximately 60% when compared to pre-treatment baseline. Crisaborole maintains its dose-dependent effect in treatment of psoriasis and significantly reduces psoriatic plaques when compared to controls. Adverse effects were mild, frequency of events varied between studies. Crisaborole was well tolerated when applied to sensitive skin. Topical tavaborole significantly reduced or eliminated onychomycosis with minimal side effects compared to placebo. Tavaborole was effective in treating recalcitrant onychomycosis. Boron-based compounds form stable interactions with enzyme targets and are safe medications for the treatment of atopic dermatitis, psoriasis, and onychomycosis. The mild and rare side effects of topical boron-based compounds may make them ideal treatments for individuals with sensitive skin and pediatric populations.

Leveraging model-informed approaches for drug discovery and development in the cardiovascular space.

PubMed

Dockendorf, Marissa F; Vargo, Ryan C; Gheyas, Ferdous; Chain, Anne S Y; Chatterjee, Manash S; Wenning, Larissa A

2018-06-01

Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.

Overcoming barriers to the use of osteopathic manipulation techniques in the emergency department.

PubMed

Roberge, Raymond J; Roberge, Marc R

2009-08-01

Osteopathic Manipulation Techniques (OMT) have been shown to be effective therapeutic modalities in various clinical settings, but appear to be underutilized in the emergency department (ED) setting. To examine barriers to the use of OMT in the ED and provide suggestions to ameliorate these barriers. Literature review While the medical literature cites numerous obstacles to the use of OMT in the ED setting, most can be positively addressed through education, careful planning, and ongoing research into use of these techniques. Recent prospective clinical trials of OMT have demonstrated the utility of these modalities. Osteopathic Manipulation Techniques are useful therapeutic modalities that could be utilized to a greater degree in the ED. As the number of osteopathic emergency physicians increases, the opportunity to employ these techniques should increase.

Clinical staging and operative reporting for multi-institutional trials in head and neck squamous cell carcinoma.

PubMed

Weymuller, E A

1997-12-01

A Strategic Planning Conference (jointly supported by NCI and NIDCD) was convened to consider potential improvements in surgical patient data for multi-institutional trials. The thesis underlying this project is that inadequacies in staging, pretreatment patient stratification, and the details of surgical resection may have obscured the detection of treatment effect. The goals of this project were multiple: (1) to consider the utility of new clinical stratification variables, (2) to increase the precision of tumor staging, and (3) to improve operative reporting for multi-institutional trials in head and neck cancer. The conference attendees came to a number of important conclusions: (1) TNM status is inadequate for describing head and neck cancer in a multi-institutional trial setting. A detailed anatomic reporting scheme is proposed; (2) comorbidity measures should be included as patient descriptors, especially those that meet the criteria "definitely important and easy to obtain"; (3) surgical reporting in multi-institutional trials should use a format that is compatible with computer analysis and use the same items as the revised (anatomic) staging system; (4) the surgeon should be personally responsible for data coding and should interact directly with the pathologist in marking the surgical specimen; (5) pathologic reporting should use an anatomic template identical to the staging and operative reporting formats.

Economic analysis: randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer.

PubMed

Bradbury, Penelope A; Tu, Dongsheng; Seymour, Lesley; Isogai, Pierre K; Zhu, Liting; Ng, Raymond; Mittmann, Nicole; Tsao, Ming-Sound; Evans, William K; Shepherd, Frances A; Leighl, Natasha B

2010-03-03

The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non-small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer-related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94,638 per life-year gained (95% confidence interval = $52,359 to $429,148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated advanced non-small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment.

The impact of persistence with bisphosphonates on health resource utilization and fracture risk in the UK: a study of patient records from the UK Clinical Practice Research Datalink.

PubMed

Ferguson, Samara; Feudjo Tepie, Maurille; Taylor, Andrew; Roddam, Andrew; Critchlow, Cathy; Iqbal, Mazhar; Spangler, Leslie; Bayly, Jonathan

2016-02-01

Clinical trial data suggest that patients who have received bisphosphonates continue to benefit from them after discontinuation. However, data from real-world clinical practice are inconclusive. We assessed the impact of persistence and discontinuation on health resource utilization (HRU) and fracture rate in women who were prescribed oral bisphosphonates. The study used data from the UK Clinical Practice Research Datalink. Women aged 50 years or older with a first prescription of oral bisphosphonate therapy between January 2000 and December 2007 were included. Multivariate modelling compared rate ratios for fracture and HRU between patients who had discontinued medication (shorter persistence group) and patients who took their medication for longer (longer persistence group). The interactions of elapsed time (measured as 6-month intervals) with HRU and with fracture rate for all patients within paired groups were also assessed. Overall, 36 320 patients were included. Pairwise comparisons showed that HRU and fracture rates were lower in longer persistence groups than in shorter persistence groups. Analysis by 6-month interval showed that, across all patients in persistence group pairs, HRU significantly increased for each additional 6 months elapsed; trends towards increased risk of fracture were also seen. In contrast to results from clinical trials, in this patient population the protective effect of oral bisphosphonates after discontinuation was not sufficient to reduce HRU and fracture rates to the levels that would be seen if patients had continued on therapy. Reducing the rate of treatment discontinuation may decrease the burden that osteoporosis places on both patients and health care systems. © 2015 AMGEN Inc. Journal of Evaluation in Clinical Practice published by John Wiley & Sons, Ltd.

Utility, reliability, sensitivity and validity of an online test system designed to monitor changes in cognitive function in clinical trials.

PubMed

Wesnes, Keith A; Brooker, Helen; Ballard, Clive; McCambridge, Laura; Stenton, Robert; Corbett, Anne

2017-12-01

The advent of long-term remotely conducted clinical trials requires assessments which can be administered online. This paper considers the utility, reliability, sensitivity and validity of an internet-based system for measuring changes in cognitive function which is being used in one such trial. The Platform for Research Online to investigate Genetics and Cognition in Ageing is a 10-year longitudinal and entirely remote study launched in November 2015. The CogTrack TM System is being used to monitor changes in important aspects of cognitive function using tests of attention, information processing and episodic memory. On study entry, the participants performed CogTrack TM up to three times over seven days, and these data are evaluated in this paper. During the first six months of the study, 14 531 individuals aged 50 to 94 years enrolled and performed the CogTrack TM System, 8627 of whom completed three test sessions. On the first administration, 99.4% of the study tasks were successfully completed. Repeated testing showed training/familiarisation effects on four of the ten measures which had largely stabilised by the third test session. The factor structure of the various measures was found to be robust. Evaluation of the influence of age identified clinically relevant declines over the age range of the population on one or more measures from all tasks. The results of these analyses identify CogTrack TM to be a practical and valid method to reliably, sensitively, remotely and repeatedly collect cognitive data from large samples of individuals aged 50 and over. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

PubMed

Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily

2014-07-03

The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P<0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P<0.01). There were no serious adverse events. Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

Use of Pharmacogenomics and Biomarkers in the Development of New Drugs for Alzheimer Disease in Japan.

PubMed

Otsubo, Yasuto

2015-08-01

Pharmacogenomics (PGx) and biomarkers have been utilized for improving the benefit/risk ratios of drugs and the efficiency of drug development. In the development of drugs for Alzheimer disease (AD), a number of clinical trials have failed to demonstrate clinical efficacy. To overcome this circumstance, the importance of using PGx/biomarkers for enhancing recruitment into clinical trials and for evaluating the efficacy of treatments has been increasingly recognized. In this article, the current status and examples of the use of PGx/biomarkers in Japan for drug development are explained. Guidelines, notifications, and administrative notices related to PGx/biomarkers were downloaded from the Web sites of the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration, and the European Medicines Agency. Data from clinical studies of AD drugs were obtained from the review reports of the PMDA. To analyze the current status of the use of PGx/biomarkers in Japan, "Issues to Consider in the Clinical Evaluation and Development of Drugs for Alzheimer's Disease (Interim Summary)" was also downloaded from PMDA Web site. There are 2 major measures of utilizing PGx/biomarkers for drug development: (1) biomarker qualification and (2) companion diagnostics. Recently, the PMDA issued a number of guidelines and notifications for their practical use. Although examples of qualified PGx/biomarkers and approved companion diagnostics are limited at present, it is expected that the use of PGx/biomarkers for the development of drugs against AD would increase. For promoting the use of PGx/biomarkers in the development of drugs against AD, PGx/biomarkers should be qualified as early as possible. To that end, accumulating data on PGx/biomarkers from nonclinical or clinical trials and the concurrent development of reliable diagnostics in the early stage of the development process are indispensable. It is important to strengthen collaboration among the academia, industries, and regulatory agencies, followed by the establishment of an effective guideline in the area of AD. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease

PubMed Central

Blennow, Kaj; Dubois, Bruno; Fagan, Anne M.; Lewczuk, Piotr; de Leon, Mony J.; Hampel, Harald

2015-01-01

Several potential disease-modifying drugs for Alzheimer’s disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF bio-markers for both clinical trials and routine clinical diagnosis of AD. PMID:24795085

Influence of Prior Heart Failure Hospitalization on Cardiovascular Events in Patients with Reduced and Preserved Ejection Fraction

PubMed Central

Bello, Natalie A.; Claggett, Brian; Desai, Akshay S.; McMurray, John J.V.; Granger, Christopher B.; Yusuf, Salim; Swedberg, Karl; Pfeffer, Marc A.; Solomon, Scott D.

2014-01-01

Background Hospitalization for acute heart failure (HF) is associated with high rates of subsequent mortality and readmission. We assessed the influence of the time interval between prior HF hospitalization and randomization in the CHARM trials on clinical outcomes in patients with both reduced and preserved ejection fraction. Methods and Results CHARM enrolled 7,599 patients with NYHA class II-IV heart failure, of whom 5,426 had a history of prior HF hospitalization. Cox proportional hazards regression models were utilized to assess the association between time from prior HF hospitalization and randomization and the primary outcome of cardiovascular death or unplanned admission to hospital for the management of worsening HF over a median of 36.6 months. For patients with HF and reduced (HFrEF) or preserved (HFpEF) ejection fraction, rates of CV mortality and HF hospitalization were higher among patients with prior HF hospitalization than those without. The risk for mortality and hospitalization varied inversely with the time interval between hospitalization and randomization. Rates were higher for HFrEF patients within each category. Event rates for those with HFpEF and a HF hospitalization in the 6 months prior to randomization were comparable to the rate in HFrEF patients with no prior HF hospitalization. Conclusions Rates of CV death or HF hospitalization are greatest in those who have been previously hospitalized for HF. Independent of EF, rates of death and readmission decline as time from HF hospitalization to trial enrollment increased. Recent HF hospitalization identifies a high risk population for future clinical trials in HFrEF and HFpEF. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00634400. PMID:24874200

Efficacy and safety of Gantong Granules in the treatment of common cold with wind-heat syndrome: study protocol for a randomized controlled trial.

PubMed

Min, Jie; Li, Xiao-qiang; She, Bin; Chen, Yan; Mao, Bing

2015-05-19

Although the common cold is generally mild and self-limiting, it is a leading cause of consultations with doctors and missed days from school and work. In light of its favorable effects of relieving symptoms and minimal side-effects, Traditional Chinese Medicine (TCM) has been widely used to treat the common cold. However, there is a lack of robust evidence to support the clinical utility of such a treatment. This study is designed to evaluate the efficacy and safety of Gantong Granules compared with placebo in patients with the common cold with wind-heat syndrome (CCWHS). This is a multicenter, phase IIb, double-blind, placebo-controlled and randomized clinical trial. A total of 240 patients will be recruited, from 5 centers across China and randomly assigned to the high-dose group, medium-dose group, low-dose group or placebo control group in a 1:1:1:1 ratio. All subjects will receive the treatment for 3 to 5 days, followed by a 7-day follow-up period. The primary outcome is the duration of all symptoms. Secondary outcomes include the duration of primary symptoms and each symptom, time to fever relief and time to fever clearance, change in TCM symptom score, and change in Symptom and Sign Score. This trial will provide high-quality evidence on the efficacy and safety of Gantong Granules in treating CCWHS, and help to optimize the dose selection for a phase III clinical trial. The registration number is ChiCTR-TRC-14004255 , which was assigned by the Chinese Clinical Trial Registry on 12 February 2014.

Study protocol of an economic evaluation of an extended implementation strategy for the treatment of low back pain in general practice: a cluster randomised controlled trial.

PubMed

Jensen, Cathrine Elgaard; Riis, Allan; Pedersen, Kjeld Møller; Jensen, Martin Bach; Petersen, Karin Dam

2014-10-08

In Denmark, guidelines on low back pain management are currently being implemented; in association with this, a clinical trial is conducted. A health economic evaluation is carried out alongside the clinical trial to assess the cost-effectiveness of an extended implementation strategy to increase the general practitioners' adherence to the guidelines. In addition to usual dissemination, the extended implementation strategy is composed of visits from a guideline facilitator, stratification tools, and feedback on guideline adherence. The aim of this paper is to provide the considerations on the design of the health economic evaluation. The economic evaluation is carried out alongside a cluster randomised controlled trial consisting of 60 general practices in the North Denmark Region. An expected 1,200 patients between the age of 18 and 65 years with a low back pain diagnosis will be enrolled. The economic evaluation comprises both a cost-effectiveness analyses and a cost-utility analysis. Effectiveness measures include referral to secondary care, health-related quality of life measured by EQ-5D-5L, and disability measured by the Roland Morris disability questionnaire. Cost measures include all relevant additional costs of the extended implementation strategy compared to usual implementation. The economic evaluation will be performed from both a societal perspective and a health sector perspective with a 12-month time horizon. It is expected that the extended implementation strategy will reduce the number of patients referred to secondary care. It is hypothesised that the additional upfront cost of extended implementation will be counterbalanced by improvements in clinical practice and patient-related outcomes, thereby rendering the extended implementation strategy cost-effective. ClinicalTrials.gov: NCT01699256.

Interdisciplinary team-based care for patients with chronic pain on long-term opioid treatment in primary care (PPACT) - Protocol for a pragmatic cluster randomized trial.

PubMed

DeBar, Lynn; Benes, Lindsay; Bonifay, Allison; Deyo, Richard A; Elder, Charles R; Keefe, Francis J; Leo, Michael C; McMullen, Carmit; Mayhew, Meghan; Owen-Smith, Ashli; Smith, David H; Trinacty, Connie M; Vollmer, William M

2018-04-01

Chronic pain is one of the most common, disabling, and expensive public health problems in the United States. Interdisciplinary pain management treatments that employ behavioral approaches have been successful in helping patients with chronic pain reduce symptoms and regain functioning. However, most patients lack access to such treatments. We are conducting a pragmatic clinical trial to test the hypothesis that patients who receive an interdisciplinary biopsychosocial intervention, the Pain Program for Active Coping and Training (PPACT), at their primary care clinic will have a greater reduction in pain impact in the year following than patients receiving usual care. This is an effectiveness-implementation hybrid pragmatic clinical trial in which we randomize clusters of primary care providers and their patients with chronic pain who are on long-term opioid therapy to 1) receive an interdisciplinary behavioral intervention in conjunction with their current health care or 2) continue with current health care services. Our primary outcome is pain impact (a composite of pain intensity and pain-related interference) measured using the PEG, a validated three-item assessment. Secondary outcomes include pain-related disability, patient satisfaction, opioids dispensed and health care utilization. An economic evaluation assesses the resources and costs necessary to deliver the intervention and its cost-effectiveness compared with usual care. A formative evaluation employs mixed methods to understand the context for implementation in the participating health care systems. This trial will inform the feasibility of implementing interdisciplinary behavioral approaches to pain management in the primary care setting, potentially providing a more effective, safer, and more satisfactory alternative to opioid-based chronic pain treatment. Clinical Trials Registration Number: NCT02113592. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Interdisciplinary team-based care for patients with chronic pain on long-term opioid treatment in primary care (PPACT) – Protocol for a pragmatic cluster randomized trial

PubMed Central

DeBar, Lynn; Benes, Lindsay; Bonifay, Allison; Deyo, Richard A.; Elder, Charles R.; Keefe, Francis J.; Leo, Michael C.; McMullen, Carmit; Mayhew, Meghan; Owen-Smith, Ashli; Smith, David H.; Trinacty, Connie M.; Vollmer, William M.

2018-01-01

Background Chronic pain is one of the most common, disabling, and expensive public health problems in the United States. Interdisciplinary pain management treatments that employ behavioral approaches have been successful in helping patients with chronic pain reduce symptoms and regain functioning. However, most patients lack access to such treatments. We are conducting a pragmatic clinical trial to test the hypothesis that patients who receive an interdisciplinary biopsychosocial intervention, the Pain Program for Active Coping and Training (PPACT), at their primary care clinic will have a greater reduction in pain impact in the year following than patients receiving usual care. Methods/design This is an effectiveness-implementation hybrid pragmatic clinical trial in which we randomize clusters of primary care providers and their patients with chronic pain who are on long-term opioid therapy to 1) receive an interdisciplinary behavioral intervention in conjunction with their current health care or 2) continue with current health care services. Our primary outcome is pain impact (a composite of pain intensity and pain-related interference) measured using the PEG, a validated three-item assessment. Secondary outcomes include pain-related disability, patient satisfaction, opioids dispensed and health care utilization. An economic evaluation assesses the resources and costs necessary to deliver the intervention and its cost-effectiveness compared with usual care. A formative evaluation employs mixed methods to understand the context for implementation in the participating health care systems. Discussion This trial will inform the feasibility of implementing interdisciplinary behavioral approaches to pain management in the primary care setting, potentially providing a more effective, safer, and more satisfactory alternative to opioid-based chronic pain treatment. Clinical Trials Registration Number: NCT02113592 PMID:29522897

The cost-effectiveness of a treatment-based classification system for low back pain: design of a randomised controlled trial and economic evaluation

PubMed Central

2010-01-01

Background Systematic reviews have shown that exercise therapy and spinal manipulation are both more effective for low back pain (LBP) than no treatment at all. However, the effects are at best modest. To enhance the clinical outcomes, recommendations are to improve the patient selection process, and to identify relevant subgroups to guide clinical decision-making. One of the systems that has potentials to improve clinical decision-making is a treatment-based classification system that is intended to identify those patients who are most likely to respond to direction-specific exercises, manipulation, or stabilisation exercises. Methods/Design The primary aim of this randomised controlled trial will be to assess the effectiveness of a classification-based system. A sample of 150 patients with subacute and chronic LBP who attend a private physical therapy clinic for treatment will be recruited. At baseline, all participants will undergo a standard evaluation by trained research physical therapists and will be classified into one of the following subgroups: direction-specific exercises, manipulation, or stabilisation. The patient will not be informed about the results of the examination. Patients will be randomly assigned to classification-based treatment or usual care according to the Dutch LBP guidelines, and will complete questionnaires at baseline, and 8, 26, and 52 weeks after the start of the treatment. The primary outcomes will be general perceived recovery, functional status, and pain intensity. Alongside this trial, an economic evaluation of cost-effectiveness and cost-utility will be conducted from a societal perspective. Discussion The present study will contribute to our knowledge about the effectiveness and cost-effectiveness of classification-based treatment in patients with LBP. Trial registration Trial registration number: NTR1176 PMID:20346133

Prenatal health care beyond the obstetrics service: Utilization and predictors of unscheduled care

PubMed Central

Magriples, Urania; Kershaw, Trace S.; Rising, Sharon Schindler; Massey, Zohar; Ickovics, Jeannette R.

2008-01-01

OBJECTIVE The objective of the study was to describe the patient characteristics of prenatal care utilization within and outside of routine obstetric care, and the clinical and psychosocial factors that predict care utilization. STUDY DESIGN Four hundred twenty pregnant women enrolled in a randomized controlled trial receiving prenatal care in a university-affiliated clinic. All hospital encounters were obtained by review of computerized databases. The Kotelchuck index (KI) was computed, and the characteristics of inadequate, adequate, or excessive prenatal care were described. Demographic and psychosocial predictors of unscheduled visits were evaluated. RESULTS A total of 50.5% of women were adequate users by KI, with 19% being inadequate. An average of 5 additional unscheduled encounters occurred (standard deviation 4.2; range, 0−26). Almost 75% of participants made an unscheduled obstetric visit, with 38% making 2 or more unscheduled visits. Overweight/obese, younger women, high symptom distress, and excessive and inadequate prenatal users were more likely to utilize the labor floor before delivery. CONCLUSION Unscheduled care is common during pregnancy. PMID:18166312

Patient Utilization of Cognitive-Behavioral Therapy for OCD

PubMed Central

Mancebo, Maria C.; Eisen, Jane L.; Sibrava, Nicholas; Dyck, Ingrid R.; Rasmussen, Steven A.

2012-01-01

The current study examined utilization of cognitive-behavioral therapy (CBT) by individuals receiving treatment for obsessive-compulsive disorder (OCD). Participants were 202 adults with primary DSM-IV OCD who enrolled in a longitudinal, observational study of the course of OCD and completed 2 years of annual follow-up interviews using the Longitudinal Interval Follow-Up Evaluation. One hundred twenty participants reported that a mental health professional recommended CBT for their OCD symptoms at some point during the 2-year follow-up period. One quarter (n = 31) of these participants did not initiate CBT despite receiving a treatment recommendation. Thirty-one percent of the 89 participants who entered CBT endorsed dropping out of CBT prematurely and less than one third received an adequate “dose” of CBT sessions. Self-reported CBT drop-out rates were significantly greater than attrition rates reported in clinical trials using intensive schedules of exposure and ritual prevention (EX/RP). Perceived environmental barriers and fears regarding treatment participation were the most frequently endorsed reasons for not participating or dropping out of CBT. Despite its efficacy for OCD, many individuals with clinically significant symptoms fail to initiate CBT when recommended by a mental health professional, receive treatments that are less intensive than those used in clinical trials, or drop out of treatment prematurely. Financial costs of CBT, difficulty attending sessions, and fears regarding treatment are significant barriers to initiating and completing therapy. PMID:21658523

The rehabilitation enhancing aging through connected health (REACH) study: study protocol for a quasi-experimental clinical trial.

PubMed

Ni, Meng; Brown, Lorna G; Lawler, Danielle; Ellis, Terry D; Deangelis, Tamara; Latham, Nancy K; Perloff, Jennifer; Atlas, Steve J; Percac-Lima, Sanja; Bean, Jonathan F

2017-09-20

Mobility limitations among older adults increase the risk for disability and healthcare utilization. Rehabilitative care is identified as the most efficacious treatment for maintaining physical function. However, there is insufficient evidence identifying a healthcare model that targets prevention of mobility decline among older adults. The objective of this study is to evaluate the preliminary effectiveness of a physical therapy program, augmented with mobile tele-health technology, on mobility function and healthcare utilization among older adults. This is a quasi-experimental 12-month clinical trial conducted within a metropolitan-based healthcare system in the northeastern United States. It is in parallel with an existing longitudinal cohort study evaluating mobility decline among community-dwelling older adult primary care patients over one year. Seventy-five older adults (≥ 65-95 years) are being recruited using identical inclusion/exclusion criteria to the cohort study. Three aims will be evaluated: the effect of our program on 1) physical function, 2) healthcare utilization, and 3) healthcare costs. Changes in patient-reported function over 1 year in those receiving the intervention (aim 1) will be compared to propensity score matched controls (N = 150) from the cohort study. For aims 2 and 3, propensity scores, derived from logistic regression model that includes demographic and diagnostic information available through claims and enrollment information, will be used to match treatment and control patients in a ratio of 1:2 or 1:3 from a Medicare Claims Registry derived from the same geographic region. The intervention consists of a one-year physical therapy program that is divided between a combination of outpatient and home visits (6-10 total visits) and is augmented on a computerized tablet using of a commercially available application to deliver a progressive home-based exercise program emphasizing lower-extremity function and a walking program. Incorporating mobile health into current healthcare models of rehabilitative care has the potential to decrease hospital visits and provide a longer duration of care. If the hypotheses are supported and demonstrate improved mobility and reduced healthcare utilization, this innovative care model would be applicable for optimizing the maintenance of functional independence among community-dwelling older adults. ClinicalTrial.gov Identifier: NCT02580409 (Date of registration October 14, 2015).

Progress on core outcome sets for critical care research.

PubMed

Blackwood, Bronagh; Marshall, John; Rose, Louise

2015-10-01

Appropriate selection and definition of outcome measures are essential for clinical trials to be maximally informative. Core outcome sets (an agreed, standardized collection of outcomes measured and reported in all trials for a specific clinical area) were developed due to established inconsistencies in trial outcome selection. This review discusses the rationale for, and methods of, core outcome set development, as well as current initiatives in critical care. Recent systematic reviews of reported outcomes and measurement instruments relevant to the critically ill highlight inconsistencies in outcome selection, definition, and measurement, thus establishing the need for core outcome sets. Current critical care initiatives include development of core outcome sets for trials aimed at reducing mechanical ventilation duration; rehabilitation following critical illness; long-term outcomes in acute respiratory failure; and epidemic and pandemic studies of severe acute respiratory infection. Development and utilization of core outcome sets for studies relevant to the critically ill is in its infancy compared to other specialties. Notwithstanding, core outcome set development frameworks and guidelines are available, several sets are in various stages of development, and there is strong support from international investigator-led collaborations including the International Forum for Acute Care Trialists.

Partnerships and pathways of dissemination: the National Institute on Drug Abuse-Substance Abuse and Mental Health Services Administration Blending Initiative in the Clinical Trials Network.

PubMed

Martino, Steve; Brigham, Gregory S; Higgins, Christine; Gallon, Steve; Freese, Thomas E; Albright, Lonnetta M; Hulsey, Eric G; Krom, Laurie; Storti, Susan A; Perl, Harold; Nugent, Cathrine D; Pintello, Denise; Condon, Timothy P

2010-06-01

Since 2001, the National Drug Abuse Treatment Clinical Trials Network (CTN) has worked to put the results of its trials into the hands of community treatment programs, in large part through its participation in the National Institute on Drug Abuse-Substance Abuse and Mental Health Services Administration Blending Initiative and its close involvement with the Center for Substance Abuse Treatment's Addiction Technology Transfer Centers. This article describes (a) the CTN's integral role in the Blending Initiative, (b) key partnerships and dissemination pathways through which the results of CTN trials are developed into blending products and then transferred to community treatment programs, and (c) three blending initiatives involving buprenorphine, motivational incentives, and motivational interviewing. The Blending Initiative has resulted in high utilization of its products, preparation of more than 200 regional trainers, widespread training of service providers in most U.S. States, Puerto Rico, and the U.S. Virgin Islands and movement toward the development of Web-based implementation supports and technical assistance. Implications for future directions of the Blending Initiative and opportunities for research are discussed.

Year in review 2005: Critical Care – nephrology

PubMed Central

Ricci, Zaccaria; Ronco, Claudio

2006-01-01

We summarize original research in the field of critical care nephrology accepted or published in 2005 in Critical Care and, when considered relevant or directly linked to this research, in other journals. The articles have been grouped into four categories to facilitate a rapid overview. First, physiopathology, epidemiology and prognosis of acute renal failure (ARF): an extensive review and some observational studies have been performed with the aim of describing aspects of ARF physiopathology, precise epidemiology and long-term outcomes. Second, several authors have performed clinical trials utilizing a potential nephro-protective drug, fenoldopam, with different results. Third, the issue of continuous renal replacement therapies dose has been addressed in a small prospective study and a large observational trial. And fourth, alternative indications to extracorporeal treatment of ARF and systemic inflammatory response syndrome have been explored by three original clinical studies. PMID:16919174

A potential new treatment for rheumatoid arthritis: thunder god vine.

PubMed

Lipsky, P E; Tao, X L

1997-04-01

Various extracts of the vinelike plant Tripterygium wilfordii Hook f have been widely used in China to treat patients with a number of autoimmune diseases. Although most of the clinical experience has derived from uncontrolled trials, one placebo-controlled double-blind trial has clearly demonstrated efficacy in rheumatoid arthritis. Studies in laboratory animals have indicated that extracts of Tripterygium wilfordii Hook f suppress both immune and inflammatory responses and also effectively treat a number of models of autoimmune disease. More detailed in vitro analysis has indicated that components of Tripterygium wilfordii Hook f suppress immune responses by inhibiting transcription of cytokine genes, including interleukin-2 and gamma interferon. The current status of knowledge of the potential clinical benefit of this herbal remedy and possible mechanisms accounting for its utility are considered in this review.

Application of person-centered analytic methodology in longitudinal research: exemplars from the Women's Health Initiative Clinical Trial data.

PubMed

Zaslavsky, Oleg; Cochrane, Barbara B; Herting, Jerald R; Thompson, Hilaire J; Woods, Nancy F; Lacroix, Andrea

2014-02-01

Despite the variety of available analytic methods, longitudinal research in nursing has been dominated by use of a variable-centered analytic approach. The purpose of this article is to present the utility of person-centered methodology using a large cohort of American women 65 and older enrolled in the Women's Health Initiative Clinical Trial (N = 19,891). Four distinct trajectories of energy/fatigue scores were identified. Levels of fatigue were closely linked to age, socio-demographic factors, comorbidities, health behaviors, and poor sleep quality. These findings were consistent regardless of the methodological framework. Finally, we demonstrated that energy/fatigue levels predicted future hospitalization in non-disabled elderly. Person-centered methods provide unique opportunities to explore and statistically model the effects of longitudinal heterogeneity within a population. © 2013 Wiley Periodicals, Inc.

Identifying and collecting pertinent medical records for centralized abstraction in a multi-center randomized clinical trial: the model used by the American College of Radiology arm of the National Lung Screening Trial.

PubMed

Gareen, Ilana F; Sicks, JoRean D; Jain, Amanda Adams; Moline, Denise; Coffman-Kadish, Nancy

2013-01-01

In clinical trials and epidemiologic studies, information on medical care utilization and health outcomes is often obtained from medical records. For multi-center studies, this information may be gathered by personnel at individual sites or by staff at a central coordinating center. We describe the process used to develop a HIPAA-compliant centralized process to collect medical record information for a large multi-center cancer screening trial. The framework used to select, request, and track medical records incorporated a participant questionnaire with unique identifiers for each medical provider. De-identified information from the questionnaires was sent to the coordinating center indexed by these identifiers. The central coordinating center selected specific medical providers for abstraction and notified sites using these identifiers. The site personnel then linked the identifiers with medical provider information. Staff at the sites collected medical records and provided them for central abstraction. Medical records were successfully obtained and abstracted to ascertain information on outcomes and health care utilization in a study with over 18,000 study participants. Collection of records required for outcomes related to positive screening examinations and lung cancer diagnosis exceeded 90%. Collection of records for all aims was 87.32%. We designed a successful centralized medical record abstraction process that may be generalized to other research settings, including observational studies. The coordinating center received no identifying data. The process satisfied requirements imposed by the Health Insurance Portability and Accountability Act and concerns of site institutional review boards with respect to protected health information. Copyright © 2012 Elsevier Inc. All rights reserved.

Identifying and collecting pertinent medical records for centralized abstraction in a multi-center randomized clinical trial: The model used by the American College of Radiology arm of the National Lung Screening Trial

PubMed Central

Gareen, Ilana F.; Sicks, JoRean; Adams, Amanda; Moline, Denise; Coffman-Kadish, Nancy

2012-01-01

Background In clinical trials and epidemiologic studies, information on medical care utilization and health outcomes is often obtained from medical records. For multi-center studies, this information may be gathered by personnel at individual sites or by staff at a central coordinating center. We describe the process used to develop a HIPAA-compliant centralized process to collect medical record information for a large multi-center cancer screening trial. Methods The framework used to select, request, and track medical records incorporated a participant questionnaire with unique identifiers for each medical provider. De-identified information from the questionnaires was sent to the coordinating center indexed by these identifiers. The central coordinating center selected specific medical providers for abstraction and notified sites using these identifiers. The site personnel then linked the identifiers with medical provider information. Staff at the sites collected medical records and provided them for central abstraction. Results Medical records were successfully obtained and abstracted to ascertain information on outcomes and health care utilization in a study with over 18,000 study participants. Collection of records required for outcomes related to positive screening examinations and lung cancer diagnosis exceeded 90%. Collection of records for all aims was 87.32%. Conclusions We designed a successful centralized medical record abstraction process that may be generalized to other research settings, including observational studies. The coordinating center received no identifying data. The process satisfied requirements imposed by the Health Insurance Portability and Accountability Act and concerns of site institutional review boards with respect to protected health information. PMID:22982342

PCR analysis of a prescription vegetarian diet and use in three dogs with cutaneous adverse food reactions.

PubMed

Aufox, Erin E; May, Elizabeth R; Frank, Linda A; Kania, Stephen A

2018-04-24

Cutaneous adverse food reaction (CAFR) is diagnosed by performing an elimination diet trial utilizing prescription or home-cooked diets followed by provocative challenge. To report findings of PCR analysis of a prescription vegetarian diet (RCV) for undeclared proteins of animal origin, as well as to describe its utilization for diagnosis and management of dogs suspected of having CAFR. Three client-owned dogs. PCR analysis of RCV for 11 mammalian species and poultry. In three dogs, clinical examination, cytology, aerobic culture (if indicated) and at least one elimination diet trial with RCV. In our case series, all dogs had a history of pruritus and recurrent pyoderma that resolved with infection control and an elimination diet trial. In cases 1 and 2, a diagnosis of CAFR was made following an elimination trial with RCV and provocative challenge. Case 3 had a previously confirmed diagnosis of CAFR and RCV was successfully used to maintain remission of CAFR-related signs. PCR testing of RCV was negative for 11 mammalian species and poultry. The RCV diet was found not to contain any undeclared mammalian or avian proteins. In this case series, the RCV was successfully used to diagnose and maintain three dogs with CAFR. © 2018 ESVD and ACVD.

Measurement properties of self-report physical activity assessment tools in stroke: a protocol for a systematic review

PubMed Central

Martins, Júlia Caetano; Aguiar, Larissa Tavares; Nadeau, Sylvie; Scianni, Aline Alvim; Teixeira-Salmela, Luci Fuscaldi; Faria, Christina Danielli Coelho de Morais

2017-01-01

Introduction Self-report physical activity assessment tools are commonly used for the evaluation of physical activity levels in individuals with stroke. A great variety of these tools have been developed and widely used in recent years, which justify the need to examine their measurement properties and clinical utility. Therefore, the main objectives of this systematic review are to examine the measurement properties and clinical utility of self-report measures of physical activity and discuss the strengths and limitations of the identified tools. Methods and analysis A systematic review of studies that investigated the measurement properties and/or clinical utility of self-report physical activity assessment tools in stroke will be conducted. Electronic searches will be performed in five databases: Medical Literature Analysis and Retrieval System Online (MEDLINE) (PubMed), Excerpta Medica Database (EMBASE), Physiotherapy Evidence Database (PEDro), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Electronic Library Online (SciELO), followed by hand searches of the reference lists of the included studies. Two independent reviewers will screen all retrieve titles, abstracts, and full texts, according to the inclusion criteria and will also extract the data. A third reviewer will be referred to solve any disagreement. A descriptive summary of the included studies will contain the design, participants, as well as the characteristics, measurement properties, and clinical utility of the self-report tools. The methodological quality of the studies will be evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and the clinical utility of the identified tools will be assessed considering predefined criteria. This systematic review will follow the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. Discussion This systematic review will provide an extensive review of the measurement properties and clinical utility of self-report physical activity assessment tools used in individuals with stroke, which would benefit clinicians and researchers. Trial registration number PROSPERO CRD42016037146. PMID:28193848

Cost-Utility Analysis of the EVOLVO Study on Remote Monitoring for Heart Failure Patients With Implantable Defibrillators: Randomized Controlled Trial

PubMed Central

Landolina, Maurizio; Marzegalli, Maurizio; Lunati, Maurizio; Perego, Giovanni B; Guenzati, Giuseppe; Curnis, Antonio; Valsecchi, Sergio; Borghetti, Francesca; Borghi, Gabriella; Masella, Cristina

2013-01-01

Background Heart failure patients with implantable defibrillators place a significant burden on health care systems. Remote monitoring allows assessment of device function and heart failure parameters, and may represent a safe, effective, and cost-saving method compared to conventional in-office follow-up. Objective We hypothesized that remote device monitoring represents a cost-effective approach. This paper summarizes the economic evaluation of the Evolution of Management Strategies of Heart Failure Patients With Implantable Defibrillators (EVOLVO) study, a multicenter clinical trial aimed at measuring the benefits of remote monitoring for heart failure patients with implantable defibrillators. Methods Two hundred patients implanted with a wireless transmission–enabled implantable defibrillator were randomized to receive either remote monitoring or the conventional method of in-person evaluations. Patients were followed for 16 months with a protocol of scheduled in-office and remote follow-ups. The economic evaluation of the intervention was conducted from the perspectives of the health care system and the patient. A cost-utility analysis was performed to measure whether the intervention was cost-effective in terms of cost per quality-adjusted life year (QALY) gained. Results Overall, remote monitoring did not show significant annual cost savings for the health care system (€1962.78 versus €2130.01; P=.80). There was a significant reduction of the annual cost for the patients in the remote arm in comparison to the standard arm (€291.36 versus €381.34; P=.01). Cost-utility analysis was performed for 180 patients for whom QALYs were available. The patients in the remote arm gained 0.065 QALYs more than those in the standard arm over 16 months, with a cost savings of €888.10 per patient. Results from the cost-utility analysis of the EVOLVO study show that remote monitoring is a cost-effective and dominant solution. Conclusions Remote management of heart failure patients with implantable defibrillators appears to be cost-effective compared to the conventional method of in-person evaluations. Trial Registration ClinicalTrials.gov NCT00873899; http://clinicaltrials.gov/show/NCT00873899 (Archived by WebCite at http://www.webcitation.org/6H0BOA29f). PMID:23722666

Long-term cost-effectiveness of disease management in systolic heart failure.

PubMed

Miller, George; Randolph, Stephen; Forkner, Emma; Smith, Brad; Galbreath, Autumn Dawn

2009-01-01

Although congestive heart failure (CHF) is a primary target for disease management programs, previous studies have generated mixed results regarding the effectiveness and cost savings of disease management when applied to CHF. We estimated the long-term impact of systolic heart failure disease management from the results of an 18-month clinical trial. We used data generated from the trial (starting population distributions, resource utilization, mortality rates, and transition probabilities) in a Markov model to project results of continuing the disease management program for the patients' lifetimes. Outputs included distribution of illness severity, mortality, resource consumption, and the cost of resources consumed. Both cost and effectiveness were discounted at a rate of 3% per year. Cost-effectiveness was computed as cost per quality-adjusted life year (QALY) gained. Model results were validated against trial data and indicated that, over their lifetimes, patients experienced a lifespan extension of 51 days. Combined discounted lifetime program and medical costs were $4850 higher in the disease management group than the control group, but the program had a favorable long-term discounted cost-effectiveness of $43,650/QALY. These results are robust to assumptions regarding mortality rates, the impact of aging on the cost of care, the discount rate, utility values, and the targeted population. Estimation of the clinical benefits and financial burden of disease management can be enhanced by model-based analyses to project costs and effectiveness. Our results suggest that disease management of heart failure patients can be cost-effective over the long term.

Optimal threshold estimator of a prognostic marker by maximizing a time-dependent expected utility function for a patient-centered stratified medicine.

PubMed

Dantan, Etienne; Foucher, Yohann; Lorent, Marine; Giral, Magali; Tessier, Philippe

2018-06-01

Defining thresholds of prognostic markers is essential for stratified medicine. Such thresholds are mostly estimated from purely statistical measures regardless of patient preferences potentially leading to unacceptable medical decisions. Quality-Adjusted Life-Years are a widely used preferences-based measure of health outcomes. We develop a time-dependent Quality-Adjusted Life-Years-based expected utility function for censored data that should be maximized to estimate an optimal threshold. We performed a simulation study to compare estimated thresholds when using the proposed expected utility approach and purely statistical estimators. Two applications illustrate the usefulness of the proposed methodology which was implemented in the R package ROCt ( www.divat.fr ). First, by reanalysing data of a randomized clinical trial comparing the efficacy of prednisone vs. placebo in patients with chronic liver cirrhosis, we demonstrate the utility of treating patients with a prothrombin level higher than 89%. Second, we reanalyze the data of an observational cohort of kidney transplant recipients: we conclude to the uselessness of the Kidney Transplant Failure Score to adapt the frequency of clinical visits. Applying such a patient-centered methodology may improve future transfer of novel prognostic scoring systems or markers in clinical practice.

The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop

PubMed Central

Khoury, Muin J.; McBride, Colleen M.; Schully, Sheri D.; Ioannidis, John P. A.; Feero, W. Gregory; Janssens, A. Cecile J. W.; Gwinn, Marta; Simons-Morton, Denise G.; Bernhardt, Jay M.; Cargill, Michele; Chanock, Stephen J.; Church, George M.; Coates, Ralph J.; Collins, Francis S.; Croyle, Robert T.; Davis, Barry R.; Downing, Gregory J.; DuRoss, Amy; Friedman, Susan; Gail, Mitchell H.; Ginsburg, Geoffrey S.; Green, Robert C.; Greene, Mark H.; Greenland, Philip; Gulcher, Jeffrey R.; Hsu, Andro; Hudson, Kathy L.; Kardia, Sharon L. R.; Kimmel, Paul L.; Lauer, Michael S.; Miller, Amy M.; Offit, Kenneth; Ransohoff, David F.; Roberts, J. Scott; Rasooly, Rebekah S.; Stefansson, Kari; Terry, Sharon F.; Teutsch, Steven M.; Trepanier, Angela; Wanke, Kay L.; Witte, John S.; Xu, Jianfeng

2010-01-01

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed. PMID:19617843

Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke: Results From the SWIFT-PRIME Trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke).

PubMed

Shireman, Theresa I; Wang, Kaijun; Saver, Jeffrey L; Goyal, Mayank; Bonafé, Alain; Diener, Hans-Christoph; Levy, Elad I; Pereira, Vitor M; Albers, Gregory W; Cognard, Christophe; Hacke, Werner; Jansen, Olav; Jovin, Tudor G; Mattle, Heinrich P; Nogueira, Raul G; Siddiqui, Adnan H; Yavagal, Dileep R; Devlin, Thomas G; Lopes, Demetrius K; Reddy, Vivek K; du Mesnil de Rochemont, Richard; Jahan, Reza; Vilain, Katherine A; House, John; Lee, Jin-Moo; Cohen, David J

2017-02-01

Clinical trials have demonstrated improved 90-day outcomes for patients with acute ischemic stroke treated with stent retriever thrombectomy plus tissue-type plasminogen activator (SST+tPA) compared with tPA. Previous studies suggested that this strategy may be cost-effective, but models were derived from pooled data and older assumptions. In this prospective economic substudy conducted alongside the SWIFT-PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), in-trial costs were measured for patients using detailed medical resource utilization and hospital billing data. Utility weights were assessed at 30 and 90 days using the EuroQol-5 dimension questionnaire. Post-trial costs and life-expectancy were estimated for each surviving patient using a model based on trial data and inputs derived from a contemporary cohort of ischemic stroke survivors. Index hospitalization costs were $17 183 per patient higher for SST+tPA than for tPA ($45 761 versus $28 578; P<0.001), driven by initial procedure costs. Between discharge and 90 days, costs were $4904 per patient lower for SST+tPA than for tPA ($11 270 versus $16 174; P=0.014); total 90-day costs remained higher with SST+tPA ($57 031 versus $44 752; P<0.001). Higher utility values for SST+tPA led to higher in-trial quality-adjusted life years (0.131 versus 0.105; P=0.005). In lifetime projections, SST+tPA was associated with substantial gains in quality-adjusted life years (6.79 versus 5.05), cost savings of $23 203 per patient and was economically dominant when compared with tPA in 90% of bootstrap replicates. Among patients with acute ischemic stroke enrolled in the SWIFT-PRIME trial, SST increased initial treatment costs, but was projected to improve quality-adjusted life-expectancy and reduce healthcare costs over a lifetime horizon compared with tPA. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657461. © 2016 American Heart Association, Inc.

Methods of data collection and analysis for the economic evaluation alongside a national, multi-centre trial in the UK: Conventional ventilation or ECMO for Severe Adult Respiratory Failure (CESAR)

PubMed Central

Thalanany, Mariamma M; Mugford, Miranda; Hibbert, Clare; Cooper, Nicola J; Truesdale, Ann; Robinson, Steven; Tiruvoipati, Ravindranath; Elbourne, Diana R; Peek, Giles J; Clemens, Felicity; Hardy, Polly; Wilson, Andrew

2008-01-01

Background Extracorporeal Membrane Oxygenation (ECMO) is a technology used in treatment of patients with severe but potentially reversible respiratory failure. A multi-centre randomised controlled trial (CESAR) was funded in the UK to compare care including ECMO with conventional intensive care management. The protocol and funding for the CESAR trial included plans for economic data collection and analysis. Given the high cost of treatment, ECMO is considered an expensive technology for many funding systems. However, conventional treatment for severe respiratory failure is also one of the more costly forms of care in any health system. Methods/Design The objectives of the economic evaluation are to compare the costs of a policy of referral for ECMO with those of conventional treatment; to assess cost-effectiveness and the cost-utility at 6 months follow-up; and to assess the cost-utility over a predicted lifetime. Resources used by patients in the trial are identified. Resource use data are collected from clinical report forms and through follow up interviews with patients. Unit costs of hospital intensive care resources are based on parallel research on cost functions in UK NHS intensive care units. Other unit costs are based on published NHS tariffs. Cost effectiveness analysis uses the outcome: survival without severe disability. Cost utility analysis is based on quality adjusted life years gained based on the Euroqol EQ-5D at 6 months. Sensitivity analysis is planned to vary assumptions about transport costs and method of costing intensive care. Uncertainty will also be expressed in analysis of individual patient data. Probabilities of cost effectiveness given different funding thresholds will be estimated. Discussion In our view it is important to record our methods in detail and present them before publication of the results of the trial so that a record of detail not normally found in the final trial reports can be made available in the public domain. Trial Registrations The CESAR trial registration number is ISRCTN47279827. PMID:18447931

Creating a "culture of research" in a community hospital: Strategies and tools from the National Cancer Institute Community Cancer Centers Program.

PubMed

Dimond, Eileen P; St Germain, Diane; Nacpil, Lianne M; Zaren, Howard A; Swanson, Sandra M; Minnick, Christopher; Carrigan, Angela; Denicoff, Andrea M; Igo, Kathleen E; Acoba, Jared D; Gonzalez, Maria M; McCaskill-Stevens, Worta

2015-06-01

The value of community-based cancer research has long been recognized. In addition to the National Cancer Institute's Community Clinical and Minority-Based Oncology Programs established in 1983, and 1991 respectively, the National Cancer Institute established the National Cancer Institute Community Cancer Centers Program in 2007 with an aim of enhancing access to high-quality cancer care and clinical research in the community setting where most cancer patients receive their treatment. This article discusses strategies utilized by the National Cancer Institute Community Cancer Centers Program to build research capacity and create a more entrenched culture of research at the community hospitals participating in the program over a 7-year period. To facilitate development of a research culture at the community hospitals, the National Cancer Institute Community Cancer Centers Program required leadership or chief executive officer engagement; utilized a collaborative learning structure where best practices, successes, and challenges could be shared; promoted site-to-site mentoring to foster faster learning within and between sites; required research program assessments that spanned clinical trial portfolio, accrual barriers, and outreach; increased identification and use of metrics; and, finally, encouraged research team engagement across hospital departments (navigation, multidisciplinary care, pathology, and disparities) to replace the traditionally siloed approach to clinical trials. The health-care environment is rapidly changing while complexity in research increases. Successful research efforts are impacted by numerous factors (e.g. institutional review board reviews, physician interest, and trial availability). The National Cancer Institute Community Cancer Centers Program sites, as program participants, had access to the required resources and support to develop and implement the strategies described. Metrics are an important component yet often challenging to identify and collect. The model requires a strong emphasis on outreach that challenges hospitals to improve and expand their reach, particularly into underrepresented populations and catchment areas. These efforts build on trust and a referral pipeline within the community which take time and significant commitment to establish. The National Cancer Institute Community Cancer Centers Program experience provides a relevant model to broadly address creating a culture of research in community hospitals that are increasingly networked via systems and consortiums. The strategies used align well with the National Cancer Institute-American Society of Clinical Oncology Accrual Symposium recommendations for patient-/community-, physician-/provider-, and site-/organizational-level approaches to clinical trials; they helped sites achieve organizational culture shifts that enhanced their cancer research programs. The National Cancer Institute Community Cancer Centers Program hospitals reported that the strategies were challenging to implement yet proved valuable as they provided useful metrics for programmatic assessment, planning, reporting, and growth. While focused on oncology trials, these concepts may be useful within other disease-focused research as well. © The Author(s) 2015.

Long-term air humidification therapy is cost-effective for patients with moderate or severe chronic obstructive pulmonary disease or bronchiectasis.

PubMed

Milne, Richard J; Hockey, Hans; Rea, Harry

2014-06-01

To establish the cost-effectiveness of long-term humidification therapy (LTHT) added to usual care for patients with moderate or severe chronic obstructive pulmonary disease or bronchiectasis. Resource usage in a 12-month clinical trial of LTHT was estimated from hospital records, patient diaries, and the equipment supplier. Health state utility values were derived from the St. Georges Respiratory Questionnaire (SGRQ) total score. All patients who remained in the trial for 12 months and who had at least 90 days of diary records were included (87 of 108). Clinical costs were NZ $3973 (95% confidence interval [CI] $1614-$6332) for the control group and NZ $3331 (95% CI $948-$6920) for the intervention group. The mean health benefit per patient was -6.9 SGRQ units (95% CI -13.0 to -7.2; P < 0.05) or +0.0678 quality-adjusted life-years (95% CI 0.001-0.135). With the intervention costing NZ $2059 annually, the mean cost per quality-adjusted life-year was NZ $20,902 (US $18,907) and the bootstrap median was NZ $19,749 (2.5th percentile -$40,923, 97.5th percentile $221,275). At a willingness-to-pay (WTP) threshold of NZ $30,000, the probability of cost-effectiveness was 61%, ranging from 49% to 72% as the cost of LTHT was varied by ±30%. At a WTP of NZ $20,000, the probability was 49% (range 34%-61%). LTHT is moderately cost-effective for patients with moderate to severe chronic obstructive pulmonary disease or bronchiectasis at a WTP threshold that is acceptable for public funding of medicines in New Zealand. These findings must be interpreted with caution because of the modest size of the clinical study, necessary lack of blinding in the clinical trial, and uncertainty in estimating health state utility from the SQRQ. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Recommendations for clinical biomarker specimen preservation and stability assessments.

PubMed

Dakappagari, Naveen; Zhang, Hui; Stephen, Laurie; Amaravadi, Lakshmi; Khan, Masood U

2017-04-01

With the wide use of biomarkers to enable critical drug-development decisions, there is a growing concern from scientific community on the need for a 'standardized process' for ensuring biomarker specimen stability and hence, a strong desire to share best practices on preserving the integrity of biomarker specimens in clinical trials and the design of studies to evaluate analyte stability. By leveraging representative industry experience, we have attempted to provide an overview of critical aspects of biomarker specimen stability commonly encountered during clinical development, including: planning of clinical sample collection procedures, clinical site training, selection of sample preservation buffers, shipping logistics, fit-for-purpose stability assessments in the analytical laboratory and presentation of case studies covering widely utilized biomarker specimen types.

Cluster randomized trials utilizing primary care electronic health records: methodological issues in design, conduct, and analysis (eCRT Study)

PubMed Central

2014-01-01

Background There is growing interest in conducting clinical and cluster randomized trials through electronic health records. This paper reports on the methodological issues identified during the implementation of two cluster randomized trials using the electronic health records of the Clinical Practice Research Datalink (CPRD). Methods Two trials were completed in primary care: one aimed to reduce inappropriate antibiotic prescribing for acute respiratory infection; the other aimed to increase physician adherence with secondary prevention interventions after first stroke. The paper draws on documentary records and trial datasets to report on the methodological experience with respect to research ethics and research governance approval, general practice recruitment and allocation, sample size calculation and power, intervention implementation, and trial analysis. Results We obtained research governance approvals from more than 150 primary care organizations in England, Wales, and Scotland. There were 104 CPRD general practices recruited to the antibiotic trial and 106 to the stroke trial, with the target number of practices being recruited within six months. Interventions were installed into practice information systems remotely over the internet. The mean number of participants per practice was 5,588 in the antibiotic trial and 110 in the stroke trial, with the coefficient of variation of practice sizes being 0.53 and 0.56 respectively. Outcome measures showed substantial correlations between the 12 months before, and after intervention, with coefficients ranging from 0.42 for diastolic blood pressure to 0.91 for proportion of consultations with antibiotics prescribed, defining practice and participant eligibility for analysis requires careful consideration. Conclusions Cluster randomized trials may be performed efficiently in large samples from UK general practices using the electronic health records of a primary care database. The geographical dispersal of trial sites presents a difficulty for research governance approval and intervention implementation. Pretrial data analyses should inform trial design and analysis plans. Trial registration Current Controlled Trials ISRCTN 47558792 and ISRCTN 35701810 (both registered on 17 March 2010). PMID:24919485

NADPH oxidase inhibitors: a patent review.

PubMed

Kim, Jung-Ae; Neupane, Ganesh Prasad; Lee, Eung Seok; Jeong, Byeong-Seon; Park, Byung Chul; Thapa, Pritam

2011-08-01

NADPH oxidases, a family of multi-subunit enzyme complexes, catalyze the production of reactive oxygen species (ROS), which may contribute to the pathogenesis of a variety of diseases. In addition to the first NADPH oxidase found in phagocytes, four non-phagocytic NADPH oxidase isoforms have been identified, which all differ in their catalytic subunit (Nox1-5) and tissue distribution. This paper provides a comprehensive review of the patent literature on NADPH oxidase inhibitors, small molecule Nox inhibitors, peptides and siRNAs. Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility.

The Role of Biomarkers in Clinical Trials for Alzheimer Disease

PubMed Central

Thal, Leon J.; Kantarci, Kejal; Reiman, Eric M.; Klunk, William E.; Weiner, Michael W.; Zetterberg, Henrik; Galasko, Douglas; Praticò, Domenico; Griffin, Sue; Schenk, Dale; Siemers, Eric

2007-01-01

Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer’s Association’s Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed. PMID:16493230

Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy

PubMed Central

Al-Zaidy, Samiah A.; Sahenk, Zarife; Rodino-Klapac, Louise R.; Kaspar, Brian; Mendell, Jerry R.

2015-01-01

Abstract Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker muscular dystrophy as well as the future directions for clinical gene therapy trials using follistatin. PMID:27858738

Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy.

PubMed

Al-Zaidy, Samiah A; Sahenk, Zarife; Rodino-Klapac, Louise R; Kaspar, Brian; Mendell, Jerry R

2015-09-02

Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker muscular dystrophy as well as the future directions for clinical gene therapy trials using follistatin.

Treatment selection in a randomized clinical trial via covariate-specific treatment effect curves.

PubMed

Ma, Yunbei; Zhou, Xiao-Hua

2017-02-01

For time-to-event data in a randomized clinical trial, we proposed two new methods for selecting an optimal treatment for a patient based on the covariate-specific treatment effect curve, which is used to represent the clinical utility of a predictive biomarker. To select an optimal treatment for a patient with a specific biomarker value, we proposed pointwise confidence intervals for each covariate-specific treatment effect curve and the difference between covariate-specific treatment effect curves of two treatments. Furthermore, to select an optimal treatment for a future biomarker-defined subpopulation of patients, we proposed confidence bands for each covariate-specific treatment effect curve and the difference between each pair of covariate-specific treatment effect curve over a fixed interval of biomarker values. We constructed the confidence bands based on a resampling technique. We also conducted simulation studies to evaluate finite-sample properties of the proposed estimation methods. Finally, we illustrated the application of the proposed method in a real-world data set.

Medicare Utilization of Vertebral Augmentation 2001 to 2014: Effects of Randomized Clinical Trials and Guidelines on Vertebroplasty and Kyphoplasty.

PubMed

Degnan, Andrew J; Hemingway, Jennifer; Hughes, Danny R

2017-08-01

Vertebral fractures have a substantial impact on the health and quality of life of elderly individuals as one of the most common complications of osteoporosis. Vertebral augmentation procedures including vertebroplasty and kyphoplasty have been supported as means of reducing pain and mitigating disability associated with these fractures. However, use of vertebroplasty is debated, with negative randomized controlled trials published in 2009 and divergent clinical guidelines. The effect of changing evidence and guidelines on different practitioners' utilization of both kyphoplasty and vertebroplasty in the years after these developments and publication of data supporting their use is poorly understood. Using national aggregate Medicare claims data from 2002 through 2014, vertebroplasty and kyphoplasty procedures were identified by provider type. Changes in utilization by procedure type and provider were studied. Total vertebroplasty billing increased 101.6% from 2001 (18,911) through 2008 (38,123). Total kyphoplasty billing frequency increased 17.2% from 2006 (54,329) through 2008 (63,684). Vertebroplasty billing decreased 60.9% from 2008 through 2014 to its lowest value (14,898). Kyphoplasty billing decreased 8.4% from 2008 (63,684) through 2010 (58,346), but then increased 7.6% from 2010 to 2013 (62,804). Vertebroplasty billing decreased substantially beginning in 2009 and continued to decrease through 2014 despite publication of more favorable studies in 2010 to 2012, suggesting studies published in 2009 and AAOS guidelines in 2010 may have had a persistent negative effect. Kyphoplasty did not decrease as substantially and increased in more recent years, suggesting a clinical practice response to favorable studies published during this period. Copyright © 2017 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Utilizing direct skin feeding assays for development of vaccines that interrupt malaria transmission: A systematic review of methods and case study.

PubMed

Brickley, Elizabeth B; Coulibaly, Mamadou; Gabriel, Erin E; Healy, Sara A; Hume, Jen C C; Sagara, Issaka; Traore, Sekou F; Doumbo, Ogobara; Duffy, Patrick E

2016-11-21

Shifting the malaria priorities from a paradigm of control and elimination to a goal of global eradication calls for renewed attention to the interruption of malaria transmission. Sustained progress toward eradication will require both improved understanding of infectious reservoirs and efficient development of novel transmission-blocking interventions, such as rapidly acting and highly efficacious therapeutics and vaccines. Here, we review the direct skin feeding assay (DSF), which has been proposed as a valuable tool for measuring the in natura transmission of malaria parasites from human hosts to mosquito vectors across heterogeneous populations. To capture the methodological breadth of this assay's use, we first systematically review and qualitatively synthesize previously published investigations using DSFs to study malaria transmission in humans. Then, using a recent Phase 1 trial in Mali of the Pfs25H-EPA/Alhydrogel® vaccine candidate (NCT01867463) designed to interrupt Plasmodium falciparum transmission as a case study, we describe the potential opportunities and current limitations of utilizing the endpoints measured by DSF in making early clinical decisions for individually randomized transmission-interrupting intervention candidates. Using simulations based on the data collected in the clinical trial, we demonstrate that the capacity of the DSF to serve as an evaluative tool is limited by the statistical power constraints of the "effective sample size" (i.e. the number of subjects that are capable of transmitting at the time of feeding). Altogether, our findings suggest DSFs have great potential utility for assessing the public health impacts of emerging antimalarial tools, but additional research is needed to address issues of scalability and to establish correlation with community-wide clinical endpoints as well as complementary in vitro measures, such as standard membrane feeding assays. Published by Elsevier Ltd.

Effects of antenatal care and HIV treatment integration on elements of the PMTCT cascade: Results from the SHAIP cluster-randomized controlled trial in Kenya

PubMed Central

Turan, Janet M.; Onono, Maricianah; Steinfeld, Rachel L.; Shade, Starley B.; Owuor, Kevin; Washington, Sierra; Bukusi, Elizabeth A.; Ackers, Marta L.; Kioko, Jackson; Interis, Evelyn C.; Cohen, Craig R.

2015-01-01

Background Integrating antenatal care (ANC) and HIV care may improve uptake and retention in services along the prevention of mother-to-child transmission (PMTCT) cascade. The current study aimed to determine if integration of HIV services into ANC settings improves PMTCT service utilization outcomes. Methods ANC clinics in rural Kenya were randomized to integrated (6 clinics, 569 women) or non-integrated (6 clinics, 603 women) services. Intervention clinics provided all HIV services, including highly active antiretroviral therapy (HAART), while control clinics provided PMTCT services but referred women to HIV care clinics within the same facility. PMTCT utilization outcomes among HIV-infected women (maternal HIV care enrollment, HAART initiation, and 3-month infant HIV testing uptake) were compared using generalized estimating equations and Cox regression. Results HIV care enrollment was higher in intervention compared to control clinics (69% versus 36%, Odds Ratio (OR)=3.94, 95% Confidence Interval (CI): 1.14–13.63). Median time to enrollment was significantly shorter among intervention arm women (0 versus 8 days, Hazard Ratio (HR)=2.20, 95% CI: 1.62–3.01). Eligible women in the intervention arm were more likely to initiate HAART (40% versus 17%, OR=3.22, 95% CI: 1.81–5.72). Infant testing was more common in the intervention arm (25% versus 18%), however not statistically different. No significant differences were detected in postnatal service uptake or maternal retention. Conclusions Service integration increased maternal HIV care enrollment and HAART uptake. However, PMTCT utilization outcomes were still suboptimal, and postnatal service utilization remained poor in both study arms. Further improvements in the PMTCT cascade will require additional research and interventions. PMID:25967269

Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

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

Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long

2011-10-22

Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor.more » These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.« less

Quality of Life in Patients with Knee Osteoarthritis: A Commentary on Nonsurgical and Surgical Treatments

PubMed Central

Farr II, Jack; Miller, Larry E.; Block, Jon E.

2013-01-01

Knee osteoarthritis (OA) has a significant negative impact on health-related quality of life (HRQoL). Identification of therapies that improve HRQoL in patients with knee OA may mitigate the clinical, economic, and social burden of this disease. The purpose of this commentary is to report the impact of knee OA on HRQoL, describe the change in HRQoL attributable to common knee OA interventions, and summarize findings from clinical trials of a promising therapy. Nonsurgical therapies do not reliably modify HRQoL in knee OA patients given their general inability to alleviate physical manifestations of OA. Surgical knee OA interventions generally result in good to excellent patient outcomes. However, there are significant barriers to considering surgery, which limits clinical utility. Therapies that most effectively control OA-related pain with a low risk: benefit ratio will likely have the greatest benefit on HRQoL with greater rates of patient adoption. Initial clinical trial findings suggest that less invasive joint unloading implants hold promise in bridging the therapeutic gap between nonsurgical and surgical treatments for the knee OA patient. PMID:24285987

WE-G-217BCD-04: Diagnostic Image Quality Evaluation of a Dedicated Extremity Cone- Beam CT Scanner: Pre-Clinical Studies and First Clinical Results.

PubMed

Muhit, A; Zbijewski, W; Stayman, J; Thawait, G; Yorkston, J; Foos, D; Packard, N; Yang, D; Senn, R; Carrino, J; Siewerdsen, J

2012-06-01

To assess the diagnostic performance of a prototype cone-beam CT (CBCT) scanner developed for musculoskeletal extremity imaging. Studies involved controlled observer studies conducted subsequent to rigorous technical assessment as well as patient images from the first clinical trial in imaging the hand and knee. Performance assessment included: 1.) rigorous technical assessment; 2.) controlled observer studies using CBCT images of cadaveric specimens; and 3.) first clinical images. Technical assessment included measurement of spatial resolution (MTF), constrast, and noise (SDNR) versus kVp and dose using standard CT phantoms. Diagnostic performance in comparison to multi- detector CT (MDCT) was assessed in controlled observer studies involving 12 cadaveric hands and knees scanned with and without abnormality (fracture). Observer studies involved five radiologists rating pertinent diagnostics tasks in 9-point preference and 10-point diagnostic satisfaction scales. Finally, the first clinical images from an ongoing pilot study were assessed in terms of diagnostic utility in disease assessment and overall workflow in patient setup. Quantitative assessment demonstrated sub-mm spatial resolution (MTF exceeding 10% out to 15-20 cm-1) and SDNR sufficient for relevant soft-tissue visualization tasks at dose <10 mGy. Observer studies confirmed optimal acquisition techniques and demonstrated superior utility of combined soft-tissue visualization and isotropic spatial resolution in diagnostic tasks. Images from the patient trial demonstrate exquisite contrast and detail and the ability to detect tissue impingement in weight-bearing exams. The prototype CBCT scanner provides isotropic spatial resolution superior to standard-protocol MDCT with soft-tissue visibility sufficient for a broad range of diagnostic tasks in musculoskeletal radiology. Dosimetry and workflow were advantageous in comparison to whole-body MDCT. Multi-mode and weight-bearing capabilities add valuable functionality. An ongoing clinical study further assesses diagnostic utility and defines the role of such technology in the diagnostic arsenal. - Research Grant, Carestream Health - Research Grant, National Institutes of Health 2R01-CA-112163. © 2012 American Association of Physicists in Medicine.

Influence of Clinical Trial Site Enrollment on Patient Characteristics, Protocol Completion, and End Points: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

PubMed

Greene, Stephen J; Hernandez, Adrian F; Sun, Jie-Lena; Metra, Marco; Butler, Javed; Ambrosy, Andrew P; Ezekowitz, Justin A; Starling, Randall C; Teerlink, John R; Schulte, Phillip J; Voors, Adriaan A; Armstrong, Paul W; O'Connor, Christopher M; Mentz, Robert J

2016-09-01

Most international acute heart failure trials have failed to show benefit with respect to key end points. The impact of site enrollment and protocol execution on trial performance is unclear. We assessed the impact of varying site enrollment volume among all 7141 acute heart failure patients from the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). Overall, 398 sites enrolled ≥1 patient, and median enrollment was 12 patients (interquartile range, 5-23). Patients from high enrolling sites (>60 patients/site) tended to have lower ejection fraction, worse New York Heart Association functional class, and lower utilization of guideline-directed medical therapy but fewer comorbidities and lower B-type natriuretic peptide level. Every 10 patient increase (up to 100 patients) in site enrollment correlated with lower likelihood of protocol noncompletion (odds ratio, 0.93; 95% confidence interval [CI], 0.89-0.98). After adjustment, increasing site enrollment predicted higher risk of persistent dyspnea at 6 hours (per 10 patient increase: odds ratio 1.02; 95% CI, 1.01-1.03) but not at 24 hours (odds ratio, 0.99; 95% CI, 0.98-1.00). Higher site enrollment was independently associated with lower risk of 30-day death or rehospitalization (per 10 patient increase: odds ratio, 0.98, 95% CI, 0.96-0.99) but not 180-day mortality (hazard ratio, 0.99; 95% CI, 0.98-1.01). The influence of increasing site enrollment on clinical end points varied across geographic regions with strongest associations in Latin America and Asia-Pacific (all interaction P<0.01). In this large, acute heart failure trial, site enrollment correlated with protocol completion and was independently associated with trial end points. Individual and regional site performance present challenges to be considered in design of future acute heart failure trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. © 2016 American Heart Association, Inc.

Effect of maternal vitamin D3 supplementation on maternal health, birth outcomes, and infant growth among HIV-infected Tanzanian pregnant women: study protocol for a randomized controlled trial.

PubMed

Sudfeld, Christopher R; Manji, Karim P; Duggan, Christopher P; Aboud, Said; Muhihi, Alfa; Sando, David M; Al-Beity, Fadhlun M Alwy; Wang, Molin; Fawzi, Wafaie W

2017-09-04

Vitamin D has significant immunomodulatory effects on both adaptive and innate immune responses. Observational studies indicate that adults infected with HIV with low vitamin D status may be at increased risk of mortality, pulmonary tuberculosis, and HIV disease progression. Growing observational evidence also suggests that low vitamin D status in pregnancy may increase the risk of adverse birth and infant health outcomes. As a result, antiretroviral therapy (ART) adjunct vitamin D 3 supplementation may improve the health of HIV-infected pregnant women and their children. The Trial of Vitamins-5 (ToV5) is an individually randomized, double-blind, placebo-controlled trial of maternal vitamin D 3 (cholecalciferol) supplementation conducted among 2300 HIV-infected pregnant women receiving triple-drug ART under Option B+ in Dar es Salaam, Tanzania. HIV-infected pregnant women of 12-27 weeks gestation are randomized to either: 1) 3000 IU vitamin D 3 taken daily from randomization in pregnancy until trial discharge at 12 months postpartum; or 2) a matching placebo regimen. Maternal participants are followed-up at monthly clinic visits during pregnancy, at delivery, and then with their children at monthly postpartum clinic visits. The primary efficacy outcomes of the trial are: 1) maternal HIV disease progression or death; 2) risk of small-for-gestational age (SGA) births; and 3) risk of infant stunting at 1 year of age. The primary safety outcome of the trial is incident maternal hypercalcemia. Secondary outcomes include a range of clinical and biological maternal and child health outcomes. The ToV5 will provide causal evidence on the effect of vitamin D 3 supplementation on HIV progression and death, SGA births, and infant stunting at 1 year of age. The results of the trial are likely generalizable to HIV-infected pregnant women and their children in similar resource-limited settings utilizing the Option B+ approach. ClinicalTrials.gov identifier: NCT02305927 . Registered on 29 October 2014.

CNS sites cooperate to detect duplicate subjects with a clinical trial subject registry.

PubMed

Shiovitz, Thomas M; Wilcox, Charles S; Gevorgyan, Lilit; Shawkat, Adnan

2013-02-01

To report the results of the first 1,132 subjects in a pilot project where local central nervous system trial sites collaborated in the use of a subject database to identify potential duplicate subjects. Central nervous system sites in Los Angeles and Orange County, California, were contacted by the lead author to seek participation in the project. CTSdatabase, a central nervous system-focused trial subject registry, was utilized to track potential subjects at pre-screen. Subjects signed an institutional review board-approved authorization prior to participation, and site staff entered their identifiers by accessing a website. Sites were prompted to communicate with each other or with the database administrator when a match occurred between a newly entered subject and a subject already in the database. Between October 30, 2011, and August 31, 2012, 1,132 subjects were entered at nine central nervous system sites. Subjects continue to be entered, and more sites are anticipated to begin participation by the time of publication. Initially, there were concerns at a few sites over patient acceptance, financial implications, and/or legal and privacy issues, but these were eventually overcome. Patient acceptance was estimated to be above 95 percent. Duplicate Subjects (those that matched several key identifiers with subjects at different sites) made up 7.78 percent of the sample and Certain Duplicates (matching identifiers with a greater than 1 in 10 million likelihood of occurring by chance in the general population) accounted for 3.45 percent of pre-screens entered into the database. Many of these certain duplicates were not consented for studies because of the information provided by the registry. The use of a clinical trial subject registry and cooperation between central nervous system trial sites can reduce the number of duplicate and professional subjects entering clinical trials. To be fully effective, a trial subject database could be integrated into protocols across pharmaceutical companies, thereby mandating site participation and increasing the likelihood that duplicate subjects will be removed before they enter (and negatively affect) clinical trials.

Clinical translation of controlled protein delivery systems for tissue engineering.

PubMed

Spiller, Kara L; Vunjak-Novakovic, Gordana

2015-04-01

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed.

Are prenatal care resources distributed efficiently across high-risk and low-risk mothers?

PubMed

Mukhopadhyay, Sankar; Wendel, Jeanne

2008-09-01

The Institute for Clinical Systems Improvement recommends reducing the number of prenatal care visits recommended for low-risk women, citing evidence from a randomized clinical trial indicating that the reduction would not adversely impact infant health. We investigate the implicit hypothesis that prenatal care resources are not distributed efficiently across high-risk and low-risk women. Using clinic-reported prenatal care and an inclusive measure of infant health, we report evidence indicating inefficient resource utilization: prenatal care only boosts infant health when mothers have specific pre-existing diagnoses, but women with high potential to benefit from care do not obtain more care than other women.

Clinical translation of controlled protein delivery systems for tissue engineering

PubMed Central

Spiller, Kara L.; Vunjak-Novakovic, Gordana

2013-01-01

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed. PMID:25787736

Predictive Utility of Personality Disorder in Depression: Comparison of Outcomes and Taxonomic Approach.

PubMed

Newton-Howes, Giles; Mulder, Roger; Ellis, Pete M; Boden, Joseph M; Joyce, Peter

2017-09-19

There is debate around the best model for diagnosing personality disorder, both in terms of its relationship to the empirical data and clinical utility. Four randomized controlled trials examining various treatments for depression were analyzed at an individual patient level. Three different approaches to the diagnosis of personality disorder were analyzed in these patients. A total of 578 depressed patients were included in the analysis. Personality disorder, however measured, was of little predictive utility in the short term but added significantly to predictive modelling of medium-term outcomes, accounting for more than twice as much of the variance in social functioning outcome as depression psychopathology. Personality disorder assessment is of predictive utility with longer timeframes and when considering social outcomes as opposed to symptom counts. This utility is sufficiently great that there appears to be value in assessing personality; however, no particular approach outperforms any other.

Comparative effectiveness and cost-effectiveness of Chuna manual therapy versus conventional usual care for nonacute low back pain: study protocol for a pilot multicenter, pragmatic randomized controlled trial (pCRN study).

PubMed

Shin, Byung-Cheul; Kim, Me-Riong; Cho, Jae-Heung; Jung, Jae-Young; Kim, Koh-Woon; Lee, Jun-Hwan; Nam, Kibong; Lee, Min Ho; Hwang, Eui-Hyoung; Heo, Kwang-Ho; Kim, Namkwen; Ha, In-Hyuk

2017-01-17

While Chuna manual therapy is a Korean manual therapy widely used primarily for low back pain (LBP)-related disorders in Korea, well-designed studies on the comparative effectiveness of Chuna manual therapy are scarce. This study is the protocol for a three-armed, multicenter, pragmatic randomized controlled pilot trial. Sixty severe nonacute LBP patients (pain duration of at least 3 weeks, Numeric Rating Scale (NRS) ≥5) will be recruited at four Korean medicine hospitals. Participants will be randomly allocated to the Chuna group (n = 20), usual care group (n = 20), or Chuna plus usual care group (n = 20) for 6 weeks of treatment. Usual care will consist of orally administered conventional medicine, physical therapy, and back pain care education. The trial will be conducted with outcome assessor and statistician blinding. The primary endpoint will be NRS of LBP at week 7 post randomization. Secondary outcomes include NRS of leg pain, the Oswestry Disability Index (ODI), the Patient Global Impression of Change (PGIC), the Credibility and Expectancy Questionnaire, lumbar range of motion (ROM), the EuroQol-5 Dimension (EQ-5D) health survey, the Health Utility Index III (HUI-III), and economic evaluation and safety data. Post-treatment follow-ups will be conducted at 1, 4, and 10 weeks after conclusion of treatment. This study will assess the comparative effectiveness of Chuna manual therapy compared to conventional usual care. Costs and effectiveness (utility) data will be analyzed for exploratory cost-effectiveness analysis. If this pilot study does not reach a definite conclusion due to its small sample size, these results will be used as preliminary results to calculate sample size for future large-scale clinical trials and contribute in the assessment of feasibility of a full-scale multicenter trial. Clinical Research Information Service (CRIS), KCT0001850 . Registered on 17 March 2016.

Design and methodological considerations of an effectiveness trial of a computer-assisted intervention: an example from the NIDA Clinical Trials Network.

PubMed

Campbell, Aimee N C; Nunes, Edward V; Miele, Gloria M; Matthews, Abigail; Polsky, Daniel; Ghitza, Udi E; Turrigiano, Eva; Bailey, Genie L; VanVeldhuisen, Paul; Chapdelaine, Rita; Froias, Autumn; Stitzer, Maxine L; Carroll, Kathleen M; Winhusen, Theresa; Clingerman, Sara; Perez, Livangelie; McClure, Erin; Goldman, Bruce; Crowell, A Rebecca

2012-03-01

Computer-assisted interventions hold the promise of minimizing two problems that are ubiquitous in substance abuse treatment: the lack of ready access to treatment and the challenges to providing empirically-supported treatments. Reviews of research on computer-assisted treatments for mental health and substance abuse report promising findings, but study quality and methodological limitations remain an issue. In addition, relatively few computer-assisted treatments have been tested among illicit substance users. This manuscript describes the methodological considerations of a multi-site effectiveness trial conducted within the National Institute on Drug Abuse's (NIDA's) National Drug Abuse Treatment Clinical Trials Network (CTN). The study is evaluating a web-based version of the Community Reinforcement Approach, in addition to prize-based contingency management, among 500 participants enrolled in 10 outpatient substance abuse treatment programs. Several potential effectiveness trial designs were considered and the rationale for the choice of design in this study is described. The study uses a randomized controlled design (with independent treatment arm allocation), intention-to-treat primary outcome analysis, biological markers for the primary outcome of abstinence, long-term follow-up assessments, precise measurement of intervention dose, and a cost-effectiveness analysis. Input from community providers during protocol development highlighted potential concerns and helped to address issues of practicality and feasibility. Collaboration between providers and investigators supports the utility of infrastructures that enhance research partnerships to facilitate effectiveness trials and dissemination of promising, technologically innovative treatments. Outcomes from this study will further the empirical knowledge base on the effectiveness and cost-effectiveness of computer-assisted treatment in clinical treatment settings. Copyright © 2011 Elsevier Inc. All rights reserved.

Financial returns on R&D: looking back at history, looking forward to adaptive licensing.

PubMed

Scannell, J W; Hinds, S; Evans, R

2015-01-01

Investment in R&D for drugs launched in the late 1970s to early 1990s generated good returns for investors. R&D was inexpensive. Clinical trial success rates were high. Consumption was increasing. Drug prices were outstripping inflation, which raised profit margins. Tax rates were falling. However, returns on R&D have been falling since the early 1990s given rising clinical trial costs, rising trial failure rates, and lower consumption growth in developed markets. Many investors believe that average financial returns on today's R&D will be below the cost of capital, particularly if US drug price inflation moderates. Thus R&D investment by major drug companies is flat or perhaps falling in real terms. Various regulatory initiatives have tried to streamline clinical development and approval. The latest is Adaptive Licensing (AL). The near-term effect of AL on industry-level financial returns will be modest. AL will, however, be salient for decisions to invest in specific trials and may make it easier for smaller companies to fund development. AL could become more important in the long run if it helps shift industry, regulators, and payers from what has been an increasingly linear model of innovation; predicated on the ideas that basic science predicts, trials test predictions, and trial results form a complete description of a drug's attributes. History shows that many drugs become important because doctors and patients discover utility that was not initially apparent to regulators, payers, or investors. One hope for AL, therefore, is that it will bring more acceptably safe chemical diversity into real world use at lower R&D cost.

Design and Methodological Considerations of an Effectiveness Trial of a Computer-assisted Intervention: An Example from the NIDA Clinical Trials Network

PubMed Central

Campbell, Aimee N. C.; Nunes, Edward V.; Miele, Gloria M.; Matthews, Abigail; Polsky, Daniel; Ghitza, Udi E.; Turrigiano, Eva; Bailey, Genie L.; VanVeldhuisen, Paul; Chapdelaine, Rita; Froias, Autumn; Stitzer, Maxine L.; Carroll, Kathleen M.; Winhusen, Theresa; Clingerman, Sara; Perez, Livangelie; McClure, Erin; Goldman, Bruce; Crowell, A. Rebecca

2011-01-01

Computer-assisted interventions hold the promise of minimizing two problems that are ubiquitous in substance abuse treatment: the lack of ready access to treatment and the challenges to providing empirically-supported treatments. Reviews of research on computer-assisted treatments for mental health and substance abuse report promising findings, but study quality and methodological limitations remain an issue. In addition, relatively few computer-assisted treatments have been tested among illicit substance users. This manuscript describes the methodological considerations of a multi-site effectiveness trial conducted within the National Institute on Drug Abuse's (NIDA's) National Drug Abuse Treatment Clinical Trials Network (CTN). The study is evaluating a web-based version of the Community Reinforcement Approach, in addition to prize-based contingency management, among 500 participants enrolled in 10 outpatient substance abuse treatment programs. Several potential effectiveness trial designs were considered and the rationale for the choice of design in this study is described. The study uses a randomized controlled design (with independent treatment arm allocation), intention-to-treat primary outcome analysis, biological markers for the primary outcome of abstinence, long-term follow-up assessments, precise measurement of intervention dose, and a cost-effectiveness analysis. Input from community providers during protocol development highlighted potential concerns and helped to address issues of practicality and feasibility. Collaboration between providers and investigators supports the utility of infrastructures that enhance research partnerships to facilitate effectiveness trials and dissemination of promising, technologically innovative treatments. Outcomes from this study will further the empirical knowledge base on the effectiveness and cost-effectiveness of computer-assisted treatment in clinical treatment settings. PMID:22085803

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

PubMed

Messager, Mathieu; Mirabel, Xavier; Tresch, Emmanuelle; Paumier, Amaury; Vendrely, Véronique; Dahan, Laetitia; Glehen, Olivier; Vasseur, Frederique; Lacornerie, Thomas; Piessen, Guillaume; El Hajbi, Farid; Robb, William B; Clisant, Stéphanie; Kramar, Andrew; Mariette, Christophe; Adenis, Antoine

2016-05-18

Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

[Features of Clinical Register of Chinese Medicine and Pharmacy Based on ClinicalTrials.gov. (USA)].

PubMed

Lu, Peng-fei; Liao, Xing; Xie, Yan-ming; Wang, Zhi-guo

2015-11-01

In recent 10 years, clinical trials of Chinese medicine and pharmacy (cMP) at clinicalTrials.gov.(USA) are gradually increasing. In order to analyze features of CMP clinical register, ClinicalTrials.gov register database were comprehensively retrieved in this study. Included clinical trials were input one item after another using EXCEL. A final of 348 CMP clinical trials were included. Results showed that China occupied the first place in CMP clinical register, followed by USA. CMP clinical trials, sponsored mainly by colleges/universities and hospitals, mostly covered interventional studies on evaluating safety/effectiveness of CMP. The proportions of studies, sponsored by mainland China and companies, recruitment trials and multi-center clinical trials in interventional trials were increasing. The proportions of studies sponsored by Hong Kong and Taiwan, research completed trials, unclear research status, phase III clinical trials, and published research trials in interventional trials were decreasing. Published ratios of CMP clinical trials were quite low. There were more missing types and higher proportions in trial register information.

ACR Appropriateness Criteria®  Resectable Rectal Cancer

PubMed Central

2012-01-01

The management of resectable rectal cancer continues to be guided by clinical trials and advances in technique. Although surgical advances including total mesorectal excision continue to decrease rates of local recurrence, the management of locally advanced disease (T3-T4 or N+) benefits from a multimodality approach including neoadjuvant concomitant chemotherapy and radiation. Circumferential resection margin, which can be determined preoperatively via MRI, is prognostic. Toxicity associated with radiation therapy is decreased by placing the patient in the prone position on a belly board, however for patients who cannot tolerate prone positioning, IMRT decreases the volume of normal tissue irradiated. The use of IMRT requires knowledge of the patterns of spreads and anatomy. Clinical trials demonstrate high variability in target delineation without specific guidance demonstrating the need for peer review and the use of a consensus atlas. Concomitant with radiation, fluorouracil based chemotherapy remains the standard, and although toxicity is decreased with continuous infusion fluorouracil, oral capecitabine is non-inferior to the continuous infusion regimen. Additional chemotherapeutic agents, including oxaliplatin, continue to be investigated, however currently should only be utilized on clinical trials as increased toxicity and no definitive benefit has been demonstrated in clinical trials. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID:23006527

Test of memory malingering (TOMM) trial 1 as a screening measure for insufficient effort.

PubMed

O'Bryant, Sid E; Engel, Lisa R; Kleiner, Jennifer S; Vasterling, Jennifer J; Black, F William

2007-05-01

The identification of insufficient effort is critical to neuropsychological evaluation, and several existing instruments assess effort on neuropsychological tasks. Yet instruments designed to detect insufficient effort are underutilized in standard neuropsychological assessments, perhaps in part because they typically require significant administration time and are, therefore, not ideally suited to screening contexts. The Test of Memory Malingering (TOMM) is a commonly administered, well-validated symptom validity test. This study evaluates the utility of TOMM Trial 1 as a relatively brief screening measure of insufficient effort. Results suggest that TOMM Trial 1 demonstrates high diagnostic accuracy and is a viable option for screening insufficient effort. Diagnostic accuracy estimates are presented for a range of base rates. The need for more comprehensive SVT assessment in most clinical and forensic situation is discussed.

Including whey protein and whey permeate in ready-to-use supplementary food improves recovery rates in children with moderate acute malnutrition: A randomized, double-blind clinical trial

USDA-ARS?s Scientific Manuscript database

The utility of dairy ingredients in the supplementary foods used in the treatment of childhood moderate acute malnutrition (MAM) remains unsettled. We evaluated the effectiveness of a peanut-based ready-to-use supplementary food (RUSF) with soy protein compared with a novel RUSF containing dairy in...