Informing efficient randomised controlled trials: exploration of challenges in developing progression criteria for internal pilot studies.

PubMed

Avery, Kerry N L; Williamson, Paula R; Gamble, Carrol; O'Connell Francischetto, Elaine; Metcalfe, Chris; Davidson, Peter; Williams, Hywel; Blazeby, Jane M

2017-02-17

Designing studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or 'progression' criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. A structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders. There is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decision-making process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented. Systematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Design and analysis of group-randomized trials in cancer: A review of current practices.

PubMed

Murray, David M; Pals, Sherri L; George, Stephanie M; Kuzmichev, Andrey; Lai, Gabriel Y; Lee, Jocelyn A; Myles, Ranell L; Nelson, Shakira M

2018-06-01

The purpose of this paper is to summarize current practices for the design and analysis of group-randomized trials involving cancer-related risk factors or outcomes and to offer recommendations to improve future trials. We searched for group-randomized trials involving cancer-related risk factors or outcomes that were published or online in peer-reviewed journals in 2011-15. During 2016-17, in Bethesda MD, we reviewed 123 articles from 76 journals to characterize their design and their methods for sample size estimation and data analysis. Only 66 (53.7%) of the articles reported appropriate methods for sample size estimation. Only 63 (51.2%) reported exclusively appropriate methods for analysis. These findings suggest that many investigators do not adequately attend to the methodological challenges inherent in group-randomized trials. These practices can lead to underpowered studies, to an inflated type 1 error rate, and to inferences that mislead readers. Investigators should work with biostatisticians or other methodologists familiar with these issues. Funders and editors should ensure careful methodological review of applications and manuscripts. Reviewers should ensure that studies are properly planned and analyzed. These steps are needed to improve the rigor and reproducibility of group-randomized trials. The Office of Disease Prevention (ODP) at the National Institutes of Health (NIH) has taken several steps to address these issues. ODP offers an online course on the design and analysis of group-randomized trials. ODP is working to increase the number of methodologists who serve on grant review panels. ODP has developed standard language for the Application Guide and the Review Criteria to draw investigators' attention to these issues. Finally, ODP has created a new Research Methods Resources website to help investigators, reviewers, and NIH staff better understand these issues. Published by Elsevier Inc.

Achieving appropriate design for developing world heath care: the case of a low-cost autoclave for primary health clinics.

PubMed

Cho, Hallie S; Tao, Gregory D; Winter, Amos

2012-01-01

In developing world health clinics, incidence of surgical site infection is 2 to 10 times higher than in developed world hospitals. This paper identifies lack of availability of appropriately designed, low-cost autoclaves in developing world health clinics as a major contributing factor to the dramatic gap in surgical site infection rates. The paper describes the process of developing a low-cost autoclave that addresses the unique challenges faced by developing world primary health clinics and discusses how appropriateness of design was determined. The resulting pressure cooker-based autoclave design was fabricated and tested against the CDC specifications. Twelve partnering clinics in Nepal trialed these autoclaves from July until December 2012.

Bayesian adaptive phase II screening design for combination trials

PubMed Central

Cai, Chunyan; Yuan, Ying; Johnson, Valen E

2013-01-01

Background Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Methods Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Results Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments. Limitations The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. Conclusions The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial. PMID:23359875

Cause-effect relationships in nutritional intervention studies for health claims substantiation: guidance for trial design.

PubMed

Navas-Carretero, Santiago; Martinez, J Alfredo

2015-07-01

The growing worldwide interest on functional food research has been accompanied by increasing regulatory guidelines in this area, with the aim of ensuring that any claimed effect in foods, beyond their nutritional role, is based on scientific unequivocal evidence. In order to assess the cause-effect relationship between the regular consumption of a food or a food component and the beneficial outcome for the consumer, an appropriate study design is required. Previous knowledge and research on the specific claimed food or product may be an adequate basis for defining a hypothesis and accurate objectives. Other key factors to take into account are based on the outcomes studied, the length of the trial, sample size and type, as well as the transparency on reporting the results obtained. Based on the Consolidated Standards on Reporting Trials statement (CONSORT), together with the specific guidelines published by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies, the present article aims at summarizing key questions conducting to the most appropriate study design for solid health claim substantiation.

Design of a randomized clinical trial of a colorectal cancer screening decision aid to promote appropriate screening in community-dwelling older adults.

PubMed

Kistler, Christine E; Golin, Carol; Morris, Carolyn; Dalton, Alexandra F; Harris, Russell P; Dolor, Rowena; Ferrari, Renée M; Brewer, Noel T; Lewis, Carmen L

2017-12-01

Appropriate colorectal cancer screening in older adults should be aligned with the likelihood of net benefit. In general, patient decision aids improve knowledge and values clarity, but in older adults, they may also help patients identify their individual likelihood of benefit and foster individualized decision-making. We report on the design of a randomized clinical trial to understand the effects of a patient decision aid on appropriate colorectal cancer screening. This report includes a description of the baseline characteristics of participants. English-speaking primary care patients aged 70-84 years who were not currently up to date with screening were recruited into a randomized clinical trial comparing a tailored colorectal cancer screening decision aid with an attention control. The intervention group received a decision aid that included a values clarification exercise and individualized decision-making worksheet, while the control group received an educational pamphlet on safe driving behaviors. The primary outcome was appropriate screening at 6 months based on chart review. We used a composite measure to define appropriate screening as screening for participants in good health, a discussion about screening for patients in intermediate health, and no screening for patients in poor health. Health state was objectively determined using patients' Charlson Comorbidity Index score and age. A total of 14 practices in central North Carolina participated as part of a practice-based research network. In total, 424 patients were recruited to participate and completed a baseline visit. Overall, 79% of participants were White and 58% female, with a mean age of 76.8 years. Patient characteristics between groups were similar by age, gender, race, education, insurance coverage, or work status. Overall, 70% had some college education or more, 57% were married, and virtually all had Medicare insurance (90%). The three primary medical conditions among the cohort were a history of diabetes, pneumonia, and cancer (28%, 26%, and 21%, respectively). We designed a randomized clinical trial to test a novel use of a patient decision aid to promote appropriate colorectal cancer screening and have recruited a diverse study population that seems similar between the intervention and control groups. The study should be able to determine the ability of a patient decision aid to increase individualized and appropriate colorectal cancer screening.

Proposed variations of the stepped-wedge design can be used to accommodate multiple interventions.

PubMed

Lyons, Vivian H; Li, Lingyu; Hughes, James P; Rowhani-Rahbar, Ali

2017-06-01

Stepped-wedge design (SWD) cluster-randomized trials have traditionally been used for evaluating a single intervention. We aimed to explore design variants suitable for evaluating multiple interventions in an SWD trial. We identified four specific variants of the traditional SWD that would allow two interventions to be conducted within a single cluster-randomized trial: concurrent, replacement, supplementation, and factorial SWDs. These variants were chosen to flexibly accommodate study characteristics that limit a one-size-fits-all approach for multiple interventions. In the concurrent SWD, each cluster receives only one intervention, unlike the other variants. The replacement SWD supports two interventions that will not or cannot be used at the same time. The supplementation SWD is appropriate when the second intervention requires the presence of the first intervention, and the factorial SWD supports the evaluation of intervention interactions. The precision for estimating intervention effects varies across the four variants. Selection of the appropriate design variant should be driven by the research question while considering the trade-off between the number of steps, number of clusters, restrictions for concurrent implementation of the interventions, lingering effects of each intervention, and precision of the intervention effect estimates. Copyright © 2017 Elsevier Inc. All rights reserved.

Series: Pragmatic trials and real world evidence: Paper 1. Introduction.

PubMed

Zuidgeest, Mira G P; Goetz, Iris; Groenwold, Rolf H H; Irving, Elaine; van Thiel, Ghislaine J M W; Grobbee, Diederick E

2017-08-01

This is the introductory paper in a series of eight papers. In this series, we integrate the theoretical design options with the practice of conducting pragmatic trials. For most new market-approved treatments, the clinical evidence is insufficient to fully guide physicians and policy makers in choosing the optimal treatment for their patients. Pragmatic trials can fill this gap, by providing evidence on the relative effectiveness of a treatment strategy in routine clinical practice, already in an early phase of development, while maintaining the strength of randomized controlled trials. Selecting the setting, study population, mode of intervention, comparator, and outcome are crucial in designing pragmatic trials. In combination with monitoring and data collection that does not change routine care, this will enable appropriate generalization to the target patient group in clinical practice. To benefit from the full potential of pragmatic trials, there is a need for guidance and tools in designing these studies while ensuring operational feasibility. This paper introduces the concept of pragmatic trial design. The complex interplay between pragmatic design options, feasibility, stakeholder acceptability, validity, precision, and generalizability will be clarified. In this way, balanced design choices can be made in pragmatic trials with an optimal chance of success in practice. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Changing the Paradigm for the Treatment and Development of New Therapies for FSGS

PubMed Central

Spino, Cathie; Jahnke, Jordan S.; Selewski, David T.; Massengill, Susan; Troost, Jonathan; Gipson, Debbie S.

2016-01-01

Focal segmental glomerulosclerosis (FSGS) is a renal pathology finding that represents a constellation of rare kidney diseases, which manifest as proteinuria, edema nephrotic syndrome, hypertension, and increased risk for kidney failure. Therapeutic options for FSGS are reviewed displaying the expected efficacy from 25 to 69% depending on specific therapy, patient characteristics, cost, and common side effects. This variability in treatment response is likely caused, in part, by the heterogeneity in the etiology and active molecular mechanisms of FSGS. Clinical trials in FSGS have been scant in number and slow to recruit, which may stem, in part, from reliance on classic clinical trial design paradigms. Traditional clinical trial designs based on the “learn and confirm” paradigm may not be appropriate for rare diseases, such as FSGS. Future drug development and testing will require novel approaches to trial designs that have the capacity to enrich study populations and adapt the trial in a planned way to gain efficiencies in trial completion timelines. A clinical trial simulation is provided that compares a classical and more modern design to determine the maximum tolerated dose in FSGS. PMID:27047908

In Defense of the Randomized Controlled Trial for Health Promotion Research

PubMed Central

Rosen, Laura; Manor, Orly; Engelhard, Dan; Zucker, David

2006-01-01

The overwhelming evidence about the role lifestyle plays in mortality, morbidity, and quality of life has pushed the young field of modern health promotion to center stage. The field is beset with intense debate about appropriate evaluation methodologies. Increasingly, randomized designs are considered inappropriate for health promotion research. We have reviewed criticisms against randomized trials that raise philosophical and practical issues, and we will show how most of these criticisms can be overcome with minor design modifications. By providing rebuttal to arguments against randomized trials, our work contributes to building a sound methodological base for health promotion research. PMID:16735622

Proposed variations of the stepped-wedge design can be used to accommodate multiple interventions

PubMed Central

Lyons, Vivian H; Li, Lingyu; Hughes, James P; Rowhani-Rahbar, Ali

2018-01-01

Objective Stepped wedge design (SWD) cluster randomized trials have traditionally been used for evaluating a single intervention. We aimed to explore design variants suitable for evaluating multiple interventions in a SWD trial. Study Design and Setting We identified four specific variants of the traditional SWD that would allow two interventions to be conducted within a single cluster randomized trial: Concurrent, Replacement, Supplementation and Factorial SWDs. These variants were chosen to flexibly accommodate study characteristics that limit a one-size-fits-all approach for multiple interventions. Results In the Concurrent SWD, each cluster receives only one intervention, unlike the other variants. The Replacement SWD supports two interventions that will not or cannot be employed at the same time. The Supplementation SWD is appropriate when the second intervention requires the presence of the first intervention, and the Factorial SWD supports the evaluation of intervention interactions. The precision for estimating intervention effects varies across the four variants. Conclusion Selection of the appropriate design variant should be driven by the research question while considering the trade-off between the number of steps, number of clusters, restrictions for concurrent implementation of the interventions, lingering effects of each intervention, and precision of the intervention effect estimates. PMID:28412466

Systemic Sclerosis Disease Modification Clinical Trials Design: Quo Vadis?

PubMed Central

Mendoza, Fabian A.; Keyes-Elstein, Lynette L.; Jimenez, Sergio A.

2012-01-01

The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should be of at least 12 months. Sample size calculations should consider differences that exceed the Minimal Important Difference. Other relevant trial designs and potential threats to study validity are also discussed. Previous SSc-disease modifying trials have been beset by high dropout rates. Analyses on the subset of subjects completing the trial or applying the last-observation-carried-forward approach can potentially lead to biased estimates and false conclusions. Strategies for retention of subjects should be included at the design stage and analyses to account for missing data should be performed. PMID:22422541

Comparative Effectiveness Research in Oncology

PubMed Central

2013-01-01

Although randomized controlled trials represent the gold standard for comparative effective research (CER), a number of additional methods are available when randomized controlled trials are lacking or inconclusive because of the limitations of such trials. In addition to more relevant, efficient, and generalizable trials, there is a need for additional approaches utilizing rigorous methodology while fully recognizing their inherent limitations. CER is an important construct for defining and summarizing evidence on effectiveness and safety and comparing the value of competing strategies so that patients, providers, and policymakers can be offered appropriate recommendations for optimal patient care. Nevertheless, methodological as well as political and social challenges for CER remain. CER requires constant and sophisticated methodological oversight of study design and analysis similar to that required for randomized trials to reduce the potential for bias. At the same time, if appropriately conducted, CER offers an opportunity to identify the most effective and safe approach to patient care. Despite rising and unsustainable increases in health care costs, an even greater challenge to the implementation of CER arises from the social and political environment questioning the very motives and goals of CER. Oncologists and oncology professional societies are uniquely positioned to provide informed clinical and methodological expertise to steer the appropriate application of CER toward critical discussions related to health care costs, cost-effectiveness, and the comparative value of the available options for appropriate care of patients with cancer. PMID:23697601

Cognitive Behavioral Therapy for 4- to 7-Year-Old Children with Anxiety Disorders: A Randomized Clinical Trial

ERIC Educational Resources Information Center

Hirshfeld-Becker, Dina R.; Masek, Bruce; Henin, Aude; Blakely, Lauren Raezer; Pollock-Wurman, Rachel A.; McQuade, Julia; DePetrillo, Lillian; Briesch, Jacquelyn; Ollendick, Thomas H.; Rosenbaum, Jerrold F.; Biederman, Joseph

2010-01-01

Objective: To examine the efficacy of a developmentally appropriate parent-child cognitive behavioral therapy (CBT) protocol for anxiety disorders in children ages 4-7 years. Method: Design: Randomized wait-list controlled trial. Conduct: Sixty-four children (53% female, mean age 5.4 years, 80% European American) with anxiety disorders were…

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

PubMed

Hicks, Karen A; Mahaffey, Kenneth W; Mehran, Roxana; Nissen, Steven E; Wiviott, Stephen D; Dunn, Billy; Solomon, Scott D; Marler, John R; Teerlink, John R; Farb, Andrew; Morrow, David A; Targum, Shari L; Sila, Cathy A; Hai, Mary T Thanh; Jaff, Michael R; Joffe, Hylton V; Cutlip, Donald E; Desai, Akshay S; Lewis, Eldrin F; Gibson, C Michael; Landray, Martin J; Lincoff, A Michael; White, Christopher J; Brooks, Steven S; Rosenfield, Kenneth; Domanski, Michael J; Lansky, Alexandra J; McMurray, John J V; Tcheng, James E; Steinhubl, Steven R; Burton, Paul; Mauri, Laura; O'Connor, Christopher M; Pfeffer, Marc A; Hung, H M James; Stockbridge, Norman L; Chaitman, Bernard R; Temple, Robert J

2018-02-27

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials. © 2018 American Heart Association, Inc.

Hypothesis testing in clinical trials.

PubMed

Green, S B

2000-08-01

In designing and analyzing any clinical trial, two issues related to patient heterogeneity must be considered: (1) the effect of chance and (2) the effect of bias. These issues are addressed by enrolling adequate numbers of patients in the study and using randomization for treatment assignment. An "intention-to-treat" analysis of outcome data includes all individuals randomized and counted in the group to which they are randomized. There is an increased risk of spurious results with a greater number of subgroup analyses, particularly when these analyses are data derived. Factorial designs are sometimes appropriate and can lead to efficiencies by addressing more than one comparison of interventions in a single trial.

Some design issues in trials of microbicides for the prevention of HIV infection.

PubMed

Fleming, Thomas R; Richardson, Barbra A

2004-08-15

Trials for the prevention of human immunodeficiency virus (HIV) infection that evaluate microbicides provide significant design challenges. Three of these design issues deserve more careful consideration. The first issue relates to the benefits of using both blinded and unblinded control groups when the placebo regimen may not be inert and when the effectiveness of an intervention heavily depends on behavioral, as well as biological, factors. The second issue relates to the strength of evidence required for regulatory approval for the marketing of drugs and biologics when only a single pivotal phase 3 clinical trial has provided such evidence. The third issue relates to the appropriate next step after the completion of phase 1 trials, as well as the specific merits of conducting phase 2b screening trials that assess the effects on the same clinical efficacy end point that will be the primary end point in a phase 3 trial. The issues considered in microbicide trials for the prevention of HIV infection are also of importance in many other clinical scenarios.

Evidence based general practice: a retrospective study of interventions in one training practice.

PubMed Central

Gill, P.; Dowell, A. C.; Neal, R. D.; Smith, N.; Heywood, P.; Wilson, A. E.

1996-01-01

OBJECTIVES--To estimate the proportion of interventions in general practice that are based on evidence from clinical trials and to assess the appropriateness of such an evaluation. DESIGN--Retrospective review of case notes. SETTING--One suburban training general practice. SUBJECTS--122 consecutive doctor-patient consultations over two days. MAIN OUTCOME MEASURES--Proportions of interventions based on randomised controlled trials (from literature search with Medline, pharmaceutical databases, and standard textbooks), on convincing non-experimental evidence, and without substantial evidence. RESULTS--21 of the 122 consultations recorded were excluded due to insufficient data; 31 of the interventions were based on randomised controlled trial evidence and 51 based on convincing non-experimental evidence. Hence 82/101 (81%) of interventions were based on evidence meeting our criteria. CONCLUSIONS--Most interventions within general practice are based on evidence from clinical trials, but the methods used in such trials may not be the most appropriate to apply to this setting. PMID:8608291

Recommendations for the Design and Analysis 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 Over the past 60 years the view that “alcoholism” is a disease for which the only acceptable goal of treatment is abstinence has given way to the recognition that alcohol use disorders (AUDs) occur on a continuum of severity, for which a variety of treatment options are appropriate. However, because the available treatments for AUDs are not effective for everyone, more research is needed to develop novel and more efficacious treatments to address the range of AUD severity in diverse populations. Here we offer recommendations for the design and analysis of alcohol treatment trials, with a specific focus on the careful conduct of randomized clinical trials of medications and non-pharmacological interventions for AUDs. Methods Narrative review of the quality of published clinical trials and recommendations for the optimal design and analysis of treatment trials for AUDs. Results Despite considerable improvements in the design of alcohol clinical trials over the past two decades, many studies of AUD treatments have used faulty design features and statistical methods that are known to produce biased estimates of treatment efficacy. Conclusions The published statistical and methodological literatures provide clear guidance on methods to improve clinical trial design and analysis. Consistent use of state-of-the-art design features and analytic approaches will enhance the internal and external validity of treatment trials for AUDs across the spectrum of severity. The ultimate result of this attention to methodological rigor is that better treatment options will be identified for patients with an AUD. PMID:26250333

21 CFR 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.

Code of Federal Regulations, 2011 CFR

2011-04-01

... effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate...

21 CFR 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.

Code of Federal Regulations, 2013 CFR

2013-04-01

... effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate...

21 CFR 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.

Code of Federal Regulations, 2014 CFR

2014-04-01

... effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate...

21 CFR 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.

Code of Federal Regulations, 2012 CFR

2012-04-01

... effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate...

21 CFR 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.

Code of Federal Regulations, 2010 CFR

2010-04-01

... effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate...

Are multiple-trial experiments appropriate for eyewitness identification studies? Accuracy, choosing, and confidence across trials.

PubMed

Mansour, J K; Beaudry, J L; Lindsay, R C L

2017-12-01

Eyewitness identification experiments typically involve a single trial: A participant views an event and subsequently makes a lineup decision. As compared to this single-trial paradigm, multiple-trial designs are more efficient, but significantly reduce ecological validity and may affect the strategies that participants use to make lineup decisions. We examined the effects of a number of forensically relevant variables (i.e., memory strength, type of disguise, degree of disguise, and lineup type) on eyewitness accuracy, choosing, and confidence across 12 target-present and 12 target-absent lineup trials (N = 349; 8,376 lineup decisions). The rates of correct rejections and choosing (across both target-present and target-absent lineups) did not vary across the 24 trials, as reflected by main effects or interactions with trial number. Trial number had a significant but trivial quadratic effect on correct identifications (OR = 0.99) and interacted significantly, but again trivially, with disguise type (OR = 1.00). Trial number did not significantly influence participants' confidence in correct identifications, confidence in correct rejections, or confidence in target-absent selections. Thus, multiple-trial designs appear to have minimal effects on eyewitness accuracy, choosing, and confidence. Researchers should thus consider using multiple-trial designs for conducting eyewitness identification experiments.

PIPELINEs: Creating Comparable Clinical Knowledge Efficiently by Linking Trial Platforms

PubMed Central

Shrier, AA; Antonijevic, Z; Beckman, RA; Campbell, RK; Chen, C; Flaherty, KT; Loewy, J; Lacombe, D; Madhavan, S; Selker, HP; Esserman, LJ

2016-01-01

Adaptive, seamless, multisponsor, multitherapy clinical trial designs executed as large scale platforms, could create superior evidence more efficiently than single‐sponsor, single‐drug trials. These trial PIPELINEs also could diminish barriers to trial participation, increase the representation of real‐world populations, and create systematic evidence development for learning throughout a therapeutic life cycle, to continually refine its use. Comparable evidence could arise from multiarm design, shared comparator arms, and standardized endpoints—aiding sponsors in demonstrating the distinct value of their innovative medicines; facilitating providers and patients in selecting the most appropriate treatments; assisting regulators in efficacy and safety determinations; helping payers make coverage and reimbursement decisions; and spurring scientists with translational insights. Reduced trial times and costs could enable more indications, reduced development cycle times, and improved system financial sustainability. Challenges to overcome range from statistical to operational to collaborative governance and data exchange. PMID:27643536

Conducting non-commercial international clinical trials: the ICR-CTSU experience.

PubMed

Fox, Lisa; Toms, Christy; Kernaghan, Sarah; Snowdon, Claire; Bliss, Judith M

2017-09-26

Academic clinical trials play a fundamental role in the development of new treatments, the repurposing of existing treatments and in addressing areas of unmet clinical need. With cancer treatments increasingly targeted at molecular subtypes, and with priority placed on developing new treatments for rare tumour types, the need for international trial participation to access sufficient patient numbers for successful trial conduct is growing. However, lack of harmonisation of international legal, ethical and financial systems can make this challenging and the cost and effort of conducting trials internationally can be considered prohibitive, particularly where the sample size is comparatively small. The Institute of Cancer Research - Clinical Trials and Statistics Unit (ICR-CTSU) is a UK-based academic clinical trials unit that specialises in the design, conduct and analysis of clinical trials of cancer treatments with an expanding portfolio of trials in molecular subtypes of breast and urological cancers and in other rare cancer types. Implementing appropriate mechanisms to enable international participation has therefore been imperative. In this article, we explain how we have approached the challenges involved and describe examples of successful international trial conduct, achieved through robust collaborations with academic and industry partners. Conducting academic trials internationally is challenging but can and should be achieved through appropriate governance mechanisms and strong collaborations.

A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios.

PubMed

Ryeznik, Yevgen; Sverdlov, Oleksandr

2018-06-04

Randomization designs for multiarm clinical trials are increasingly used in practice, especially in phase II dose-ranging studies. Many new methods have been proposed in the literature; however, there is lack of systematic, head-to-head comparison of the competing designs. In this paper, we systematically investigate statistical properties of various restricted randomization procedures for multiarm trials with fixed and possibly unequal allocation ratios. The design operating characteristics include measures of allocation balance, randomness of treatment assignments, variations in the allocation ratio, and statistical characteristics such as type I error rate and power. The results from the current paper should help clinical investigators select an appropriate randomization procedure for their clinical trial. We also provide a web-based R shiny application that can be used to reproduce all results in this paper and run simulations under additional user-defined experimental scenarios. Copyright © 2018 John Wiley & Sons, Ltd.

[Radiotherapy phase I trials' methodology: Features].

PubMed

Rivoirard, R; Vallard, A; Langrand-Escure, J; Guy, J-B; Ben Mrad, M; Yaoxiong, X; Diao, P; Méry, B; Pigne, G; Rancoule, C; Magné, N

2016-12-01

In clinical research, biostatistical methods allow the rigorous analysis of data collection and should be defined from the trial design to obtain the appropriate experimental approach. Thus, if the main purpose of phase I is to determine the dose to use during phase II, methodology should be finely adjusted to experimental treatment(s). Today, the methodology for chemotherapy and targeted therapy is well known. For radiotherapy and chemoradiotherapy phase I trials, the primary endpoint must reflect both effectiveness and potential treatment toxicities. Methodology should probably be complex to limit failures in the following phases. However, there are very few data about methodology design in the literature. The present study focuses on these particular trials and their characteristics. It should help to raise existing methodological patterns shortcomings in order to propose new and better-suited designs. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Design, analysis and presentation of factorial randomised controlled trials

PubMed Central

Montgomery, Alan A; Peters, Tim J; Little, Paul

2003-01-01

Background The evaluation of more than one intervention in the same randomised controlled trial can be achieved using a parallel group design. However this requires increased sample size and can be inefficient, especially if there is also interest in considering combinations of the interventions. An alternative may be a factorial trial, where for two interventions participants are allocated to receive neither intervention, one or the other, or both. Factorial trials require special considerations, however, particularly at the design and analysis stages. Discussion Using a 2 × 2 factorial trial as an example, we present a number of issues that should be considered when planning a factorial trial. The main design issue is that of sample size. Factorial trials are most often powered to detect the main effects of interventions, since adequate power to detect plausible interactions requires greatly increased sample sizes. The main analytical issues relate to the investigation of main effects and the interaction between the interventions in appropriate regression models. Presentation of results should reflect the analytical strategy with an emphasis on the principal research questions. We also give an example of how baseline and follow-up data should be presented. Lastly, we discuss the implications of the design, analytical and presentational issues covered. Summary Difficulties in interpreting the results of factorial trials if an influential interaction is observed is the cost of the potential for efficient, simultaneous consideration of two or more interventions. Factorial trials can in principle be designed to have adequate power to detect realistic interactions, and in any case they are the only design that allows such effects to be investigated. PMID:14633287

Designing effective drug and device development programs for hospitalized heart failure: A proposal for pretrial registries

PubMed Central

Greene, Stephen J.; Shah, Ami N.; Butler, Javed; Ambrosy, Andrew P.; Anker, Stefan D.; Chioncel, Ovidiu; Collins, Sean P.; Dinh, Wilfried; Dunnmon, Preston M.; Fonarow, Gregg C.; Lam, Carolyn S. P.; Mentz, Robert J.; Pieske, Burkert; Roessig, Lothar; Rosano, Giuseppe M. C.; Sato, Naoki; Vaduganathan, Muthiah; Gheorghiade, Mihai

2014-01-01

Recent international phase III clinical trials of novel therapies for hospitalized heart failure (HHF) have failed to improve the unacceptably high postdischarge event rate. These large studies have demonstrated notable geographic and site-specific variation in patient profiles and enrollment. Possible contributors to the lack of success in HHF outcome trials include challenges in selecting clinical sites capable of (1) providing adequate numbers of appropriately selected patients and (2) properly executing the study protocol. We propose a “pretrial registry” as a novel tool for improving the efficiency and quality of international HHF trials by focusing on the selection and cultivation of high-quality sites. A pretrial registry may help assess a site’s ability to achieve adequate enrollment of the target patient population, integrate protocol requirements into clinical workflow, and accomplish appropriate follow-up. Although such a process would be associated with additional upfront resource investment, this appropriation may be modest in comparison with the downstream costs associated with maintenance of poorly performing sites, failed clinical trials, and the global health and economic burden of HHF. This review is based on discussions between scientists, clinical trialists, and regulatory representatives regarding methods for improving international HHF trials that took place at the United States Food and Drug Administration on January 12th, 2012. PMID:25066552

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

Further statistics in dentistry. Part 4: Clinical trials 2.

PubMed

Petrie, A; Bulman, J S; Osborn, J F

2002-11-23

The principles which underlie a well-designed clinical trial were introduced in a previous paper. The trial should be controlled (to ensure that the appropriate comparisons are made), randomised (to avoid allocation bias) and, preferably, blinded (to obviate assessment bias). However, taken in isolation, these concepts will not necessarily ensure that meaningful conclusions can be drawn from the study. It is essential that the sample size is large enough to enable the effects of interest to be estimated precisely, and to detect any real treatment differences.

Methodological issues in the design of clinical trials for the treatment of multidrug-resistant tuberculosis: challenges and opportunities.

PubMed

Lienhardt, C; Davies, G

2010-05-01

The burden of multidrug-resistant tuberculosis (MDR-TB) is increasing dramatically in the world today, severely hampering global TB control. Treatment of MDR-TB is complex, prolonged, expensive and requires appropriate clinical and laboratory infrastructure. The majority of MDR-TB patients still do not have access to adequate diagnostic services or quality assured second-line drugs, leading to high levels of morbidity and mortality. More effective and efficient MDR-TB treatment with reduced toxicity that could be safely delivered to patients co-infected with human immunodeficiency virus (HIV) is an urgent research priority that could be cost-saving for health systems overall. In this context, understanding how best to design and execute randomised controlled trials to improve MDR-TB treatment has taken on new urgency, to identify the optimal combination(s) of existing and new drugs to assemble in efficient and safe regimen(s), preferably of short duration, that can be easily delivered to patients and safely combined with antiretroviral treatment. In the present report, we address the methodological issues in the design and execution of Phase II and Phase III trials arising from this goal. We suggest that a rational selection of appropriate designs and outcome measures, associated with the application of new diagnostic technology, could overcome many of the methodological and logistical problems. These advances could be key to historic improvements in the treatment of patients suffering from MDR-TB, and perhaps ultimately drug-susceptible TB. As with HIV, clinical trials in patients with drug-resistant disease may provide a quicker and less expensive path to licensure than trials for treatment of drug-susceptible disease.

Beliefs Alter Holistic Face Processing…If Response Bias is not Taken into Account

PubMed Central

Richler, Jennifer J.; Cheung, Olivia S.; Gauthier, Isabel

2012-01-01

The composite paradigm is widely used to quantify holistic processing (HP) of faces, but there is debate regarding the appropriate design (partial vs. complete) and measures in this task. Here, we argue that some operational definitions of HP are problematic because they are sensitive to top-down influences, even though the underlying concept is assumed to be cognitively impenetrable. In Experiment 1, we told one group of participants that the target face half would remain the same on 75% of trials, and another group that it would change on 75% of trials. The true proportion of same/different trials was 50% - groups only differed in their beliefs about the target halves. In Experiment 2, we manipulated the actual proportion of same/different trials in the experiment (75% of trials were same for one group, 75% of trials were different for another group), but did not give explicit instructions about proportions. In both experiments these manipulations influenced response biases that altered partial design measures of HP while the complete design measure was unaffected. We argue that the partial design should be abandoned because it has poor construct validity. PMID:22101018

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

PubMed

Hicks, Karen A; Mahaffey, Kenneth W; Mehran, Roxana; Nissen, Steven E; Wiviott, Stephen D; Dunn, Billy; Solomon, Scott D; Marler, John R; Teerlink, John R; Farb, Andrew; Morrow, David A; Targum, Shari L; Sila, Cathy A; Thanh Hai, Mary T; Jaff, Michael R; Joffe, Hylton V; Cutlip, Donald E; Desai, Akshay S; Lewis, Eldrin F; Gibson, C Michael; Landray, Martin J; Lincoff, A Michael; White, Christopher J; Brooks, Steven S; Rosenfield, Kenneth; Domanski, Michael J; Lansky, Alexandra J; McMurray, John J V; Tcheng, James E; Steinhubl, Steven R; Burton, Paul; Mauri, Laura; O'Connor, Christopher M; Pfeffer, Marc A; Hung, H M James; Stockbridge, Norman L; Chaitman, Bernard R; Temple, Robert J

2018-03-06

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials. Copyright © 2018 American College of Cardiology Foundation and American Heart Association, Inc. Published by Elsevier Inc. All rights reserved.

Recommendations for the Design and Analysis of Treatment Trials for Alcohol Use Disorders.

PubMed

Witkiewitz, Katie; Finney, John W; Harris, Alex H S; Kivlahan, Daniel R; Kranzler, Henry R

2015-09-01

Over the past 60 years, the view that "alcoholism" is a disease for which the only acceptable goal of treatment is abstinence has given way to the recognition that alcohol use disorders (AUDs) occur on a continuum of severity, for which a variety of treatment options are appropriate. However, because the available treatments for AUDs are not effective for everyone, more research is needed to develop novel and more efficacious treatments to address the range of AUD severity in diverse populations. Here we offer recommendations for the design and analysis of alcohol treatment trials, with a specific focus on the careful conduct of randomized clinical trials of medications and nonpharmacological interventions for AUDs. This paper provides a narrative review of the quality of published clinical trials and recommendations for the optimal design and analysis of treatment trials for AUDs. Despite considerable improvements in the design of alcohol clinical trials over the past 2 decades, many studies of AUD treatments have used faulty design features and statistical methods that are known to produce biased estimates of treatment efficacy. The published statistical and methodological literatures provide clear guidance on methods to improve clinical trial design and analysis. Consistent use of state-of-the-art design features and analytic approaches will enhance the internal and external validity of treatment trials for AUDs across the spectrum of severity. The ultimate result of this attention to methodological rigor is that better treatment options will be identified for patients with an AUD. Copyright © 2015 by the Research Society on Alcoholism.

When ethics constrains clinical research: trial design of control arms in "greater than minimal risk" pediatric trials.

PubMed

de Melo-Martín, Inmaculada; Sondhi, Dolan; Crystal, Ronald G

2011-09-01

For more than three decades clinical research in the United States has been explicitly guided by the idea that ethical considerations must be central to research design and practice. In spite of the centrality of this idea, attempting to balance the sometimes conflicting values of advancing scientific knowledge and protecting human subjects continues to pose challenges. Possible conflicts between the standards of scientific research and those of ethics are particularly salient in relation to trial design. Specifically, the choice of a control arm is an aspect of trial design in which ethical and scientific issues are deeply entwined. Although ethical quandaries related to the choice of control arms may arise when conducting any type of clinical trials, they are conspicuous in early phase gene transfer trials that involve highly novel approaches and surgical procedures and have children as the research subjects. Because of children's and their parents' vulnerabilities, in trials that investigate therapies for fatal, rare diseases affecting minors, the scientific and ethical concerns related to choosing appropriate controls are particularly significant. In this paper we use direct gene transfer to the central nervous system to treat late infantile neuronal ceroid lipofuscinosis to illustrate some of these ethical issues and explore possible solutions to real and apparent conflicts between scientific and ethical considerations.

Introducing rapid diagnostic tests for malaria into drug shops in Uganda: design and implementation of a cluster randomized trial.

PubMed

Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare I R; Hansen, Kristian S; Lal, Sham; Cundill, Bonnie; Lynch, Caroline A; Clarke, Siân E

2014-07-29

An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop vendors and implemented supporting interventions to orientate local communities (patients) and the public sector (health facility staff and district officials) to the behavioral changes in diagnosis, treatment and referral being introduced in drug shops. The intervention was designed to be evaluated through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions on diagnosis and treatment of malaria at drug shops, and affordable prices for mRDTs and ACTs in order to inform the design of the intervention and implementation modalities. The intervention required careful design with the intention to be acceptable, sustainable and effective. Critical components of intervention were: community sensitization and creating awareness, training of drug shop vendors to diagnose malaria with mRDTs, treat and refer customers to formal health facilities, giving pre-referral rectal artesunate and improved record-keeping. The primary outcome was the proportion of patients receiving appropriately-targeted treatment with ACT, evaluated against microscopy on a research blood slide. Introducing mRDTs in drug shops may seem simple, but our experience of intervention design, conduct and evaluation showed this to be a complex process requiring multiple interventions and evaluation components drawing from a combination of epidemiological, social science and health economics methodologies. The trial was conducted in phases sequenced such that each benefited from the other. The main challenges in designing this trial were maintaining a balance between a robust intervention to support effective behaviour change and introducing practices that would be sustainable in a real-life situation in tropical Africa; as well as achieving a detailed evaluation without inadvertently influencing prescribing behaviour. NCT01194557 registered with ClinicalTrials.gov 2 September 2010.

Immediate vs. delayed insertion of intrauterine contraception after second trimester abortion: study protocol for a randomized controlled trial

PubMed Central

2011-01-01

Background We describe the rationale and protocol for a randomized controlled trial (RCT) to assess whether intrauterine contraception placed immediately after a second trimester abortion will result in fewer pregnancies than current recommended practice of intended placement at 4 weeks post-abortion. Decision analysis suggests the novel strategy could substantially reduce subsequent unintended pregnancies and abortions. This paper highlights considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion. Methods/Design Consenting women choosing to use intrauterine contraception after abortion for a pregnancy of 12 to 24 weeks will be randomized to insertion timing groups either immediately (experimental intervention) or four weeks (recommended care) post abortion. Primary outcome measure is pregnancy rate at one year. Secondary outcomes include: cumulative pregnancy rates over five year follow-up period, comprehensive health economic analyses comparing immediate and delayed insertion groups, and device retention rates, complication rates (infection, expulsion) and, contraceptive method satisfaction. Web-based Contraception Satisfaction Questionnaires, clinical records and British Columbia linked health databases will be used to assess primary and secondary outcomes. Enrolment at all clinics in the province performing second trimester abortions began in May 2010 and is expected to complete in late 2011. Data on one year outcomes will be available for analysis in 2014. Discussion The RCT design combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry and hospital records, offers a unique opportunity to evaluate such an approach by determining pregnancy rate at one through five years among enrolled women. We highlight considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion. Trial registration Current Controlled Trials ISRCTN19506752 PMID:21672213

Pediatric obesity pharmacotherapy: current state of the field, review of the literature and clinical trial considerations.

PubMed

Kelly, A S; Fox, C K; Rudser, K D; Gross, A C; Ryder, J R

2016-07-01

Despite the increasing number of medications recently approved to treat obesity among adults, few agents have been formally evaluated in children or adolescents for this indication. Moreover, there is a paucity of guidance in the literature addressing best practices with regard to pediatric obesity pharmacotherapy clinical trial design, and only general recommendations have been offered by regulatory agencies on this topic. The purposes of this article are to (1) offer a background of the current state of the field of pediatric obesity medicine, (2) provide a brief review of the literature summarizing pediatric obesity pharmacotherapy clinical trials, and (3) highlight and discuss some of the unique aspects that should be considered when designing and conducting high-quality clinical trials evaluating the safety and efficacy of obesity medications in children and adolescents. Suggestions are offered in the areas of target population and eligibility criteria, clinical trial end-point selection, trial duration, implementation of lifestyle modification therapy and recruitment and retention of participants. Efforts should be made to design and conduct trials appropriately to ensure that high-quality evidence is generated on the safety and efficacy of various medications used to treat pediatric obesity.

Pediatric Obesity Pharmacotherapy: Current State of the Field, Review of the Literature, and Clinical Trial Considerations

PubMed Central

Kelly, Aaron S.; Fox, Claudia K.; Rudser, Kyle D.; Gross, Amy C.; Ryder, Justin R.

2017-01-01

Despite the increasing number of medications recently approved to treat obesity among adults, few agents have been formally evaluated in children or adolescents for this indication. Moreover, there is a paucity of guidance in the literature addressing best practices in regard to pediatric obesity pharmacotherapy clinical trial design, and only general recommendations have been offered by regulatory agencies on this topic. The purposes of this article are to: 1) offer a background of the current state of the field of pediatric obesity medicine; 2) provide a brief review of the literature summarizing pediatric obesity pharmacotherapy clinical trials; and 3) highlight and discuss some of the unique aspects that should be considered when designing and conducting high-quality clinical trials evaluating the safety and efficacy of obesity medications in children and adolescents. Suggestions are offered in the areas of target population and eligibility criteria, clinical trial endpoint selection, trial duration, implementation of lifestyle modification therapy, and recruitment and retention of participants. Efforts should be made to design and conduct trials appropriately to ensure that high-quality evidence is generated on the safety and efficacy of various medications used to treat pediatric obesity. PMID:27113643

Effects of an alert system on implantable cardioverter defibrillator-related anxiety: rationale, design, and endpoints of the PANORAMIC multicentre trial.

PubMed

Duru, Firat; Dorian, Paul; Favale, Stefano; Perings, Christian; Pedersen, Susanne S; Willems, Vincent

2010-05-01

Implantable cardioverter defibrillators (ICD) can prevent sudden cardiac death by delivering high-energy shocks in patients at risk of life-threatening ventricular tachyarrhythmias. Patients may be anxious about receiving inappropriate shocks in case of device or lead system malfunction, or about failing to receive needed therapy for the same reason. New devices include programmable vibrating patient notifiers (PN), which, by warning patients of a possible device dysfunction, might lower device-related anxiety. PAtient NOtifier feature for Reduction of Anxiety: a Multicentre ICD study (PANORAMIC) is a multicentre, randomized, clinical trial designed to examine the effects of the awareness of an active vibrating alert system on device-related anxiety. The trial will randomly assign 356 patients in a 1:1 design to a control group (PN OFF) vs. a treatment group (PN ON). Patients will be followed for 12 months, with visits scheduled at 6 and 12 months. During clinical follow-up visits, the ICD will be interrogated, and all patients will complete the Hospital Anxiety and Depression Scale and a device-related anxiety questionnaire. The sensitivity and specificity of PN, the effect of personality on anxiety, using the Type D scale (DS14), the number of delivered appropriate and inappropriate ICD therapies, changes in anxiety related to the delivery of appropriate or inappropriate shocks, crossovers from the assigned group, the number of hospitalizations, and the mortality rate will also be assessed. ClinicalTrials.gov Identifier: NCT00559559.

Design of trials for interrupting the transmission of endemic pathogens.

PubMed

Silkey, Mariabeth; Homan, Tobias; Maire, Nicolas; Hiscox, Alexandra; Mukabana, Richard; Takken, Willem; Smith, Thomas A

2016-06-06

Many interventions against infectious diseases have geographically diffuse effects. This leads to contamination between arms in cluster-randomized trials (CRTs). Pathogen elimination is the goal of many intervention programs against infectious agents, but contamination means that standard CRT designs and analyses do not provide inferences about the potential of interventions to interrupt pathogen transmission at maximum scale-up. A generic model of disease transmission was used to simulate infections in stepped wedge cluster-randomized trials (SWCRTs) of a transmission-reducing intervention, where the intervention has spatially diffuse effects. Simulations of such trials were then used to examine the potential of such designs for providing generalizable causal inferences about the impact of such interventions, including measurements of the contamination effects. The simulations were applied to the geography of Rusinga Island, Lake Victoria, Kenya, the site of the SolarMal trial on the use of odor-baited mosquito traps to eliminate Plasmodium falciparum malaria. These were used to compare variants in the proposed SWCRT designs for the SolarMal trial. Measures of contamination effects were found that could be assessed in the simulated trials. Inspired by analyses of trials of insecticide-treated nets against malaria when applied to the geography of the SolarMal trial, these measures were found to be robust to different variants of SWCRT design. Analyses of the likely extent of contamination effects supported the choice of cluster size for the trial. The SWCRT is an appropriate design for trials that assess the feasibility of local elimination of a pathogen. The effects of incomplete coverage can be estimated by analyzing the extent of contamination between arms in such trials, and the estimates also support inferences about causality. The SolarMal example illustrates how generic transmission models incorporating spatial smoothing can be used to simulate such trials for a power calculation and optimization of cluster size and randomization strategies. The approach is applicable to a range of infectious diseases transmitted via environmental reservoirs or via arthropod vectors.

Methodological Issues in Trials of Complementary and Alternative Medicine Interventions

PubMed Central

Sikorskii, Alla; Wyatt, Gwen; Victorson, David; Faulkner, Gwen; Rahbar, Mohammad Hossein

2010-01-01

Background Complementary and alternative medicine (CAM) use is widespread among cancer patients. Information on safety and efficacy of CAM therapies is needed for both patients and health care providers. Well-designed randomized clinical trials (RCTs) of CAM therapy interventions can inform both clinical research and practice. Objectives To review important issues that affect the design of RCTs for CAM interventions. Methods Using the methods component of the Consolidated Standards for Reporting Trials (CONSORT) as a guiding framework, and a National Cancer Institute-funded reflexology study as an exemplar, methodological issues related to participants, intervention, objectives, outcomes, sample size, randomization, blinding, and statistical methods were reviewed. Discussion Trials of CAM interventions designed and implemented according to appropriate methodological standards will facilitate the needed scientific rigor in CAM research. Interventions in CAM can be tested using proposed methodology, and the results of testing will inform nursing practice in providing safe and effective supportive care and improving the well-being of patients. PMID:19918155

Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable.

PubMed

Fisher, Marc; Albers, Gregory W; Donnan, Geoffrey A; Furlan, Anthony J; Grotta, James C; Kidwell, Chelsea S; Sacco, Ralph L; Wechsler, Lawrence R

2005-08-01

Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies.

Randomized Controlled Trials in Music Therapy: Guidelines for Design and Implementation.

PubMed

Bradt, Joke

2012-01-01

Evidence from randomized controlled trials (RCTs) plays a powerful role in today's healthcare industry. At the same time, it is important that multiple types of evidence contribute to music therapy's knowledge base and that the dialogue of clinical effectiveness in music therapy is not dominated by the biomedical hierarchical model of evidence-based practice. Whether or not one agrees with the hierarchical model of evidence in the current healthcare climate, RCTs can contribute important knowledge to our field. Therefore, it is important that music therapists are prepared to design trials that meet current methodological standards and, equally important, are able to respond appropriately to those design aspects that may not be feasible in music therapy research. To provide practical guidelines to music therapy researchers for the design and implementation of RCTs as well as to enable music therapists to be well-informed consumers of RCT evidence. This article reviews key design aspects of RCTs and discusses how to best implement these standards in music therapy trials. A systematic presentation of basic randomization methods, allocation concealment strategies, issues related to blinding in music therapy trials and strategies for implementation, the use of treatment manuals, types of control groups, outcome selection, and sample size computation is provided. Despite the challenges of meeting all key design demands typical of an RCT, it is possible to design rigorous music therapy RCTs that accurately estimate music therapy treatment benefits.

How do you design randomised trials for smaller populations? A framework.

PubMed

Parmar, Mahesh K B; Sydes, Matthew R; Morris, Tim P

2016-11-25

How should we approach trial design when we can get some, but not all, of the way to the numbers required for a randomised phase III trial?We present an ordered framework for designing randomised trials to address the problem when the ideal sample size is considered larger than the number of participants that can be recruited in a reasonable time frame. Staying with the frequentist approach that is well accepted and understood in large trials, we propose a framework that includes small alterations to the design parameters. These aim to increase the numbers achievable and also potentially reduce the sample size target. The first step should always be to attempt to extend collaborations, consider broadening eligibility criteria and increase the accrual time or follow-up time. The second set of ordered considerations are the choice of research arm, outcome measures, power and target effect. If the revised design is still not feasible, in the third step we propose moving from two- to one-sided significance tests, changing the type I error rate, using covariate information at the design stage, re-randomising patients and borrowing external information.We discuss the benefits of some of these possible changes and warn against others. We illustrate, with a worked example based on the Euramos-1 trial, the application of this framework in designing a trial that is feasible, while still providing a good evidence base to evaluate a research treatment.This framework would allow appropriate evaluation of treatments when large-scale phase III trials are not possible, but where the need for high-quality randomised data is as pressing as it is for common diseases.

Improving psychotropic drug prescription in nursing home patients with dementia: design of a cluster randomized controlled trial

PubMed Central

2013-01-01

Background Neuropsychiatric symptoms are highly prevalent in nursing home patients with dementia. Despite modest effectiveness and considerable side effects, psychotropic drugs are frequently prescribed for these neuropsychiatric symptoms. This raises questions whether psychotropic drugs are appropriately prescribed. The aim of the PROPER (PRescription Optimization of Psychotropic drugs in Elderly nuRsing home patients with dementia) II study is to investigate the efficacy of an intervention for improving the appropriateness of psychotropic drug prescription in nursing home patients with dementia. Methods/design The PROPER II study is a multi-center cluster randomized controlled, pragmatic trial using parallel groups. It has a duration of eighteen months and four six-monthly assessments. Six nursing homes will participate in the intervention and six will continue care as usual. The nursing homes will be located throughout the Netherlands, each participating with two dementia special care units with an average of fifteen patients per unit, resulting in 360 patients. The intervention consists of a structured and repeated multidisciplinary medication review supported by education and continuous evaluation. It is conducted by pharmacists, physicians, and nurses and consists of three components: 1) preparation and education, 2) conduct, and 3) evaluation/guidance. The primary outcome is the proportion of patients with appropriate psychotropic drug use. Secondary outcomes are the overall frequency of psychotropic drug use, neuropsychiatric symptoms, quality of life, activities of daily living, psychotropic drug side effects and adverse events (including cognition, comorbidity, and mortality). Besides, a process analysis on the intervention will be carried out. Discussion This study is expected to improve the appropriateness of psychotropic drug prescription for neuropsychiatric symptoms in nursing home patients with dementia by introducing a structured and repeated multidisciplinary medication review supported by education and continuous evaluation. Trial registration Netherlands Trial Registry (NTR): NTR3569. PMID:24180295

Fracture healing: a consensus report from the International Osteoporosis Foundation Fracture Working Group.

PubMed

Silverman, S L; Kupperman, E S; Bukata, S V

2016-07-01

We used the RAND UCLA appropriateness method to decide appropriateness of use of osteoporosis medication after incident fracture and potential for fracture healing and make suggestions for trial design for clinical and preclinical research. To develop appropriateness criteria to assist in the use and study of osteoporosis medications in patients with recent fracture and in the potential use of osteoporosis medications to enhance delayed fracture healing. To promote further research by suggesting preclinical and clinical trial design for studies where fracture healing is the endpoint. RAND/UCLA appropriateness method (RUAM). A panel of experts, both members and non-members of the International Osteoporosis Foundation Fracture Working Group, were identified consisting of geriatricians, rheumatologists, orthopedists, endocrinologists, and internists. This resulted in a round 1 panel of 15 panelists, round 2 panel of 15 members, and a round 3 panel of 14 members. Agreement on statements and scenarios using RUAM. Three rounds of voting by panelists took place. Agreement in a third round was reached for 111 statements and scenarios, measured by median panel ratings and the amount of dispersion of panel ratings, based on the interpercentile range. An expert panel validated a set of statements and scenarios about the use of osteoporosis medications after incident fracture and use of these medications to enhance delayed fracture healing and made recommendations for study designs to investigate the effect of osteoporosis medications on fracture healing. The result of this exercise is intended to assist in improving patient care by identifying the appropriateness of use of osteoporosis medications after fracture and in fracture healing and to make suggestions for further preclinical and clinical research.

MODUL-a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach.

PubMed

Schmoll, Hans-Joachim; Arnold, Dirk; de Gramont, Aimery; Ducreux, Michel; Grothey, Axel; O'Dwyer, Peter J; Van Cutsem, Eric; Hermann, Frank; Bosanac, Ivan; Bendahmane, Belguendouz; Mancao, Christoph; Tabernero, Josep

2018-06-01

The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response. MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study. MODUL is ongoing and its adaptable nature permits timely and efficient recruitment of patients into the most appropriate cohort. Recruitment will take place over approximately 5 years in Europe, Asia, Africa, and South America. The design of MODUL with ongoing parallel/sequential treatment cohorts means that the overall size and duration of the trial can be modified/prolonged based on accumulation of new data. The early success of the current trial suggests that the design may provide definitive leads in a patient-friendly and relatively economical trial structure. Along with other biomarker-driven trials that are currently underway, it is hoped that MODUL will contribute to the continuing evolution of clinical trial design and permit a more 'tailored' approach to the treatment of patients with mCRC.

When Ethics Constrains Clinical Research: Trial Design of Control Arms in “Greater Than Minimal Risk” Pediatric Trials

PubMed Central

de Melo-Martín, Inmaculada; Sondhi, Dolan

2011-01-01

Abstract For more than three decades clinical research in the United States has been explicitly guided by the idea that ethical considerations must be central to research design and practice. In spite of the centrality of this idea, attempting to balance the sometimes conflicting values of advancing scientific knowledge and protecting human subjects continues to pose challenges. Possible conflicts between the standards of scientific research and those of ethics are particularly salient in relation to trial design. Specifically, the choice of a control arm is an aspect of trial design in which ethical and scientific issues are deeply entwined. Although ethical quandaries related to the choice of control arms may arise when conducting any type of clinical trials, they are conspicuous in early phase gene transfer trials that involve highly novel approaches and surgical procedures and have children as the research subjects. Because of children's and their parents' vulnerabilities, in trials that investigate therapies for fatal, rare diseases affecting minors, the scientific and ethical concerns related to choosing appropriate controls are particularly significant. In this paper we use direct gene transfer to the central nervous system to treat late infantile neuronal ceroid lipofuscinosis to illustrate some of these ethical issues and explore possible solutions to real and apparent conflicts between scientific and ethical considerations. PMID:21446781

Design and analysis issues for economic analysis alongside clinical trials.

PubMed

Marshall, Deborah A; Hux, Margaret

2009-07-01

Clinical trials can offer a valuable and efficient opportunity to collect the health resource use and outcomes data for economic evaluation. However, economic and clinical studies differ fundamentally in the question they seek to answer. The design and analysis of trial-based cost-effectiveness studies require special consideration, which are reviewed in this article. Traditional randomized controlled trials, using an experimental design with a controlled protocol, are designed to measure safety and efficacy for product registration. Cost-effectiveness analysis seeks to measure effectiveness in the context of routine clinical practice, and requires collection of health care resources to allow estimation of cost over an equal timeframe for each treatment alternative. In assessing suitability of a trial for economic data collection, the comparator treatment and other protocol factors need to reflect current clinical practice and the trial follow-up must be sufficiently long to capture important costs and effects. The broadest available population and a measure of effectiveness reflecting important benefits for patients are preferred for economic analyses. Special analytical issues include dealing with missing and censored cost data, assessing uncertainty of the incremental cost-effectiveness ratio, and accounting for the underlying heterogeneity in patient subgroups. Careful consideration also needs to be given to data from multinational studies since practice patterns can differ across countries. Although clinical trials can be an efficient opportunity to collect data for economic evaluation, careful consideration of the suitability of the study design, and appropriate analytical methods must be applied to obtain rigorous results.

Current challenges for clinical trials of cardiovascular medical devices.

PubMed

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

2014-07-15

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

Randomised trials comparing different healthcare settings: an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges.

PubMed

Corbett, Mark S; Watson, Judith; Eastwood, Alison

2016-10-19

We recently published a systematic review of different healthcare settings (such as outpatient, community or home) for administering intravenous chemotherapy, and concluded that performing conventionally designed randomised trials was difficult. The main problems were achieving adequate trial accrual rates and recruiting a study population which adequately represented the target population of interest. These issues stemmed from the fact that potential participants may have had pre-trial perceptions about the trial settings they may be allocated; such preferences will sometimes be strong enough for patients to decline an invitation to participate in a trial. A patient preference trial design (in which patients can choose, or be randomised to, an intervention) may have obviated these recruitment issues, although none of the trials used such a design. In order to gain a better understanding of the broader prevalence and extent of these preference issues (and any other methodological challenges), we undertook an exploratory review of settings trials in any area of healthcare treatment research. We searched The Cochrane Library and Google Scholar and used snowballing methods to identify trials comparing different healthcare settings. Trial accrual was affected by patient preferences for a setting in 15 of the 16 identified studies; birth setting trials were the most markedly affected, with between 68 % and 85 % of eligible women declining to participate specifically because of preference for a particular healthcare setting. Recruitment into substance abuse and chemotherapy setting studies was also notably affected by preferences. Only four trials used a preference design: the proportion of eligible patients choosing to participate via a preference group ranged from between 33 % and 67 %. In trials of healthcare settings, accrual may be seriously affected by patient preferences. The use of trial designs which incorporate a preference component should therefore strongly be considered. When designing such trials, investigators should consider settings to be complex interventions, which are likely to have linked components which may be difficult to control for. Careful thought is also needed regarding the choice of comparator settings and the most appropriate outcome measures to be used.

Two-stage phase II oncology designs using short-term endpoints for early stopping.

PubMed

Kunz, Cornelia U; Wason, James Ms; Kieser, Meinhard

2017-08-01

Phase II oncology trials are conducted to evaluate whether the tumour activity of a new treatment is promising enough to warrant further investigation. The most commonly used approach in this context is a two-stage single-arm design with binary endpoint. As for all designs with interim analysis, its efficiency strongly depends on the relation between recruitment rate and follow-up time required to measure the patients' outcomes. Usually, recruitment is postponed after the sample size of the first stage is achieved up until the outcomes of all patients are available. This may lead to a considerable increase of the trial length and with it to a delay in the drug development process. We propose a design where an intermediate endpoint is used in the interim analysis to decide whether or not the study is continued with a second stage. Optimal and minimax versions of this design are derived. The characteristics of the proposed design in terms of type I error rate, power, maximum and expected sample size as well as trial duration are investigated. Guidance is given on how to select the most appropriate design. Application is illustrated by a phase II oncology trial in patients with advanced angiosarcoma, which motivated this research.

FDA: Evidentiary Standards for Drug Development and Approval

PubMed Central

Katz, Russell

2004-01-01

Summary: The United States Food and Drug Administration is charged with approving drug treatments that have been shown to be safe and effective. Relevant statutes and regulations provide a legal framework for establishing safety and effectiveness that is sufficiently flexible to ensure that appropriate scientific data are collected for specific treatments targeted to particular diseases. Nonetheless, all clinical trials proposed to establish effectiveness must incorporate common elements in order for the appropriate legal and scientific standards of drug approval to be met. This article will discuss the relevant laws and regulations pertaining to the current effectiveness standard and will discuss the most important clinical trial design elements currently considered acceptable for applications for treatments of neurologic and psychiatric illness. PMID:15717032

Statistical lessons learned for designing cluster randomized pragmatic clinical trials from the NIH Health Care Systems Collaboratory Biostatistics and Design Core.

PubMed

Cook, Andrea J; Delong, Elizabeth; Murray, David M; Vollmer, William M; Heagerty, Patrick J

2016-10-01

Pragmatic clinical trials embedded within health care systems provide an important opportunity to evaluate new interventions and treatments. Networks have recently been developed to support practical and efficient studies. Pragmatic trials will lead to improvements in how we deliver health care and promise to more rapidly translate research findings into practice. The National Institutes of Health (NIH) Health Care Systems Collaboratory was formed to conduct pragmatic clinical trials and to cultivate collaboration across research areas and disciplines to develop best practices for future studies. Through a two-stage grant process including a pilot phase (UH2) and a main trial phase (UH3), investigators across the Collaboratory had the opportunity to work together to improve all aspects of these trials before they were launched and to address new issues that arose during implementation. Seven Cores were created to address the various considerations, including Electronic Health Records; Phenotypes, Data Standards, and Data Quality; Biostatistics and Design Core; Patient-Reported Outcomes; Health Care Systems Interactions; Regulatory/Ethics; and Stakeholder Engagement. The goal of this article is to summarize the Biostatistics and Design Core's lessons learned during the initial pilot phase with seven pragmatic clinical trials conducted between 2012 and 2014. Methodological issues arose from the five cluster-randomized trials, also called group-randomized trials, including consideration of crossover and stepped wedge designs. We outlined general themes and challenges and proposed solutions from the pilot phase including topics such as study design, unit of randomization, sample size, and statistical analysis. Our findings are applicable to other pragmatic clinical trials conducted within health care systems. Pragmatic clinical trials using the UH2/UH3 funding mechanism provide an opportunity to ensure that all relevant design issues have been fully considered in order to reliably and efficiently evaluate new interventions and treatments. The integrity and generalizability of trial results can only be ensured if rigorous designs and appropriate analysis choices are an essential part of their research protocols. © The Author(s) 2016.

Evaluation of a novel vital sign device to reduce maternal mortality and morbidity in low-resource settings: a mixed method feasibility study for the CRADLE-3 trial.

PubMed

Vousden, Nicola; Lawley, Elodie; Nathan, Hannah L; Seed, Paul T; Brown, Adrian; Muchengwa, Tafadzwa; Charantimath, Umesh; Bellad, Mrutyunjaya; Gidiri, Muchabayiwa Francis; Goudar, Shivaprasad; Chappell, Lucy C; Sandall, Jane; Shennan, Andrew H

2018-04-27

The CRADLE-3 trial is a stepped-wedge randomised controlled trial aiming to reduce maternal mortality and morbidity by implementing a novel vital sign device (CRADLE Vital Sign Alert) and training package into routine maternity care in 10 low-income sites. The MRC Guidance on complex interventions proposes that interventions and implementation strategies be shaped by early phase piloting and development work. We present the findings of a three-month mixed-methodology feasibility study for this trial, describe how this was informed by the MRC guidance and the study design was refined. The fidelity, dose, feasibility and acceptability of implementation and training materials were assessed in three representative non-trial sites (Zimbabwe, Ethiopia, India) using multiple-choice questionnaires, evaluation of clinical management (action log), healthcare provider (HCP) semi-structured interviews and focus groups 4-10 weeks after implementation. Simultaneously, the 10 sites included in the main trial (eight countries) collected primary outcome data to inform the power calculation and randomisation allocation and assess the feasibility of data collection. The package was implemented with high fidelity (85% of HCP trained, n = 204). The questionnaires indicated a good understanding of device use with 75% of participants scoring > 75% (n = 97; 90% of those distributed). Action logs were inconsistently completed but indicated that the majority of HCP responded appropriately to abnormal results. From 18 HCP interviews and two focus groups it was widely reported that the intervention improved capacity to make clinical decisions, escalate care and make appropriate referrals. Nine of the ten main trial sites achieved ethical approval for pilot data collection. Intensive care was an inconsistent marker of morbidity and stroke an infrequent outcome and therefore they were removed from the main trial composite outcome. Tools and methods of data collection were optimized and event rates used to inform randomisation. This feasibility study demonstrates that the components of the intervention were acceptable, methods of implementing were successful and the main trial design would be feasible. Qualitative work identified key moderators that informed the main trial process evaluation. Changes to the training package, implementation strategy, study design and processes were identified to refine the implementation in the main trial. ISRCTN41244132 ; Registered 24/11/2015.

On framing the research question and choosing the appropriate research design.

PubMed

Parfrey, Patrick S; Ravani, Pietro

2015-01-01

Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires definition of patients, interventions, controls, and outcomes. The goal of research design is to minimize error, to ensure adequate samples, to measure input and output variables appropriately, to consider external and internal validities, to limit bias, and to address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision-making places randomized controlled trials (RCT) or systematic review of good quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies.

On framing the research question and choosing the appropriate research design.

PubMed

Parfrey, Patrick; Ravani, Pietro

2009-01-01

Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires the definition of patients, interventions, controls, and outcomes. The goal of research design is to minimize error, ensure adequate samples, measure input and output variables appropriately, consider external and internal validities, limit bias, and address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision making places randomized controlled trials (RCT) or systematic review of good quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies.

Waiting list randomized controlled trial within a case-finding design: methodological considerations.

PubMed

Ronaldson, Sarah; Adamson, Joy; Dyson, Lisa; Torgerson, David

2014-10-01

Randomized controlled trials (RCTs) are widely used in health care research to provide high-quality evidence of effectiveness of an intervention. However, sometimes a study does not require an RCT in order to answer its primary objective; a case-finding design may be more appropriate. The aim of this paper was to introduce a new study design that nests a waiting list RCT within a case-finding study. An example of the new study design is the DOC Study, which primarily aims to determine the diagnostic accuracy of lung function tests for chronic obstructive pulmonary disease. It also investigates the impact of lung function tests on smoking behaviour through use of a waiting list design. The first step of the study design is to obtain participants' consent. Individuals are then randomized to one of two groups; either the 'intervention now' group or the 'intervention later' group, that is, participants are placed on a waiting list. All participants receive the same intervention; the only difference between the groups is the timing of the intervention. The design addresses patient preference issues and recruitment issues that can arise in other trial designs. Potential limitations include differential attrition between study groups and potential demoralization for the 'intervention later' group. The 'waiting list case-finding trial' design is a valuable method that could be applied to case-finding studies; the design enables the case-finding component of a study to be maintained while simultaneously exploring additional hypotheses through conducting a trial. © 2014 John Wiley & Sons, Ltd.

Evidence-based practice within nutrition: what are the barriers for improving the evidence and how can they be dealt with?

PubMed

Laville, Martine; Segrestin, Berenice; Alligier, Maud; Ruano-Rodríguez, Cristina; Serra-Majem, Lluis; Hiesmayr, Michael; Schols, Annemie; La Vecchia, Carlo; Boirie, Yves; Rath, Ana; Neugebauer, Edmund A M; Garattini, Silvio; Bertele, Vittorio; Kubiak, Christine; Demotes-Mainard, Jacques; Jakobsen, Janus C; Djurisic, Snezana; Gluud, Christian

2017-09-11

Evidence-based clinical research poses special barriers in the field of nutrition. The present review summarises the main barriers to research in the field of nutrition that are not common to all randomised clinical trials or trials on rare diseases and highlights opportunities for improvements. Systematic academic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. Many nutrients occur in multiple forms that differ in biological activity, and several factors can alter their bioavailability which raises barriers to their assessment. These include specific difficulties with blinding procedures, with assessments of dietary intake, and with selecting appropriate outcomes as patient-centred outcomes may occur decennia into the future. The methodologies and regulations for drug trials are, however, applicable to nutrition trials. Research on clinical nutrition should start by collecting clinical data systematically in databases and registries. Measurable patient-centred outcomes and appropriate study designs are needed. International cooperation and multistakeholder engagement are key for success.

Research designs for studies evaluating the effectiveness of change and improvement strategies.

PubMed

Eccles, M; Grimshaw, J; Campbell, M; Ramsay, C

2003-02-01

The methods of evaluating change and improvement strategies are not well described. The design and conduct of a range of experimental and non-experimental quantitative designs are considered. Such study designs should usually be used in a context where they build on appropriate theoretical, qualitative and modelling work, particularly in the development of appropriate interventions. A range of experimental designs are discussed including single and multiple arm randomised controlled trials and the use of more complex factorial and block designs. The impact of randomisation at both group and individual levels and three non-experimental designs (uncontrolled before and after, controlled before and after, and time series analysis) are also considered. The design chosen will reflect both the needs (and resources) in any particular circumstances and also the purpose of the evaluation. The general principle underlying the choice of evaluative design is, however, simple-those conducting such evaluations should use the most robust design possible to minimise bias and maximise generalisability.

Cognitive bias modification for social anxiety in adults who stutter: a feasibility study of a randomised controlled trial

PubMed Central

Gascoine, Sally; Carroll, Amy; Humby, Kate; Kingston, Mary; Shepstone, Lee; Risebro, Helen; Mackintosh, Bundy; Thompson, Tammy Davidson; Hodgekins, Jo

2017-01-01

Objective To determine the feasibility and acceptability of a computerised treatment for social anxiety disorder for adults who stutter including identification of recruitment, retention and completion rates, large cost drivers and selection of most appropriate outcome measure(s) to inform the design of a future definitive trial. Design Two-group parallel design (treatment vs placebo), double-blinded feasibility study. Participants: 31 adults who stutter. Intervention Attention training via an online probe detection task in which the stimuli were images of faces displaying neutral and disgusted expressions. Main outcome measures Psychological measures: Structured Clinical Interview Global Assessment of Functioning score; Liebowitz Social Anxiety Scale; Social Phobia and Anxiety Inventory; State-Trait Anxiety Inventory; Unhelpful Thoughts and Beliefs about Stuttering. Speech fluency: percent syllables stuttered. Economic evaluation: resource use questionnaire; EuroQol three-dimension questionnaire. Acceptability: Likert Scale questionnaire of experience of trial, acceptability of the intervention and randomisation procedure. Results Feasibility of recruitment strategy was demonstrated. Participant feedback indicated that the intervention and definitive trial, including randomisation, would be acceptable to adults who stutter. Of the 31 participants who were randomised, 25 provided data at all three data collection points. Conclusions The feasibility study informed components of the intervention. Modifications to the design are needed before a definitive trial can be undertaken. Trial registration number I SRCTN55065978; Post-results. PMID:29061602

Challenges in designing, conducting, and reporting oral health behavioral intervention studies in primary school age children: methodological issues

PubMed Central

Cooper, Anna Mary; Coffey, Margaret; Dugdill, Lindsey

2014-01-01

Often within oral health, clinical outcome measures dominate trial design rather than behavioral outcome measures, and often there is a reliance on proxy self-reporting of children’s behavior with no corroboration through triangulation of measures. The complexity of the interventions involved in oral health intervention is often overlooked in trial design, and more flexible pragmatic designs that take account of the research context may be more appropriate. Some of the limitations in oral health behavioral intervention studies (trials) in primary school age children were reported in a recently published Cochrane review. This paper aims to critically discuss the findings of a recent Cochrane review in terms of the methodological implications that arise for future design, development, measurement, and reporting of oral health trials in primary school age children. Key components of the UK Medical Research Council’s framework for the design and evaluation of complex interventions are discussed in relation to using taxonomies of behavior change. This paper is not designed to be a definitive guide but aims to bring learning from other areas of public health and health promotion into dental public health. Ultimately, the aim is to aid the design of more successful interventions that produce long-term behavioral changes in children in relation to toothbrushing and nighttime sugar snacking. PMID:27774028

Improving clinical trials in the critically ill.

PubMed

Angus, Derek C; Mira, Jean-Paul; Vincent, Jean-Louis

2010-02-01

To propose ways in which clinical trials in intensive care can be improved. An international roundtable conference was convened focused on improvement in three broad areas: translation of new knowledge from bench to bedside; design and conduct of clinical trials; and clinical trial infrastructure and environment. The roundtable recommendations were: improvement in clinical trials is a multistep process from better preclinical studies to better clinical trial methodology; new technologies should be used to improve models of critical illness; diseasomes and theragnostics will aid inpatient population selection and more appropriate targeting of interventions; broader study end points should include morbidity as well as mortality; more multicenter studies should be conducted by national and international networks or clinical trials groups; and better collaboration is needed with the industry. There was broad agreement among the roundtable participants regarding a number of explicit opportunities for the improvement of clinical trials in critical care.

7 CFR 1755.3 - Field trials.

Code of Federal Regulations, 2011 CFR

2011-01-01

... installations of the materials or equipment in closely monitored situations designed to determine, to RUS's... concepts untried within the telephone industry is defined as “an experiment” and shall be handled as a special case using procedures considered appropriate by RUS to meet the individual experiment. (b) To...

Can context justify an ethical double standard for clinical research in developing countries?

PubMed Central

Landes, Megan

2005-01-01

Background The design of clinical research deserves special caution so as to safeguard the rights of participating individuals. While the international community has agreed on ethical standards for the design of research, these frameworks still remain open to interpretation, revision and debate. Recently a breach in the consensus of how to apply these ethical standards to research in developing countries has occurred, notably beginning with the 1994 placebo-controlled trials to reduce maternal to child transmission of HIV-1 in Africa, Asia and the Caribbean. The design of these trials sparked intense debate with the inclusion of a placebo-control group despite the existence of a 'gold standard' and trial supporters grounded their justifications of the trial design on the context of scarcity in resource-poor settings. Discussion These 'contextual' apologetics are arguably an ethical loophole inherent in current bioethical methodology. However, this convenient appropriation of 'contextual' analysis simply fails to acknowledge the underpinnings of feminist ethical analysis upon which it must stand. A more rigorous analysis of the political, social, and economic structures pertaining to the global context of developing countries reveals that the bioethical principles of beneficence and justice fail to be met in this trial design. Conclusion Within this broader, and theoretically necessary, understanding of context, it becomes impossible to justify an ethical double standard for research in developing countries. PMID:16045801

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

PubMed

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

2008-01-01

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

The use of systematic reviews in the planning, design and conduct of randomised trials: a retrospective cohort of NIHR HTA funded trials.

PubMed

Jones, Ashley P; Conroy, Elizabeth; Williamson, Paula R; Clarke, Mike; Gamble, Carrol

2013-03-25

A systematic review, with or without a meta-analysis, should be undertaken to determine if the research question of interest has already been answered before a new trial begins. There has been limited research on how systematic reviews are used within the design of new trials, the aims of this study were to investigate how systematic reviews of earlier trials are used in the planning and design of new randomised trials. Documentation from the application process for all randomised trials funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) between 2006 and 2008 were obtained. This included the: commissioning brief (if appropriate), outline application, minutes of the Board meeting in which the outline application was discussed, full application, detailed project description, referee comments, investigator response to referee comments, Board minutes on the full application and the trial protocol. Data were extracted on references to systematic reviews and how any such reviews had been used in the planning and design of the trial. 50 randomised trials were funded by NIHR HTA during this period and documentation was available for 48 of these. The cohort was predominately individually randomised parallel trials aiming to detect superiority between two treatments for a single primary outcome. 37 trials (77.1%) referenced a systematic review within the application and 20 of these (i.e. 41.7% of the total) used information contained in the systematic review in the design or planning of the new trial. The main areas in which systematic reviews were used were in the selection or definition of an outcome to be measured in the trial (7 of 37, 18.9%), the sample size calculation (7, 18.9%), the duration of follow up (8, 21.6%) and the approach to describing adverse events (9, 24.3%). Boards did not comment on the presence/absence or use of systematic reviews in any application. Systematic reviews were referenced in most funded applications but just over half of these used the review to inform the design. There is an expectation from funders that applicants will use a systematic review to justify the need for a new trial but no expectation regarding further use of a systematic review to aid planning and design of the trial. Guidelines for applicants and funders should be developed to promote the use of systematic reviews in the design and planning of randomised trials, to optimise delivery of new studies informed by the most up-to-date evidence base and to minimise waste in research.

COACH trial: A randomized controlled trial of nurse practitioner/community health worker cardiovascular disease risk reduction in urban community health centers: Rationale and design

PubMed Central

Allen, Jerilyn K; Himmelfarb, Cheryl R Dennison; Szanton, Sarah L; Bone, Lee; Hill, Martha N; Levine, David M

2011-01-01

Background Despite well-publicized guidelines on the appropriate management of cardiovascular disease (CVD) and type 2 diabetes, implementation of risk-reducing practices remains poor. This paper describes the rationale and design of a randomized controlled clinical trial evaluating the effectiveness of a comprehensive program of CVD risk reduction delivered by nurse practitioner (NP)/community health worker (CHW) teams versus enhanced usual care in improving the proportion of patients in urban community health centers who achieve goal levels recommended by national guidelines for lipids, blood pressure, HbA1c and prescription of appropriate medications. Methods The COACH (Community Outreach and Cardiovascular Health) trial is a randomized controlled trial in which patients at federally-qualified community health centers were randomly assigned to one of two groups: comprehensive intensive management of CVD risk factors for one year by a NP/CHW team or an enhanced usual care control group. Results A total of 3899 patients were assessed for eligibility and 525 were randomized. Groups were comparable at baseline on sociodemographic and clinical characteristics with the exception of statistically significant differences in total cholesterol and hemoglobin A1c. Conclusions This study is a novel amalgam of multilevel interdisciplinary strategies to translate highly efficacious therapies to low-income federally-funded health centers that care for patients who carry a disproportionate burden of CVD, type 2 diabetes and uncontrolled CVD risk factors. The impact of such a community clinic-based intervention is potentially enormous. PMID:21241828

COACH trial: a randomized controlled trial of nurse practitioner/community health worker cardiovascular disease risk reduction in urban community health centers: rationale and design.

PubMed

Allen, Jerilyn K; Himmelfarb, Cheryl R Dennison; Szanton, Sarah L; Bone, Lee; Hill, Martha N; Levine, David M

2011-05-01

Despite well-publicized guidelines on the appropriate management of cardiovascular disease (CVD) and type 2 diabetes, implementation of risk-reducing practices remains poor. This paper describes the rationale and design of a randomized controlled clinical trial evaluating the effectiveness of a comprehensive program of CVD risk reduction delivered by nurse practitioner (NP)/community health worker (CHW) teams versus enhanced usual care in improving the proportion of patients in urban community health centers who achieve goal levels recommended by national guidelines for lipids, blood pressure, HbA1c and prescription of appropriate medications. The COACH (Community Outreach and Cardiovascular Health) trial is a randomized controlled trial in which patients at federally-qualified community health centers were randomly assigned to one of two groups: comprehensive intensive management of CVD risk factors for one year by a NP/CHW team or an enhanced usual care control group. A total of 3899 patients were assessed for eligibility and 525 were randomized. Groups were comparable at baseline on sociodemographic and clinical characteristics with the exception of statistically significant differences in total cholesterol and hemoglobin A1c. This study is a novel amalgam of multilevel interdisciplinary strategies to translate highly efficacious therapies to low-income federally-funded health centers that care for patients who carry a disproportionate burden of CVD, type 2 diabetes and uncontrolled CVD risk factors. The impact of such a community clinic-based intervention is potentially enormous. Copyright © 2011 Elsevier Inc. All rights reserved.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

PubMed

Hendrix, James A; Bateman, Randall J; Brashear, H Robert; Duggan, Cynthia; Carrillo, Maria C; Bain, Lisa J; DeMattos, Ronald; Katz, Russell G; Ostrowitzki, Susanne; Siemers, Eric; Sperling, Reisa; Vitolo, Ottavio V

2016-05-01

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders. Copyright © 2016 Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

The trials methodological research agenda: results from a priority setting exercise.

PubMed

Tudur Smith, Catrin; Hickey, Helen; Clarke, Mike; Blazeby, Jane; Williamson, Paula

2014-01-23

Research into the methods used in the design, conduct, analysis, and reporting of clinical trials is essential to ensure that effective methods are available and that clinical decisions made using results from trials are based on the best available evidence, which is reliable and robust. An on-line Delphi survey of 48 UK Clinical Research Collaboration registered Clinical Trials Units (CTUs) was undertaken. During round one, CTU Directors were asked to identify important topics that require methodological research. During round two, their opinion about the level of importance of each topic was recorded, and during round three, they were asked to review the group's average opinion and revise their previous opinion if appropriate. Direct reminders were sent to maximise the number of responses at each round. Results are summarised using descriptive methods. Forty one (85%) CTU Directors responded to at least one round of the Delphi process: 25 (52%) responded in round one, 32 (67%) responded in round two, 24 (50%) responded in round three. There were only 12 (25%) who responded to all three rounds and 18 (38%) who responded to both rounds two and three. Consensus was achieved amongst CTU Directors that the top three priorities for trials methodological research were 'Research into methods to boost recruitment in trials' (considered the highest priority), 'Methods to minimise attrition' and 'Choosing appropriate outcomes to measure'. Fifty other topics were included in the list of priorities and consensus was reached that two topics, 'Radiotherapy study designs' and 'Low carbon trials', were not priorities. This priority setting exercise has identified the research topics felt to be most important to the key stakeholder group of Directors of UKCRC registered CTUs. The use of robust methodology to identify these priorities will help ensure that this work informs the trials methodological research agenda, with a focus on topics that will have most impact and relevance.

Time and expected value of sample information wait for no patient.

PubMed

Eckermann, Simon; Willan, Andrew R

2008-01-01

The expected value of sample information (EVSI) from prospective trials has previously been modeled as the product of EVSI per patient, and the number of patients across the relevant time horizon less those "used up" in trials. However, this implicitly assumes the eligible patient population to which information from a trial can be applied across a time horizon are independent of time for trial accrual, follow-up and analysis. This article demonstrates that in calculating the EVSI of a trial, the number of patients who benefit from trial information should be reduced by those treated outside as well as within the trial over the time until trial evidence is updated, including time for accrual, follow-up and analysis. Accounting for time is shown to reduce the eligible patient population: 1) independent of the size of trial in allowing for time of follow-up and analysis, and 2) dependent on the size of trial for time of accrual, where the patient accrual rate is less than incidence. Consequently, the EVSI and expected net gain (ENG) at any given trial size are shown to be lower when accounting for time, with lower ENG reinforced in the case of trials undertaken while delaying decisions by additional opportunity costs of time. Appropriately accounting for time reduces the EVSI of trial design and increase opportunity costs of trials undertaken with delay, leading to lower likelihood of trialing being optimal and smaller trial designs where optimal.

Optimal design of clinical trials with biologics using dose-time-response models.

PubMed

Lange, Markus R; Schmidli, Heinz

2014-12-30

Biologics, in particular monoclonal antibodies, are important therapies in serious diseases such as cancer, psoriasis, multiple sclerosis, or rheumatoid arthritis. While most conventional drugs are given daily, the effect of monoclonal antibodies often lasts for months, and hence, these biologics require less frequent dosing. A good understanding of the time-changing effect of the biologic for different doses is needed to determine both an adequate dose and an appropriate time-interval between doses. Clinical trials provide data to estimate the dose-time-response relationship with semi-mechanistic nonlinear regression models. We investigate how to best choose the doses and corresponding sample size allocations in such clinical trials, so that the nonlinear dose-time-response model can be precisely estimated. We consider both local and conservative Bayesian D-optimality criteria for the design of clinical trials with biologics. For determining the optimal designs, computer-intensive numerical methods are needed, and we focus here on the particle swarm optimization algorithm. This metaheuristic optimizer has been successfully used in various areas but has only recently been applied in the optimal design context. The equivalence theorem is used to verify the optimality of the designs. The methodology is illustrated based on results from a clinical study in patients with gout, treated by a monoclonal antibody. Copyright © 2014 John Wiley & Sons, Ltd.

Comparison of study designs for acute otitis media trials.

PubMed

Pichichero, Michael E; Casey, Janet R

2008-06-01

A framework for evaluating the efficacy of antibiotics in development as well as those currently approved for acute otitis media (AOM) is needed. Review strengths and limitations of various antibiotic trial designs and their outcome measures. A review of 157 published trials involving 36,710 subjects for the treatment of AOM. AOM trials have three designs: (1) clinical, clinical diagnosis and assessment of outcomes; (2) single tympanocentesis, microbiologic diagnosis (by middle ear fluid culture) and clinical assessment of outcomes; and (3) double tympanocentesis, microbiologic diagnosis and microbiologic outcome assessment. Identifiable strengths and limitations of each design are reviewed. Case definitions for entry of children in trials of AOM vary widely. The lack of stringent diagnostic criteria in a clinical design allows for inclusion of a significant proportion of children with a non-bacterial etiology (i.e., viral AOM or otitis media with effusion). Tympanocentesis increases diagnostic accuracy at study entry; however, the procedure is confounding because of its potentially therapeutic benefit and the procedure is not performed in a uniform manner. A second tympanocentesis allows a high sensitivity to detect microbiologic eradication, but it does not correlate with clinical outcomes in half of the cases. The timing of outcome assessment also varies widely among trials. Improved clinical diagnosis criteria for AOM are needed to enhance specificity; emphasis on a bulging tympanic membrane has the best evidence base. Tympanocentesis within study designs has merits. At study entry it assures diagnostic accuracy but may alter outcomes and it is useful to document microbiologic outcomes but lacks specificity for clinical outcomes. For all designs, test of cure assessment 2-7 days after completion of therapy seems most appropriate.

Design and rationale of the assessment of proper physiologic response with rate adaptive pacing driven by minute ventilation or accelerometer (APPROPRIATE) trial.

PubMed

Gilliam, F Roosevelt; Giudici, Michael; Benn, Andrew; Koplan, Bruce; Berg, Kellie Jean Chase; Kraus, Stacia Merkel; Stolen, Kira Q; Alvarez, Guy E; Hopper, Donald L; Wilkoff, Bruce L

2011-02-01

Rate-adaptive sensors are designed to restore a physiologic heart rate response to activity, in particular for patients that have chronotropic incompetence (CI). Limited data exist comparing two primary types of sensors; an accelerometer (XL) sensor which detects activity or motion and a minute ventilation (MV) sensor, which detects the product of respiration rate and tidal volume. The APPROPRIATE study will evaluate the MV sensor compared with the XL sensor for superiority in improving functional capacity (peak VO(2)) in pacemaker patients that have CI. This study is a double-blind, randomized, two-arm trial that will enroll approximately 1,000 pacemaker patients. Patients will complete a 6-min walk test at the 2-week visit to screen for potential CI. Those projected to have CI will advance to a 1-month visit. At the 1-month visit, final determination of CI will be done by completing a peak exercise treadmill test while the pacemaker is programmed to DDDR with the device sensors set to passive. Patients failing to meet the study criteria for CI will not continue further in the trial. Patients that demonstrate CI will be randomized to program their rate-adaptive sensors to either MV or XL in a 1:1 ratio. The rate-adaptive sensor will be optimized for each patient using a short walk to determine the appropriate response factor. At a 2-month visit, patients will complete a CPX test with the rate-adaptive sensors in their randomized setting.

Treatment Trials for Neonatal Seizures: The Effect of Design on Sample Size

PubMed Central

Stevenson, Nathan J.; Boylan, Geraldine B.; Hellström-Westas, Lena; Vanhatalo, Sampsa

2016-01-01

Neonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (Td) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, Td and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in Td between groups in analysis will be valid and minimise sample size. PMID:27824913

Interim analysis: A rational approach of decision making in clinical trial.

PubMed

Kumar, Amal; Chakraborty, Bhaswat S

2016-01-01

Interim analysis of especially sizeable trials keeps the decision process free of conflict of interest while considering cost, resources, and meaningfulness of the project. Whenever necessary, such interim analysis can also call for potential termination or appropriate modification in sample size, study design, and even an early declaration of success. Given the extraordinary size and complexity today, this rational approach helps to analyze and predict the outcomes of a clinical trial that incorporate what is learned during the course of a study or a clinical development program. Such approach can also fill the gap by directing the resources toward relevant and optimized clinical trials between unmet medical needs and interventions being tested currently rather than fulfilling only business and profit goals.

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial

PubMed Central

2013-01-01

Background The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for ‘point of care’ management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. Design/methods We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma—the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis—the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. Discussion This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. Trial registration ClinicalTrials.gov: NCT01815710 PMID:23692634

Alternatives for discounting in the analysis of noninferiority trials.

PubMed

Snapinn, Steven M

2004-05-01

Determining the efficacy of an experimental therapy relative to placebo on the basis of an active-control noninferiority trial requires reference to historical placebo-controlled trials. The validity of the resulting comparison depends on two key assumptions: assay sensitivity and constancy. Since the truth of these assumptions cannot be verified, it seems logical to raise the standard of evidence required to declare efficacy; this concept is referred to as discounting. It is not often recognized that two common design and analysis approaches, setting a noninferiority margin and requiring preservation of a fraction of the standard therapy's effect, are forms of discounting. The noninferiority margin is a particularly poor approach, since its degree of discounting depends on an irrelevant factor. Preservation of effect is more reasonable, but it addresses only the constancy assumption, not the issue of assay sensitivity. Gaining consensus on the most appropriate approach to the design and analysis of noninferiority trials will require a common understanding of the concept of discounting.

Trial Prospector: Matching Patients with Cancer Research Studies Using an Automated and Scalable Approach

PubMed Central

Sahoo, Satya S; Tao, Shiqiang; Parchman, Andrew; Luo, Zhihui; Cui, Licong; Mergler, Patrick; Lanese, Robert; Barnholtz-Sloan, Jill S; Meropol, Neal J; Zhang, Guo-Qiang

2014-01-01

Cancer is responsible for approximately 7.6 million deaths per year worldwide. A 2012 survey in the United Kingdom found dramatic improvement in survival rates for childhood cancer because of increased participation in clinical trials. Unfortunately, overall patient participation in cancer clinical studies is low. A key logistical barrier to patient and physician participation is the time required for identification of appropriate clinical trials for individual patients. We introduce the Trial Prospector tool that supports end-to-end management of cancer clinical trial recruitment workflow with (a) structured entry of trial eligibility criteria, (b) automated extraction of patient data from multiple sources, (c) a scalable matching algorithm, and (d) interactive user interface (UI) for physicians with both matching results and a detailed explanation of causes for ineligibility of available trials. We report the results from deployment of Trial Prospector at the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center (Case CCC) with 1,367 clinical trial eligibility evaluations performed with 100% accuracy. PMID:25506198

Adjuvant bisphosphonate treatment for breast cancer: why did something so elegant become so complicated?

PubMed

Clemons, Mark; Russell, Kent; Costa, Luis; Addison, Christina L

2012-07-01

Bisphosphonate therapy has revolutionized the care of patients with metastatic bone disease. With its demonstrated activity and anti-tumour effects in preclinical studies it was natural to transition these agents to testing in the adjuvant setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest or no benefit or even harm. We sought to explore whether there were specific patient cohorts or treatment strategies that were most likely to benefit from adjuvant bisphosphonate therapy. We compared trial designs, patient characteristics and outcomes from the six published and two presented randomized adjuvant bisphosphonate trials. Differences in trial design and patient populations make direct comparisons complicated. The most efficacious use of adjuvant bisphosphonates appears to be in patients with either biopsy evidence of osseous micrometastases, were post-menopausal or had estrogen receptor-positive tumours. Despite tremendous optimism regarding adjuvant bisphosphonate therapy, results from large trials are conflicting. Further investigation into factors influencing response to bisphosphonate treatment or selection of appropriate sub-groups of patients with desirable response characteristics is warranted.

Defining a Clinically Meaningful Effect for the Design and Interpretation of Randomized Controlled Trials

PubMed Central

Kraemer, Helena C.; Epstein, Robert S.; Frank, Ellen; Haynes, Ginger; Laughren, Thomas P.; Mcnulty, James; Reed, Shelby D.; Sanchez, Juan; Leon, Andrew C.

2013-01-01

Objective: This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. Design: Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. Setting: The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. Participants: The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. Results: The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. Conclusion: There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials. PMID:23882433

Defining a clinically meaningful effect for the design and interpretation of randomized controlled trials.

PubMed

Keefe, Richard S E; Kraemer, Helena C; Epstein, Robert S; Frank, Ellen; Haynes, Ginger; Laughren, Thomas P; McNulty, James; Reed, Shelby D; Sanchez, Juan; Leon, Andrew C

2013-05-01

This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.

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

PubMed

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

2014-07-01

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

Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome

PubMed Central

2013-01-01

Background Designs and analyses of clinical trials with a time-to-event outcome almost invariably rely on the hazard ratio to estimate the treatment effect and implicitly, therefore, on the proportional hazards assumption. However, the results of some recent trials indicate that there is no guarantee that the assumption will hold. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials. Methods The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. We consider the design of such trials according to a wide range of possible survival distributions in the control and research arm(s). The distributions are conveniently defined as piecewise exponential distributions and can be specified through piecewise constant hazards and time-fixed or time-dependent hazard ratios. Such designs can embody proportional or non-proportional hazards of the treatment effect. Results We demonstrate the use of restricted mean survival time and a test of the difference in restricted means as an alternative measure of treatment effect. We support the approach through the results of simulation studies and in real examples from several cancer trials. We illustrate the required sample size under proportional and non-proportional hazards, also the significance level and power of the proposed test. Values are compared with those from the standard approach which utilizes the logrank test. Conclusions We conclude that the hazard ratio cannot be recommended as a general measure of the treatment effect in a randomized controlled trial, nor is it always appropriate when designing a trial. Restricted mean survival time may provide a practical way forward and deserves greater attention. PMID:24314264

The Effectiveness of Disaster Risk Communication: A Systematic Review of Intervention Studies

PubMed Central

Bradley, Declan T; McFarland, Marie; Clarke, Mike

2014-01-01

Introduction: A disaster is a serious disruption to the functioning of a community that exceeds its capacity to cope within its own resources. Risk communication in disasters aims to prevent and mitigate harm from disasters, prepare the population before a disaster, disseminate information during disasters and aid subsequent recovery. The aim of this systematic review is to identify, appraise and synthesise the findings of studies of the effects of risk communication interventions during four stages of the disaster cycle. Methods: We searched the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, PsycInfo, Sociological Abstracts, Web of Science and grey literature sources for randomised trials, cluster randomised trials, controlled and uncontrolled before and after studies, interrupted time series studies and qualitative studies of any method of disaster risk communication to at-risk populations. Outcome criteria were disaster-related knowledge and behaviour, and health outcomes. Results: Searches yielded 5,224 unique articles, of which 100 were judged to be potentially relevant. Twenty-five studies met the inclusion criteria, and two additional studies were identified from other searching. The studies evaluated interventions in all four stages of the disaster cycle, included a variety of man-made, natural and infectious disease disasters, and were conducted in many disparate settings. Only one randomised trial and one cluster randomised trial were identified, with less robust designs used in the other studies. Several studies reported improvements in disaster-related knowledge and behaviour. Discussion: We identified and appraised intervention studies of disaster risk communication and present an overview of the contemporary literature. Most studies used non-randomised designs that make interpretation challenging. We do not make specific recommendations for practice but highlight the need for high-quality randomised trials and appropriately-analysed cluster randomised trials in the field of disaster risk communication where these can be conducted within an appropriate research ethics framework. PMID:25642365

Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop.

PubMed

Coffey, Christopher S; Levin, Bruce; Clark, Christina; Timmerman, Cate; Wittes, Janet; Gilbert, Peter; Harris, Sara

2012-12-01

The clinical trials community has a never-ending search for dependable and reliable ways to improve clinical research. This exploration has led to considerable interest in adaptive clinical trial designs, which provide the flexibility to adjust trial characteristics on the basis of data reviewed at interim stages. Statisticians and clinical investigators have proposed or implemented a wide variety of adaptations in clinical trials, but specific approaches have met with differing levels of support. Within industry, investigators are actively exploring the benefits and pitfalls associated with adaptive designs (ADs). For example, a Drug Information Association (DIA) working group on ADs has engaged regulatory agencies in discussions. Many researchers working on publicly funded clinical trials, however, are not yet fully engaged in this discussion. We organized the Scientific Advances in Adaptive Clinical Trial Designs Workshop to begin a conversation about using ADs in publicly funded research. Held in November of 2009, the 1½-day workshop brought together representatives from the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the European Medicines Agency (EMA), the pharmaceutical industry, nonprofit foundations, the patient advocacy community, and academia. The workshop offered a forum for participants to address issues of ADs that arise at the planning, designing, and execution stages of clinical trials, and to hear the perspectives of influential members of the clinical trials community. The participants also set forth recommendations for guiding action to promote the appropriate use of ADs. These recommendations have since been presented, discussed, and vetted in a number of venues including the University of Pennsylvania Conference on Statistical Issues in Clinical Trials and the Society for Clinical Trials annual meeting. To provide a brief overview of ADs, describe the rationale behind conducting the workshop, and summarize the main recommendations that were produced as a result of this workshop. There is a growing interest in the use of adaptive clinical trial designs. However, a number of logistical barriers need to be addressed in order to obtain the potential advantages of an AD. Currently, the pharmaceutical industry is well ahead of academic trialists with respect to addressing these barriers. Academic trialists will need to address important issues such as education, infrastructure, modifications to existing funding models, and the impact on Data and Safety Monitoring Boards (DSMB) in order to achieve the possible benefits of adaptive clinical trial designs.

Evaluating the importance of sham controlled trials in the investigation of medical devices in interventional cardiology.

PubMed

Byrne, Robert A; Capodanno, Davide; Mahfoud, Felix; Fajadet, Jean; Windecker, Stephan; Jüni, Peter; Baumbach, Andreas; Wijns, William; Haude, Michael

2018-05-22

Cardiovascular medicine is one of the specialties that has relied most heavily on evidence from randomized clinical trials in determining best practice for the management of common disease conditions. When comparing treatment approaches, trials incorporating random allocation are the most appropriate method for protecting against treatment allocation bias. In order to protect against performance and ascertainment bias, trial designs including placebo control are preferable where feasible. In contrast to testing of medicines, treatments based on procedures or use of medical devices are more challenging to assess, as sham procedures are necessary to facilitate blinding of participants. However, in many cases, ethical concerns exist, as individual patients allocated to sham procedure are exposed only to risk without potential for benefit. Accordingly, the potential benefits to the general patient population must be carefully weighed against the risks of the exposed individuals. For this reason, trial design and study conduct are critically important to ensure that the investigation has the best chance of answering the study question at hand. In the current manuscript, we aim to review issues relating to the conduct of sham-controlled trials and discuss a number of recent examples in the field of interventional cardiology.

The reduction of intoxication and disorder in premises licensed to serve alcohol: An exploratory randomised controlled trial

PubMed Central

2010-01-01

Background Licensed premises offer a valuable point of intervention to reduce alcohol-related harm. Objective To describe the research design for an exploratory trial examining the feasibility and acceptability of a premises-level intervention designed to reduce severe intoxication and related disorder. The study also aims to assess the feasibility of a potential future large scale effectiveness trial and provide information on key trial design parameters including inclusion criteria, premises recruitment methods, strategies to implement the intervention and trial design, outcome measures, data collection methods and intra-cluster correlations. Design A randomised controlled trial in licensed premises that had experienced at least one assault in the year preceding the intervention, documented in police or hospital Emergency Department (ED) records. Premises were recruited from four study areas by piloting four recruitment strategies of varying intensity. Thirty two licensed premises were grouped into matched pairs to reduce potential bias and randomly allocated to the control or intervention condition. The study included a nested process evaluation to provide information on intervention acceptability and implementation. Outcome measures included police-recorded violent incidents, assault-related attendances at each premises' local ED and patron Breath Alcohol Concentration assessed on exiting and entering study premises. Results The most successful recruitment method involved local police licensing officers and yielded a 100% success rate. Police-records of violence provided the most appropriate source of data about disorder at the premises level. Conclusion The methodology of an exploratory trial is presented and despite challenges presented by the study environment it is argued an exploratory trial is warranted. Initial investigations in recruitment methods suggest that study premises should be recruited with the assistance of police officers. Police data were of sufficient quality to identify disorder and street surveys are a feasible method for measuring intoxication at the individual level. Trial registration UKCRN 7090; ISRCTN: 80875696 Funding Medical Research Council (G0701758) to Simon Moore, Simon Murphy, Laurence Moore and Jonathan Shepherd PMID:20946634

OARSI Clinical Trials Recommendations: Design, conduct, and reporting of clinical trials for knee osteoarthritis.

PubMed

McAlindon, T E; Driban, J B; Henrotin, Y; Hunter, D J; Jiang, G-L; Skou, S T; Wang, S; Schnitzer, T

2015-05-01

The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct, and reporting of clinical trials for knee OA we initially drafted recommendations through an iterative process. Members of the working group included representatives from industry and academia. After the working group members reviewed a final draft, they scored the appropriateness for recommendations. After the members voted we calculated the median score among the nine members of the working group who completed the score. The document includes 25 recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes (PRO), selecting a study population and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Guidelines for the Design and Conduct of Clinical Studies in Knee Articular Cartilage Repair

PubMed Central

Mithoefer, Kai; Saris, Daniel B.F.; Farr, Jack; Kon, Elizaveta; Zaslav, Kenneth; Cole, Brian J.; Ranstam, Jonas; Yao, Jian; Shive, Matthew; Levine, David; Dalemans, Wilfried; Brittberg, Mats

2011-01-01

Objective: To summarize current clinical research practice and develop methodological standards for objective scientific evaluation of knee cartilage repair procedures and products. Design: A comprehensive literature review was performed of high-level original studies providing information relevant for the design of clinical studies on articular cartilage repair in the knee. Analysis of cartilage repair publications and synopses of ongoing trials were used to identify important criteria for the design, reporting, and interpretation of studies in this field. Results: Current literature reflects the methodological limitations of the scientific evidence available for articular cartilage repair. However, clinical trial databases of ongoing trials document a trend suggesting improved study designs and clinical evaluation methodology. Based on the current scientific information and standards of clinical care, detailed methodological recommendations were developed for the statistical study design, patient recruitment, control group considerations, study endpoint definition, documentation of results, use of validated patient-reported outcome instruments, and inclusion and exclusion criteria for the design and conduct of scientifically sound cartilage repair study protocols. A consensus statement among the International Cartilage Repair Society (ICRS) and contributing authors experienced in clinical trial design and implementation was achieved. Conclusions: High-quality clinical research methodology is critical for the optimal evaluation of current and new cartilage repair technologies. In addition to generally applicable principles for orthopedic study design, specific criteria and considerations apply to cartilage repair studies. Systematic application of these criteria and considerations can facilitate study designs that are scientifically rigorous, ethical, practical, and appropriate for the question(s) being addressed in any given cartilage repair research project. PMID:26069574

Randomised clinical trials with clinician-preferred treatment.

PubMed

Korn, E L; Baumrind, S

1991-01-19

The standard design for randomised clinical trials may be inappropriate when the clinician believes that one of the treatments being tested is superior for the patient, or when the clinician has a preference for one of the treatments. For such instances the suggestion is that the patient is randomly allocated to treatment only when there is clinical disagreement about treatment of choice for that patient, and then the patient is assigned to a clinician who had thought that the regimen allocated is the one most appropriate for that patient.

A clinical trial design using the concept of proportional time using the generalized gamma ratio distribution.

PubMed

Phadnis, Milind A; Wetmore, James B; Mayo, Matthew S

2017-11-20

Traditional methods of sample size and power calculations in clinical trials with a time-to-event end point are based on the logrank test (and its variations), Cox proportional hazards (PH) assumption, or comparison of means of 2 exponential distributions. Of these, sample size calculation based on PH assumption is likely the most common and allows adjusting for the effect of one or more covariates. However, when designing a trial, there are situations when the assumption of PH may not be appropriate. Additionally, when it is known that there is a rapid decline in the survival curve for a control group, such as from previously conducted observational studies, a design based on the PH assumption may confer only a minor statistical improvement for the treatment group that is neither clinically nor practically meaningful. For such scenarios, a clinical trial design that focuses on improvement in patient longevity is proposed, based on the concept of proportional time using the generalized gamma ratio distribution. Simulations are conducted to evaluate the performance of the proportional time method and to identify the situations in which such a design will be beneficial as compared to the standard design using a PH assumption, piecewise exponential hazards assumption, and specific cases of a cure rate model. A practical example in which hemorrhagic stroke patients are randomized to 1 of 2 arms in a putative clinical trial demonstrates the usefulness of this approach by drastically reducing the number of patients needed for study enrollment. Copyright © 2017 John Wiley & Sons, Ltd.

Evaluation and validation of social and psychological markers in randomised trials of complex interventions in mental health: a methodological research programme.

PubMed

Dunn, Graham; Emsley, Richard; Liu, Hanhua; Landau, Sabine; Green, Jonathan; White, Ian; Pickles, Andrew

2015-11-01

The development of the capability and capacity to evaluate the outcomes of trials of complex interventions is a key priority of the National Institute for Health Research (NIHR) and the Medical Research Council (MRC). The evaluation of complex treatment programmes for mental illness (e.g. cognitive-behavioural therapy for depression or psychosis) not only is a vital component of this research in its own right but also provides a well-established model for the evaluation of complex interventions in other clinical areas. In the context of efficacy and mechanism evaluation (EME) there is a particular need for robust methods for making valid causal inference in explanatory analyses of the mechanisms of treatment-induced change in clinical outcomes in randomised clinical trials. The key objective was to produce statistical methods to enable trial investigators to make valid causal inferences about the mechanisms of treatment-induced change in these clinical outcomes. The primary objective of this report is to disseminate this methodology, aiming specifically at trial practitioners. The three components of the research were (1) the extension of instrumental variable (IV) methods to latent growth curve models and growth mixture models for repeated-measures data; (2) the development of designs and regression methods for parallel trials; and (3) the evaluation of the sensitivity/robustness of findings to the assumptions necessary for model identifiability. We illustrate our methods with applications from psychological and psychosocial intervention trials, keeping the technical details to a minimum, leaving the reporting of the more theoretical and mathematically demanding results for publication in appropriate specialist journals. We show how to estimate treatment effects and introduce methods for EME. We explain the use of IV methods and principal stratification to evaluate the role of putative treatment effect mediators and therapeutic process measures. These results are extended to the analysis of longitudinal data structures. We consider the design of EME trials. We focus on designs to create convincing IVs, bearing in mind assumptions needed to attain model identifiability. A key area of application that has become apparent during this work is the potential role of treatment moderators (predictive markers) in the evaluation of treatment effect mechanisms for personalised therapies (stratified medicine). We consider the role of targeted therapies and multiarm trials and the use of parallel trials to help elucidate the evaluation of mediators working in parallel. In order to demonstrate both efficacy and mechanism, it is necessary to (1) demonstrate a treatment effect on the primary (clinical) outcome, (2) demonstrate a treatment effect on the putative mediator (mechanism) and (3) demonstrate a causal effect from the mediator to the outcome. Appropriate regression models should be applied for (3) or alternative IV procedures, which account for unmeasured confounding, provided that a valid instrument can be identified. Stratified medicine may provide a setting where such instruments can be designed into the trial. This work could be extended by considering improved trial designs, sample size considerations and measurement properties. The project presents independent research funded under the MRC-NIHR Methodology Research Programme (grant reference G0900678).

Are You "Tilting at Windmills" or Undertaking a Valid Clinical Trial?

PubMed Central

Zariffa, Jose; Kramer, John L.K.

2011-01-01

In this review, several aspects surrounding the choice of a therapeutic intervention and the conduct of clinical trials are discussed. Some of the background for why human studies have evolved to their current state is also included. Specifically, the following questions have been addressed: 1) What criteria should be used to determine whether a scientific discovery or invention is worthy of translation to human application? 2) What recent scientific advance warrants a deeper understanding of clinical trials by everyone? 3) What are the different types and phases of a clinical trial? 4) What characteristics of a human disorder should be noted, tracked, or stratified for a clinical trial and what inclusion /exclusion criteria are important to enrolling appropriate trial subjects? 5) What are the different study designs that can be used in a clinical trial program? 6) What confounding factors can alter the accurate interpretation of clinical trial outcomes? 7) What are the success rates of clinical trials and what can we learn from previous clinical trials? 8) What are the essential principles for the conduct of valid clinical trials? PMID:21786433

Response: Reading between the lines of cancer screening trials: using modeling to understand the evidence.

PubMed

Etzioni, Ruth; Gulati, Roman

2013-04-01

In our article about limitations of basing screening policy on screening trials, we offered several examples of ways in which modeling, using data from large screening trials and population trends, provided insights that differed somewhat from those based only on empirical trial results. In this editorial, we take a step back and consider the general question of whether randomized screening trials provide the strongest evidence for clinical guidelines concerning population screening programs. We argue that randomized trials provide a process that is designed to protect against certain biases but that this process does not guarantee that inferences based on empirical results from screening trials will be unbiased. Appropriate quantitative methods are key to obtaining unbiased inferences from screening trials. We highlight several studies in the statistical literature demonstrating that conventional survival analyses of screening trials can be misleading and list a number of key questions concerning screening harms and benefits that cannot be answered without modeling. Although we acknowledge the centrality of screening trials in the policy process, we maintain that modeling constitutes a powerful tool for screening trial interpretation and screening policy development.

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

PubMed

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

2018-03-01

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

A cross-sectional analysis of HIV and hepatitis C clinical trials 2007 to 2010: the relationship between industry sponsorship and randomized study design.

PubMed

Goswami, Neela D; Tsalik, Ephraim L; Naggie, Susanna; Miller, William C; Horton, John R; Pfeiffer, Christopher D; Hicks, Charles B

2014-01-22

The proportion of clinical research sponsored by industry will likely continue to expand as federal funds for academic research decreases, particularly in the fields of HIV/AIDS and hepatitis C (HCV). While HIV and HCV continue to burden the US population, insufficient data exists as to how industry sponsorship affects clinical trials involving these infectious diseases. Debate exists about whether pharmaceutical companies undertake more market-driven research practices to promote therapeutics, or instead conduct more rigorous trials than their non-industry counterparts because of increased resources and scrutiny. The ClinicalTrials.gov registry, which allows investigators to fulfill a federal mandate for public trial registration, provides an opportunity for critical evaluation of study designs for industry-sponsored trials, independent of publication status. As part of a large public policy effort, the Clinical Trials Transformation Initiative (CTTI) recently transformed the ClinicalTrials.gov registry into a searchable dataset to facilitate research on clinical trials themselves. We conducted a cross-sectional analysis of 477 HIV and HCV drug treatment trials, registered with ClinicalTrials.gov from 1 October 2007 to 27 September 2010, to study the relationship of study sponsorship with randomized study design. The likelihood of using randomization given industry (versus non-industry) sponsorship was reported with prevalence ratios (PR). PRs were estimated using crude and stratified tabular analysis and Poisson regression adjusting for presence of a data monitoring committee, enrollment size, study phase, number of study sites, inclusion of foreign study sites, exclusion of persons older than age 65, and disease condition. The crude PR was 1.17 (95% CI 0.94, 1.45). Adjusted Poisson models produced a PR of 1.13 (95% CI 0.82, 1.56). There was a trend toward mild effect measure modification by study phase, but this was not statistically significant. In stratified tabular analysis the adjusted PR was 1.14 (95% CI 0.78, 1.68) among phase 2/3 trials and 1.06 (95% CI 0.50, 2.22) among phase 4 trials. No significant relationship was found between industry sponsorship and use of randomization in trial design in this cross-sectional study. Prospective studies evaluating other aspects of trial design may shed further light on the relationship between industry sponsorship and appropriate trial methodology.

A cross-sectional analysis of HIV and hepatitis C clinical trials 2007 to 2010: the relationship between industry sponsorship and randomized study design

PubMed Central

2014-01-01

Background The proportion of clinical research sponsored by industry will likely continue to expand as federal funds for academic research decreases, particularly in the fields of HIV/AIDS and hepatitis C (HCV). While HIV and HCV continue to burden the US population, insufficient data exists as to how industry sponsorship affects clinical trials involving these infectious diseases. Debate exists about whether pharmaceutical companies undertake more market-driven research practices to promote therapeutics, or instead conduct more rigorous trials than their non-industry counterparts because of increased resources and scrutiny. The ClinicalTrials.gov registry, which allows investigators to fulfill a federal mandate for public trial registration, provides an opportunity for critical evaluation of study designs for industry-sponsored trials, independent of publication status. As part of a large public policy effort, the Clinical Trials Transformation Initiative (CTTI) recently transformed the ClinicalTrials.gov registry into a searchable dataset to facilitate research on clinical trials themselves. Methods We conducted a cross-sectional analysis of 477 HIV and HCV drug treatment trials, registered with ClinicalTrials.gov from 1 October 2007 to 27 September 2010, to study the relationship of study sponsorship with randomized study design. The likelihood of using randomization given industry (versus non-industry) sponsorship was reported with prevalence ratios (PR). PRs were estimated using crude and stratified tabular analysis and Poisson regression adjusting for presence of a data monitoring committee, enrollment size, study phase, number of study sites, inclusion of foreign study sites, exclusion of persons older than age 65, and disease condition. Results The crude PR was 1.17 (95% CI 0.94, 1.45). Adjusted Poisson models produced a PR of 1.13 (95% CI 0.82, 1.56). There was a trend toward mild effect measure modification by study phase, but this was not statistically significant. In stratified tabular analysis the adjusted PR was 1.14 (95% CI 0.78, 1.68) among phase 2/3 trials and 1.06 (95% CI 0.50, 2.22) among phase 4 trials. Conclusions No significant relationship was found between industry sponsorship and use of randomization in trial design in this cross-sectional study. Prospective studies evaluating other aspects of trial design may shed further light on the relationship between industry sponsorship and appropriate trial methodology. PMID:24450313

A comparison of interventional clinical trials in rare versus non-rare diseases: an analysis of ClinicalTrials.gov.

PubMed

Bell, Stuart A; Tudur Smith, Catrin

2014-11-26

To provide a comprehensive characterisation of rare disease clinical trials registered in ClinicalTrials.gov, and compare against characteristics of trials in non-rare diseases. Registry based study of ClinicalTrials.gov registration entries. The ClinicalTrials.gov registry comprised 133,128 studies registered to September 27, 2012. By annotating medical subject heading descriptors to condition terms we could identify rare and non-rare disease trials. A total of 24,088 Interventional trials registered after January 1, 2006, conducted in the United States, Canada and/or the European Union were categorised as rare or non-rare. Characteristics of the respective trials were extracted and summarised with comparative statistics calculated where appropriate. Characteristics of interventional trials reported in the database categorised by rare and non-rare conditions to allow comparison. Of the 24,088 trials categorised 2,759 (11.5%) were classified as rare disease trials and 21,329 (88.5%) related to non-rare conditions. Despite the limitations of the database we found that rare disease trials differed to non-rare disease trials across all characteristics that we examined. Rare disease trials enrolled fewer participants (median 29 vs. 62), were more likely to be single arm (63.0% vs. 29.6%), non-randomised (64.5% vs. 36.1%) and open label (78.7% vs. 52.2%). A higher proportion of rare disease trials were terminated early (13.7% vs. 6.3%) and proportionally fewer rare disease studies were actively pursuing, or waiting to commence, enrolment (15.9% vs. 38.5%). Rare disease interventional trials differ from those in non-rare conditions with notable differences in enrolment, design, blinding and randomisation. However, clinical trials should aim to implement the highest trial design standards possible, regardless of whether diseases are rare or not.

A predictive Bayesian approach to the design and analysis of bridging studies.

PubMed

Gould, A Lawrence; Jin, Tian; Zhang, Li Xin; Wang, William W B

2012-09-01

Pharmaceutical product development culminates in confirmatory trials whose evidence for the product's efficacy and safety supports regulatory approval for marketing. Regulatory agencies in countries whose patients were not included in the confirmatory trials often require confirmation of efficacy and safety in their patient populations, which may be accomplished by carrying out bridging studies to establish consistency for local patients of the effects demonstrated by the original trials. This article describes and illustrates an approach for designing and analyzing bridging studies that fully incorporates the information provided by the original trials. The approach determines probability contours or regions of joint predictive intervals for treatment effect and response variability, or endpoints of treatment effect confidence intervals, that are functions of the findings from the original trials, the sample sizes for the bridging studies, and possible deviations from complete consistency with the original trials. The bridging studies are judged consistent with the original trials if their findings fall within the probability contours or regions. Regulatory considerations determine the region definitions and appropriate probability levels. Producer and consumer risks provide a way to assess alternative region and probability choices. [Supplemental materials are available for this article. Go to the Publisher's online edition of the Journal of Biopharmaceutical Statistics for the following free supplemental resource: Appendix 2: R code for Calculations.].

Clinical trials in neonates and children: Report of the pulmonary hypertension academic research consortium pediatric advisory committee

PubMed Central

Adatia, Ian; Haworth, Sheila G.; Wegner, Max; Barst, Robyn J.; Ivy, Dunbar; Stenmark, Kurt R.; Karkowsky, Abraham; Rosenzweig, Erika; Aguilar, Christopher

2013-01-01

Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal. PMID:23662203

ACOG Committee Opinion No. 646: Ethical Considerations for Including Women as Research Participants.

PubMed

2015-11-01

Inclusion of women in research studies is necessary for valid inferences about health and disease in women. The generalization of results from trials conducted in men may yield erroneous conclusions that fail to account for the biologic differences between men and women. Although significant changes in research design and practice have led to an increase in the proportion of women included in research trials, knowledge gaps remain because of a continued lack of inclusion of women, especially those who are pregnant, in premarketing research trials. This document provides a historical overview of issues surrounding women as participants in research trials, followed by an ethical framework and discussion of the issues of informed consent, contraception requirements, intimate partner consent, and the appropriate inclusion of pregnant women in research studies.

Rethinking non-inferiority: a practical trial design for optimising treatment duration.

PubMed

Quartagno, Matteo; Walker, A Sarah; Carpenter, James R; Phillips, Patrick Pj; Parmar, Mahesh Kb

2018-06-01

Background Trials to identify the minimal effective treatment duration are needed in different therapeutic areas, including bacterial infections, tuberculosis and hepatitis C. However, standard non-inferiority designs have several limitations, including arbitrariness of non-inferiority margins, choice of research arms and very large sample sizes. Methods We recast the problem of finding an appropriate non-inferior treatment duration in terms of modelling the entire duration-response curve within a pre-specified range. We propose a multi-arm randomised trial design, allocating patients to different treatment durations. We use fractional polynomials and spline-based methods to flexibly model the duration-response curve. We call this a 'Durations design'. We compare different methods in terms of a scaled version of the area between true and estimated prediction curves. We evaluate sensitivity to key design parameters, including sample size, number and position of arms. Results A total sample size of ~ 500 patients divided into a moderate number of equidistant arms (5-7) is sufficient to estimate the duration-response curve within a 5% error margin in 95% of the simulations. Fractional polynomials provide similar or better results than spline-based methods in most scenarios. Conclusion Our proposed practical randomised trial 'Durations design' shows promising performance in the estimation of the duration-response curve; subject to a pending careful investigation of its inferential properties, it provides a potential alternative to standard non-inferiority designs, avoiding many of their limitations, and yet being fairly robust to different possible duration-response curves. The trial outcome is the whole duration-response curve, which may be used by clinicians and policymakers to make informed decisions, facilitating a move away from a forced binary hypothesis testing paradigm.

Constructing common cohorts from trials with overlapping eligibility criteria: implications for comparing effect sizes between trials.

PubMed

Mount, David L; Feeney, Patricia; Fabricatore, Anthony N; Coday, Mace; Bahnson, Judy; Byington, Robert; Phelan, Suzanne; Wilmoth, Sharon; Knowler, William C; Hramiak, Irene; Osei, Kwame; Sweeney, Mary Ellen; Espeland, Mark A

2009-10-01

Comparing findings from separate trials is necessary to choose among treatment options, however differences among study cohorts may impede these comparisons. As a case study, to examine the overlap of study cohorts in two large randomized controlled clinical trials that assess interventions to reduce risk of major cardiovascular disease events in adults with type 2 diabetes in order to explore the feasibility of cross-trial comparisons The Action for Health in Diabetes (Look AHEAD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials enrolled 5145 and 10,251 adults with type 2 diabetes, respectively. Look AHEAD assesses the efficacy of an intensive lifestyle intervention designed to produce weight loss; ACCORD tests pharmacological therapies for control of glycemia, hyperlipidemia, and hypertension. Incidence of major cardiovascular disease events is the primary outcome for both trials. A sample was constructed to include participants from each trial who appeared to meet eligibility criteria and be appropriate candidates for the other trial's interventions. Demographic characteristics, health status, and outcomes of members and nonmembers of this constructed sample were compared. Nearly 80% of Look AHEAD participants were projected to be ineligible for ACCORD; ineligibility was primarily due to better glycemic control or no early history of cardiovascular disease. Approximately 30% of ACCORD participants were projected to be ineligible for Look AHEAD, often for reasons linked to poorer health. The characteristics of participants projected to be jointly eligible for both trials continued to reflect differences between trials according to factors likely linked to retention, adherence, and study outcomes. Accurate ascertainment of cross-trial eligibility was hampered by differences between protocols. Despite several similarities, the Look AHEAD and ACCORD cohorts represent distinct populations. Even within the subsets of participants who appear to be eligible and appropriate candidates for trials of both modes of intervention, differences remained. Direct comparisons of results from separate trials of lifestyle and pharmacologic interventions are compromised by marked differences in enrolled cohorts.

Clinical Trials in Late Life: New Science in Old Paradigms

ERIC Educational Resources Information Center

Lebowitz, Barry D.

2004-01-01

This article, based on a Lawton Award Lecture, addresses the subject of the need to enhance the evidence base in our field in order to influence processes of policy development. Four issues are identified as critical to this: theory-driven targets of public health significance, use of appropriate and sophisticated approaches to research design and…

Stem Cell Trials for Cardiovascular Medicine: Ethical Rationale

PubMed Central

Teraa, Martin; Hesam, Husna; van Delden, Johannes J.M.; Verhaar, Marianne C.; Bredenoord, Annelien L.

2014-01-01

Stem cell-based interventions provide new treatment prospects for many disease conditions, including cardiovascular disorders. Clinical trials are necessary to collect adequate evidence on (long-term) safety and efficacy of novel interventions such as stem cells, but the design and launch of clinical trials, from first-in-human studies to larger randomized controlled trials (RCTs), is scientifically and ethically challenging. Stem cells are different from traditional pharmaceuticals, surgical procedures, and medical devices in the following ways: the novelty and complexity of stem cells, the invasiveness of the procedures, and the novel aim of regeneration. These specifics, combined with the characteristics of the study population, will have an impact on the design and ethics of RCTs. The recently closed JUVENTAS trial will serve as an example to identify the (interwoven) scientific and ethical challenges in the design and launch of stem cell RCTs. The JUVENTAS trial has investigated the efficacy of autologous bone marrow cells in end-stage vascular patients, in a double-blind sham-controlled design. We first describe the choices, considerations, and experiences of the JUVENTAS team. Subsequently, we identify the main ethical and scientific challenges and discuss what is important to consider in the design of future stem cell RCTs: assessment of risks and benefits, the choice for outcome measures, the choice for the comparator, the appropriate selection of participants, and adequate informed consent. Additionally, the stem cell field is highly in the spotlight due to the (commercial) interests and expectations. This warrants a cautious pace of translation and scrupulous set up of clinical trials, as failures could put the field in a negative light. At the same time, knowledge from clinical trials is necessary for the field to progress. We conclude that in the scientifically and ethically challenging field of stem cell RCTs, researchers and clinicians have to maneuver between the Skylla of hyper accelerated translation without rigorously conducted RCTs and the Charybdis of the missed opportunity of valuable knowledge. PMID:24164351

Evaluation of agile designs in first-in-human (FIH) trials--a simulation study.

PubMed

Perlstein, Itay; Bolognese, James A; Krishna, Rajesh; Wagner, John A

2009-12-01

The aim of the investigation was to evaluate alternatives to standard first-in-human (FIH) designs in order to optimize the information gained from such studies by employing novel agile trial designs. Agile designs combine adaptive and flexible elements to enable optimized use of prior information either before and/or during conduct of the study to seamlessly update the study design. A comparison of the traditional 6 + 2 (active + placebo) subjects per cohort design with alternative, reduced sample size, agile designs was performed by using discrete event simulation. Agile designs were evaluated for specific adverse event models and rates as well as dose-proportional, saturated, and steep-accumulation pharmacokinetic profiles. Alternative, reduced sample size (hereafter referred to as agile) designs are proposed for cases where prior knowledge about pharmacokinetics and/or adverse event relationships are available or appropriately assumed. Additionally, preferred alternatives are proposed for a general case when prior knowledge is limited or unavailable. Within the tested conditions and stated assumptions, some agile designs were found to be as efficient as traditional designs. Thus, simulations demonstrated that the agile design is a robust and feasible approach to FIH clinical trials, with no meaningful loss of relevant information, as it relates to PK and AE assumptions. In some circumstances, applying agile designs may decrease the duration and resources required for Phase I studies, increasing the efficiency of early clinical development. We highlight the value and importance of useful prior information when specifying key assumptions related to safety, tolerability, and PK.

TERMTrial--terminology-based documentation systems for cooperative clinical trials.

PubMed

Merzweiler, A; Weber, R; Garde, S; Haux, R; Knaup-Gregori, P

2005-04-01

Within cooperative groups of multi-center clinical trials a standardized documentation is a prerequisite for communication and sharing of data. Standardizing documentation systems means standardizing the underlying terminology. The management and consistent application of terminology systems is a difficult and fault-prone task, which should be supported by appropriate software tools. Today, documentation systems for clinical trials are often implemented as so-called Remote-Data-Entry-Systems (RDE-systems). Although there are many commercial systems, which support the development of RDE-systems there is none offering a comprehensive terminological support. Therefore, we developed the software system TERMTrial which consists of a component for the definition and management of terminology systems for cooperative groups of clinical trials and two components for the terminology-based automatic generation of trial databases and terminology-based interactive design of electronic case report forms (eCRFs). TERMTrial combines the advantages of remote data entry with a comprehensive terminological control.

Randomization in clinical trials in orthodontics: its significance in research design and methods to achieve it.

PubMed

Pandis, Nikolaos; Polychronopoulou, Argy; Eliades, Theodore

2011-12-01

Randomization is a key step in reducing selection bias during the treatment allocation phase in randomized clinical trials. The process of randomization follows specific steps, which include generation of the randomization list, allocation concealment, and implementation of randomization. The phenomenon in the dental and orthodontic literature of characterizing treatment allocation as random is frequent; however, often the randomization procedures followed are not appropriate. Randomization methods assign, at random, treatment to the trial arms without foreknowledge of allocation by either the participants or the investigators thus reducing selection bias. Randomization entails generation of random allocation, allocation concealment, and the actual methodology of implementing treatment allocation randomly and unpredictably. Most popular randomization methods include some form of restricted and/or stratified randomization. This article introduces the reasons, which make randomization an integral part of solid clinical trial methodology, and presents the main randomization schemes applicable to clinical trials in orthodontics.

Decision aids for randomised controlled trials: a qualitative exploration of stakeholders’ views

PubMed Central

Gillies, Katie; Skea, Zoë C; Campbell, Marion K

2014-01-01

Objectives To explore stakeholders’ perceptions of decision aids designed to support the informed consent decision-making process for randomised controlled trials. Design Qualitative semistructured interviews. Participants were provided with prototype trial decision aids in advance to stimulate discussion. Interviews were analysed using an established interpretive approach. Participants 23 stakeholders: Trial Managers (n=5); Research Nurses (n=5); Ethics Committee Chairs (n=5); patients (n=4) and Clinical Principal Investigators (n=4). Setting Embedded within two ongoing randomised controlled trials. All interviews conducted with UK-based participants. Results Certain key aspects (eg, values clarification exercises, presentation of probabilities, experiences of others and balance of options) in the prototype decision aids were perceived by all stakeholders as having a significant advantage (over existing patient information leaflets) in terms of supporting well informed appropriate decisions. However, there were some important differences between the stakeholder groups on specific content (eg, language used in the section on positive and negative features of taking part in a trial and the overall length of the trial decision aids). Generally the stakeholders believed trial decision aids have the potential to better engage potential participants in the decision-making process and allow them to make more personally relevant decisions about their participation. Conclusions Compared to existing patient information leaflets, stakeholders perceived decision aids for trial participation to have the potential to promote a more ‘informed’ decision-making process. Further efforts to develop, refine and formally evaluate trial decision aids should be explored. PMID:25138811

Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol

PubMed Central

2012-01-01

Background Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease. Methods/Design We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance. Discussion Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials. Trial registration Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18. PMID:22305183

Changing cluster composition in cluster randomised controlled trials: design and analysis considerations

PubMed Central

2014-01-01

Background There are many methodological challenges in the conduct and analysis of cluster randomised controlled trials, but one that has received little attention is that of post-randomisation changes to cluster composition. To illustrate this, we focus on the issue of cluster merging, considering the impact on the design, analysis and interpretation of trial outcomes. Methods We explored the effects of merging clusters on study power using standard methods of power calculation. We assessed the potential impacts on study findings of both homogeneous cluster merges (involving clusters randomised to the same arm of a trial) and heterogeneous merges (involving clusters randomised to different arms of a trial) by simulation. To determine the impact on bias and precision of treatment effect estimates, we applied standard methods of analysis to different populations under analysis. Results Cluster merging produced a systematic reduction in study power. This effect depended on the number of merges and was most pronounced when variability in cluster size was at its greatest. Simulations demonstrate that the impact on analysis was minimal when cluster merges were homogeneous, with impact on study power being balanced by a change in observed intracluster correlation coefficient (ICC). We found a decrease in study power when cluster merges were heterogeneous, and the estimate of treatment effect was attenuated. Conclusions Examples of cluster merges found in previously published reports of cluster randomised trials were typically homogeneous rather than heterogeneous. Simulations demonstrated that trial findings in such cases would be unbiased. However, simulations also showed that any heterogeneous cluster merges would introduce bias that would be hard to quantify, as well as having negative impacts on the precision of estimates obtained. Further methodological development is warranted to better determine how to analyse such trials appropriately. Interim recommendations include avoidance of cluster merges where possible, discontinuation of clusters following heterogeneous merges, allowance for potential loss of clusters and additional variability in cluster size in the original sample size calculation, and use of appropriate ICC estimates that reflect cluster size. PMID:24884591

Analysis and design of randomised clinical trials involving competing risks endpoints.

PubMed

Tai, Bee-Choo; Wee, Joseph; Machin, David

2011-05-19

In randomised clinical trials involving time-to-event outcomes, the failures concerned may be events of an entirely different nature and as such define a classical competing risks framework. In designing and analysing clinical trials involving such endpoints, it is important to account for the competing events, and evaluate how each contributes to the overall failure. An appropriate choice of statistical model is important for adequate determination of sample size. We describe how competing events may be summarised in such trials using cumulative incidence functions and Gray's test. The statistical modelling of competing events using proportional cause-specific and subdistribution hazard functions, and the corresponding procedures for sample size estimation are outlined. These are illustrated using data from a randomised clinical trial (SQNP01) of patients with advanced (non-metastatic) nasopharyngeal cancer. In this trial, treatment has no effect on the competing event of loco-regional recurrence. Thus the effects of treatment on the hazard of distant metastasis were similar via both the cause-specific (unadjusted csHR = 0.43, 95% CI 0.25 - 0.72) and subdistribution (unadjusted subHR 0.43; 95% CI 0.25 - 0.76) hazard analyses, in favour of concurrent chemo-radiotherapy followed by adjuvant chemotherapy. Adjusting for nodal status and tumour size did not alter the results. The results of the logrank test (p = 0.002) comparing the cause-specific hazards and the Gray's test (p = 0.003) comparing the cumulative incidences also led to the same conclusion. However, the subdistribution hazard analysis requires many more subjects than the cause-specific hazard analysis to detect the same magnitude of effect. The cause-specific hazard analysis is appropriate for analysing competing risks outcomes when treatment has no effect on the cause-specific hazard of the competing event. It requires fewer subjects than the subdistribution hazard analysis for a similar effect size. However, if the main and competing events are influenced in opposing directions by an intervention, a subdistribution hazard analysis may be warranted.

The use of clinical trials in comparative effectiveness research on mental health

PubMed Central

Blanco, Carlos; Rafful, Claudia; Olfson, Mark

2013-01-01

Objectives A large body of research on comparative effectiveness research (CER) focuses on the use of observational and quasi-experimental approaches. We sought to examine the use of clinical trials as a tool for CER, particularly in mental health. Study Design and Setting Examination of three ongoing randomized clinical trials in psychiatry that address issues which would pose difficulties for non-experimental CER methods. Results Existing statistical approaches to non-experimental data appear insufficient to compensate for biases that may arise when the pattern of missing data cannot be properly modeled such as when there are no standards for treatment, when affected populations have limited access to treatment, or when there are high rates of treatment dropout. Conclusions Clinical trials should retain an important role in CER, particularly in cases of high disorder prevalence, large expected effect sizes, difficult to reach populations or when examining sequential treatments or stepped-care algorithms. Progress in CER in mental health will require careful consideration of appropriate selection between clinical trials and non-experimental designs and on allocation of research resources to optimally inform key treatment decisions for each individual patient. PMID:23849150

Accounting for interim safety monitoring of an adverse event upon termination of a clinical trial.

PubMed

Dallas, Michael J

2008-01-01

Upon termination of a clinical trial that uses interim evaluations to determine whether the trial can be stopped, a proper statistical analysis must account for the interim evaluations. For example, in a group-sequential design where the efficacy of a treatment regimen is evaluated at interim stages, and the opportunity to stop the trial based on positive efficacy findings exists, the terminal p-value, point estimate, and confidence limits of the outcome of interest must be adjusted to eliminate bias. While it is standard practice to adjust terminal statistical analyses due to opportunities to stop for "positive" findings, adjusting due to opportunities to stop for "negative" findings is also important. Stopping rules for negative findings are particularly useful when monitoring a specific rare serious adverse event in trials designed to show safety with respect to the event. In these settings, establishing conservative stopping rules are appropriate, and therefore accounting for the interim monitoring can have a substantial effect on the final results. Here I present a method to account for interim safety monitoring and illustrate its usefulness. The method is demonstrated to have advantages over methodology that does not account for interim monitoring.

Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials.

PubMed

Hilbrich, Lutz; Sleight, Peter

2006-09-01

Randomized clinical trials (RCTs) are the definitive contributors to evidence-based medicine. RCTs assessing serious outcomes in cardiovascular disease have grown, with 'megatrials' becoming more common with the realization that wrong conclusions resulted from random error in inadequately sized trials. Simple design and a heterogeneous patient population were early features, but multinational trials have increased in scientific, logistical, bureaucratic, regulatory, and legal complexity. These studies now exceed the financial means of academia or medical charities. Governments have left the bill with the pharmaceutical industry, encouraging a symbiosis with academics, who contribute medical and scientific expertise, and access to patients. Industry provides pharmacological, pharmaceutical, technical and regulatory know-how, good clinical practice expertise, and legal assistance during the trial. Study supervision is then in the hands of an independent steering committee and associated subcommittees, until appropriate dissemination of results. Prospectively defined interaction with the sponsor facilitates unbiased design and conduct, but arrangements need careful implementation to avoid conflicts of interest. The patient is protected by a strong data safety monitoring board that is wholly independent. Megatrials are under threat from over-regulation, increasing costs, and difficulties in execution. These issues merit urgent public and political education and debate.

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.

[Prosthodontic research design from the standpoint of statistical analysis: learning and knowing the research design].

PubMed

Tanoue, Naomi

2007-10-01

For any kind of research, "Research Design" is the most important. The design is used to structure the research, to show how all of the major parts of the research project. It is necessary for all the researchers to begin the research after planning research design for what is the main theme, what is the background and reference, what kind of data is needed, and what kind of analysis is needed. It seems to be a roundabout route, but, in fact, it will be a shortcut. The research methods must be appropriate to the objectives of the study. Regarding the hypothesis-testing research that is the traditional style of the research, the research design based on statistics is undoubtedly necessary considering that the research basically proves "a hypothesis" with data and statistics theory. On the subject of the clinical trial, which is the clinical version of the hypothesis-testing research, the statistical method must be mentioned in a clinical trial planning. This report describes the basis of the research design for a prosthodontics study.

Prostate cancer prevention agent development: Criteria and pipeline for candidate chemoprevention agents.

PubMed

Nelson, W G; Wilding, G

2001-04-01

Epidemiologic data suggest that prostate cancer morbidity and mortality ought to be preventable. New insights into the molecular pathogenesis of prostate cancer offer new opportunities for the discovery of prostate cancer chemoprevention drugs and new challenges for their development. Established pathways that lead to US Food and Drug Administration (FDA) approval of drugs for advanced prostate cancer may not be appropriate for the development of drugs for prostate cancer chemoprevention. For example, large randomized clinical trials designed to test the efficacy of new chemoprevention drugs on prostate cancer survival in the general population are likely to be conducted at great expense and take many years, threatening to increase commercial development risks while decreasing exclusive marketing revenues. As a consequence, to accelerate progress in research, new validated surrogate and strategic clinical trial endpoints, and new clinical trial designs featuring more precisely defined high-risk clinical trial cohorts, are needed. In this review, 10 criteria for prostate cancer chemoprevention agent development are offered and the pipeline of new prostate cancer chemoprevention drug candidates is considered.

Establishing HIV treatment as prevention in the HIV Prevention Trials Network 052 randomized trial: an ethical odyssey.

PubMed

Cohen, Myron S; McCauley, Marybeth; Sugarman, Jeremy

2012-06-01

Obtaining the definitive data necessary to determine the safety and efficacy of using antiretroviral treatment (ART) to reduce the sexual transmission of HIV in heterosexual couples encountered an array of ethical challenges that threatened to compromise HIV Prevention Trials Network (HPTN) 052, the multinational clinical trial addressing this issue that has profound public health implications. To describe and analyze the major ethical challenges faced in HPTN 052. The ethical issues and modifications of HPTN 052 in response to these issues were cataloged by the principal investigator, the lead coordinator, and the ethicist working on the trial. The major ethical issues that were unique to the trial were then described and analyzed in light of the published literature as well as guidances and policies. The ethical challenges that must be addressed in many clinical trials, such as those related to obtaining informed consent and making provisions for ancillary care, are not described. When HPTN 052 was being designed, ethical questions emerged related to the relevance of the research question itself given data from observational research and a range of beliefs about the appropriate means of preventing and treating HIV infection and AIDS. Furthermore, ethical challenges were faced regarding site selection since there was a scientific need to conduct the research in settings where HIV incidence was high, but alternatives to study participation should be available. As in most HIV-prevention research, ethical questions surrounded the determination of the appropriate prevention package for all of those enrolled. During the course of the trial, guidance documents and policies emerged that were of direct relevance to the research questions, calling for a balancing of concerns for the research subjects and trial integrity. When the study results were made public, there was a need to ensure access to the treatment shown to be effective that in some cases differed from the guidelines used at the sites where the research was being conducted. In addition, questions were raised about whether there was an obligation to notify subjects about 'unlinked' transmissions of HIV, that is, infections acquired from someone other than the designated sexual partner enrolled in the study. The ethical issues described are limited to those discerned by the authors and not those of other stakeholders who may have identified additional issues or had a different perspective in analyzing them. Understanding the ethical challenges faced in HPTN 052 promises to inform the design and conduct of future complex, long-term clinical trials aimed at addressing critical scientific and public health questions, where data and practice patterns emerge over the course of the trial.

Methodology of clinical trials evaluating the incorporation of new drugs in the first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review.

PubMed

Iacoboni, G; Zucca, E; Ghielmini, M; Stathis, A

2018-05-01

The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been carried out over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Reports of phase III trials evaluating the addition of molecularly targeted agents or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phases I and II trials which preceded these phase III trials were also reviewed. Among six phase III trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary end point. The other five trials did not show an improved outcome with the addition of the new agent. The preceding phases I and II trials were very heterogeneous in their end points and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase III trials. The standard of care for DLBCL is still R-CHOP. Phase I/II trials failed to predict the results of subsequent phase III trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase II trials evaluating new agents in DLBCL needs to be better defined in the future.

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.

Immediate vs. delayed insertion of intrauterine contraception after second trimester abortion: study protocol for a randomized controlled trial.

PubMed

Norman, Wendy V; Kaczorowski, Janusz; Soon, Judith A; Brant, Rollin; Bryan, Stirling; Trouton, Konia J; Dicus, Lyda

2011-06-14

We describe the rationale and protocol for a randomized controlled trial (RCT) to assess whether intrauterine contraception placed immediately after a second trimester abortion will result in fewer pregnancies than current recommended practice of intended placement at 4 weeks post-abortion. Decision analysis suggests the novel strategy could substantially reduce subsequent unintended pregnancies and abortions. This paper highlights considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion. Consenting women choosing to use intrauterine contraception after abortion for a pregnancy of 12 to 24 weeks will be randomized to insertion timing groups either immediately (experimental intervention) or four weeks (recommended care) post abortion. Primary outcome measure is pregnancy rate at one year. Secondary outcomes include: cumulative pregnancy rates over five year follow-up period, comprehensive health economic analyses comparing immediate and delayed insertion groups, and device retention rates, complication rates (infection, expulsion) and, contraceptive method satisfaction. Web-based Contraception Satisfaction Questionnaires, clinical records and British Columbia linked health databases will be used to assess primary and secondary outcomes. Enrolment at all clinics in the province performing second trimester abortions began in May 2010 and is expected to complete in late 2011. Data on one year outcomes will be available for analysis in 2014. The RCT design combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry and hospital records, offers a unique opportunity to evaluate such an approach by determining pregnancy rate at one through five years among enrolled women. We highlight considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion.

Quality of reporting of pilot and feasibility cluster randomised trials: a systematic review

PubMed Central

Chan, Claire L; Leyrat, Clémence; Eldridge, Sandra M

2017-01-01

Objectives To systematically review the quality of reporting of pilot and feasibility of cluster randomised trials (CRTs). In particular, to assess (1) the number of pilot CRTs conducted between 1 January 2011 and 31 December 2014, (2) whether objectives and methods are appropriate and (3) reporting quality. Methods We searched PubMed (2011–2014) for CRTs with ‘pilot’ or ‘feasibility’ in the title or abstract; that were assessing some element of feasibility and showing evidence the study was in preparation for a main effectiveness/efficacy trial. Quality assessment criteria were based on the Consolidated Standards of Reporting Trials (CONSORT) extensions for pilot trials and CRTs. Results Eighteen pilot CRTs were identified. Forty-four per cent did not have feasibility as their primary objective, and many (50%) performed formal hypothesis testing for effectiveness/efficacy despite being underpowered. Most (83%) included ‘pilot’ or ‘feasibility’ in the title, and discussed implications for progression from the pilot to the future definitive trial (89%), but fewer reported reasons for the randomised pilot trial (39%), sample size rationale (44%) or progression criteria (17%). Most defined the cluster (100%), and number of clusters randomised (94%), but few reported how the cluster design affected sample size (17%), whether consent was sought from clusters (11%), or who enrolled clusters (17%). Conclusions That only 18 pilot CRTs were identified necessitates increased awareness of the importance of conducting and publishing pilot CRTs and improved reporting. Pilot CRTs should primarily be assessing feasibility, avoiding formal hypothesis testing for effectiveness/efficacy and reporting reasons for the pilot, sample size rationale and progression criteria, as well as enrolment of clusters, and how the cluster design affects design aspects. We recommend adherence to the CONSORT extensions for pilot trials and CRTs. PMID:29122791

The Importance of Considering Differences in Study Design in Network Meta-analysis: An Application Using Anti-Tumor Necrosis Factor Drugs for Ulcerative Colitis.

PubMed

Cameron, Chris; Ewara, Emmanuel; Wilson, Florence R; Varu, Abhishek; Dyrda, Peter; Hutton, Brian; Ingham, Michael

2017-11-01

Adaptive trial designs present a methodological challenge when performing network meta-analysis (NMA), as data from such adaptive trial designs differ from conventional parallel design randomized controlled trials (RCTs). We aim to illustrate the importance of considering study design when conducting an NMA. Three NMAs comparing anti-tumor necrosis factor drugs for ulcerative colitis were compared and the analyses replicated using Bayesian NMA. The NMA comprised 3 RCTs comparing 4 treatments (adalimumab 40 mg, golimumab 50 mg, golimumab 100 mg, infliximab 5 mg/kg) and placebo. We investigated the impact of incorporating differences in the study design among the 3 RCTs and presented 3 alternative methods on how to convert outcome data derived from one form of adaptive design to more conventional parallel RCTs. Combining RCT results without considering variations in study design resulted in effect estimates that were biased against golimumab. In contrast, using the 3 alternative methods to convert outcome data from one form of adaptive design to a format more consistent with conventional parallel RCTs facilitated more transparent consideration of differences in study design. This approach is more likely to yield appropriate estimates of comparative efficacy when conducting an NMA, which includes treatments that use an alternative study design. RCTs based on adaptive study designs should not be combined with traditional parallel RCT designs in NMA. We have presented potential approaches to convert data from one form of adaptive design to more conventional parallel RCTs to facilitate transparent and less-biased comparisons.

Systematic review finds major deficiencies in sample size methodology and reporting for stepped-wedge cluster randomised trials

PubMed Central

Martin, James; Taljaard, Monica; Girling, Alan; Hemming, Karla

2016-01-01

Background Stepped-wedge cluster randomised trials (SW-CRT) are increasingly being used in health policy and services research, but unless they are conducted and reported to the highest methodological standards, they are unlikely to be useful to decision-makers. Sample size calculations for these designs require allowance for clustering, time effects and repeated measures. Methods We carried out a methodological review of SW-CRTs up to October 2014. We assessed adherence to reporting each of the 9 sample size calculation items recommended in the 2012 extension of the CONSORT statement to cluster trials. Results We identified 32 completed trials and 28 independent protocols published between 1987 and 2014. Of these, 45 (75%) reported a sample size calculation, with a median of 5.0 (IQR 2.5–6.0) of the 9 CONSORT items reported. Of those that reported a sample size calculation, the majority, 33 (73%), allowed for clustering, but just 15 (33%) allowed for time effects. There was a small increase in the proportions reporting a sample size calculation (from 64% before to 84% after publication of the CONSORT extension, p=0.07). The type of design (cohort or cross-sectional) was not reported clearly in the majority of studies, but cohort designs seemed to be most prevalent. Sample size calculations in cohort designs were particularly poor with only 3 out of 24 (13%) of these studies allowing for repeated measures. Discussion The quality of reporting of sample size items in stepped-wedge trials is suboptimal. There is an urgent need for dissemination of the appropriate guidelines for reporting and methodological development to match the proliferation of the use of this design in practice. Time effects and repeated measures should be considered in all SW-CRT power calculations, and there should be clarity in reporting trials as cohort or cross-sectional designs. PMID:26846897

Critical appraisal of fundamental items in approved clinical trial research proposals in Mashhad University of Medical Sciences

PubMed Central

Shakeri, Mohammad-Taghi; Taghipour, Ali; Sadeghi, Masoumeh; Nezami, Hossein; Amirabadizadeh, Ali-Reza; Bonakchi, Hossein

2017-01-01

Background: Writing, designing, and conducting a clinical trial research proposal has an important role in achieving valid and reliable findings. Thus, this study aimed at critically appraising fundamental information in approved clinical trial research proposals in Mashhad University of Medical Sciences (MUMS) from 2008 to 2014. Methods: This cross-sectional study was conducted on all 935 approved clinical trial research proposals in MUMS from 2008 to 2014. A valid and reliable as well as comprehensive, simple, and usable checklist in sessions with biostatisticians and methodologists, consisting of 11 main items as research tool, were used. Agreement rate between the reviewers of the proposals, who were responsible for data collection, was assessed during 3 sessions, and Kappa statistics was calculated at the last session as 97%. Results: More than 60% of the research proposals had a methodologist consultant, moreover, type of study or study design had been specified in almost all of them (98%). Appropriateness of study aims with hypotheses was not observed in a significant number of research proposals (585 proposals, 62.6%). The required sample size for 66.8% of the approved proposals was based on a sample size formula; however, in 25% of the proposals, sample size formula was not in accordance with the study design. Data collection tool was not selected appropriately in 55.2% of the approved research proposals. Type and method of randomization were unknown in 21% of the proposals and dealing with missing data had not been described in most of them (98%). Inclusion and exclusion criteria were (92%) fully and adequately explained. Moreover, 44% and 31% of the research proposals were moderate and weak in rank, respectively, with respect to the correctness of the statistical analysis methods. Conclusion: Findings of the present study revealed that a large portion of the approved proposals were highly biased or ambiguous with respect to randomization, blinding, dealing with missing data, data collection tool, sampling methods, and statistical analysis. Thus, it is essential to consult and collaborate with a methodologist in all parts of a proposal to control the possible and specific biases in clinical trials. PMID:29445703

Critical appraisal of fundamental items in approved clinical trial research proposals in Mashhad University of Medical Sciences.

PubMed

Shakeri, Mohammad-Taghi; Taghipour, Ali; Sadeghi, Masoumeh; Nezami, Hossein; Amirabadizadeh, Ali-Reza; Bonakchi, Hossein

2017-01-01

Background: Writing, designing, and conducting a clinical trial research proposal has an important role in achieving valid and reliable findings. Thus, this study aimed at critically appraising fundamental information in approved clinical trial research proposals in Mashhad University of Medical Sciences (MUMS) from 2008 to 2014. Methods: This cross-sectional study was conducted on all 935 approved clinical trial research proposals in MUMS from 2008 to 2014. A valid and reliable as well as comprehensive, simple, and usable checklist in sessions with biostatisticians and methodologists, consisting of 11 main items as research tool, were used. Agreement rate between the reviewers of the proposals, who were responsible for data collection, was assessed during 3 sessions, and Kappa statistics was calculated at the last session as 97%. Results: More than 60% of the research proposals had a methodologist consultant, moreover, type of study or study design had been specified in almost all of them (98%). Appropriateness of study aims with hypotheses was not observed in a significant number of research proposals (585 proposals, 62.6%). The required sample size for 66.8% of the approved proposals was based on a sample size formula; however, in 25% of the proposals, sample size formula was not in accordance with the study design. Data collection tool was not selected appropriately in 55.2% of the approved research proposals. Type and method of randomization were unknown in 21% of the proposals and dealing with missing data had not been described in most of them (98%). Inclusion and exclusion criteria were (92%) fully and adequately explained. Moreover, 44% and 31% of the research proposals were moderate and weak in rank, respectively, with respect to the correctness of the statistical analysis methods. Conclusion: Findings of the present study revealed that a large portion of the approved proposals were highly biased or ambiguous with respect to randomization, blinding, dealing with missing data, data collection tool, sampling methods, and statistical analysis. Thus, it is essential to consult and collaborate with a methodologist in all parts of a proposal to control the possible and specific biases in clinical trials.

Formative research methods for designing culturally appropriate, integrated child nutrition and development interventions: An overview

PubMed Central

Bentley, Margaret E.; Johnson, Susan L.; Wasser, Heather; Creed-Kanashiro, Hilary; Shroff, Monal; Fernandez-Rao, Sylvia; Cunningham, Melissa

2014-01-01

Nutritional and developmental insults in the first few years of life have profound public health implications, including substantial contributions to neonatal, infant, and early childhood morbidity and mortality, as well as longer term impacts on cognitive development, school achievement, and worker productivity. Optimal development that can lead to the attainment of the individual's fullest potential therefore requires a combination of genetic capacity, adequate nutrition, psychosocial stimulation, and safe, clean physical environments. Researchers and policymakers have called for integrated child nutrition and development interventions for more than twenty years, yet there are only a handful of efficacy trials and even fewer examples of integrated interventions that have been taken to scale. While a critical component to the design of such interventions is formative research, there is a dearth of information in both the literature and policy arenas to guide this phase of the process. To move the field forward, this paper first provides an overview of formative research methods with a focus on qualitative inquiry, a description of the critical domains to be assessed (infant and young child feeding, responsive feeding, and child development), and currently available resources. Application of these methods is provided through a real-world case study—the design of an integrated nutrition and child development efficacy trial in Andhra Pradesh, India. Recommendations for next steps are discussed, the most important of which is the need for a comprehensive set of formative guidelines for designing locally tailored, culturally appropriate integrated interventions. PMID:24673167

Delivery of inhaled drugs for infants and small children: a commentary on present and future needs.

PubMed

Fink, James B

2012-11-01

Although the manufacture of inhaled medications is a multibillion dollar industry, virtually no pharmaceutical drug/device combination has been approved for inhalation across the range of pediatric patient ages and sizes. The clinician who treats neonates, infants, or toddlers is often faced with the dilemma of prescribing inhaled medications that may be disease appropriate but have not been approved for use in patients in these age categories. Their use is thus technically "off label," with limited empirical data to guide both dose and device selection. This dilemma requires the prescribing physician to go beyond the limitations of the product label, often without benefit of appropriately designed clinical trials, in an attempt to select safe and effective doses for use with these smallest of patients. The vast majority of drugs approved for inhalation were studied by using aerosol devices designed for older children and adults using a mouthpiece interface, which may not be practical for use in infants and patients aged <4 years. The selection of the most age-appropriate device and interface is critical for the effective administration of the prescribed therapy. In the absence of industry-sponsored clinical trials in neonates, infants, and toddlers, in vitro and in vivo strategies may help guide age-appropriate dosing, device, and interface selection to better inform clinical practice. In this commentary, the challenges in developing and prescribing effective formulations for aerosol delivery across the range of pediatric ages and sizes are explored, with guidance for device and interface selection. Recommendations for future collaborative sharing of in vitro models and age-specific breathing patterns between academic and industry researchers could help regulators and clinicians better understand the impact age and size have on pulmonary drug delivery. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

The reduction of intoxication and disorder in premises licensed to serve alcohol: an exploratory randomised controlled trial.

PubMed

Moore, Simon C; Brennan, Iain R; Murphy, Simon; Byrne, Ellie; Moore, Susan N; Shepherd, Jonathan P; Moore, Laurence

2010-10-14

Licensed premises offer a valuable point of intervention to reduce alcohol-related harm. To describe the research design for an exploratory trial examining the feasibility and acceptability of a premises-level intervention designed to reduce severe intoxication and related disorder. The study also aims to assess the feasibility of a potential future large scale effectiveness trial and provide information on key trial design parameters including inclusion criteria, premises recruitment methods, strategies to implement the intervention and trial design, outcome measures, data collection methods and intra-cluster correlations. A randomised controlled trial in licensed premises that had experienced at least one assault in the year preceding the intervention, documented in police or hospital Emergency Department (ED) records. Premises were recruited from four study areas by piloting four recruitment strategies of varying intensity. Thirty two licensed premises were grouped into matched pairs to reduce potential bias and randomly allocated to the control or intervention condition. The study included a nested process evaluation to provide information on intervention acceptability and implementation. Outcome measures included police-recorded violent incidents, assault-related attendances at each premises' local ED and patron Breath Alcohol Concentration assessed on exiting and entering study premises. The most successful recruitment method involved local police licensing officers and yielded a 100% success rate. Police-records of violence provided the most appropriate source of data about disorder at the premises level. The methodology of an exploratory trial is presented and despite challenges presented by the study environment it is argued an exploratory trial is warranted. Initial investigations in recruitment methods suggest that study premises should be recruited with the assistance of police officers. Police data were of sufficient quality to identify disorder and street surveys are a feasible method for measuring intoxication at the individual level. UKCRN 7090; ISRCTN: 80875696. Medical Research Council (G0701758) to Simon Moore, Simon Murphy, Laurence Moore and Jonathan Shepherd.

Hazard identification and risk assessment for biologics targeting the immune system.

PubMed

Weir, Andrea B

2008-01-01

Biologic pharmaceuticals include a variety of products, such as monoclonal antibodies, fusion proteins and cytokines. Products in those classes include immunomodulatory biologics, which are intended to enhance or diminish the activity of the immune system. Immunomodulatory biologics have been approved by the U.S. FDA for a variety of indications, including cancer and inflammatory conditions. Prior to gaining approval for marketing, sponsoring companies for all types of products must demonstrate a product's safety in toxicology studies conducted in animals and show safety and efficacy in clinical trials conducted in patients. The overall goal of toxicology studies, which applies to immunomodulatory and other product types, is to identify the hazards that products pose to humans. Because biologics are generally highly selective for specific targets (receptors/epitopes), conducting toxicology studies in animal models with the target is essential. Such animals are referred to as pharmacologically relevant. Endpoints routinely included in toxicology studies, such as hematology, organ weight and histopathology, can be used to assess the effect of a product on the structure of the immune system. Additionally, specialized endpoints, such as immunophenotyping and immune function tests, can be used to define effects of immunomodulatory products on the immune system. Following hazard identification, risks posed to patients are assessed and managed. Risks can be managed through clinical trial design and risk communication, a practice that applies to immunomodulatory and other product types. Examples of risk management in clinical trial design include establishing a safe starting dose, defining the appropriate patient population and establishing appropriate patient monitoring. Risk communication starts during clinical trials and continues after product approval. A combination of hazard identification, risk assessment and risk management allows for drug development to proceed with minimum risks to patients.

Defining Feasibility and Pilot Studies in Preparation for Randomised Controlled Trials: Development of a Conceptual Framework

PubMed Central

Eldridge, Sandra M.; Lancaster, Gillian A.; Campbell, Michael J.; Thabane, Lehana; Hopewell, Sally; Coleman, Claire L.; Bond, Christine M.

2016-01-01

We describe a framework for defining pilot and feasibility studies focusing on studies conducted in preparation for a randomised controlled trial. To develop the framework, we undertook a Delphi survey; ran an open meeting at a trial methodology conference; conducted a review of definitions outside the health research context; consulted experts at an international consensus meeting; and reviewed 27 empirical pilot or feasibility studies. We initially adopted mutually exclusive definitions of pilot and feasibility studies. However, some Delphi survey respondents and the majority of open meeting attendees disagreed with the idea of mutually exclusive definitions. Their viewpoint was supported by definitions outside the health research context, the use of the terms ‘pilot’ and ‘feasibility’ in the literature, and participants at the international consensus meeting. In our framework, pilot studies are a subset of feasibility studies, rather than the two being mutually exclusive. A feasibility study asks whether something can be done, should we proceed with it, and if so, how. A pilot study asks the same questions but also has a specific design feature: in a pilot study a future study, or part of a future study, is conducted on a smaller scale. We suggest that to facilitate their identification, these studies should be clearly identified using the terms ‘feasibility’ or ‘pilot’ as appropriate. This should include feasibility studies that are largely qualitative; we found these difficult to identify in electronic searches because researchers rarely used the term ‘feasibility’ in the title or abstract of such studies. Investigators should also report appropriate objectives and methods related to feasibility; and give clear confirmation that their study is in preparation for a future randomised controlled trial designed to assess the effect of an intervention. PMID:26978655

Defining Feasibility and Pilot Studies in Preparation for Randomised Controlled Trials: Development of a Conceptual Framework.

PubMed

Eldridge, Sandra M; Lancaster, Gillian A; Campbell, Michael J; Thabane, Lehana; Hopewell, Sally; Coleman, Claire L; Bond, Christine M

2016-01-01

We describe a framework for defining pilot and feasibility studies focusing on studies conducted in preparation for a randomised controlled trial. To develop the framework, we undertook a Delphi survey; ran an open meeting at a trial methodology conference; conducted a review of definitions outside the health research context; consulted experts at an international consensus meeting; and reviewed 27 empirical pilot or feasibility studies. We initially adopted mutually exclusive definitions of pilot and feasibility studies. However, some Delphi survey respondents and the majority of open meeting attendees disagreed with the idea of mutually exclusive definitions. Their viewpoint was supported by definitions outside the health research context, the use of the terms 'pilot' and 'feasibility' in the literature, and participants at the international consensus meeting. In our framework, pilot studies are a subset of feasibility studies, rather than the two being mutually exclusive. A feasibility study asks whether something can be done, should we proceed with it, and if so, how. A pilot study asks the same questions but also has a specific design feature: in a pilot study a future study, or part of a future study, is conducted on a smaller scale. We suggest that to facilitate their identification, these studies should be clearly identified using the terms 'feasibility' or 'pilot' as appropriate. This should include feasibility studies that are largely qualitative; we found these difficult to identify in electronic searches because researchers rarely used the term 'feasibility' in the title or abstract of such studies. Investigators should also report appropriate objectives and methods related to feasibility; and give clear confirmation that their study is in preparation for a future randomised controlled trial designed to assess the effect of an intervention.

Design of a multi-arm randomized clinical trial with no control arm.

PubMed

Magaret, Amalia; Angus, Derek C; Adhikari, Neill K J; Banura, Patrick; Kissoon, Niranjan; Lawler, James V; Jacob, Shevin T

2016-01-01

Clinical trial designs that include multiple treatments are currently limited to those that perform pairwise comparisons of each investigational treatment to a single control. However, there are settings, such as the recent Ebola outbreak, in which no treatment has been demonstrated to be effective; and therefore, no standard of care exists which would serve as an appropriate control. For illustrative purposes, we focused on the care of patients presenting in austere settings with critically ill 'sepsis-like' syndromes. Our approach involves a novel algorithm for comparing mortality among arms without requiring a single fixed control. The algorithm allows poorly-performing arms to be dropped during interim analyses. Consequently, the study may be completed earlier than planned. We used simulation to determine operating characteristics for the trial and to estimate the required sample size. We present a potential study design targeting a minimal effect size of a 23% relative reduction in mortality between any pair of arms. Using estimated power and spurious significance rates from the simulated scenarios, we show that such a trial would require 2550 participants. Over a range of scenarios, our study has 80 to 99% power to select the optimal treatment. Using a fixed control design, if the control arm is least efficacious, 640 subjects would be enrolled into the least efficacious arm, while our algorithm would enroll between 170 and 430. This simulation method can be easily extended to other settings or other binary outcomes. Early dropping of arms is efficient and ethical when conducting clinical trials with multiple arms. Copyright © 2015 Elsevier Inc. All rights reserved.

Patient reported outcomes (PROs) in clinical trials: is 'in-trial' guidance lacking? a systematic review.

PubMed

Kyte, Derek G; Draper, Heather; Ives, Jonathan; Liles, Clive; Gheorghe, Adrian; Calvert, Melanie

2013-01-01

Patient reported outcomes (PROs) are increasingly assessed in clinical trials, and guidelines are available to inform the design and reporting of such trials. However, researchers involved in PRO data collection report that specific guidance on 'in-trial' activity (recruitment, data collection and data inputting) and the management of 'concerning' PRO data (i.e., data which raises concern for the well-being of the trial participant) appears to be lacking. The purpose of this review was to determine the extent and nature of published guidelines addressing these areas. Systematic review of 1,362 articles identified 18 eligible papers containing 'in-trial' guidelines. Two independent authors undertook a qualitative content analysis of the selected papers. Guidelines presented in each of the articles were coded according to an a priori defined coding frame, which demonstrated reliability (pooled Kappa 0.86-0.97), and validity (<2% residual category coding). The majority of guidelines present were concerned with 'pre-trial' activities (72%), for example, outcome measure selection and study design issues, or 'post-trial' activities (16%) such as data analysis, reporting and interpretation. 'In-trial' guidelines represented 9.2% of all guidance across the papers reviewed, with content primarily focused on compliance, quality control, proxy assessment and reporting of data collection. There were no guidelines surrounding the management of concerning PRO data. The findings highlight there are minimal in-trial guidelines in publication regarding PRO data collection and management in clinical trials. No guidance appears to exist for researchers involved with the handling of concerning PRO data. Guidelines are needed, which support researchers to manage all PRO data appropriately and which facilitate unbiased data collection.

Factorial versus multi-arm multi-stage designs for clinical trials with multiple treatments.

PubMed

Jaki, Thomas; Vasileiou, Despina

2017-02-20

When several treatments are available for evaluation in a clinical trial, different design options are available. We compare multi-arm multi-stage with factorial designs, and in particular, we will consider a 2 × 2 factorial design, where groups of patients will either take treatments A, B, both or neither. We investigate the performance and characteristics of both types of designs under different scenarios and compare them using both theory and simulations. For the factorial designs, we construct appropriate test statistics to test the hypothesis of no treatment effect against the control group with overall control of the type I error. We study the effect of the choice of the allocation ratios on the critical value and sample size requirements for a target power. We also study how the possibility of an interaction between the two treatments A and B affects type I and type II errors when testing for significance of each of the treatment effects. We present both simulation results and a case study on an osteoarthritis clinical trial. We discover that in an optimal factorial design in terms of minimising the associated critical value, the corresponding allocation ratios differ substantially to those of a balanced design. We also find evidence of potentially big losses in power in factorial designs for moderate deviations from the study design assumptions and little gain compared with multi-arm multi-stage designs when the assumptions hold. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Participant selection for preventive Regenerative Medicine trials: ethical challenges of selecting individuals at risk.

PubMed

Niemansburg, Sophie L; Habets, Michelle G J L; Dhert, Wouter J A; van Delden, Johannes J M; Bredenoord, Annelien L

2015-11-01

The innovative field of Regenerative Medicine (RM) is expected to extend the possibilities of prevention or early treatment in healthcare. Increasingly, clinical trials will be developed for people at risk of disease to investigate these RM interventions. These individuals at risk are characterised by their susceptibility for developing clinically manifest disease in future due to the existence of degenerative abnormalities. So far, there has been little debate about the ethical appropriateness of including such individuals at risk in clinical trials. We discuss three main challenges of selecting this participant model for testing RM interventions: the challenge of achieving a proportional risk-benefit balance; complexities in the trial design in terms of follow-up and sample size; and the difficulty of obtaining informed consent due to the many uncertainties. We conclude that selecting the model is not ethically justifiable for first-in-man trials with RM interventions due to the high risks and uncertainties. However, the model can be ethically appropriate for testing the efficacy of RM interventions under the following conditions: interventions should be low risk; the degenerative abnormalities (and other risk factors) should be strongly related with disease within a short time frame; robust preclinical evidence of efficacy needs to be present; and the informed consent procedure should contain extra safeguards with regard to communication on uncertainties. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Psychological therapies for thalassaemia.

PubMed

Anie, Kofi A; Massaglia, Pia

2014-03-06

Thalassaemia is a group of genetic blood disorders characterised by the absence or reduction in the production of haemoglobin. Severity is variable from less severe anaemia, through thalassaemia intermedia, to profound severe anaemia (thalassaemia major). In thalassaemia major other complications include growth retardation, bone deformation, and enlarged spleen. Blood transfusion is required to treat severe forms of thalassaemia, but this results in excessive accumulation of iron in the body (iron overload), removed mostly by a drug called desferrioxamine through 'chelation therapy'. Non-routine treatments are bone marrow transplantation (which is age restricted), and possibly hydroxyurea, designed to raise foetal haemoglobin level, thus reducing anaemia. In addition, psychological therapies seem appropriate to improving outcome and adherence to medical treatment. To examine the evidence that in people with thalassaemia, psychological treatments improve the ability to cope with the condition, and improve both medical and psychosocial outcomes. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Searches on the Internet were also performed.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 11 November 2013. All randomised or quasi-randomised controlled trials comparing the use of psychological intervention to no (psychological) intervention in people with thalassaemia. No trials of psychological therapies have been found in the literature for inclusion in this review. There are currently no results to be reported. As a chronic disease with a considerable role for self-management, psychological support seems appropriate for managing thalassaemia. However, from the information currently available, no conclusions can be made about the use of specific psychological therapies in thalassaemia. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre, randomised controlled trials assessing the effectiveness of specific psychological interventions for thalassaemia.

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.

The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan.

PubMed

Delaney, Anthony P; Peake, Sandra L; Bellomo, Rinaldo; Cameron, Peter; Holdgate, Anna; Howe, Belinda; Higgins, Alisa; Presneill, Jeffrey; Webb, Steve

2013-09-01

The Australasian Resuscitation in Sepsis Evaluation (ARISE) study is an international, multicentre, randomised, controlled trial designed to evaluate the effectiveness of early goal-directed therapy compared with standard care for patients presenting to the emergency department with severe sepsis. In keeping with current practice, and considering aspects of trial design and reporting specific to non-pharmacological interventions, our plan outlines the principles and methods for analysing and reporting the trial results. The document is prepared before completion of recruitment into the ARISE study, without knowledge of the results of the interim analysis conducted by the data safety and monitoring committee and before completion of the two related international studies. Our statistical analysis plan was designed by the ARISE chief investigators, and reviewed and approved by the ARISE steering committee. We reviewed the data collected by the research team as specified in the study protocol and detailed in the study case report form. We describe information related to baseline characteristics, characteristics of delivery of the trial interventions, details of resuscitation, other related therapies and other relevant data with appropriate comparisons between groups. We define the primary, secondary and tertiary outcomes for the study, with description of the planned statistical analyses. We have developed a statistical analysis plan with a trial profile, mock-up tables and figures. We describe a plan for presenting baseline characteristics, microbiological and antibiotic therapy, details of the interventions, processes of care and concomitant therapies and adverse events. We describe the primary, secondary and tertiary outcomes with identification of subgroups to be analysed. We have developed a statistical analysis plan for the ARISE study, available in the public domain, before the completion of recruitment into the study. This will minimise analytical bias and conforms to current best practice in conducting clinical trials.

A framework for evaluating the appropriateness of clinical decision support alerts and responses

PubMed Central

Waitman, Lemuel R; Lewis, Julia B; Wright, Julie A; Choma, David P; Miller, Randolph A; Peterson, Josh F

2011-01-01

Objective Alerting systems, a type of clinical decision support, are increasingly prevalent in healthcare, yet few studies have concurrently measured the appropriateness of alerts with provider responses to alerts. Recent reports of suboptimal alert system design and implementation highlight the need for better evaluation to inform future designs. The authors present a comprehensive framework for evaluating the clinical appropriateness of synchronous, interruptive medication safety alerts. Methods Through literature review and iterative testing, metrics were developed that describe successes, justifiable overrides, provider non-adherence, and unintended adverse consequences of clinical decision support alerts. The framework was validated by applying it to a medication alerting system for patients with acute kidney injury (AKI). Results Through expert review, the framework assesses each alert episode for appropriateness of the alert display and the necessity and urgency of a clinical response. Primary outcomes of the framework include the false positive alert rate, alert override rate, provider non-adherence rate, and rate of provider response appropriateness. Application of the framework to evaluate an existing AKI medication alerting system provided a more complete understanding of the process outcomes measured in the AKI medication alerting system. The authors confirmed that previous alerts and provider responses were most often appropriate. Conclusion The new evaluation model offers a potentially effective method for assessing the clinical appropriateness of synchronous interruptive medication alerts prior to evaluating patient outcomes in a comparative trial. More work can determine the generalizability of the framework for use in other settings and other alert types. PMID:21849334

International Pediatric MS Study Group Clinical Trials Summit: meeting report.

PubMed

Chitnis, Tanuja; Tardieu, Marc; Amato, Maria Pia; Banwell, Brenda; Bar-Or, Amit; Ghezzi, Angelo; Kornberg, Andrew; Krupp, Lauren B; Pohl, Daniela; Rostasy, Kevin; Tenembaum, Silvia; Waubant, Emmanuelle; Wassmer, Evangeline

2013-03-19

Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research. The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions. The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge. Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.

Preventing falls in older multifocal glasses wearers by providing single-lens distance glasses: the protocol for the VISIBLE randomised controlled trial

PubMed Central

Haran, Mark J; Lord, Stephen R; Cameron, Ian D; Ivers, Rebecca Q; Simpson, Judy M; Lee, Bonsan B; Porwal, Mamta; Kwan, Marcella MS; Severino, Connie

2009-01-01

Background Recent research has shown that wearing multifocal glasses increases the risk of trips and falls in older people. The aim of this study is to determine whether the provision of single-lens distance glasses to older multifocal glasses wearers, with recommendations for wearing them for walking and outdoor activities, can prevent falls. We will also measure the effect of the intervention on health status, lifestyle activities and fear of falling, as well as the extent of adherence to the program. Methods/Design Approximately 580 older people who are regular wearers of multifocal glasses people will be recruited. Participants will be randomly allocated to either an intervention group (provision of single lens glasses, with counselling and advice about appropriate use) or a control group (usual care). The primary outcome measure will be falls (measured with 13 monthly calendars). Secondary measures will be quality of life, falls efficacy, physical activity levels and adverse events. Discussions The study will determine the impact of providing single-lens glasses, with advice about appropriate use, on preventing falls in older regular wearers of multifocal glasses. This pragmatic intervention, if found to be effective, will guide practitioners with regard to recommending appropriate glasses for minimising the risk of falls in older people. Trial Registration The protocol for this study was registered with the Clinical Trials.gov Protocol Registration System on June 7th 2006 (#350855). PMID:19321012

Outcome Measures for Clinical Trials in Down Syndrome

PubMed Central

Esbensen, Anna J.; Hooper, Stephen R.; Fidler, Deborah; Hartley, Sigan; Edgin, Jamie; d’Ardhuy, Xavier Liogier; Capone, George; Conners, Frances; Mervis, Carolyn B.; Abbeduto, Leonard; Rafii, Michael; Krinsky-McHale, Sharon J.; Urv, Tiina

2017-01-01

Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the NIH assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This paper focuses on measures in the areas of cognition and behavior. PMID:28452584

A risk-management approach for effective integration of biomarkers in clinical trials: perspectives of an NCI, NCRI, and EORTC working group.

PubMed

Hall, Jacqueline Anne; Salgado, Roberto; Lively, Tracy; Sweep, Fred; Schuh, Anna

2014-04-01

Clinical cancer research today often includes testing the value of biomarkers to direct treatment and for drug development. However, the practical challenges of integration of molecular information into clinical trial protocols are increasingly appreciated. Inherent difficulties include evidence gaps in available biomarker data, a paucity of robust assay methods, and the design of appropriate studies within the constraints of feasible trial operations, and finite resources. Scalable and proportionate approaches are needed to systematically cope with these challenges. Therefore, we assembled international experts from three clinical trials organisations to identify the common challenges and common solutions. We present a practical risk-assessment framework allowing targeting of scarce resources to crucial issues coupled with a library of useful resources and a simple actionable checklist of recommendations. We hope that these practical methods will be useful for running biomarker-driven trials and ultimately help to develop biomarkers that are ready for integration in routine practice. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

Evaluating the Accuracy of Results for Teacher Implemented Trial-Based Functional Analyses.

PubMed

Rispoli, Mandy; Ninci, Jennifer; Burke, Mack D; Zaini, Samar; Hatton, Heather; Sanchez, Lisa

2015-09-01

Trial-based functional analysis (TBFA) allows for the systematic and experimental assessment of challenging behavior in applied settings. The purposes of this study were to evaluate a professional development package focused on training three Head Start teachers to conduct TBFAs with fidelity during ongoing classroom routines. To assess the accuracy of the TBFA results, the effects of a function-based intervention derived from the TBFA were compared with the effects of a non-function-based intervention. Data were collected on child challenging behavior and appropriate communication. An A-B-A-C-D design was utilized in which A represented baseline, and B and C consisted of either function-based or non-function-based interventions counterbalanced across participants, and D represented teacher implementation of the most effective intervention. Results showed that the function-based intervention produced greater decreases in challenging behavior and greater increases in appropriate communication than the non-function-based intervention for all three children. © The Author(s) 2015.

A repeated measures model for analysis of continuous outcomes in sequential parallel comparison design studies.

PubMed

Doros, Gheorghe; Pencina, Michael; Rybin, Denis; Meisner, Allison; Fava, Maurizio

2013-07-20

Previous authors have proposed the sequential parallel comparison design (SPCD) to address the issue of high placebo response rate in clinical trials. The original use of SPCD focused on binary outcomes, but recent use has since been extended to continuous outcomes that arise more naturally in many fields, including psychiatry. Analytic methods proposed to date for analysis of SPCD trial continuous data included methods based on seemingly unrelated regression and ordinary least squares. Here, we propose a repeated measures linear model that uses all outcome data collected in the trial and accounts for data that are missing at random. An appropriate contrast formulated after the model has been fit can be used to test the primary hypothesis of no difference in treatment effects between study arms. Our extensive simulations show that when compared with the other methods, our approach preserves the type I error even for small sample sizes and offers adequate power and the smallest mean squared error under a wide variety of assumptions. We recommend consideration of our approach for analysis of data coming from SPCD trials. Copyright © 2013 John Wiley & Sons, Ltd.

Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production.

PubMed

Oyarzún, Patricio; Kobe, Bostjan

2016-03-03

Novel vaccination approaches based on rational design of B- and T-cell epitopes - epitope-based vaccines - are making progress in the clinical trial pipeline. The epitope-focused recombinant protein-based malaria vaccine (termed RTS,S) is a next-generation approach that successfully reached phase-III trials, and will potentially become the first commercial vaccine against a human parasitic disease. Progress made on methods such as recombinant DNA technology, advanced cell-culture techniques, immunoinformatics and rational design of immunogens are driving the development of these novel concepts. Synthetic recombinant proteins comprising both B- and T-cell epitopes can be efficiently produced through modern biotechnology and bioprocessing methods, and can enable the induction of large repertoires of immune specificities. In particular, the inclusion of appropriate CD4+ T-cell epitopes is increasingly considered a key vaccine component to elicit robust immune responses, as suggested by results coming from HIV-1 clinical trials. In silico strategies for vaccine design are under active development to address genetic variation in pathogens and several broadly protective "universal" influenza and HIV-1 vaccines are currently at different stages of clinical trials. Other methods focus on improving population coverage in target populations by rationally considering specificity and prevalence of the HLA proteins, though a proof-of-concept in humans has not been demonstrated yet. Overall, we expect immunoinformatics and bioprocessing methods to become a central part of the next-generation epitope-based vaccine development and production process.

USING FORMATIVE RESEARCH TO DEVELOP A CONTEXT-SPECIFIC APPROACH TO INFORMED CONSENT FOR CLINICAL TRIALS

PubMed Central

Corneli, Amy L.; Bentley, Margaret E.; Sorenson, James R.; Henderson, Gail E.; van der Horst, Charles; Moses, Agnes; Nkhoma, Jacqueline; Tenthani, Lyson; Ahmed, Yusuf; Heilig, Charles M.; Jamieson, Denise J.

2009-01-01

Participant understanding is of particular concern when obtaining informed consent. Recommendations for improving understanding include disclosing information using culturally appropriate and innovative approaches. To increase the effectiveness of the consent process for a clinical trial in Malawi on interventions to prevent mother-to-child transmission of HIV during breastfeeding, formative research was conducted to explore the community’s understanding of medical research as well as how to explain research through local terms and meanings. Contextual analogies and other approaches were identified to explain consent information. Guided by theory, strategies for developing culturally appropriate interventions, and recommendations from the literature, we demonstrate how the formative data were used to develop culturally appropriate counseling cards specifically for the trial in Malawi. With appropriate contextual modifications, the steps outlined here could be applied in other clinical trials conducted elsewhere, as well as in other types of research. PMID:19385837

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

PubMed

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

2016-04-01

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

Rationale and design of the ENhancing outcomes through Goal Assessment and Generating Engagement in Diabetes Mellitus (ENGAGE-DM) pragmatic trial.

PubMed

Lauffenburger, Julie C; Lewey, Jennifer; Jan, Saira; Nanchanatt, Gina; Makanji, Sagar; Ferro, Christina A; Sheehan, John; Wittbrodt, Eric; Morawski, Kyle; Lee, Jessica; Ghazinouri, Roya; Choudhry, Niteesh K

2017-08-01

Poor glycemic control among patients with diabetes may stem from poor medication and lifestyle adherence or a failure to appropriately intensify therapy. A patient-centered approach could discern the most likely possibility and would then, as appropriate, address patient barriers to non-adherence (using behavioral interviewing methods such as motivational interviewing) or help facilitate choices among treatment augmentation options (using methods such as shared decision-making). To test the impact of a novel telephone-based patient-centered intervention on glycemic control for patients with poorly-controlled diabetes. ENGAGE-DM (ENhancing outcomes through Goal Assessment and Generating Engagement in Diabetes Mellitus) is a pragmatic trial of patients with poorly-controlled diabetes receiving treatment with an oral hypoglycemic agent. We randomized 1400 patients in a large health insurer to intervention or usual care. The intervention is delivered over the telephone by a pharmacist and consists of a 2-step process that integrates brief negotiated interviewing and shared decision-making to identify patient-concordant goals and options for enhancing patients' diabetes management. The trial's primary outcome is disease control, assessed using glycosylated hemoglobin values. Secondary outcomes include medication adherence measures, assessed using pharmacy claims data. This trial will determine whether a novel highly-scalable patient engagement strategy improves disease control and adherence to medications among individuals with poorly-controlled diabetes. Copyright © 2017. Published by Elsevier Inc.

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial.

PubMed

Jabbour, Mona; Curran, Janet; Scott, Shannon D; Guttman, Astrid; Rotter, Thomas; Ducharme, Francine M; Lougheed, M Diane; McNaughton-Filion, M Louise; Newton, Amanda; Shafir, Mark; Paprica, Alison; Klassen, Terry; Taljaard, Monica; Grimshaw, Jeremy; Johnson, David W

2013-05-22

The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for 'point of care' management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma--the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis--the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. ClinicalTrials.gov: NCT01815710.

Issues Surrounding Clinical Trial Endpoints in Solid Malignancies With a Focus on Metastatic Non-Small Cell Lung Cancer

PubMed Central

Garon, Edward B

2013-01-01

Summary Relative to best supportive care alone, cytotoxic chemotherapy has an established role in prolonging overall survival (OS) in patients with or without previous treatment for metastatic non-small cell lung cancer (NSCLC). OS has been the principal endpoint influencing regulatory decisions regarding targeted therapies for metastatic NSCLC, including the vascular endothelial growth factor monoclonal antibody bevacizumab in the frontline setting and the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib in patients after prior treatment. Progression-free survival (PFS), another common endpoint in oncology clinical trials, has been discussed as a potential surrogate for OS in metastatic NSCLC. A number of phase III clinical trials of investigational targeted agents for treatment of metastatic NSCLC are ongoing, with OS designated as the primary endpoint in some cases and PFS in others. Both endpoints have been developed largely to evaluate outcomes in unselected populations in which a fraction of patients are anticipated to derive significant benefit. New approaches are being considered for the evaluation of targeted agents. Recent high profile trials have been designed to assess PFS using a randomized discontinuation design and disease control rate after 8 weeks of treatment. With a series of recent advances towards increasingly personalized biomarker-directed anticancer therapies, the appropriateness of the traditional regulatory approach has been questioned. PMID:22795702

STI in remote communities: improved and enhanced primary health care (STRIVE) study protocol: a cluster randomised controlled trial comparing ‘usual practice’ STI care to enhanced care in remote primary health care services in Australia

PubMed Central

2013-01-01

Background Despite two decades of interventions, rates of sexually transmissible infections (STI) in remote Australian Aboriginal communities remain unacceptably high. Routine notifications data from 2011 indicate rates of chlamydia and gonorrhoea among Aboriginal people in remote settings were 8 and 61 times higher respectively than in the non-Indigenous population. Methods/design STRIVE is a stepped-wedge cluster randomised trial designed to compare a sexual health quality improvement program (SHQIP) to usual STI clinical care delivered in remote primary health care services. The SHQIP is a multifaceted intervention comprising annual assessments of sexual health service delivery, implementation of a sexual health action plan, six-monthly clinical service activity data reports, regular feedback meetings with a regional coordinator, training and financial incentive payments. The trial clusters comprise either a single community or several communities grouped together based on geographic proximity and cultural ties. The primary outcomes are: prevalence of chlamydia, gonorrhoea and trichomonas in Aboriginal residents aged 16–34 years, and performance in clinical management of STIs based on best practice indicators. STRIVE will be conducted over five years comprising one and a half years of trial initiation and community consultation, three years of trial conditions, and a half year of data analysis. The trial was initiated in 68 remote Aboriginal health services in the Northern Territory, Queensland and Western Australia. Discussion STRIVE is the first cluster randomised trial in STI care in remote Aboriginal health services. The trial will provide evidence to inform future culturally appropriate STI clinical care and control strategies in communities with high STI rates. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12610000358044 PMID:24016143

The importance of communication in promoting voluntary participation in an experimental trial: A qualitative study based on the assessment of the gamma-interferon test for the diagnosis of bovine tuberculosis in France

PubMed Central

Dufour, Barbara; Praud, Anne

2017-01-01

Understanding the factors leading each stakeholder to participate in an experimental trial is a key element for improving trial set-up and for identifying selection bias in statistical analyses. An experimental protocol, validated by the European Commission, was developed in France to assess the ability of the gamma-interferon test in terms of accuracy to replace the second intradermal skin test in cases of suspected bovine tuberculosis. Implemented between 2013 and 2015, this experimental trial was based on voluntary participation. To determine and understand the motivation or reluctance of farmers to take part in this trial, we carried out a sociological survey in France. Our study was based on semi-structured interviews with the farmers and other stakeholders involved. The analysis of findings demonstrated that shortening the lock-up period during tuberculosis suspicion, following the use of a gamma-interferon test, was an important aim and a genuine challenge for the animal health stakeholders. However, some farmers did not wish to continue the trial because it could potentially have drastic consequences for them. Moreover, misunderstandings and confusion concerning the objectives and consequences of the trial led stakeholders to reject it forcefully. Based on our results, we offer some recommendations: clear and appropriate communication tools should be prepared to explain the protocol and its aims. In addition, these types of animal health trials should be designed with the stakeholders’ interests in mind. This study provides a better understanding of farmer motivations and stakeholder influences on trial participation and outcomes. The findings can be used to help design trials so that they promote participation by farmers and by all animal health stakeholders in general. PMID:28973018

Designing a definitive trial for adjuvant targeted therapy in genotype defined lung cancer: the ALCHEMIST trials.

PubMed

Alden, Ryan S; Mandrekar, Sumithra J; Oxnard, Geoffrey R

2015-09-01

Genotype-directed targeted therapies have revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC) but they have not yet been comprehensively studied in the adjuvant setting. Previous trials of adjuvant targeted therapy in unselected early stage NSCLC patients showed no benefit versus placebo, however retrospective data suggests improved disease free survival (DFS) with epidermal growth factor receptor (EGFR) inhibitors in patients with appropriate molecular alterations. A definitive prospective, randomized, placebo-controlled trial of targeted therapies for NSCLC is needed to determine the efficacy of targeted therapy following surgical resection and standard adjuvant therapy. The principal challenges facing such a trial are (I) identification of actionable alterations in early stage patients; and (II) realization of sufficient enrollment to power definitive analyses. The ALCHEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) was designed to overcome these challenges. Using the national clinical trials network (NCTN) of the National Cancer Institute (NCI), several thousand patients with operable NSCLC will undergo tumor genotyping for EGFR mutations or rearrangement of anaplastic lymphoma kinase (ALK). Following resection and completion of standard adjuvant therapy, patients with EGFR-mutant NSCLC will be randomized to erlotinib versus placebo (1:1), those with ALK-rearranged NSCLC will be randomized to crizotinib versus placebo (1:1), while those not enrolled onto the adjuvant trials will continue to be followed on the screening trial. ALCHEMIST also provides for the collection of tissue at baseline and at recurrence (if available) to characterize mechanisms of recurrence and of resistance to targeted therapy. Thus, ALCHEMIST is a platform for validation of targeted therapy as part of curative care in NSCLC and creates an opportunity to advance our understanding of disease biology.

Accrual and drop out in a primary prevention randomised controlled trial: qualitative study.

PubMed

Eborall, Helen C; Stewart, Marlene C W; Cunningham-Burley, Sarah; Price, Jackie F; Fowkes, F Gerry R

2011-01-11

Recruitment and retention of participants are critical to the success of a randomised controlled trial. Gaining the views of potential trial participants who decline to enter a trial and of trial participants who stop the trial treatment is important and can help to improve study processes. Limited research on these issues has been conducted on healthy individuals recruited for prevention trials in the community. Semi-structured interviews with people who were eligible but had declined to participate in the Aspirin for Asymptomatic Atherosclerosis (AAA) trial (N = 11), and AAA trial participants who had stopped taking the trial medication (N = 11). A focus group with further participants who had stopped taking the trial medication (N = 6). (Total participants N = 28). Explanations for declining to participate could be divided into two groups: the first group were characterised by a lack of necessity to participate and a tendency to prioritise other largely mundane problems. The second group's concern was with a high level of perceived risk from participating.Explanations for stopping trial medication fell into four categories: side effects attributed to the trial medication; starting on aspirin or medication contraindicating to aspirin; experiencing an outcome event, and changing one's mind. These results indicate that when planning trials (especially in preventive medicine) particular attention should be given to designing appropriate recruitment materials and processes that fully inform potential recruits of the risks and benefits of participation. ISRCTN66587262.

Analysis of repeated measurement data in the clinical trials

PubMed Central

Singh, Vineeta; Rana, Rakesh Kumar; Singhal, Richa

2013-01-01

Statistics is an integral part of Clinical Trials. Elements of statistics span Clinical Trial design, data monitoring, analyses and reporting. A solid understanding of statistical concepts by clinicians improves the comprehension and the resulting quality of Clinical Trials. In biomedical research it has been seen that researcher frequently use t-test and ANOVA to compare means between the groups of interest irrespective of the nature of the data. In Clinical Trials we record the data on the patients more than two times. In such a situation using the standard ANOVA procedures is not appropriate as it does not consider dependencies between observations within subjects in the analysis. To deal with such types of study data Repeated Measure ANOVA should be used. In this article the application of One-way Repeated Measure ANOVA has been demonstrated by using the software SPSS (Statistical Package for Social Sciences) Version 15.0 on the data collected at four time points 0 day, 15th day, 30th day, and 45th day of multicentre clinical trial conducted on Pandu Roga (~Iron Deficiency Anemia) with an Ayurvedic formulation Dhatrilauha. PMID:23930038

Evidence into practice: evaluating a child-centred intervention for diabetes medicine management The EPIC Project

PubMed Central

2010-01-01

Background There is a lack of high quality, child-centred and effective health information to support development of self-care practices and expertise in children with acute and long-term conditions. In type 1 diabetes, clinical guidelines indicate that high-quality, child-centred information underpins achievement of optimal glycaemic control with the aim of minimising acute readmissions and reducing the risk of complications in later life. This paper describes the development of a range of child-centred diabetes information resources and outlines the study design and protocol for a randomized controlled trial to evaluate the information resources in routine practice. The aim of the diabetes information intervention is to improve children and young people's quality of life by increasing self-efficacy in managing their type 1 diabetes. Methods/Design We used published evidence, undertook qualitative research and consulted with children, young people and key stakeholders to design and produce a range of child-centred, age-appropriate children's diabetes diaries, carbohydrate recording sheets, and assembled child-centred, age-appropriate diabetes information packs containing published information in a folder that can be personalized by children and young people with pens and stickers. Resources have been designed for children/young people 6-10; 11-15; and 16-18 years. To evaluate the information resources, we designed a pragmatic randomized controlled trial to assess the effectiveness, cost effectiveness, and implementation in routine practice of individually tailored, age-appropriate diabetes diaries and information packs for children and young people age 6-18years, compared with currently available standard practice. Children and young people will be stratified by gender, length of time since diagnosis (< 2years and > 2years) and age (6-10; 11-15; and 16-18 years). The following data will be collected at baseline, 3 and 6 months: PedsQL (generic, diabetes and parent versions), and EQ-5 D (parent and child); NHS resource use and process data (questionnaire and interview). Baseline and subsequent HbA1c measurements, blood glucose meter use, readings and insulin dose will be taken from routine test results and hand-held records when attending routine 3-4 monthly clinic visits. The primary outcome measure is diabetes self-efficacy and quality-of-life (Diabetes PedsQL). Secondary outcomes include: HbA1c, generic quality of life, routinely collected NHS/child-held data, costs, service use, acceptability and utility. Trial Registration ISRCTN17551624. PMID:20875112

Phase-II trials in osteosarcoma recurrences: A systematic review of past experience.

PubMed

Omer, Natacha; Le Deley, Marie-Cécile; Piperno-Neumann, Sophie; Marec-Berard, Perrine; Italiano, Antoine; Corradini, Nadège; Bellera, Carine; Brugières, Laurence; Gaspar, Nathalie

2017-04-01

The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. To study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Systematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point. Copyright © 2017 Elsevier Ltd. All rights reserved.

Outcome Measures for Clinical Trials in Down Syndrome.

PubMed

Esbensen, Anna J; Hooper, Stephen R; Fidler, Deborah; Hartley, Sigan L; Edgin, Jamie; d'Ardhuy, Xavier Liogier; Capone, George; Conners, Frances A; Mervis, Carolyn B; Abbeduto, Leonard; Rafii, Michael; Krinsky-McHale, Sharon J; Urv, Tiina

2017-05-01

Increasingly individuals with intellectual and developmental disabilities, including Down syndrome, are being targeted for clinical trials. However, a challenge exists in effectively evaluating the outcomes of these new pharmacological interventions. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials with individuals with Down syndrome have been identified. To address this challenge, the National Institutes of Health (NIH) assembled leading clinicians and scientists to review existing measures and identify those that currently are appropriate for trials; those that may be appropriate after expansion of age range addition of easier items, and/or downward extension of psychometric norms; and areas where new measures need to be developed. This article focuses on measures in the areas of cognition and behavior.

Formative research methods for designing culturally appropriate, integrated child nutrition and development interventions: an overview.

PubMed

Bentley, Margaret E; Johnson, Susan L; Wasser, Heather; Creed-Kanashiro, Hilary; Shroff, Monal; Fernandez Rao, Sylvia; Cunningham, Melissa

2014-01-01

Nutritional and developmental insults in the first few years of life have profound public health implications, including substantial contributions to neonatal, infant, and early childhood morbidity and mortality, as well as longer term effects on cognitive development, school achievement, and worker productivity. Optimal development that can lead to the attainment of an individual's fullest potential, therefore, requires a combination of genetic capacity, adequate nutrition, psychosocial stimulation, and safe, clean physical environments. Researchers and policymakers have called for integrated child nutrition and development interventions for more than 20 years, yet there are only a handful of efficacy trials and even fewer examples of integrated interventions that have been taken to scale. While a critical component in the design of such interventions is formative research, there is a dearth of information in both the literature and policy arenas to guide this phase of the process. To move the field forward, this paper first provides an overview of formative research methods with a focus on qualitative inquiry, a description of the critical domains to be assessed (infant and young child feeding, responsive feeding, and child development), and currently available resources. Application of these methods is provided through a real-world case study--the design of an integrated nutrition and child development efficacy trial in Andhra Pradesh, India. Recommendations for next steps are discussed, the most important of which is the need for a comprehensive set of formative guidelines for designing locally tailored, culturally appropriate, integrated interventions. © 2013 New York Academy of Sciences.

Can research assessments themselves cause bias in behaviour change trials? A systematic review of evidence from solomon 4-group studies.

PubMed

McCambridge, Jim; Butor-Bhavsar, Kaanan; Witton, John; Elbourne, Diana

2011-01-01

The possible effects of research assessments on participant behaviour have attracted research interest, especially in studies with behavioural interventions and/or outcomes. Assessments may introduce bias in randomised controlled trials by altering receptivity to intervention in experimental groups and differentially impacting on the behaviour of control groups. In a Solomon 4-group design, participants are randomly allocated to one of four arms: (1) assessed experimental group; (2) unassessed experimental group (3) assessed control group; or (4) unassessed control group. This design provides a test of the internal validity of effect sizes obtained in conventional two-group trials by controlling for the effects of baseline assessment, and assessing interactions between the intervention and baseline assessment. The aim of this systematic review is to evaluate evidence from Solomon 4-group studies with behavioural outcomes that baseline research assessments themselves can introduce bias into trials. Electronic databases were searched, supplemented by citation searching. Studies were eligible if they reported appropriately analysed results in peer-reviewed journals and used Solomon 4-group designs in non-laboratory settings with behavioural outcome measures and sample sizes of 20 per group or greater. Ten studies from a range of applied areas were included. There was inconsistent evidence of main effects of assessment, sparse evidence of interactions with behavioural interventions, and a lack of convincing data in relation to the research question for this review. There were too few high quality completed studies to infer conclusively that biases stemming from baseline research assessments do or do not exist. There is, therefore a need for new rigorous Solomon 4-group studies that are purposively designed to evaluate the potential for research assessments to cause bias in behaviour change trials.

Primary outcome indices in illicit drug dependence treatment research: systematic approach to selection and measurement of drug use end-points in clinical trials

PubMed Central

Donovan, Dennis M.; Bigelow, George E.; Brigham, Gregory S.; Carroll, Kathleen M.; Cohen, Allan J.; Gardin, John G.; Hamilton, John A.; Huestis, Marilyn A.; Hughes, John R.; Lindblad, Robert; Marlatt, G. Alan; Preston, Kenzie L.; Selzer, Jeffrey A.; Somoza, Eugene C.; Wakim, Paul G.; Wells, Elizabeth A.

2012-01-01

Aims Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug-dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials. Methods A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug-taking behavior, as measured by self-report and qualitative or quantitative biological markers, are evaluated. Results Drug-taking behavior, measured ideally by a combination of self-report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials. Conclusions We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them. PMID:21781202

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

PubMed

Dodd, Lori E; Proschan, Michael A; Neuhaus, Jacqueline; Koopmeiners, Joseph S; Neaton, James; Beigel, John D; Barrett, Kevin; Lane, Henry Clifford; Davey, Richard T

2016-06-15

Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy. We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility. Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A Decision Aid to Promote Appropriate Colorectal Cancer Screening among Older Adults: A Randomized Controlled Trial.

PubMed

Lewis, Carmen L; Kistler, Christine E; Dalton, Alexandra F; Morris, Carolyn; Ferrari, Renée; Barclay, Colleen; Brewer, Noel T; Dolor, Rowena; Harris, Russell; Vu, Maihan; Golin, Carol E

2018-07-01

Concerns have been raised about both over- and underutilization of colorectal cancer (CRC) screening in older patients and the need to align screening behavior with likelihood of net benefit. The purpose of this study was to test a novel use of a patient decision aid (PtDA) to promote appropriate CRC screening in older adults. A total of 424 patients ages 70 to 84 y who were not up to date with CRC screening participated in a double-blinded randomized controlled trial of a PtDA targeted to older adults making decisions about whether to undergo CRC screening from March 2012 to February 2015. Patients were randomized to a targeted PtDA or an attention control. The PtDA was designed to facilitate individualized decision making-helping patients understand the potential risks, benefits, and uncertainties of CRC screening given advanced age, health state, preferences, and values. Two composite outcomes, appropriate CRC screening behavior 6 mo after the index visit and appropriate screening intent immediately after the visit, were defined as completed screening or intent for patients in good health, discussion about screening with their provider for patients in intermediate health, and no screening or intent for patients in poor health. Health state was determined by age and Charlson Comorbidity Index. Four hundred twelve (97%) and 421 (99%) patients were analyzed for the primary and secondary outcomes, respectively. Appropriate screening behavior at 6 mo was higher in the intervention group (55% v. 45%, P = 0.023) as was appropriate screening intent following the provider visit (61% v. 47%, P = 0.003). The study took place in a single geographic region. The appropriate CRC screening classification system used in this study has not been formally validated. A PtDA for older adults promoted appropriate CRC screening behavior and intent. Clinicaltrials.gov, registration number NCT01575990. https://clinicaltrials.gov/ct2/show/NCT01575990?term=epic-d&rank=1.

Comparative effectiveness research for the clinician researcher: a framework for making a methodological design choice.

PubMed

Williams, Cylie M; Skinner, Elizabeth H; James, Alicia M; Cook, Jill L; McPhail, Steven M; Haines, Terry P

2016-08-17

Comparative effectiveness research compares two active forms of treatment or usual care in comparison with usual care with an additional intervention element. These types of study are commonly conducted following a placebo or no active treatment trial. Research designs with a placebo or non-active treatment arm can be challenging for the clinician researcher when conducted within the healthcare environment with patients attending for treatment.A framework for conducting comparative effectiveness research is needed, particularly for interventions for which there are no strong regulatory requirements that must be met prior to their introduction into usual care. We argue for a broader use of comparative effectiveness research to achieve translatable real-world clinical research. These types of research design also affect the rapid uptake of evidence-based clinical practice within the healthcare setting.This framework includes questions to guide the clinician researcher into the most appropriate trial design to measure treatment effect. These questions include consideration given to current treatment provision during usual care, known treatment effectiveness, side effects of treatments, economic impact, and the setting in which the research is being undertaken.

Placebo use in vaccine trials: Recommendations of a WHO expert panel

PubMed Central

Rid, Annette; Saxena, Abha; Baqui, Abdhullah H.; Bhan, Anant; Bines, Julie; Bouesseau, Marie-Charlotte; Caplan, Arthur; Colgrove, James; Dhai, Ames; Gomez-Diaz, Rita; Green, Shane K.; Kang, Gagandeep; Lagos, Rosanna; Loh, Patricia; London, Alex John; Mulholland, Kim; Neels, Pieter; Pitisuttithum, Punee; Sarr, Samba Cor; Selgelid, Michael; Sheehan, Mark; Smith, Peter G.

2014-01-01

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease. PMID:24768580

Comparative trial of benzoyl peroxide versus benzoyl peroxide with urea in inflammatory acne.

PubMed

Prince, R A; Harris, J M; Maroc, J A

1982-06-01

Improvement in vehicle design may improve the delivery of drugs to the target site. A clinical trial was performed to evaluate an improved vehicle for topical benzoyl peroxide. Thirty-nine subjects participated in a split-face, double-blind trial of topical benzoyl peroxide 5 percent versus benzoyl peroxide 5 percent in 8 percent urea. All subjects had grade II or III acne as described by Pillsbury. Study solutions were randomly assigned to a selected side of the subject's face and applied twice a day to the appropriate side of the face for eight weeks. Total and inflammatory lesion counts were performed by the same investigator during the eight weeks of study at biweekly intervals. No overall differences in the response to the study preparations were observed when assessed objectively and subjectively.

Impact of non-uniform correlation structure on sample size and power in multiple-period cluster randomised trials.

PubMed

Kasza, J; Hemming, K; Hooper, R; Matthews, Jns; Forbes, A B

2017-01-01

Stepped wedge and cluster randomised crossover trials are examples of cluster randomised designs conducted over multiple time periods that are being used with increasing frequency in health research. Recent systematic reviews of both of these designs indicate that the within-cluster correlation is typically taken account of in the analysis of data using a random intercept mixed model, implying a constant correlation between any two individuals in the same cluster no matter how far apart in time they are measured: within-period and between-period intra-cluster correlations are assumed to be identical. Recently proposed extensions allow the within- and between-period intra-cluster correlations to differ, although these methods require that all between-period intra-cluster correlations are identical, which may not be appropriate in all situations. Motivated by a proposed intensive care cluster randomised trial, we propose an alternative correlation structure for repeated cross-sectional multiple-period cluster randomised trials in which the between-period intra-cluster correlation is allowed to decay depending on the distance between measurements. We present results for the variance of treatment effect estimators for varying amounts of decay, investigating the consequences of the variation in decay on sample size planning for stepped wedge, cluster crossover and multiple-period parallel-arm cluster randomised trials. We also investigate the impact of assuming constant between-period intra-cluster correlations instead of decaying between-period intra-cluster correlations. Our results indicate that in certain design configurations, including the one corresponding to the proposed trial, a correlation decay can have an important impact on variances of treatment effect estimators, and hence on sample size and power. An R Shiny app allows readers to interactively explore the impact of correlation decay.

Analysis and interpretation of cost data in randomised controlled trials: review of published studies

PubMed Central

Barber, Julie A; Thompson, Simon G

1998-01-01

Objective To review critically the statistical methods used for health economic evaluations in randomised controlled trials where an estimate of cost is available for each patient in the study. Design Survey of published randomised trials including an economic evaluation with cost values suitable for statistical analysis; 45 such trials published in 1995 were identified from Medline. Main outcome measures The use of statistical methods for cost data was assessed in terms of the descriptive statistics reported, use of statistical inference, and whether the reported conclusions were justified. Results Although all 45 trials reviewed apparently had cost data for each patient, only 9 (20%) reported adequate measures of variability for these data and only 25 (56%) gave results of statistical tests or a measure of precision for the comparison of costs between the randomised groups. Only 16 (36%) of the articles gave conclusions which were justified on the basis of results presented in the paper. No paper reported sample size calculations for costs. Conclusions The analysis and interpretation of cost data from published trials reveal a lack of statistical awareness. Strong and potentially misleading conclusions about the relative costs of alternative therapies have often been reported in the absence of supporting statistical evidence. Improvements in the analysis and reporting of health economic assessments are urgently required. Health economic guidelines need to be revised to incorporate more detailed statistical advice. Key messagesHealth economic evaluations required for important healthcare policy decisions are often carried out in randomised controlled trialsA review of such published economic evaluations assessed whether statistical methods for cost outcomes have been appropriately used and interpretedFew publications presented adequate descriptive information for costs or performed appropriate statistical analysesIn at least two thirds of the papers, the main conclusions regarding costs were not justifiedThe analysis and reporting of health economic assessments within randomised controlled trials urgently need improving PMID:9794854

Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol.

PubMed

Heatley, Gerald; Sood, Poornima; Goldstein, Daniel; Uriel, Nir; Cleveland, Joseph; Middlebrook, Don; Mehra, Mandeep R

2016-04-01

The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662 patients will be enrolled to reach a total of 1,028 patients for evaluation of the secondary end-point of pump replacement at 2 years. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Training and generalization of affective behavior displayed by youth with autism.

PubMed Central

Gena, A; Krantz, P J; McClannahan, L E; Poulson, C L

1996-01-01

The purpose of this study was to teach contextually appropriate affective behavior to 4 youths with autism. Treatment consisted of modeling, prompting, and reinforcement introduced in a multiple baseline design across response categories of affective behavior. During treatment, verbal praise and tokens were delivered contingent on appropriate affective responding during training trials. Modeling and verbal prompting were used as correction procedures. Each youth received treatment in either three or four response categories. Treatment systematically increased responding within the response categories for all 4 participants, with effects being specific to the affective response categories under treatment. Treatment effects occurred across untrained scenarios, therapists, time, and settings, suggesting that generalization had occurred. PMID:8926222

Does Ureaplasma spp. cause chronic lung disease of prematurity: Ask the audience?

PubMed Central

Maxwell, Nicola C.; Nuttall, Diane; Kotecha, Sailesh

2009-01-01

Ureaplasma has long been implicated in the pathogenesis of both preterm labour and neonatal morbidity, particularly chronic lung disease of prematurity (CLD), but despite numerous studies, reviews and meta-analyses, its exact role remains unclear. Many papers call for a definitive randomised control trial to determine if eradication of pulmonary Ureaplasma decreases the rates of CLD but few address in detail the obstacles to an adequately powered clinical trial. We review the evidence for Ureaplasma as a causative agent in CLD, asking why a randomised control trial has not been performed. We surveyed the opinions of senior neonatologists in the UK on whether they felt that there was sufficient evidence for Ureaplasma either causing or not causing CLD and whether a definitive trial was needed, as well as their views on the design of such a trial. Additionally, we ascertained current practice with respect to Ureaplasma detection in preterm neonates in the UK. There is clear support for an adequately powered randomised controlled clinical trial by senior neonatologists in the UK. There are no reasons why a definitive trial cannot be conducted especially as the appropriate samples, and methods to culture or identify the organism by PCR are already available. PMID:19144476

Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities: Abridged republication of a Cochrane systematic review.

PubMed

Gormez, A; Rana, F; Varghese, S

2014-07-01

We aimed to determine clinical effectiveness of pharmacological interventions for self-injurious behaviour in adults with intellectual disability. We searched the following databases: CENTRAL; MEDLINE; EMBASE; PsycINFO; CINAHL; SCI; SSCI; Conference Proceedings Citation Index - Science; Conference Proceedings Citation Index - Social Science and Humanities; ZETOC; World Cat .We also searched ClinicalTrials.gov,ICTRP and the reference lists of included trials. We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour. We found five double-blind, placebo-controlled trials, which included a total of 50 people. Four trials compared the effects of naltrexone versus placebo and one trial clomipramine versus placebo. We did not identify any relevant placebo-controlled trials for other drugs. We presented a narrative summary, as meta-analysis was not appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating self-injurious behaviour. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo. © The Author(s) 2014.

Reader reaction on estimation of treatment effects in all-comers randomized clinical trials with a predictive marker.

PubMed

Korn, Edward L; Freidlin, Boris

2017-06-01

For a fallback randomized clinical trial design with a marker, Choai and Matsui (2015, Biometrics 71, 25-32) estimate the bias of the estimator of the treatment effect in the marker-positive subgroup conditional on the treatment effect not being statistically significant in the overall population. This is used to construct and examine conditionally bias-corrected estimators of the treatment effect for the marker-positive subgroup. We argue that it may not be appropriate to correct for conditional bias in this setting. Instead, we consider the unconditional bias of estimators of the treatment effect for marker-positive patients. © 2016, The International Biometric Society.

Appropriateness and acceptability of a Tele-Yoga intervention for people with heart failure and chronic obstructive pulmonary disease: qualitative findings from a controlled pilot study.

PubMed

Selman, Lucy; McDermott, Kelly; Donesky, DorAnne; Citron, Tracie; Howie-Esquivel, Jill

2015-02-07

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are highly prevalent and associated with a large symptom burden, that is compounded in a dual HF-COPD diagnosis. Yoga has potential benefit for symptom relief; however functional impairment hinders access to usual yoga classes. We developed a Tele-Yoga intervention and evaluated it in a controlled pilot trial. This paper reports on the appropriateness and acceptability of the intervention and the evaluation design. A controlled, non-randomised trial was conducted of an 8-week Tele-Yoga intervention versus an educational control (information leaflets mailed to participants with one phone call a week). Biweekly one-hour Tele-Yoga classes were implemented via multipoint videoconferencing that connected participants to live classes via an Internet connection to their televisions. Semi-structured qualitative interviews were conducted with participants post study exit to explore reasons for and experiences of participating, including views of study outcome measures and physiological tests. Transcribed interviews were analysed using thematic content analysis. Fifteen people participated in the pilot study (7 in the intervention group, 8 in the control). Of these, 12 participants were interviewed, 6 in each group, mean age 71.2 years (SD 10.09); 3 were male. Themes are reported in the following categories: acceptability and appropriateness of the intervention, potential active ingredients of the intervention, acceptability and appropriateness of the control, participation in the research, and acceptability of the testing procedures. The intervention was acceptable and appropriate: the intervention group reported enjoying yoga and valuing the home-based aspect and participants described a high symptom burden and social isolation. However, technological problems resulted in poor video-streaming quality for some participants. Potential active ingredients included physical postures, breathing exercises and guidance in relaxation and meditation. The educational control intervention was acceptable and appropriate, with participants reporting little effect on their well-being and no impact on mechanisms hypothesised to explain yoga's effectiveness. The questionnaires and home physiological testing were acceptable to participants. Tele-Yoga is an acceptable and appropriate intervention in people with HF and COPD and further research is warranted to refine the technology used in its delivery. Findings provide guidance for researchers working in tele-interventions, yoga, and similar populations. ClinicalTrials.gov Identifier: NCT02078739 (4 March 2014).

Improving the quality of randomized controlled trials in Chinese herbal medicine, part II: control group design.

PubMed

Bian, Zhao-Xiang; Moher, David; Dagenais, Simon; Li, You-Ping; Liu, Liang; Wu, Tai-Xiang; Miao, Jiang-Xia

2006-03-01

To discuss the types of control groups in randomized controlled trials (RCTs) of Chinese herbal medicine (CHM), and to provide suggestions for improving the design of control group in future clinical studies in this therapeutic area. A search of the Cochrane Library was conducted in July 2005 to identify RCTs of CHM, and 66 RCTs with CHM for type 2 diabetes mellitus were obtained as the basis for further analysis. Of 66 RCTs with CHM for type 2 diabetes mellitus, 61 (92.4%) trials had both a treatment group and a control group. Twenty-seven (40.9%) RCTs compared CHM plus conventional drug vs conventional drug, 24 (36.4%) compared CHM vs conventional drug, 5 (7.6%) compared CHM vs placebo, 3 (4.5%) compared CHM plus conventional drug vs conventional drug plus placebo, 3 (4.5%) compared CHM plus conventional drug vs other CHM, 1 (1.5%) compared CHM vs no treatment, 1 (1.5%) compared CHM plus placebo vs conventional drug plus placebo, 1 (1.5%) compared CHM vs CHM plus conventional drug vs conventional drug vs placebo, and 1 (1.5%) compared CHM vs conventional drug vs CHM plus conventional drug. A variety of control groups were used in RCTs of CHM for type 2 diabetes mellitus, including placebo, active, and no treatment control groups. Justification for selecting particular types of control groups were not provided in the trials reviewed in this study. Different control groups may be appropriate according to the study objectives, and several factors should be considered prior to selecting control groups in future RCTs of CHM. (1) Investigators of CHM who design clinical trials should understand the rationale for selecting different types of control groups; (2) Control groups for RCTs should be selected according to study objectives; (3) Active control groups should select interventions for comparisons that have the strongest evidence of efficacy and prescribe them as recommended; (4) Placebo control groups should select a placebo that mimics the physical characteristics of test intervention as closely as possible and is completely inert; (5) No treatment control groups should only be used when withholding treatment is ethical and objectives outcomes will not be subject to bias due to absent blinding; (6) Crossover control groups may be appropriate in chronic and stable conditions.

Clinical Effects of Prebiotics in Pediatric Population.

PubMed

Orel, Rok; Reberšak, Lea Vodušek

2016-12-15

Prebiotics are non-digestible components of food that in a selective manner trigger the expansion of microbes in the gut with valuable effects for the health of the host. In our document, current literature pertaining to the clinical effects of the use of prebiotics for the treatment and prevention of some common pediatric pathology such as infantile colic, constipation, absorption of minerals, weight gain, diarrhea, respiratory infections, and eczema is reviewed. Data was collected through search of the MEDLINE, PubMed, UpToDate, Cochrane Database of Systemic Reviews, and the Cochrane Controlled Trials Register database as well as through references from relevant articles, all until September 2015. However, only the results of publications with adequate methodological quality were included. Prebiotics seem to be very appealing in treatment of many clinical conditions, explicitly in the fight against constipation, poor weight gain in preterm infants, and eczema in atopic children. In contrast to probiotics, the evidence of true clinical efficacy of prebiotics, supported with exact type and dose information are rather sparse, and there are a limited number of randomized controlled trials concerning prebiotics in children, especially beyond the age of infancy. Large well-designed, controlled, confirmatory clinical trials are required, using commercially available products, to help healthcare providers in making an appropriate decision concerning the appropriate use of prebiotics in different conditions.

The use of statistical tools in field testing of putative effects of genetically modified plants on nontarget organisms

PubMed Central

Semenov, Alexander V; Elsas, Jan Dirk; Glandorf, Debora C M; Schilthuizen, Menno; Boer, Willem F

2013-01-01

Abstract To fulfill existing guidelines, applicants that aim to place their genetically modified (GM) insect-resistant crop plants on the market are required to provide data from field experiments that address the potential impacts of the GM plants on nontarget organisms (NTO's). Such data may be based on varied experimental designs. The recent EFSA guidance document for environmental risk assessment (2010) does not provide clear and structured suggestions that address the statistics of field trials on effects on NTO's. This review examines existing practices in GM plant field testing such as the way of randomization, replication, and pseudoreplication. Emphasis is placed on the importance of design features used for the field trials in which effects on NTO's are assessed. The importance of statistical power and the positive and negative aspects of various statistical models are discussed. Equivalence and difference testing are compared, and the importance of checking the distribution of experimental data is stressed to decide on the selection of the proper statistical model. While for continuous data (e.g., pH and temperature) classical statistical approaches – for example, analysis of variance (ANOVA) – are appropriate, for discontinuous data (counts) only generalized linear models (GLM) are shown to be efficient. There is no golden rule as to which statistical test is the most appropriate for any experimental situation. In particular, in experiments in which block designs are used and covariates play a role GLMs should be used. Generic advice is offered that will help in both the setting up of field testing and the interpretation and data analysis of the data obtained in this testing. The combination of decision trees and a checklist for field trials, which are provided, will help in the interpretation of the statistical analyses of field trials and to assess whether such analyses were correctly applied. We offer generic advice to risk assessors and applicants that will help in both the setting up of field testing and the interpretation and data analysis of the data obtained in field testing. PMID:24567836

The use of statistical tools in field testing of putative effects of genetically modified plants on nontarget organisms.

PubMed

Semenov, Alexander V; Elsas, Jan Dirk; Glandorf, Debora C M; Schilthuizen, Menno; Boer, Willem F

2013-08-01

To fulfill existing guidelines, applicants that aim to place their genetically modified (GM) insect-resistant crop plants on the market are required to provide data from field experiments that address the potential impacts of the GM plants on nontarget organisms (NTO's). Such data may be based on varied experimental designs. The recent EFSA guidance document for environmental risk assessment (2010) does not provide clear and structured suggestions that address the statistics of field trials on effects on NTO's. This review examines existing practices in GM plant field testing such as the way of randomization, replication, and pseudoreplication. Emphasis is placed on the importance of design features used for the field trials in which effects on NTO's are assessed. The importance of statistical power and the positive and negative aspects of various statistical models are discussed. Equivalence and difference testing are compared, and the importance of checking the distribution of experimental data is stressed to decide on the selection of the proper statistical model. While for continuous data (e.g., pH and temperature) classical statistical approaches - for example, analysis of variance (ANOVA) - are appropriate, for discontinuous data (counts) only generalized linear models (GLM) are shown to be efficient. There is no golden rule as to which statistical test is the most appropriate for any experimental situation. In particular, in experiments in which block designs are used and covariates play a role GLMs should be used. Generic advice is offered that will help in both the setting up of field testing and the interpretation and data analysis of the data obtained in this testing. The combination of decision trees and a checklist for field trials, which are provided, will help in the interpretation of the statistical analyses of field trials and to assess whether such analyses were correctly applied. We offer generic advice to risk assessors and applicants that will help in both the setting up of field testing and the interpretation and data analysis of the data obtained in field testing.

Alternation as a form of allocation for quality improvement studies in primary healthcare settings: the on-off study design.

PubMed

Mathe, Nonsikelelo; Johnson, Steven T; Wozniak, Lisa A; Majumdar, Sumit R; Johnson, Jeffrey A

2015-08-25

Randomized controlled trials are considered the "gold standard" for scientific rigor in the assessment of benefits and harms of interventions in healthcare. They may not always be feasible, however, when evaluating quality improvement interventions in real-world healthcare settings. Non-randomized controlled trials (NCTs) are designed to answer questions of effectiveness of interventions in routine clinical practice to inform a decision or process. The on-off NCT design is a relatively new design where participant allocation is by alternation. In alternation, eligible patients are allocated to the intervention "on" or control "off " groups in time series dependent sequential clusters. We used two quality improvement studies undertaken in a Canadian primary care setting to illustrate the features of the on-off design. We also explored the perceptions and experiences of healthcare providers tasked with implementing the on-off study design. The on-off design successfully allocated patients to intervention and control groups. Imbalances between baseline variables were attributed to chance, with no detectable biases. However, healthcare providers' perspectives and experiences with the design in practice reveal some conflict. Specifically, providers described the process of allocating patients to the off group as unethical and immoral, feeling it was in direct conflict with their professional principle of providing care for all. The degree of dissatisfaction seemed exacerbated by: 1) the patient population involved (e.g., patient population viewed as high-risk (e.g., depressed or suicidal)), 2) conducting assessments without taking action (e.g., administering the PHQ-9 and not acting on the results), and 3) the (non-blinded) allocation process. Alternation, as in the on-off design, is a credible form of allocation. The conflict reported by healthcare providers in implementing the design, while not unique to the on-off design, may be alleviated by greater emphasis on the purpose of the research and having research assistants allocate patients and collect data instead of the healthcare providers implementing the trial. In addition, consultation with front-line staff implementing the trials with an on-off design on appropriateness to the setting (e.g., alignment with professional values and the patient population served) may be beneficial. Health Eating and Active Living with Diabetes: ClinicalTrials.gov identifier: NCT00991380. Date registered: 7 October 2009. Controlled trial of a collaborative primary care team model for patients with diabetes and depression: Clintrials.gov Identifier: NCT01328639 Date registered: 30 March 2011.

Methodological issues in oral health research: intervention studies.

PubMed

O'Mullane, Denis; James, Patrice; Whelton, Helen; Parnell, Carmel

2012-02-01

To provide a broad overview of methodological issues in the design and evaluation of intervention studies in dental public health, with particular emphasis on explanatory trials, pragmatic trials and complex interventions. We present a narrative summary of selected publications from the literature outlining both historical and recent challenges in the design and evaluation of intervention studies and describe some recent tools that may help researchers to address these challenges. It is now recognised that few intervention studies in dental public health are purely explanatory or pragmatic. We describe the PRECIS tool which can be used by trialists to assess and display the position of their trial on a continuum between the extremes of explanatory and pragmatic trials. The tool aims to help trialists make design decisions that are in line with their stated aims. The increasingly complex nature of dental public health interventions presents particular design and evaluation challenges. The revised Medical Research Council (MRC) guidance for the development and evaluation of complex interventions which emphasises the importance of planning and process evaluation is a welcome development. We briefly describe the MRC guidance and outline some examples of complex interventions in the field of oral health. The role of observational studies in monitoring public health interventions when the conduct of RCTs is not appropriate or feasible is acknowledged. We describe the STROBE statement and outline the implications of the STROBE guidelines for dental public health. The methodological challenges in the design, conduct and reporting of intervention studies in oral health are considerable. The need to provide reliable evidence to support innovative new strategies in oral health policy is a major impetus in these fields. No doubt the 'Methodological Issues in Oral Health Research' group will have further opportunities to highlight this work. © 2012 John Wiley & Sons A/S.

Opportunities and Challenges for Drug Development: Public-Private Partnerships, Adaptive Designs and Big Data.

PubMed

Yildirim, Oktay; Gottwald, Matthias; Schüler, Peter; Michel, Martin C

2016-01-01

Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public-private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development.

Opportunities and Challenges for Drug Development: Public–Private Partnerships, Adaptive Designs and Big Data

PubMed Central

Yildirim, Oktay; Gottwald, Matthias; Schüler, Peter; Michel, Martin C.

2016-01-01

Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public–private partnerships, adaptive designs and big data. Public–private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development. PMID:27999543

Formulating appropriate statistical hypotheses for treatment comparison in clinical trial design and analysis.

PubMed

Huang, Peng; Ou, Ai-hua; Piantadosi, Steven; Tan, Ming

2014-11-01

We discuss the problem of properly defining treatment superiority through the specification of hypotheses in clinical trials. The need to precisely define the notion of superiority in a one-sided hypothesis test problem has been well recognized by many authors. Ideally designed null and alternative hypotheses should correspond to a partition of all possible scenarios of underlying true probability models P={P(ω):ω∈Ω} such that the alternative hypothesis Ha={P(ω):ω∈Ωa} can be inferred upon the rejection of null hypothesis Ho={P(ω):ω∈Ω(o)} However, in many cases, tests are carried out and recommendations are made without a precise definition of superiority or a specification of alternative hypothesis. Moreover, in some applications, the union of probability models specified by the chosen null and alternative hypothesis does not constitute a completed model collection P (i.e., H(o)∪H(a) is smaller than P). This not only imposes a strong non-validated assumption of the underlying true models, but also leads to different superiority claims depending on which test is used instead of scientific plausibility. Different ways to partition P fro testing treatment superiority often have different implications on sample size, power, and significance in both efficacy and comparative effectiveness trial design. Such differences are often overlooked. We provide a theoretical framework for evaluating the statistical properties of different specification of superiority in typical hypothesis testing. This can help investigators to select proper hypotheses for treatment comparison inclinical trial design. Copyright © 2014 Elsevier Inc. All rights reserved.

Use of behavioral economics and social psychology to improve treatment of acute respiratory infections (BEARI): rationale and design of a cluster randomized controlled trial [1RC4AG039115-01] - study protocol and baseline practice and provider characteristics

PubMed Central

2013-01-01

Background Inappropriate antibiotic prescribing for nonbacterial infections leads to increases in the costs of care, antibiotic resistance among bacteria, and adverse drug events. Acute respiratory infections (ARIs) are the most common reason for inappropriate antibiotic use. Most prior efforts to decrease inappropriate antibiotic prescribing for ARIs (e.g., educational or informational interventions) have relied on the implicit assumption that clinicians inappropriately prescribe antibiotics because they are unaware of guideline recommendations for ARIs. If lack of guideline awareness is not the reason for inappropriate prescribing, educational interventions may have limited impact on prescribing rates. Instead, interventions that apply social psychological and behavioral economic principles may be more effective in deterring inappropriate antibiotic prescribing for ARIs by well-informed clinicians. Methods/design The Application of Behavioral Economics to Improve the Treatment of Acute Respiratory Infections (BEARI) Trial is a multisite, cluster-randomized controlled trial with practice as the unit of randomization. The primary aim is to test the ability of three interventions based on behavioral economic principles to reduce the rate of inappropriate antibiotic prescribing for ARIs. We randomized practices in a 2 × 2 × 2 factorial design to receive up to three interventions for non-antibiotic-appropriate diagnoses: 1) Accountable Justifications: When prescribing an antibiotic for an ARI, clinicians are prompted to record an explicit justification that appears in the patient electronic health record; 2) Suggested Alternatives: Through computerized clinical decision support, clinicians prescribing an antibiotic for an ARI receive a list of non-antibiotic treatment choices (including prescription options) prior to completing the antibiotic prescription; and 3) Peer Comparison: Each provider’s rate of inappropriate antibiotic prescribing relative to top-performing peers is reported back to the provider periodically by email. We enrolled 269 clinicians (practicing attending physicians or advanced practice nurses) in 49 participating clinic sites and collected baseline data. The primary outcome is the antibiotic prescribing rate for office visits with non-antibiotic-appropriate ARI diagnoses. Secondary outcomes will examine antibiotic prescribing more broadly. The 18-month intervention period will be followed by a one year follow-up period to measure persistence of effects after interventions cease. Discussion The ongoing BEARI Trial will evaluate the effectiveness of behavioral economic strategies in reducing inappropriate prescribing of antibiotics. Trials registration ClinicalTrials.gov: NCT01454947 PMID:23806017

Ethics and eplerenone.

PubMed

Gupta, Shruti; Fugh-Berman, Adriane J; Scialli, Anthony

2013-02-01

The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials?

PubMed

Finkel, Richard S; Bishop, Kathie M; Nelson, Robert M

2017-02-01

The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials.

PubMed

Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte; Khanna, Dinesh; Dellaripa, Paul F; Distler, Oliver; Flaherty, Kevin R; Frankel, Sid; Oddis, Chester V; Denton, Christopher P; Fischer, Aryeh; Kowal-Bielecka, Otylia M; LeSage, Daphne; Merkel, Peter A; Phillips, Kristine; Pittrow, David; Swigris, Jeffrey; Antoniou, Katerina; Baughman, Robert P; Castelino, Flavia V; Christmann, Romy B; Christopher-Stine, Lisa; Collard, Harold R; Cottin, Vincent; Danoff, Sonye; Highland, Kristin B; Hummers, Laura; Shah, Ami A; Kim, Dong Soon; Lynch, David A; Miller, Frederick W; Proudman, Susanna M; Richeldi, Luca; Ryu, Jay H; Sandorfi, Nora; Sarver, Catherine; Wells, Athol U; Strand, Vibeke; Matteson, Eric L; Brown, Kevin K; Seibold, James R

2014-05-01

Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

PubMed Central

Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte; Khanna, Dinesh; Dellaripa, Paul F; Distler, Oliver; Flaherty, Kevin R; Frankel, Sid; Oddis, Chester V; Denton, Christopher P; Fischer, Aryeh; Kowal-Bielecka, Otylia M; LeSage, Daphne; Merkel, Peter A; Phillips, Kristine; Pittrow, David; Swigris, Jeffrey; Antoniou, Katerina; Baughman, Robert P; Castelino, Flavia V; Christmann, Romy B; Christopher-Stine, Lisa; Collard, Harold R; Cottin, Vincent; Danoff, Sonye; Highland, Kristin B; Hummers, Laura; Shah, Ami A; Kim, Dong Soon; Lynch, David A; Miller, Frederick W; Proudman, Susanna M; Richeldi, Luca; Ryu, Jay H; Sandorfi, Nora; Sarver, Catherine; Wells, Athol U; Strand, Vibeke; Matteson, Eric L; Brown, Kevin K; Seibold, James R

2014-01-01

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field. PMID:24368713

The use of clinical trials in comparative effectiveness research on mental health.

PubMed

Blanco, Carlos; Rafful, Claudia; Olfson, Mark

2013-08-01

A large body of comparative effectiveness research (CER) focuses on the use of observational and quasi-experimental approaches. We sought to examine the use of clinical trials as a tool for CER, particularly in mental health. Examination of three ongoing randomized clinical trials in psychiatry addressing issues that would pose difficulties for nonexperimental CER methods. Existing statistical approaches to nonexperimental data appear insufficient to compensate for biases that may arise when the pattern of missing data cannot be properly modeled such as when there are no standards for treatment, when affected populations have limited access to treatment, or when there are high rates of treatment dropout. Clinical trials should retain an important role in CER, particularly in cases of high disorder prevalence, large expected effect sizes, difficult-to-reach populations, or when examining sequential treatments or stepped-care algorithms. Progress in CER on mental health will require careful consideration of appropriate selection between clinical trials and nonexperimental designs and on allocation of research resources to optimally inform key treatment decisions for each patient. Copyright © 2013 Elsevier Inc. All rights reserved.

Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available.

PubMed

Hernán, Miguel A; Robins, James M

2016-04-15

Ideally, questions about comparative effectiveness or safety would be answered using an appropriately designed and conducted randomized experiment. When we cannot conduct a randomized experiment, we analyze observational data. Causal inference from large observational databases (big data) can be viewed as an attempt to emulate a randomized experiment-the target experiment or target trial-that would answer the question of interest. When the goal is to guide decisions among several strategies, causal analyses of observational data need to be evaluated with respect to how well they emulate a particular target trial. We outline a framework for comparative effectiveness research using big data that makes the target trial explicit. This framework channels counterfactual theory for comparing the effects of sustained treatment strategies, organizes analytic approaches, provides a structured process for the criticism of observational studies, and helps avoid common methodologic pitfalls. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Case Study: Ticagrelor in PLATO and Prasugrel in TRITON-TIMI 38 and TRILOGY-ACS Trials in Patients With Acute Coronary Syndromes

PubMed Central

Husted, Steen; Boersma, Eric

2016-01-01

Cross-trial comparisons are typically inappropriate as there are often numerous differences in study designs, populations, end points, and loading doses of the study drugs. These differences are clearly reflected in the most recent updates to the European Society of Cardiology (ESC) non-ST elevation acute coronary syndrome (NSTE-ACS) and ST elevation myocardial infarction (STEMI) guidelines, which include recommendations for the use of the antiplatelet agents ticagrelor, prasugrel, and clopidogrel, based in part on results from the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38, TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY-ACS) and PLATelet inhibition and patient Outcomes (PLATO) trials. Here, we describe each of these trials in detail and explain the differences between them that make direct comparisons difficult. In conclusion, this information, along with the current guidelines and recommendations, will assist clinicians in deciding the most appropriate treatment pathway for their patients with NSTE-ACS and STEMI. PMID:25830867

Designing Studies That Would Address the Multilayered Nature of Health Care

PubMed Central

Pennell, Michael; Rhoda, Dale; Hade, Erinn M.; Paskett, Electra D.

2010-01-01

We review design and analytic methods available for multilevel interventions in cancer research with particular attention to study design, sample size requirements, and potential to provide statistical evidence for causal inference. The most appropriate methods will depend on the stage of development of the research and whether randomization is possible. Early on, fractional factorial designs may be used to screen intervention components, particularly when randomization of individuals is possible. Quasi-experimental designs, including time-series and multiple baseline designs, can be useful once the intervention is designed because they require few sites and can provide the preliminary evidence to plan efficacy studies. In efficacy and effectiveness studies, group-randomized trials are preferred when randomization is possible and regression discontinuity designs are preferred otherwise if assignment based on a quantitative score is possible. Quasi-experimental designs may be used, especially when combined with recent developments in analytic methods to reduce bias in effect estimates. PMID:20386057

Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.

PubMed

Sandilands, Euan A; Cameron, Sharon; Paterson, Frances; Donaldson, Sam; Briody, Lesley; Crowe, Jane; Donnelly, Julie; Thompson, Adrian; Johnston, Neil R; Mackenzie, Ivor; Uren, Neal; Goddard, Jane; Webb, David J; Megson, Ian L; Bateman, Nicholas; Eddleston, Michael

2012-02-03

Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease. We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance. Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials. Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.

Building the bionic eye: an emerging reality and opportunity.

PubMed

Merabet, Lotfi B

2011-01-01

Once the topic of folklore and science fiction, the notion of restoring vision to the blind is now approaching a tractable reality. Technological advances have inspired numerous multidisciplinary groups worldwide to develop visual neuroprosthetic devices that could potentially provide useful vision and improve the quality of life of profoundly blind individuals. While a variety of approaches and designs are being pursued, they all share a common principle of creating visual percepts through the stimulation of visual neural elements using appropriate patterns of electrical stimulation. Human clinical trials are now well underway and initial results have been met with a balance of excitement and cautious optimism. As remaining technical and surgical challenges continue to be solved and clinical trials move forward, we now enter a phase of development that requires careful consideration of a new set of issues. Establishing appropriate patient selection criteria, methods of evaluating long-term performance and effectiveness, and strategies to rehabilitate implanted patients will all need to be considered in order to achieve optimal outcomes and establish these devices as viable therapeutic options. Copyright © 2011 Elsevier B.V. All rights reserved.

Role of preliminary registry data in development of a clinical trial for an innovative device: a small but integral piece of a health policy initiative

PubMed Central

Ricci, Donald R.; de Vries, Joost; Blanc, Raphael

2017-01-01

ABSTRACT Establishing a national health policy at a macro level involves the integration of a series of health initiatives across a spectrum of activities, including clinical care. Evaluation of the safety and efficacy of a new medical device ultimately evolves to testing in humans. The pathway to a formal prospective clinical trial includes a stepwise appreciation of pre-clinical data and detailed analysis of data obtained from preliminary registries, where information about appropriate patient selection and use of the device is obtained. Evaluation of procedural and follow-up efficacy and safety data in a preliminary series of cases, chosen to simulate published data, allows the design and conduct of clinical trials that are required to verify preliminary observations, closing the loop on one aspect of modifying health policy decisions. PMID:28321285

Blocking, unblocking, and overexpectation in autoshaping with pigeons.

PubMed

Khallad, Y; Moore, J

1996-05-01

Three experiments used pigeons in an autoshaping procedure and a single-subject design to examine compound stimulus control in classical conditioning. Experiment 1 examined the blocking effect, and Experiment 2 examined the unblocking effect. In both experiments, response-independent food was first delivered intermittently in the presence of one distinctively colored houselight but not another. Then, conventional autoshaping trials were carried out in the presence of each houselight. In Experiment 1, the keylight readily elicited responding in the presence of the houselight that had been negatively correlated with food, but not in the presence of the houselight that had been positively correlated with food. In Experiment 2, the keylight readily elicited responding in the presence of the houselight positively correlated with food, but only when the amount of food used on the autoshaping trials was either greater or less than that previously delivered in the presence of the houselight. Experiment 3 examined the overexpectation effect. Conventional autoshaping trials were first carried out by presenting each of two keylights individually. Then, additional autoshaping trials were carried out by presenting the two keylights as a compound, with either the same amount of food or a greater amount of food per trial. Finally, the keylights were retested by again presenting them individually. The number of responses per trial elicited by the keylights decreased when the amount of food used in compound trials was the same as that used in individual trials. However, the number of responses per trial remained approximately the same when the amount of food used in compound trials was greater than that used in individual trials. Taken together, the results of the three experiments demonstrate (a) the generality of the blocking, unblocking, and overexpectation effects by virtue of their extension to appetitive unconditioned stimuli; (b) the suitability of pigeons as subjects and autoshaping as a procedure for studying classical conditioning; and (c) the appropriateness of single-subject designs.

Blocking, unblocking, and overexpectation in autoshaping with pigeons

PubMed Central

Khallad, Yacoub; Moore, Jay

1996-01-01

Three experiments used pigeons in an autoshaping procedure and a single-subject design to examine compound stimulus control in classical conditioning. Experiment 1 examined the blocking effect, and Experiment 2 examined the unblocking effect. In both experiments, response-independent food was first delivered intermittently in the presence of one distinctively colored houselight but not another. Then, conventional autoshaping trials were carried out in the presence of each houselight. In Experiment 1, the keylight readily elicited responding in the presence of the houselight that had been negatively correlated with food, but not in the presence of the houselight that had been positively correlated with food. In Experiment 2, the keylight readily elicited responding in the presence of the houselight positively correlated with food, but only when the amount of food used on the autoshaping trials was either greater or less than that previously delivered in the presence of the houselight. Experiment 3 examined the overexpectation effect. Conventional autoshaping trials were first carried out by presenting each of two keylights individually. Then, additional autoshaping trials were carried out by presenting the two keylights as a compound, with either the same amount of food or a greater amount of food per trial. Finally, the keylights were retested by again presenting them individually. The number of responses per trial elicited by the keylights decreased when the amount of food used in compound trials was the same as that used in individual trials. However, the number of responses per trial remained approximately the same when the amount of food used in compound trials was greater than that used in individual trials. Taken together, the results of the three experiments demonstrate (a) the generality of the blocking, unblocking, and overexpectation effects by virtue of their extension to appetitive unconditioned stimuli; (b) the suitability of pigeons as subjects and autoshaping as a procedure for studying classical conditioning; and (c) the appropriateness of single-subject designs. PMID:16812810

Pregnancy and Protection: The Ethics of Limiting a Pregnant Woman’s Participation in Clinical Trials

PubMed Central

Allesee, Lori; Gallagher, Colleen M.

2011-01-01

The call for the inclusion of pregnant women in clinical trials has received renewed attention recently. This interest springs from articles in various medical journals highlighting the gaps in medical knowledge and the need to improve health care for pregnant women. It is not a simple decision whether to include pregnant women in studies or not. The general thought is that it’s too dangerous for the baby if a pregnant woman is participating in a trial, and the absence of research on how medications work in pregnant women leave doctors guessing about how to safely and effectively treat patients through pregnancy. Excluding pregnant women from clinical trials are not automatic, not unethical nor is it arbitrarily determined. The regulatory framework is based on sound ethical and legal reasoning that demonstrates when inclusion in a clinical trial is appropriate or when clear and compelling reasons for exclusion are presented. Learning objective Readers will learn about limitations of research, history of the inclusion and exclusion of pregnant women in clinical trials, reticence for inclusions, as well as regulations designed using reasoned legal and ethical principles, such as: Principle of Autonomy, Informed Consent, and Beneficence and Nonmaleficence. PMID:21863146

Specific barriers to the conduct of randomised clinical trials on medical devices.

PubMed

Neugebauer, Edmund A M; Rath, Ana; Antoine, Sunya-Lee; Eikermann, Michaela; Seidel, Doerthe; Koenen, Carsten; Jacobs, Esther; Pieper, Dawid; Laville, Martine; Pitel, Séverine; Martinho, Cecilia; Djurisic, Snezana; Demotes-Mainard, Jacques; Kubiak, Christine; Bertele, Vittorio; Jakobsen, Janus C; Garattini, Silvio; Gluud, Christian

2017-09-13

Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices. Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency. The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices.

Use of partial least squares path modelling to assess the willingness of Chinese female sex workers to participate in a microbicide trial.

PubMed

Yao, N; Zeng, Q; Zhong, N X; Li, D X; Huang, L A; Shao, M Y; Ruan, H Y

2015-09-01

To investigate the willingness of Chinese female sex workers (FSWs) to participate (WTP) in a clinical trial of microbicides; to explore the potential hindrances and facilitating factors; and to provide support for future microbicide clinical trials by tailoring their design to better meet the specific needs of FSWs. Cross-sectional study. In total, 404 FSWs were investigated using structured questionnaires. Exploratory factor analysis and partial least squares path modelling were used to explore the correlations between several influencing factors and WTP. The WTP of FSWs enrolled in this study was high (53.47%, 216/404). Possible benefits from enrolment in the trial were positively associated with WTP, while concern about a hypothetical microbicide, potential physical harm, economic loss from participation, and fear of family or social isolation were negatively associated with WTP. FSWs are appropriate participants in microbicide clinical trials, and are likely to benefit from effective microbicides. In a microbicide clinical trial, it is imperative to ensure protection of the rights, dignity, safety, confidentiality and welfare of FSW participants. Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Challenges of a community based pragmatic, randomised controlled trial of weight loss maintenance.

PubMed

Randell, Elizabeth; McNamara, Rachel; Shaw, Christine; Espinasse, Aude; Simpson, Sharon Anne

2015-12-18

Randomised controlled trials (RCTs) have a reputation for being inherently difficult to deliver as planned and often face unforeseen challenges and delays, particularly in relation to organisational and governance difficulties, participant interest, constraints due to allocation of costs, local investigator interest and lengthy bureaucracy. Recruitment is often difficult and the challenges faced often impact on the cost and delivery of a successful trial within the funded period. This paper reflects upon the challenges faced in delivering a pragmatic RCT of weight loss maintenance in a community setting and suggests some potential solutions. The weight loss maintenance in adults trial aimed to evaluate the impact of a 12 month, individually tailored weight maintenance intervention on BMI 3 years from randomisation. Participants were recruited primarily from participant identification centres (PICs)-GP surgeries, exercise on referral schemes and slimming world. The intervention was delivered in community settings. A recruitment strategy implementation plan was drafted to address and monitor poor recruitment. Delays in opening and recruitment were experienced early on. Some were beyond the control of the study team such as; disagreement over allocation of national health service costs and PIC classification as well as difficulties in securing support from research networks. That the intervention was delivered in community settings was often at the root of these issues. Key items to address at the design stage of future trials include feasibility of eligibility criteria. The most effective element of the recruitment implementation plan was to refocus sources of recruitment and target only those who could fulfil the eligibility criteria immediately. Learnings from this trial should be kept in mind by those designing similar studies in the future. Considering potential governance, cost and research network support implications at the design stage of pragmatic trials of any community-based complex intervention is paramount. The appropriateness and viability of inclusion criteria also require careful consideration as does use of a targeted advertising strategy. ISRCTN35774128, 12/01/2010.

Applying quantitative bias analysis to estimate the plausible effects of selection bias in a cluster randomised controlled trial: secondary analysis of the Primary care Osteoarthritis Screening Trial (POST).

PubMed

Barnett, L A; Lewis, M; Mallen, C D; Peat, G

2017-12-04

Selection bias is a concern when designing cluster randomised controlled trials (c-RCT). Despite addressing potential issues at the design stage, bias cannot always be eradicated from a trial design. The application of bias analysis presents an important step forward in evaluating whether trial findings are credible. The aim of this paper is to give an example of the technique to quantify potential selection bias in c-RCTs. This analysis uses data from the Primary care Osteoarthritis Screening Trial (POST). The primary aim of this trial was to test whether screening for anxiety and depression, and providing appropriate care for patients consulting their GP with osteoarthritis would improve clinical outcomes. Quantitative bias analysis is a seldom-used technique that can quantify types of bias present in studies. Due to lack of information on the selection probability, probabilistic bias analysis with a range of triangular distributions was also used, applied at all three follow-up time points; 3, 6, and 12 months post consultation. A simple bias analysis was also applied to the study. Worse pain outcomes were observed among intervention participants than control participants (crude odds ratio at 3, 6, and 12 months: 1.30 (95% CI 1.01, 1.67), 1.39 (1.07, 1.80), and 1.17 (95% CI 0.90, 1.53), respectively). Probabilistic bias analysis suggested that the observed effect became statistically non-significant if the selection probability ratio was between 1.2 and 1.4. Selection probability ratios of > 1.8 were needed to mask a statistically significant benefit of the intervention. The use of probabilistic bias analysis in this c-RCT suggested that worse outcomes observed in the intervention arm could plausibly be attributed to selection bias. A very large degree of selection of bias was needed to mask a beneficial effect of intervention making this interpretation less plausible.

Australasian Resuscitation In Sepsis Evaluation trial statistical analysis plan.

PubMed

Delaney, Anthony; Peake, Sandra L; Bellomo, Rinaldo; Cameron, Peter; Holdgate, Anna; Howe, Belinda; Higgins, Alisa; Presneill, Jeffrey; Webb, Steve

2013-10-01

The Australasian Resuscitation In Sepsis Evaluation (ARISE) study is an international, multicentre, randomised, controlled trial designed to evaluate the effectiveness of early goal-directed therapy compared with standard care for patients presenting to the ED with severe sepsis. In keeping with current practice, and taking into considerations aspects of trial design and reporting specific to non-pharmacologic interventions, this document outlines the principles and methods for analysing and reporting the trial results. The document is prepared prior to completion of recruitment into the ARISE study, without knowledge of the results of the interim analysis conducted by the data safety and monitoring committee and prior to completion of the two related international studies. The statistical analysis plan was designed by the ARISE chief investigators, and reviewed and approved by the ARISE steering committee. The data collected by the research team as specified in the study protocol, and detailed in the study case report form were reviewed. Information related to baseline characteristics, characteristics of delivery of the trial interventions, details of resuscitation and other related therapies, and other relevant data are described with appropriate comparisons between groups. The primary, secondary and tertiary outcomes for the study are defined, with description of the planned statistical analyses. A statistical analysis plan was developed, along with a trial profile, mock-up tables and figures. A plan for presenting baseline characteristics, microbiological and antibiotic therapy, details of the interventions, processes of care and concomitant therapies, along with adverse events are described. The primary, secondary and tertiary outcomes are described along with identification of subgroups to be analysed. A statistical analysis plan for the ARISE study has been developed, and is available in the public domain, prior to the completion of recruitment into the study. This will minimise analytic bias and conforms to current best practice in conducting clinical trials. © 2013 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Role of the bacterial vaccine Solco-Urovac® in treatment and prevention of recurrent urinary tract infections of bacterial origin.

PubMed

Kochiashvili, D; Khuskivadze, A; Kochiashvili, G; Koberidze, G; Kvakhajelidze, V

2014-06-01

Urinary Tract Infections (UTI) represent a serious medical problem with considerably high rate of morbidity. Recurrent episodes of urinary tract infection (rUTI) may commonly develop in the way of relapse or reinfection. For patients, rUTI is always associated with costs, discomfort and decreased quality of life. Standard treatment of rUTI is through antibiotics and usually such treatment is required repeatedly. Repeat course of antibiotics leads to increase of resistance of uropathogenic strains. According to the European Association of Urology, "the present state of microbial resistance development is alarming". Our post-marketing trial was designed to demonstrate the substantial effect of the bacterial vaccine Solco-Urovac® both with independent administration and in conjunction with standard antibacterial medication within therapy and prevention of rUTI. Total of 115 patients (men and non-pregnant women) were enrolled in our open-label post-marketing trial. Each patient had more than one year history of rUTI and in the past had already taken appropriate course of standard therapy. The trial group included 50 patients: 32 men, 18 women (average age ± 32.5). 32 patients (men) of the trial group received vaccination with Solco-Urovac® together with the standard antibacterial medication. According to bacteriologic tests, in 62% cases infection was caused by Escherichia coli, and in 38% cases by Morganella morganii, Proteus mirabilis, Klebsiella pneumoniae, Enterococcus faecalis. 18 patients within the trial group were women with no recurrence episode at the start and during the trial period. Each woman was involved as the intercourse partner of the respective man within the trial group. The women received only vaccination with Solco-Urovac®. 65 patients of the control group had more than one year history of rUTI and had been treated earlier, too. Patients of the control group received appropriate antibacterial medication without Solco-Urovac®. After therapy and follow-up examination, results in the both groups were classified, also in consideration of the pathogen-specified subgroups, and then summarized and compared respectively. During the follow-up period no case of rUTI was noticed in women. In total, analysis of the medical records of 50 patients of the trial group demonstrated no case of rUTI in 46 patients during the follow-up period. Altogether, the rate of improvement of symptoms was as follows: the trial group - 92%, the control group - 74%. Through comparison with the past medical histories of patients, the higher rate of improvement and longer absence of rUTI episodes after treatment were certainly associated with the effect of Solco-Urovac®. The results of our post-marketing trial allow recommending Solco-Urovac® for appropriate reference within the Georgian National Guideline on Urologic Infections.

Parental emotional management benefits family relationships: A randomized controlled trial in Hong Kong, China.

PubMed

Fabrizio, Cecilia S; Lam, Tai Hing; Hirschmann, Malia R; Pang, Irene; Yu, Nancy Xiaonan; Wang, Xin; Stewart, Sunita M

2015-08-01

There is a shortage of culturally appropriate, brief, preventive interventions designed to be sustainable and acceptable for community participants in nonwestern cultures. Parents' ability to regulate their emotions is an important factor for psychological well-being of the family. In Chinese societies, emotional regulation may be more important in light of the cultural desirability of maintaining harmonious family relationships. The objectives of our randomized controlled trial were to test the effectiveness of our Effective Parenting Programme (EPP) to increase the use of emotional management strategies (primary outcome) and enhance the parent-child relationship (secondary outcome). We utilized design characteristics that promoted recruitment, retention, and intervention sustainability. We randomized a community sample of 412 Hong Kong middle- and low-income mothers of children aged 6-8 years to the EPP or attention control group. At 3, 6 and 12- month follow up, the Effective Parent Program group reported greater increases in the use of emotion management strategies during parent-child interactions, with small to medium effect size, and lower negative affect and greater positive affect, subjective happiness, satisfaction with the parent-child relationship, and family harmony, compared to the control group, with small to medium effect size. Our results provided evidence of effectiveness for a sustainable, preventive, culturally appropriate, cognitive behaviorally-based emotion management program, in a non-clinical setting for Chinese mothers. HKCTR-1190. Copyright © 2015 Elsevier Ltd. All rights reserved.

Family-based obesity prevention for infants: Design of the "Mothers & Others" randomized trial.

PubMed

Wasser, Heather M; Thompson, Amanda L; Suchindran, Chirayath M; Hodges, Eric A; Goldman, Barbara D; Perrin, Eliana M; Faith, Myles S; Bulik, Cynthia M; Heinig, M Jane; Bentley, Margaret E

2017-09-01

Our goal is to test the efficacy of a family-based, multi-component intervention focused on infants of African-American (AA) mothers and families, a minority population at elevated risk for pediatric obesity, versus a child safety attention-control group to promote healthy weight gain patterns during the first two years of life. The design is a two-group randomized controlled trial among 468 AA pregnant women in central North Carolina. Mothers and study partners in the intervention group receive anticipatory guidance on breastfeeding, responsive feeding, use of non-food soothing techniques for infant crying, appropriate timing and quality of complementary feeding, age-appropriate infant sleep, and minimization of TV/media. The primary delivery channel is 6 home visits by a peer educator, 4 interim newsletters and twice-weekly text messaging. Intervention families also receive 2 home visits from an International Board Certified Lactation Consultant. Assessments occur at 28 and 37weeks gestation and when infants are 1, 3, 6, 9, 12, and 15months of age. The primary outcome is infant/toddler growth and likelihood of overweight at 15months. Differences between groups are expected to be achieved through uptake of the targeted infant feeding and care behaviors (secondary outcomes) and change in caregivers' modifiable risk factors (mediators) underpinning the intervention. If successful in promoting healthy infant growth and enhancing caregiver behaviors, "Mothers and Others" will have high public health relevance for future obesity-prevention efforts aimed at children younger than 2years, including interventional research and federal, state, and community health programs. ClinicalTrials.gov, NCT01938118, August 9, 2013. Copyright © 2017 Elsevier Inc. All rights reserved.

No magic bullets: a systematic review of 102 trials of interventions to improve professional practice.

PubMed Central

Oxman, A D; Thomson, M A; Davis, D A; Haynes, R B

1995-01-01

OBJECTIVE: To determine the effectiveness of different types of interventions in improving health professional performance and health outcomes. DATA SOURCES: MEDLINE, SCISEARCH, CINAHL and the Research and Development Resource Base in CME were searched for trials of educational interventions in the health care professions published between 1970 and 1993 inclusive. STUDY SELECTION: Studies were selected if they provided objective measurements of health professional performance or health outcomes and employed random or quasi-random allocation methods in their study designs to assign individual subjects or groups. Interventions included such activities as conferences, outreach visits, the use of local opinion leaders, audit and feedback, and reminder systems. DATA EXTRACTION: Details extracted from the studies included the study design; the unit of allocation (e.g., patient, provider, practice, hospital); the characteristics of the targeted health care professionals, educational interventions and patients (when appropriate); and the main outcome measure. DATA SYNTHESIS: The inclusion criteria were met by 102 trials. Areas of behaviour change included general patient management, preventive services, prescribing practices, treatment of specific conditions such as hypertension or diabetes, and diagnostic service or hospital utilization. Dissemination-only strategies, such as conferences or the mailing of unsolicited materials, demonstrated little or no changes in health professional behaviour or health outcome when used alone. More complex interventions, such as the use of outreach visits or local opinion leaders, ranged from ineffective to highly effective but were most often moderately effective (resulting in reductions of 20% to 50% in the incidence of inappropriate performance). CONCLUSION: There are no "magic bullets" for improving the quality of health care, but there are a wide range of interventions available that, if used appropriately, could lead to important improvements in professional practice and patient outcomes. PMID:7585368

Mental health first aid for eating disorders: pilot evaluation of a training program for the public

PubMed Central

2012-01-01

Background Eating disorders cause significant burden that may be reduced by early and appropriate help-seeking. However, despite the availability of effective treatments, very few individuals with eating disorders seek treatment. Training in mental health first aid is known to be effective in increasing mental health literacy and supportive behaviours, in the social networks of individuals with mental health problems. Increases in these domains are thought to improve the likelihood that effective help is sought. However, the efficacy of mental health first aid for eating disorders has not been evaluated. The aim of this research was to examine whether specific training in mental health first aid for eating disorders was effective in changing knowledge, attitudes and behaviours towards people with eating disorders. Methods A repeated measures, uncontrolled trial was conducted to establish proof of concept and provide guidance on the future design of a randomised controlled trial. Self-report questionnaires, administered at baseline, post-training and 6-month follow-up, assessed the effectiveness of the 4-hour, single session, mental health first aid training. Results 73 participants completed the training and all questionnaires. The training intervention was associated with statistically significant increases in problem recognition and knowledge of appropriate mental health first aid strategies, which were maintained at 6-month follow-up. Sustained significant changes in attitudes and behaviours were less clear. 20 participants reported providing assistance to someone with a suspected eating disorder, seven of whom sought professional help as a result of the first aid interaction. Results provided no evidence of a negative impact on participants or the individuals they provided assistance to. Conclusions This research provides preliminary evidence for the use of training in mental health first aid as a suitable intervention for increasing community knowledge of and support for people with eating disorders to seek appropriate help. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12611001181998 PMID:22856517

A computerized handheld decision-support system to improve pulmonary embolism diagnosis: a randomized trial.

PubMed

Roy, Pierre-Marie; Durieux, Pierre; Gillaizeau, Florence; Legall, Catherine; Armand-Perroux, Aurore; Martino, Ludovic; Hachelaf, Mohamed; Dubart, Alain-Eric; Schmidt, Jeannot; Cristiano, Mirko; Chretien, Jean-Marie; Perrier, Arnaud; Meyer, Guy

2009-11-17

Testing for pulmonary embolism often differs from that recommended by evidence-based guidelines. To assess the effectiveness of a handheld clinical decision-support system to improve the diagnostic work-up of suspected pulmonary embolism among patients in the emergency department. Cluster randomized trial. Assignment was by random-number table, providers were not blinded, and outcome assessment was automated. (ClinicalTrials.gov registration number: NCT00188032). 20 emergency departments in France. 1103 and 1768 consecutive outpatients with suspected pulmonary embolism. After a preintervention period involving 20 centers and 1103 patients, in which providers grew accustomed to inputting clinical data into handheld devices and investigators assessed baseline testing, emergency departments were randomly assigned to activation of a decision-support system on the devices (10 centers, 753 patients) or posters and pocket cards that showed validated diagnostic strategies (10 centers, 1015 patients). Appropriateness of diagnostic work-up, defined as any sequence of tests that yielded a posttest probability less than 5% or greater than 85% (primary outcome) or as strict adherence to guideline recommendations (secondary outcome); number of tests per patient (secondary outcome). The proportion of patients who received appropriate diagnostic work-ups was greater during the trial than in the preintervention period in both groups, but the increase was greater in the computer-based guidelines group (adjusted mean difference in increase, 19.3 percentage points favoring computer-based guidelines [95% CI, 2.9 to 35.6 percentage points]; P = 0.023). Among patients with appropriate work-ups, those in the computer-based guidelines group received slightly fewer tests than did patients in the paper guidelines group (mean tests per patient, 1.76 [SD, 0.98] vs. 2.25 [SD, 1.04]; P < 0.001). The study was not designed to show a difference in the clinical outcomes of patients during follow-up. A handheld decision-support system improved diagnostic decision making for patients with suspected pulmonary embolism in the emergency department.

Are pilot trials useful for predicting randomisation and attrition rates in definitive studies: A review of publicly funded trials.

PubMed

Cooper, Cindy L; Whitehead, Amy; Pottrill, Edward; Julious, Steven A; Walters, Stephen J

2018-04-01

External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually predicts randomisation and attrition rates in the main trial. To assess the use of external pilot trials in trial design, we compared randomisation and attrition rates in publicly funded randomised controlled trials with rates in their pilots. Randomised controlled trials for which there was an external pilot trial were identified from reports published between 2004 and 2013 in the Health Technology Assessment Journal. Data were extracted from published papers, protocols and reports. Bland-Altman plots and descriptive statistics were used to investigate the agreement of randomisation and attrition rates between the full and external pilot trials. Of 561 reports, 41 were randomised controlled trials with pilot trials and 16 met criteria for a pilot trial with sufficient data. Mean attrition and randomisation rates were 21.1% and 50.4%, respectively, in the pilot trials and 16.8% and 65.2% in the main. There was minimal bias in the pilot trial when predicting the main trial attrition and randomisation rate. However, the variation was large: the mean difference in the attrition rate between the pilot and main trial was -4.4% with limits of agreement of -37.1% to 28.2%. Limits of agreement for randomisation rates were -47.8% to 77.5%. Results from external pilot trials to estimate randomisation and attrition rates should be used with caution as comparison of the difference in the rates between pilots and their associated full trial demonstrates high variability. We suggest using internal pilot trials wherever appropriate.

Are pilot trials useful for predicting randomisation and attrition rates in definitive studies: A review of publicly funded trials

PubMed Central

Whitehead, Amy; Pottrill, Edward; Julious, Steven A; Walters, Stephen J

2018-01-01

Background/aims: External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually predicts randomisation and attrition rates in the main trial. To assess the use of external pilot trials in trial design, we compared randomisation and attrition rates in publicly funded randomised controlled trials with rates in their pilots. Methods: Randomised controlled trials for which there was an external pilot trial were identified from reports published between 2004 and 2013 in the Health Technology Assessment Journal. Data were extracted from published papers, protocols and reports. Bland–Altman plots and descriptive statistics were used to investigate the agreement of randomisation and attrition rates between the full and external pilot trials. Results: Of 561 reports, 41 were randomised controlled trials with pilot trials and 16 met criteria for a pilot trial with sufficient data. Mean attrition and randomisation rates were 21.1% and 50.4%, respectively, in the pilot trials and 16.8% and 65.2% in the main. There was minimal bias in the pilot trial when predicting the main trial attrition and randomisation rate. However, the variation was large: the mean difference in the attrition rate between the pilot and main trial was −4.4% with limits of agreement of −37.1% to 28.2%. Limits of agreement for randomisation rates were −47.8% to 77.5%. Conclusion: Results from external pilot trials to estimate randomisation and attrition rates should be used with caution as comparison of the difference in the rates between pilots and their associated full trial demonstrates high variability. We suggest using internal pilot trials wherever appropriate. PMID:29361833

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

PubMed

Bates, Katherine E; Vetter, Victoria L; Li, Jennifer S; Cummins, Susan; Aguel, Fernando; Almond, Christopher; Dubin, Anne M; Elia, Josephine; Finkle, John; Hausner, Elizabeth A; Joseph, Francesca; Karkowsky, Abraham M; Killeen, Matthew; Lemacks, Jodi; Mathis, Lisa; McMahon, Ann W; Pinnow, Ellen; Rodriguez, Ignacio; Stockbridge, Norman L; Stockwell, Margaret; Tassinari, Melissa; Krucoff, Mitchell W

2012-10-01

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic. Copyright © 2012 Mosby, Inc. All rights reserved.

Evaluation of hospital palliative care teams: strengths and weaknesses of the before-after study design and strategies to improve it.

PubMed

Simon, S; Higginson, I J

2009-01-01

Hospital palliative care teams (HPCTs) are well established as multi-professional services to provide palliative care in an acute hospital setting and are increasing in number. However, there is still limited evaluation of them, in terms of efficacy and effectiveness. The gold standard method of evaluation is a randomised control trial, but because of methodological (e.g., randomisation), ethical and practical difficulties such trials are often not possible. HPCT is a complex intervention, and the specific situation in palliative care makes it challenging to evaluate (e.g., distress and cognitive impairment of patients). The quasi-experimental before-after study design has the advantage of enabling an experimental character without randomisation. But this has other weaknesses and is prone to bias, for example, temporal trends and selection bias. As for every study design, avoidance and minimisation of bias is important to improve validity. Therefore, strategies of selecting an appropriate control group or time series and applying valid outcomes and measurement tools help reducing bias and strengthen the methods. Special attention is needed to plan and define the design and applied method.

Ethical Challenges of Randomized Violence Intervention Trials: Examining the SHARE intervention in Rakai, Uganda

PubMed Central

Wagman, Jennifer A.; Paul, Amy; Namatovu, Fredinah; Ssekubugu, Robert; Nalugoda, Fred

2016-01-01

Objective We identify complexities encountered, including unanticipated crossover between trial arms and inadequate ‘standard of care’ violence services, during a cluster randomized trial (CRT) of a community-level intimate partner violence (IPV) and HIV prevention intervention in Uganda. Methods Concepts in public health ethics - beneficence, social value of research, fairness, standard of care, and researcher responsibilities for post-trial benefits - are used to critically reflect on lessons learned and guide discussion on practical and ethical challenges of violence intervention CRTs. Results Existing ethical guidelines provide incomplete guidance for responding to unexpected crossover in CRTs providing IPV services. We struggled to balance duty of care with upholding trial integrity, and identifying and providing appropriate standard of care. While we ultimately offered short-term IPV services to controls, we faced additional challenges related to sustaining services beyond the ‘short-term’ and post-trial. Conclusion Studies evaluating community-level violence interventions, including those combined with HIV reduction strategies, are limited yet critical for developing evidence-based approaches for effectively preventing IPV. Although CRTs are a promising design, further guidance is needed to implement trials that avoid introducing tensions between validity of findings, researchers’ responsibilities to protect participants, and equitable distribution of CRT benefits. PMID:27453794

Minimum number of clusters and comparison of analysis methods for cross sectional stepped wedge cluster randomised trials with binary outcomes: A simulation study.

PubMed

Barker, Daniel; D'Este, Catherine; Campbell, Michael J; McElduff, Patrick

2017-03-09

Stepped wedge cluster randomised trials frequently involve a relatively small number of clusters. The most common frameworks used to analyse data from these types of trials are generalised estimating equations and generalised linear mixed models. A topic of much research into these methods has been their application to cluster randomised trial data and, in particular, the number of clusters required to make reasonable inferences about the intervention effect. However, for stepped wedge trials, which have been claimed by many researchers to have a statistical power advantage over the parallel cluster randomised trial, the minimum number of clusters required has not been investigated. We conducted a simulation study where we considered the most commonly used methods suggested in the literature to analyse cross-sectional stepped wedge cluster randomised trial data. We compared the per cent bias, the type I error rate and power of these methods in a stepped wedge trial setting with a binary outcome, where there are few clusters available and when the appropriate adjustment for a time trend is made, which by design may be confounding the intervention effect. We found that the generalised linear mixed modelling approach is the most consistent when few clusters are available. We also found that none of the common analysis methods for stepped wedge trials were both unbiased and maintained a 5% type I error rate when there were only three clusters. Of the commonly used analysis approaches, we recommend the generalised linear mixed model for small stepped wedge trials with binary outcomes. We also suggest that in a stepped wedge design with three steps, at least two clusters be randomised at each step, to ensure that the intervention effect estimator maintains the nominal 5% significance level and is also reasonably unbiased.

The design and implementation of a study to investigate the effectiveness of community vs hospital eye service follow-up for patients with neovascular age-related macular degeneration with quiescent disease

PubMed Central

Taylor, J; Scott, L J; Rogers, C A; Muldrew, A; O'Reilly, D; Wordsworth, S; Mills, N; Hogg, R; Violato, M; Harding, S P; Peto, T; Townsend, D; Chakravarthy, U; Reeves, B C

2016-01-01

Introduction Standard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions. Methods The Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group. The primary outcome is a participant's judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists. Discussion This trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial. PMID:26449197

The design and implementation of a study to investigate the effectiveness of community vs hospital eye service follow-up for patients with neovascular age-related macular degeneration with quiescent disease.

PubMed

Taylor, J; Scott, L J; Rogers, C A; Muldrew, A; O'Reilly, D; Wordsworth, S; Mills, N; Hogg, R; Violato, M; Harding, S P; Peto, T; Townsend, D; Chakravarthy, U; Reeves, B C

2016-01-01

IntroductionStandard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.MethodsThe Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant's judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.DiscussionThis trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.

Ensuring Quality in AFRINEST and SATT

PubMed Central

2013-01-01

Background: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. Methods: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Conclusions: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials’ results. PMID:23945575

Robust inference for responder analysis: Innovative clinical trial design using a minimum p-value approach.

PubMed

Lin, Yunzhi

2016-08-15

Responder analysis is in common use in clinical trials, and has been described and endorsed in regulatory guidance documents, especially in trials where "soft" clinical endpoints such as rating scales are used. The procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. However, two major issues arise: 1) such dichotomized outcomes are inefficient in terms of using the information available and can seriously reduce the power of the study; and 2) the results of clinical trials depend considerably on the response cutoff chosen, yet in many disease areas there is no consensus as to what is the most appropriate cutoff. This article addresses these two issues, offering a novel approach for responder analysis that could both improve the power of responder analysis and explore different responder cutoffs if an agreed-upon common cutoff is not present. Specifically, we propose a statistically rigorous clinical trial design that pre-specifies multiple tests of responder rates between treatment groups based on a range of pre-specified responder cutoffs, and uses the minimum of the p-values for formal inference. The critical value for hypothesis testing comes from permutation distributions. Simulation studies are carried out to examine the finite sample performance of the proposed method. We demonstrate that the new method substantially improves the power of responder analysis, and in certain cases, yields power that is approaching the analysis using the original continuous (or ordinal) measure.

Patient engagement--what works?

PubMed

Coulter, Angela

2012-01-01

The recent focus on patient engagement acknowledges that patients have an important role to play in their own health care. This includes reading, understanding and acting on health information (health literacy), working together with clinicians to select appropriate treatments or management options (shared decision making), and providing feedback on health care processes and outcomes (quality improvement). Various interventions designed to help patients play an effective role have been evaluated in trials and systematic reviews. This article outlines the evidence in support of the most promising interventions.

Modified Reporting of Positive Urine Cultures to Reduce Inappropriate Treatment of Asymptomatic Bacteriuria Among Nonpregnant, Noncatheterized Inpatients: A Randomized Controlled Trial.

PubMed

Daley, Peter; Garcia, David; Inayatullah, Raheel; Penney, Carla; Boyd, Sarah

2018-05-28

DESIGNWe conducted a randomized, parallel, unblinded, superiority trial of a laboratory reporting intervention designed to reduce antibiotic treatment of asymptomatic bacteriuria (ASB).METHODSResults of positive urine cultures from 110 consecutive inpatients at 2 urban acute-care hospitals were randomized to standard report (control) or modified report (intervention). The standard report included bacterial count, bacterial identification, and antibiotic susceptibility information including drug dosage and cost. The modified report stated: "This POSITIVE urine culture may represent asymptomatic bacteriuria or urinary tract infection. If urinary tract infection is suspected clinically, please call the microbiology laboratory … for identification and susceptibility results." We used the following exclusion criteria: age <18 years, pregnancy, presence of an indwelling urinary catheter, samples from patients already on antibiotics, neutropenia, or admission to an intensive care unit. The primary efficacy outcome was the proportion of appropriate antibiotic therapy prescribed.RESULTSAccording to our intention-to-treat (ITT) analysis, the proportion of appropriate treatment (urinary tract infection treated plus ASB not treated) was higher in the modified arm than in the standard arm: 44 of 55 (80.0%) versus 29 of 55 (52.7%), respectively (absolute difference, -27.3%; RR, 0.42; P = .002; number needed to report for benefit, 3.7).CONCLUSIONSModified reporting resulted in a significant reduction in inappropriate antibiotic treatment without an increase in adverse events. Safety should be further assessed in a large effectiveness trial before implementationTRIAL REGISTRATION. clinicaltrials.gov#NCT02797613Infect Control Hosp Epidemiol 2018;1-6.

'We all want to succeed, but we've also got to be realistic about what is happening': an ethnographic study of relationships in trial oversight and their impact.

PubMed

Daykin, Anne; Selman, Lucy E; Cramer, Helen; McCann, Sharon; Shorter, Gillian W; Sydes, Matthew R; Gamble, Carrol; Macefield, Rhiannon; Lane, J Athene; Shaw, Alison

2017-12-22

The oversight and conduct of a randomised controlled trial involves several stakeholders, including a Trial Steering Committee (TSC), Trial Management Group (TMG), Data Monitoring Committee (DMC), funder and sponsor. We aimed to examine how the relationships between these stakeholders affect the trial oversight process and its rigour, to inform future revision of Good Clinical Practice guidelines. Using an ethnographic study design, we observed the oversight processes of eight trials and conducted semi-structured interviews with members of the trials' TSCs and TMGs, plus other relevant informants, including sponsors and funders of trials. Data were analysed thematically, and findings triangulated and integrated to give a multi-perspective account of current oversight practices in the UK. Eight TSC and six TMG meetings from eight trials were observed and audio-recorded, and 66 semi-structured interviews conducted with 52 purposively sampled key informants. Five themes are presented: (1) Collaboration within the TMG and role of the CTU; (2) Collaboration and conflict between oversight committees; (3) Priorities; (4) Communication between trial oversight groups and (5) Power and accountability. There was evidence of collaborative relationships, based on mutual respect, between CTUs, TMGs and TSCs, but also evidence of conflict. Relationships between trial oversight committees were influenced by stakeholders' priorities, both organisational and individual. Good communication following specific, recognised routes played a central role in ensuring that relationships were productive and trial oversight efficient. Participants described the possession of power over trials as a shifting political landscape, and there was lack of clarity regarding the roles and accountability of each committee, the sponsor and funder. Stakeholders' perceptions of their own power over a trial, and the power of others, influenced relationships between those involved in trial oversight. Recent developments in trial design and conduct have been accompanied by changes in roles and relationships between trial oversight groups. Recognising and respecting the value of differing priorities among those involved in running trials is key to successful relationships between committees, funders and sponsors. Clarity regarding appropriate lines of communication, roles and accountability is needed. We present 10 evidence-based recommendations to inform updates to international trial guidance, particularly the Medical Research Council guidelines.

Harms, benefits, and the nature of interventions in pragmatic clinical trials.

PubMed

Ali, Joseph; Andrews, Joseph E; Somkin, Carol P; Rabinovich, C Egla

2015-10-01

To produce evidence capable of informing healthcare decision making at all critical levels, pragmatic clinical trials are diverse both in terms of the type of intervention (medical, behavioral, and/or technological) and the target of intervention (patients, clinicians, and/or healthcare system processes). Patients and clinicians may be called on to participate as designers, investigators, intermediaries, or subjects of pragmatic clinical trials. Other members of the healthcare team, as well as the healthcare system itself, also may be affected directly or indirectly before, during, or after study implementation. This diversity in the types and targets of pragmatic clinical trial interventions has brought into focus the need to consider whether existing ethics and regulatory principles, policies, and procedures are appropriate for pragmatic clinical trials. Specifically, further examination is needed to identify how the types and targets of pragmatic clinical trial interventions may influence the assessment of net potential risk, understood as the balance of potential harms and benefits. In this article, we build on scholarship seeking to align ethics and regulatory requirements with potential research risks and propose an approach to the assessment of net risks that is sensitive to the diverse nature of pragmatic clinical trial interventions. We clarify the potential harms, burdens, benefits, and advantages of common types of pragmatic clinical trial interventions and discuss implications for patients, clinicians, and healthcare systems. © The Author(s) 2015.

Clinical Validation Trial of a Diagnostic for Ebola Zaire Antigen Detection: Design Rationale and Challenges to Implementation

PubMed Central

Schieffelin, John; Moses, Lina M; Shaffer, Jeffrey; Goba, Augustine; Grant, Donald S

2015-01-01

The current Ebola outbreak in West Africa has affected more people than all previous outbreaks combined. The current diagnostic method of choice, quantitative polymerase chain reaction, requires specialized conditions as well as specially trained technicians. Insufficient testing capacity has extended the time from sample collection to results. These delays have led to further delays in the transfer and treatment to Ebola Treatment Units. A sensitive and specific point-of-care device that could be used reliably in low resource settings by healthcare workers with minimal training would increase the efficiency of triage and appropriate transfer of care. This article describes a study designed to validate the sensitivity and specificity of the ReEBOVTM RDT using venous whole blood and capillary blood obtained via fingerprick. We present the scientific and clinical rationale for the decisions made in the design of a diagnostic validation study to be conducted in an outbreak setting. The multi-site strategy greatly complicated implementation. In addition, a decrease in cases in one geographic area along with a concomitant increase in other areas made site selection challenging. Initiation of clinical trials during rapidly evolving outbreaks requires significant cooperation on a national level between research teams implementing studies and clinical care providers. Coordination and streamlining of approval process is essential if trials are to be implemented in a timely fashion. PMID:26768566

The trials methodological research agenda: results from a priority setting exercise

PubMed Central

2014-01-01

Background Research into the methods used in the design, conduct, analysis, and reporting of clinical trials is essential to ensure that effective methods are available and that clinical decisions made using results from trials are based on the best available evidence, which is reliable and robust. Methods An on-line Delphi survey of 48 UK Clinical Research Collaboration registered Clinical Trials Units (CTUs) was undertaken. During round one, CTU Directors were asked to identify important topics that require methodological research. During round two, their opinion about the level of importance of each topic was recorded, and during round three, they were asked to review the group’s average opinion and revise their previous opinion if appropriate. Direct reminders were sent to maximise the number of responses at each round. Results are summarised using descriptive methods. Results Forty one (85%) CTU Directors responded to at least one round of the Delphi process: 25 (52%) responded in round one, 32 (67%) responded in round two, 24 (50%) responded in round three. There were only 12 (25%) who responded to all three rounds and 18 (38%) who responded to both rounds two and three. Consensus was achieved amongst CTU Directors that the top three priorities for trials methodological research were ‘Research into methods to boost recruitment in trials’ (considered the highest priority), ‘Methods to minimise attrition’ and ‘Choosing appropriate outcomes to measure’. Fifty other topics were included in the list of priorities and consensus was reached that two topics, ‘Radiotherapy study designs’ and ‘Low carbon trials’, were not priorities. Conclusions This priority setting exercise has identified the research topics felt to be most important to the key stakeholder group of Directors of UKCRC registered CTUs. The use of robust methodology to identify these priorities will help ensure that this work informs the trials methodological research agenda, with a focus on topics that will have most impact and relevance. PMID:24456928

Feasibility and acceptability of a decision aid designed for people facing advanced or terminal illness: a pilot randomized trial.

PubMed

Matlock, Dan D; Keech, Tarah A E; McKenzie, Marlene B; Bronsert, Michael R; Nowels, Carolyn T; Kutner, Jean S

2014-02-01

Patients nearing the end of their lives face an array of difficult decisions. This study was designed to assess the feasibility and acceptability of a decision aid (DA) designed for patients facing advanced or terminal illness. We conducted a pilot randomized clinical trial of Health Dialog's Looking Ahead: choices for medical care when you're seriously ill DA (booklet and DVD) applied to patients on a hospital-based palliative care (PC) service. University of Colorado Hospital - December 2009 and May 2010. All adult, English-speaking patients or their decision makers were potentially eligible. Patients were not approached if they were in isolation, did not speak English or if any provider felt that they were not appropriate because of issues such as family conflict or actively dying. All participants received a standard PC consultation. Participants in the intervention arm also received a copy of the DA. Measurements Primary outcomes included decision conflict and knowledge. Participants in the intervention arm also completed an acceptability questionnaire and qualitative exit interviews. Of the 239 patients or decision makers, 51(21%) enrolled in the trial. The DA had no significant effect on decision conflict or knowledge. Exit interviews indicated it was acceptable and empowering, although they wished they had access to the DA earlier. While the DA was acceptable, feasibility was limited by late-life illness challenges. Future trials of this DA should be performed on patients earlier in their illness trajectory and should include additional outcome measures such as self-efficacy and confidence. © 2011 John Wiley & Sons Ltd.

Rationale and design of the HOME trial: A pragmatic randomized controlled trial of home-based human papillomavirus (HPV) self-sampling for increasing cervical cancer screening uptake and effectiveness in a U.S. healthcare system.

PubMed

Winer, Rachel L; Tiro, Jasmin A; Miglioretti, Diana L; Thayer, Chris; Beatty, Tara; Lin, John; Gao, Hongyuan; Kimbel, Kilian; Buist, Diana S M

2018-01-01

Women who delay or do not attend Papanicolaou (Pap) screening are at increased risk for cervical cancer. Trials in countries with organized screening programs have demonstrated that mailing high-risk (hr) human papillomavirus (HPV) self-sampling kits to under-screened women increases participation, but U.S. data are lacking. HOME is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system to compare two programmatic approaches for increasing cervical cancer screening uptake and effectiveness in under-screened women (≥3.4years since last Pap) aged 30-64years: 1) usual care (annual patient reminders and ad hoc outreach by clinics) and 2) usual care plus mailed hrHPV self-screening kits. Over 2.5years, eligible women were identified through electronic medical record (EMR) data and randomized 1:1 to the intervention or control arm. Women in the intervention arm were mailed kits with pre-paid envelopes to return samples to the central clinical laboratory for hrHPV testing. Results were documented in the EMR to notify women's primary care providers of appropriate follow-up. Primary outcomes are detection and treatment of cervical neoplasia. Secondary outcomes are cervical cancer screening uptake, abnormal screening results, and women's experiences and attitudes towards hrHPV self-sampling and follow-up of hrHPV-positive results (measured through surveys and interviews). The trial was designed to evaluate whether a programmatic strategy incorporating hrHPV self-sampling is effective in promoting adherence to the complete screening process (including follow-up of abnormal screening results and treatment). The objective of this report is to describe the rationale and design of this pragmatic trial. Copyright © 2017 Elsevier Inc. All rights reserved.

Determinants of response and resistance to cytotoxics.

PubMed

Rosell, Rafael; Monzó, Mariano; Alberola, Vicente; Taron, Miquel; Barnadas, Agustin; Sánchez, Jose Miguel; Manzano, Jose Luis; Sanchez, José Javier

2002-02-01

There is an underlying feeling in the oncology community that chemotherapy has reached a therapeutic "glass ceiling" in non-small cell lung cancer, and that we will never attain the acceptable survival rates that are just beyond our reach. Multiple clinical trials have tested doublets, triplets, and sequential chemotherapy in what is often regarded as a futile attempt to break through this ceiling. Recent large randomized trials have not shown that any of these combinations is superior to any of the others. Nevertheless, the analysis of DNA and RNA from patients' serum can permit us to assess genes that may be specific targets of certain cytotoxic agents and others that may be markers of multidrug resistance. With this information, we will hopefully be able to create guidelines for individualized chemotherapy. With this in mind, the Spanish Lung Cancer Group has designed a trial to test the involvement of various genes in resistance to gemcitabine and cisplatin. With the gene corral that will emerge from this trial, we will create an up-front diagnostic test for selecting the most appropriate gemcitabine plus cisplatin regimen for the treatment of non-small cell lung cancer.

Exploring recruitment issues in stroke research: a qualitative study of nurse researchers' experiences.

PubMed

Boxall, Leigh; Hemsley, Anthony; White, Nicola

2016-05-01

To explore the practice of experienced stroke nurse researchers to understand the issues they face in recruiting participants. Participant recruitment is one of the greatest challenges in conducting clinical research, with many trials failing due to recruitment problems. Stroke research is a particularly difficult area in which to recruit; however various strategies can improve participation. Analysis revealed three main types of problems for recruiting participants to stroke research: those related to patients, those related to the nurse researcher, and those related to the study itself. Impairments affecting capacity to consent, the acute recruitment time frame of most stroke trials, paternalism by nurse researchers, and low public awareness were especially pertinent. The disabling nature of a stroke, which often includes functional and cognitive impairments, and the acute stage of illness at which patients are appropriate for many trials, make recruiting patients particularly complex and challenging. An awareness of the issues surrounding the recruitment of stroke patients may help researchers in designing and conducting trials. Future work is needed to address the complexities of obtaining informed consent when patient capacity is compromised.

Developing core outcome sets for clinical trials: issues to consider

PubMed Central

2012-01-01

The selection of appropriate outcomes or domains is crucial when designing clinical trials in order to compare directly the effects of different interventions in ways that minimize bias. If the findings are to influence policy and practice then the chosen outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set, which should be measured and reported, as a minimum, in all trials for a specific clinical area. Accumulating work in this area has identified the need for general guidance on the development of core outcome sets. Key issues to consider in the development of a core outcome set include its scope, the stakeholder groups to involve, choice of consensus method and the achievement of a consensus. PMID:22867278

Selenium and Vitamin E for Prostate Cancer: Post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) Status

PubMed Central

Ledesma, Mark C; Jung-Hynes, Brittney; Schmit, Travis L; Kumar, Raj; Mukhtar, Hasan; Ahmad, Nihal

2011-01-01

Various formulations of selenium and vitamin E, both essential human dietary components, have been shown to possess a therapeutic and preventive effect against prostate cancer. Fortuitous results of clinical trials also implied a risk-reduction effect of selenium and vitamin E supplements. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), using oral selenium and vitamin E supplementation in disease-free volunteers, was designed to test a prostate cancer chemoprevention hypothesis. SELECT was terminated early because of both safety concerns and negative data for the formulations and doses given. Here, we review and discuss the studies done before and since the inception of SELECT, as well as the parameters of the trial itself. We believe that there is a lack of appropriate in vivo preclinical studies on selenium and vitamin E despite many promising in vitro studies on these agents. It seems that the most effective doses and formulations of these agents for prostate cancer chemoprevention have yet to be tested. Also, improved understanding of selenium and vitamin E biology may facilitate the discovery of these doses and formulations. PMID:20882260

A study to assess whether fixed-width beam walking provides sufficient challenge to assess balance ability across lower limb prosthesis users.

PubMed

Sawers, Andrew; Hafner, Brian J

2018-04-01

To evaluate the feasibility of fixed-width beam walking for assessing balance in lower limb prosthesis users. Cross-sectional. Laboratory. Lower limb prosthesis users. Participants attempted 10 walking trials on three fixed-width beams (18.6, 8.60, and 4.01 wide; 5.5 m long; 3.8 cm high). Beam-walking performance was quantified using the distance walked to balance failure. Heuristic rules applied to each participant's beam-walking distance to classify each beam as "too easy," "too hard," or "appropriately challenging" and determine whether any single beam provided an appropriate challenge to all participants. The number of trials needed to achieve stable beam-walking performance was quantified for appropriately challenging beams by identifying the last inflection point in the slope of each participant's trial-by-trial cumulative performance record. In all, 30 unilateral lower limb prosthesis users participated in the study. Each of the fixed-width beams was either too easy or too hard for at least 33% of the sample. Thus, no single beam was appropriately challenging for all participants. Beam-walking performance was stable by trial 8 for all participants and by trial 6 for 90% of participants. There was no significant difference in the number of trials needed to achieve stable performance among beams ( P = 0.74). Results suggest that a clinical beam-walking test would require multiple beams to evaluate balance across a range of lower limb prosthesis users, emphasizing the need for adaptive or progressively challenging balance tests. While the administrative burden of a multiple-beam balance test may limit clinical feasibility, alternatives to ease this administrative burden are proposed.

Parents' perceived obstacles to pediatric clinical trial participation: Findings from the clinical trials transformation initiative.

PubMed

Greenberg, Rachel G; Gamel, Breck; Bloom, Diane; Bradley, John; Jafri, Hasan S; Hinton, Denise; Nambiar, Sumathi; Wheeler, Chris; Tiernan, Rosemary; Smith, P Brian; Roberts, Jamie; Benjamin, Daniel K

2018-03-01

Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation. Twenty-four parents whose children had been offered the opportunity to participate in a clinical trial were interviewed: 19 whose children had participated in at least 1 clinical trial and 5 who had declined participation in any trial. Each study aspect, from the initial explanation of the study to the end of the study, can affect the willingness of parents to consent to the proposed study and future studies. Establishing trust, appropriate timing, a transparent discussion of risks and benefits oriented to the layperson, and providing motivation for children to participate were key factors that impacted parents' decisions. In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials.

Scientific evidence and research in antimicrobial stewardship.

PubMed

Almirante, Benito; Garnacho-Montero, José; Pachón, Jerónimo; Pascual, Álvaro; Rodríguez-Baño, Jesús

2013-09-01

Evaluating the impact of antibiotic stewardship programs is challenging. There is evidence that they are effective in terms of reducing the consumption and cost of antibiotics, although establishing their impact on antimicrobial resistance (beyond restrictive policies in outbreaks caused by specific antimicrobial resistant organisms) and clinical outcomes is more difficult. Proper definitions of exposure and outcome variables, the use of advanced and appropriate statistical analyses and well-designed quasi-experimental studies would more accurately support the conclusions. Cluster randomized trials should be used whenever possible and appropriate, although the limitations of this approach should also be acknowledged. These issues are reviewed in this paper. We conclude that there are good research opportunities in the field of antibiotic stewardship. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Inadequacy of ethical conduct and reporting of stepped wedge cluster randomized trials: Results from a systematic review.

PubMed

Taljaard, Monica; Hemming, Karla; Shah, Lena; Giraudeau, Bruno; Grimshaw, Jeremy M; Weijer, Charles

2017-08-01

Background/aims The use of the stepped wedge cluster randomized design is rapidly increasing. This design is commonly used to evaluate health policy and service delivery interventions. Stepped wedge cluster randomized trials have unique characteristics that complicate their ethical interpretation. The 2012 Ottawa Statement provides comprehensive guidance on the ethical design and conduct of cluster randomized trials, and the 2010 CONSORT extension for cluster randomized trials provides guidelines for reporting. Our aims were to assess the adequacy of the ethical conduct and reporting of stepped wedge trials to date, focusing on research ethics review and informed consent. Methods We conducted a systematic review of stepped wedge cluster randomized trials in health research published up to 2014 in English language journals. We extracted details of study intervention and data collection procedures, as well as reporting of research ethics review and informed consent. Two reviewers independently extracted data from each trial; discrepancies were resolved through discussion. We identified the presence of any research participants at the cluster level and the individual level. We assessed ethical conduct by tabulating reporting of research ethics review and informed consent against the presence of research participants. Results Of 32 identified stepped wedge trials, only 24 (75%) reported review by a research ethics committee, and only 16 (50%) reported informed consent from any research participants-yet, all trials included research participants at some level. In the subgroup of 20 trials with research participants at cluster level, only 4 (20%) reported informed consent from such participants; in 26 trials with individual-level research participants, only 15 (58%) reported their informed consent. Interventions (regardless of whether targeting cluster- or individual-level participants) were delivered at the group level in more than two-thirds of trials; nine trials (28%) had no identifiable data collected from any research participants. Overall, only three trials (9%) indicated that a waiver of consent had been granted by a research ethics committee. When considering the combined requirement of research ethics review and informed consent (or a waiver), only one in three studies were compliant. Conclusion The ethical conduct and reporting of key ethical protections in stepped wedge trials, namely, research ethics review and informed consent, are inadequate. We recommend that stepped wedge trials be classified as research and reviewed and approved by a research ethics committee. We also recommend that researchers appropriately identify research participants (which may include health professionals), seek informed consent or appeal to an ethics committee for a waiver of consent, and include explicit details of research ethics approval and informed consent in the trial report.

Translation failure and medical reversal: Two sides to the same coin.

PubMed

Prasad, Vinay

2016-01-01

Translation failure occurs when the results of preclinical, observational and/or early phase studies fail to predict the results of well done (i.e. appropriately controlled, adequately powered, and properly conducted) phase III or randomised clinical trials. Some failures occur when promising basic science findings fail to replicate in human studies, while others happen when promising uncontrolled trial data show an exaggerated effect that vanishes in the setting of a randomised trial. Medical reversals occur when the results of preclinical, observational and/or early phase studies fail to predict the results of subsequent randomized clinical trials, but the practice has already gained widespread acceptance. Oncologic examples include bevacizumab and the use of autologous stem cell transplant in metastatic breast cancer. In a well-intentioned effort to reduce the rate of translation failure, oncologists must be careful that changes to regulatory processes and clinical trial design do not actually work to increase the approval of ineffective compounds. By trying to cure translation failure, we should be careful to avoid medical reversal. The rise of surrogate end-points and role of hard-wired bias in oncology trials suggest that we may be currently ignoring the simple fact that translation failure and medical reversal are two sides to the same coin. Published by Elsevier Ltd.

Addressing standards of care in resource-limited settings.

PubMed

Dawson, Liza; Klingman, Karin L; Marrazzo, Jeanne

2014-01-01

: The choice between "best-known" standards of care (SOC) or "best available" standards as the control arm in a clinical trial is a fundamental dilemma in clinical research in resource-limited settings (RLS). When the health system is delivering less than an optimal level of care, using highest standard of care in a clinical trial may produce results that cannot be implemented or sustained locally. On the other hand, using interventions that are more feasible in the local setting may involve suboptimal care, and clinical outcomes may be affected. The need for improved standards in health systems in RLS, and the difficulty in securing them, has led many researchers advocate for policy changes at the national or international level to improve clinical care more systemically. SOC decisions in a clinical trial affect the level of benefit provided to study participants and the policy implications of the trial findings. SOC choices should provide high-quality care to help advance the health care system in host countries participating in the trial, but balancing the scientific and ethical objectives of SOC choices is difficult, and there is no single formula for selecting the appropriate SOC. Despite the challenges, well-designed and conducted clinical trials can and should make significant contributions to health systems in RLS.

Emerging therapies in systemic lupus erythematous: from clinical trial to the real life.

PubMed

Zhang, Huza; Chambers, William; Sciascia, Savino; Cuadrado, Maria J

2016-01-01

Systemic lupus erythematous (SLE) is a chronic autoimmune disease characterised by multisystem involvement and a relapsing remitting course. SLE is a highly heterogeneous condition, with wide variations in both the presentation and severity of disease and the biological markers identified. The use of biologics in SLE has lagged behind that of other rheumatological conditions such as rheumatoid arthritis, in part due to the diverse clinical manifestations of SLE, making it difficult to design appropriate trials for novel treatments. As such, broad immunosuppressive treatment regimens are still widely used in SLE. Nevertheless, in recent years, elucidation of some aspects of SLE pathogenesis have allowed the development of therapies targeted at molecular mediators of SLE. This review provides an update of biological available therapies and those currently under development.

Interpersonal competencies: Responsiveness, technique, and training in psychotherapy.

PubMed

Hatcher, Robert L

2015-11-01

Professional practice in psychology is anchored in interpersonal or relational skills. These skills are essential to successful interactions with clients and their families, students, and colleagues. Expertise in these skills is desired and expected for the practicing psychologist. An important but little-studied aspect of interpersonal skills is what Stiles and colleagues (Stiles, Honos-Webb, & Surko, 1998; Stiles, 2009, 2013) have called appropriate responsiveness. In treatment relationships, appropriate responsiveness is the therapist's ability to achieve optimal benefit for the client by adjusting responses to the current state of the client and the interaction. This article was designed to clarify this aspect of responsiveness, showing its links to empathy, illustrating how responsiveness has been detected in controlled clinical trials, discussing how educators and supervisors have worked to enhance students' responsiveness, and considering how appropriate responsiveness has been assessed. The article also discusses the development of skills underlying appropriate responsiveness and the role of stable differences in talent in training of professional psychologists. Notwithstanding other pessimistic reports on psychologists' expertise, demonstrable expertise may exist in the effective, responsive use of these skills in treatment settings. Appropriate responsiveness may be a variety of executive functioning, organizing and guiding the use of many specific competencies. As such it may be a metacompetency, with implications for the design of competency schemes. Key to all of these considerations is the distinction between therapeutic techniques and their responsive use, which involves astute judgment as to when and how to utilize these responses to best effect in the treatment situation. (c) 2015 APA, all rights reserved).

Understanding acceptability of and engagement with Web-based interventions aiming to improve quality of life in cancer survivors: A synthesis of current research.

PubMed

Corbett, Teresa; Singh, Karmpaul; Payne, Liz; Bradbury, Katherine; Foster, Claire; Watson, Eila; Richardson, Alison; Little, Paul; Yardley, Lucy

2018-01-01

This review sought to summarize existing knowledge to inform the development of an online intervention that aims to improve quality of life after cancer treatment. To inform our intervention, we searched for studies relating to Web-based interventions designed to improve quality of life in adults who have completed primary treatment for breast, prostate, and colorectal cancer (as these are 3 of the most common cancers and impact a large number of cancer survivors). We included a variety of study designs (qualitative research, feasibility/pilot trials, randomized trials, and process evaluations) and extracted all available information regarding intervention characteristics, experiences, and outcomes. Data were synthesized as textual (qualitative) data and analyzed by using thematic analysis. Fifty-seven full text articles were assessed for eligibility, and 16 papers describing 9 interventions were analyzed. Our findings suggest that cancer survivors value interventions that offer content specific to their changing needs and are delivered at the right stage of the cancer trajectory. Social networking features do not always provide added benefit, and behavior change techniques need to be implemented carefully to avoid potential negative consequences for some users. Future work should aim to identify appropriate strategies for promoting health behavior change, as well as the optimal stage of cancer survivorship to facilitate intervention delivery. The development of Web-based interventions for cancer survivors requires further exploration to better understand how interventions can be carefully designed to match this group's unique needs and capabilities. User involvement during development may help to ensure that interventions are accessible, perceived as useful, and appropriate for challenges faced at different stages of the cancer survivorship trajectory. Copyright © 2017 John Wiley & Sons, Ltd.

Patient Reported Outcomes (PROs) in Clinical Trials: Is ‘In-Trial’ Guidance Lacking? A Systematic Review

PubMed Central

Kyte, Derek G.; Draper, Heather; Ives, Jonathan; Liles, Clive; Gheorghe, Adrian; Calvert, Melanie

2013-01-01

Background Patient reported outcomes (PROs) are increasingly assessed in clinical trials, and guidelines are available to inform the design and reporting of such trials. However, researchers involved in PRO data collection report that specific guidance on ‘in-trial’ activity (recruitment, data collection and data inputting) and the management of ‘concerning’ PRO data (i.e., data which raises concern for the well-being of the trial participant) appears to be lacking. The purpose of this review was to determine the extent and nature of published guidelines addressing these areas. Methods and Findings Systematic review of 1,362 articles identified 18 eligible papers containing ‘in-trial’ guidelines. Two independent authors undertook a qualitative content analysis of the selected papers. Guidelines presented in each of the articles were coded according to an a priori defined coding frame, which demonstrated reliability (pooled Kappa 0.86–0.97), and validity (<2% residual category coding). The majority of guidelines present were concerned with ‘pre-trial’ activities (72%), for example, outcome measure selection and study design issues, or ‘post-trial’ activities (16%) such as data analysis, reporting and interpretation. ‘In-trial’ guidelines represented 9.2% of all guidance across the papers reviewed, with content primarily focused on compliance, quality control, proxy assessment and reporting of data collection. There were no guidelines surrounding the management of concerning PRO data. Conclusions The findings highlight there are minimal in-trial guidelines in publication regarding PRO data collection and management in clinical trials. No guidance appears to exist for researchers involved with the handling of concerning PRO data. Guidelines are needed, which support researchers to manage all PRO data appropriately and which facilitate unbiased data collection. PMID:23560103

The feasibility of community level interventions for pre-eclampsia in South Asia and Sub-Saharan Africa: a mixed-methods design.

PubMed

Khowaja, Asif Raza; Qureshi, Rahat Najam; Sawchuck, Diane; Oladapo, Olufemi T; Adetoro, Olalekan O; Orenuga, Elizabeth A; Bellad, Mrutyunjaya; Mallapur, Ashalata; Charantimath, Umesh; Sevene, Esperança; Munguambe, Khátia; Boene, Helena Edith; Vidler, Marianne; Bhutta, Zulfiqar A; von Dadelszen, Peter

2016-06-08

Globally, pre-eclampsia and eclampsia are major contributors to maternal and perinatal mortality; of which the vast majority of deaths occur in less developed countries. In addition, a disproportionate number of morbidities and mortalities occur due to delayed access to health services. The Community Level Interventions for Pre-eclampsia (CLIP) Trial aims to task-shift to community health workers the identification and emergency management of pre-eclampsia and eclampsia to improve access and timely care. Literature revealed paucity of published feasibility assessments prior to initiating large-scale community-based interventions. Arguably, well-conducted feasibility studies can provide valuable information about the potential success of clinical trials prior to implementation. Failure to fully understand the study context risks the effective implementation of the intervention and limits the likelihood of post-trial scale-up. Therefore, it was imperative to conduct community-level feasibility assessments for a trial of this magnitude. A mixed methods design guided by normalization process theory was used for this study in Nigeria, Mozambique, Pakistan, and India to explore enabling and impeding factors for the CLIP Trial implementation. Qualitative data were collected through participant observation, document review, focus group discussion and in-depth interviews with diverse groups of community members, key informants at community level, healthcare providers, and policy makers. Quantitative data were collected through health facility assessments, self-administered community health worker surveys, and household demographic and health surveillance. Refer to CLIP Trial feasibility publications in the current and/or forthcoming supplement. Feasibility assessments for community level interventions, particularly those involving task-shifting across diverse regions, require an appropriate theoretical framework and careful selection of research methods. The use of qualitative and quantitative methods increased the data richness to better understand the community contexts. NCT01911494.

Pre-referral rectal artesunate in severe malaria: flawed trial.

PubMed

Hirji, Karim F; Premji, Zulfiqarali G

2011-08-08

Immediate injectable treatment is essential for severe malaria. Otherwise, the afflicted risk lifelong impairment or death. In rural areas of Africa and Asia, appropriate care is often miles away. In 2009, Melba Gomes and her colleagues published the findings of a randomized, placebo-controlled trial of rectal artesunate for suspected severe malaria in such remote areas. Enrolling nearly 18,000 cases, the aim was to evaluate whether, as patients were in transit to a health facility, a pre-referral artesunate suppository blocked disease progression sufficiently to reduce these risks. The affirmative findings of this, the only trial on the issue thus far, have led the WHO to endorse rectal artesunate as a pre-referral treatment for severe malaria. In the light of its public health importance and because its scientific quality has not been assessed for a systematic review, our paper provides a detailed evaluation of the design, conduct, analysis, reporting, and practical features of this trial. We performed a checklist-based and an in-depth evaluation of the trial. The evaluation criteria were based on the CONSORT statement for reporting clinical trials, the clinical trial methodology literature, and practice in malaria research. Our main findings are: The inclusion and exclusion criteria and the sample size justification are not stated. Many clearly ineligible subjects were enrolled. The training of the recruiters does not appear to have been satisfactory. There was excessive between center heterogeneity in design and conduct. Outcome evaluation schedule was not defined, and in practice, became too wide. Large gaps in the collection of key data were evident. Primary endpoints were inconsistently utilized and reported; an overall analysis of the outcomes was not done; analyses of time to event data had major flaws; the stated intent-to-treat analysis excluded a third of the randomized subjects; the design-indicated stratified or multi-variate analysis was not done; many improper subgroups were analyzed in a post-hoc fashion; the analysis and reporting metric was deficient. There are concerns relating to patient welfare at some centers. Exclusion of many cases from data analysis compromised external validity. A bias-controlled reanalysis of available data does not lend support to the conclusions drawn by the authors. This trial has numerous serious deficiencies in design, implementation, and methods of data analysis. Interpretation and manner of reporting are wanting, and the applicability of the findings is unclear. The trial conduct could have been improved to better protect patient welfare. The totality of these problems make it a flawed study whose conclusions remain subject to appreciable doubt.

Clinical trials in palliative care: a systematic review of their methodological characteristics and of the quality of their reporting.

PubMed

Bouça-Machado, Raquel; Rosário, Madalena; Alarcão, Joana; Correia-Guedes, Leonor; Abreu, Daisy; Ferreira, Joaquim J

2017-01-25

Over the past decades there has been a significant increase in the number of published clinical trials in palliative care. However, empirical evidence suggests that there are methodological problems in the design and conduct of studies, which raises questions about the validity and generalisability of the results and of the strength of the available evidence. We sought to evaluate the methodological characteristics and assess the quality of reporting of clinical trials in palliative care. We performed a systematic review of published clinical trials assessing therapeutic interventions in palliative care. Trials were identified using MEDLINE (from its inception to February 2015). We assessed methodological characteristics and describe the quality of reporting using the Cochrane Risk of Bias tool. We retrieved 107 studies. The most common medical field studied was oncology, and 43.9% of trials evaluated pharmacological interventions. Symptom control and physical dimensions (e.g. intervention on pain, breathlessness, nausea) were the palliative care-specific issues most studied. We found under-reporting of key information in particular on random sequence generation, allocation concealment, and blinding. While the number of clinical trials in palliative care has increased over time, methodological quality remains suboptimal. This compromises the quality of studies. Therefore, a greater effort is needed to enable the appropriate performance of future studies and increase the robustness of evidence-based medicine in this important field.

Multiattribute selection of acute stroke imaging software platform for Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) clinical trial.

PubMed

Churilov, Leonid; Liu, Daniel; Ma, Henry; Christensen, Soren; Nagakane, Yoshinari; Campbell, Bruce; Parsons, Mark W; Levi, Christopher R; Davis, Stephen M; Donnan, Geoffrey A

2013-04-01

The appropriateness of a software platform for rapid MRI assessment of the amount of salvageable brain tissue after stroke is critical for both the validity of the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) Clinical Trial of stroke thrombolysis beyond 4.5 hours and for stroke patient care outcomes. The objective of this research is to develop and implement a methodology for selecting the acute stroke imaging software platform most appropriate for the setting of a multi-centre clinical trial. A multi-disciplinary decision making panel formulated the set of preferentially independent evaluation attributes. Alternative Multi-Attribute Value Measurement methods were used to identify the best imaging software platform followed by sensitivity analysis to ensure the validity and robustness of the proposed solution. Four alternative imaging software platforms were identified. RApid processing of PerfusIon and Diffusion (RAPID) software was selected as the most appropriate for the needs of the EXTEND trial. A theoretically grounded generic multi-attribute selection methodology for imaging software was developed and implemented. The developed methodology assured both a high quality decision outcome and a rational and transparent decision process. This development contributes to stroke literature in the area of comprehensive evaluation of MRI clinical software. At the time of evaluation, RAPID software presented the most appropriate imaging software platform for use in the EXTEND clinical trial. The proposed multi-attribute imaging software evaluation methodology is based on sound theoretical foundations of multiple criteria decision analysis and can be successfully used for choosing the most appropriate imaging software while ensuring both robust decision process and outcomes. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Development of World Health Organization (WHO) recommendations for appropriate clinical trial endpoints for next-generation Human Papillomavirus (HPV) vaccines.

PubMed

Prabhu, Malavika; Eckert, Linda O

2016-12-01

The World Health Organization (WHO) serves as a key organization to bring together experts along the continuum of vaccine development and regulatory approval, among its other functions. Using the revision of WHO's guidelines on prophylactic human papillomavirus (HPV) vaccine as an example, we describe the process by which (1) a need to revise the guidelines was identified; (2) a group of stakeholders with complementary expertise and key questions were identified; (3) a scientific review was conducted; (4) consensus on revisions was achieved; (5) guidelines were updated, reviewed widely, and approved. This multi-year process resulted in the consensus that regulatory agencies could consider additional endpoints, such as persistent HPV infection or immune equivalence, depending on the design of the HPV vaccine trials. Updating the guidelines will now accelerate vaccine development, reduce costs of clinical trials, and lead to faster regulatory approval. Copyright © 2016. Published by Elsevier B.V.

Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations.

PubMed

Taylor, Ann M; Phillips, Kristine; Patel, Kushang V; Turk, Dennis C; Dworkin, Robert H; Beaton, Dorcas; Clauw, Daniel J; Gignac, Monique A M; Markman, John D; Williams, David A; Bujanover, Shay; Burke, Laurie B; Carr, Daniel B; Choy, Ernest H; Conaghan, Philip G; Cowan, Penney; Farrar, John T; Freeman, Roy; Gewandter, Jennifer; Gilron, Ian; Goli, Veeraindar; Gover, Tony D; Haddox, J David; Kerns, Robert D; Kopecky, Ernest A; Lee, David A; Malamut, Richard; Mease, Philip; Rappaport, Bob A; Simon, Lee S; Singh, Jasvinder A; Smith, Shannon M; Strand, Vibeke; Tugwell, Peter; Vanhove, Gertrude F; Veasley, Christin; Walco, Gary A; Wasan, Ajay D; Witter, James

2016-09-01

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

A cluster randomised feasibility trial evaluating nutritional interventions in the treatment of malnutrition in care home adult residents.

PubMed

Stow, Ruth; Ives, Natalie; Smith, Christina; Rick, Caroline; Rushton, Alison

2015-09-28

Protein energy malnutrition (PEM) predisposes individuals to disease, delays recovery from illness and reduces quality of life. Care home residents in the United Kingdom are especially vulnerable, with an estimated 30 to 42 % at risk. Evidence for nutritional interventions to address PEM in the care home setting is lacking. Widely used techniques include food-based intervention and/or the use of prescribed oral nutritional supplements. To define outcomes and optimise the design for an adequately powered definitive trial to compare the efficacy of established nutritional interventions in this setting, a cluster randomised feasibility trial with a 6-month intervention was undertaken. Care home residents with or at risk of malnutrition were identified across six UK care home sites from September to December 2013. Homes were cluster randomised to standard care (SC), food-based intervention (FB) or oral nutritional supplement intervention (ONS), for 6 months. Key outcomes were trial feasibility and the acceptability of design, allocated interventions and outcome assessments. Anthropometry, dietary intake, healthcare resource usage and participant-reported outcome measures were assessed at baseline and at 3 and 6 months. All six care homes approached were recruited and retained. Of the 110 residents at risk of malnutrition, 85 % entered the trial, and 68 % completed the 6-month intervention. Pre-specified success criteria for feasibility were met for recruitment and retention, intervention acceptability (resident compliance ≥60 %) and measurement of weight, body mass index (BMI), mid-upper arm circumference and dietary intake (data completeness >80 %). Measurement of handgrip strength and triceps skinfold thickness was not found to be feasible in this population. The 95 % confidence interval (CI) data suggested sensitivity to change in dietary intake for weight, BMI and energy intake between baseline and 3 months when each intervention (FB and ONS) was compared with SC. A definitive trial comparing the efficacy of nutritional support interventions in increasing weight and BMI in malnourished care home residents can be conducted. However, whilst the design was feasible, this trial has highlighted the lack of clinically and patient-relevant outcome measures that are appropriate for use in this setting for both research and clinical practice. In particular, this trial identified a need for a more simple measure of functional status, which considers the limitations of functional tests in the care home population. Current Controlled Trials ISRCTN38047922 , Date assigned: 22 April 2014.

Effects of protein or amino-acid supplementation on the physical growth of young children in low-income countries

PubMed Central

Arsenault, Joanne E; Brown, Kenneth H

2017-01-01

Abstract Child growth stunting is common in low-income countries, possibly due to insufficient protein intakes. Most previous studies have concluded that children’s protein intakes are adequate in relation to estimated requirements, but these studies did not consider issues of protein digestibility and effects of infection on dietary protein utilization. Using an alternative approach to assess the possible role of protein inadequacy in children’s growth restriction, the results of 18 intervention trials in which supplementary protein or amino acids were provided to children ages 6–35 months and growth outcomes were reviewed. Eight studies conducted in hospitalized children recovering from acute malnutrition found that the recommended protein intake levels for healthy children supported normal growth rates, but higher intakes were needed for accelerated rates of “catch-up” growth. Ten community-based studies did not demonstrate a consistent benefit of supplemental protein on children’s growth. However, weaknesses in the study designs limit the conclusions that can be drawn from these studies, and additional appropriately designed trials are needed to answer this question definitively. Recommendations for optimizing future study designs are provided herein. PMID:28938793

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design.

PubMed

Schwartz, Lauren M; Halloran, M Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M; Victor, John C

2017-01-03

The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Three-in-one weight, height and body mass index charts for children and adults.

PubMed

Elizabeth, K E; Muraleedharan, Manu

2003-08-01

The aim of the study was to develop four appropriate three-in-one weight, height and built in body mass index (BMI) charts, for under-fives, 0-5-year-olds, > 5-10-year-olds, > 10-18-year-olds, and adults and to delineate the normal range, underweight, overweight and obesity on the above charts. Four different charts were designed for the various age groups as indicated above. Height was made available on the x-axis, weight on the y-axis, and corresponding BMI values on the right margin. Shading of the normal range to denote the health path and marking of the cut-off curves to denote normal status, overweight, and obesity were done selecting appropriate round figures to suit both sexes in accordance with the International Obesity Task Force (IOTF) recommendations for the various age groups. Field trials were done on appropriate subjects belonging to various age groups. 500 in each group with equal male to female ratio. The field trials showed that all the studied subjects belonging to both sexes came within the purview of the chart and those with normal nutritional status, underweight, overweight, and obesity could easily be identified looking at the chart without doing any further calculation. Early intervention also could be advised as the chart could demonstrate how much weight should be gained or reduced to come within the health path. In conclusion, the charts are applicable to both sexes and are user friendly. These are appropriate for general screening of nutritional status and to determine underweight, overweight, and obesity from birth to adulthood. They give a visual display of the ideal health path with respect to weight, height, and BMI and the adjustment in weight required to reach the normal range.

Use of behavioral economics and social psychology to improve treatment of acute respiratory infections (BEARI): rationale and design of a cluster randomized controlled trial [1RC4AG039115-01]--study protocol and baseline practice and provider characteristics.

PubMed

Persell, Stephen D; Friedberg, Mark W; Meeker, Daniella; Linder, Jeffrey A; Fox, Craig R; Goldstein, Noah J; Shah, Parth D; Knight, Tara K; Doctor, Jason N

2013-06-27

Inappropriate antibiotic prescribing for nonbacterial infections leads to increases in the costs of care, antibiotic resistance among bacteria, and adverse drug events. Acute respiratory infections (ARIs) are the most common reason for inappropriate antibiotic use. Most prior efforts to decrease inappropriate antibiotic prescribing for ARIs (e.g., educational or informational interventions) have relied on the implicit assumption that clinicians inappropriately prescribe antibiotics because they are unaware of guideline recommendations for ARIs. If lack of guideline awareness is not the reason for inappropriate prescribing, educational interventions may have limited impact on prescribing rates. Instead, interventions that apply social psychological and behavioral economic principles may be more effective in deterring inappropriate antibiotic prescribing for ARIs by well-informed clinicians. The Application of Behavioral Economics to Improve the Treatment of Acute Respiratory Infections (BEARI) Trial is a multisite, cluster-randomized controlled trial with practice as the unit of randomization. The primary aim is to test the ability of three interventions based on behavioral economic principles to reduce the rate of inappropriate antibiotic prescribing for ARIs. We randomized practices in a 2 × 2 × 2 factorial design to receive up to three interventions for non-antibiotic-appropriate diagnoses: 1) Accountable Justifications: When prescribing an antibiotic for an ARI, clinicians are prompted to record an explicit justification that appears in the patient electronic health record; 2) Suggested Alternatives: Through computerized clinical decision support, clinicians prescribing an antibiotic for an ARI receive a list of non-antibiotic treatment choices (including prescription options) prior to completing the antibiotic prescription; and 3) Peer Comparison: Each provider's rate of inappropriate antibiotic prescribing relative to top-performing peers is reported back to the provider periodically by email. We enrolled 269 clinicians (practicing attending physicians or advanced practice nurses) in 49 participating clinic sites and collected baseline data. The primary outcome is the antibiotic prescribing rate for office visits with non-antibiotic-appropriate ARI diagnoses. Secondary outcomes will examine antibiotic prescribing more broadly. The 18-month intervention period will be followed by a one year follow-up period to measure persistence of effects after interventions cease. The ongoing BEARI Trial will evaluate the effectiveness of behavioral economic strategies in reducing inappropriate prescribing of antibiotics. ClinicalTrials.gov: NCT01454947.

Design, rationale, and baseline characteristics of a cluster randomized controlled trial of pay for performance for hypertension treatment: study protocol

PubMed Central

2011-01-01

Background Despite compelling evidence of the benefits of treatment and well-accepted guidelines for treatment, hypertension is controlled in less than one-half of United States citizens. Methods/design This randomized controlled trial tests whether explicit financial incentives promote the translation of guideline-recommended care for hypertension into clinical practice and improve blood pressure (BP) control in the primary care setting. Using constrained randomization, we assigned 12 Veterans Affairs hospital outpatient clinics to four study arms: physician-level incentive; group-level incentive; combination of physician and group incentives; and no incentives (control). All participants at the hospital (cluster) were assigned to the same study arm. We enrolled 83 full-time primary care physicians and 42 non-physician personnel. The intervention consisted of an educational session about guideline-recommended care for hypertension, five audit and feedback reports, and five disbursements of incentive payments. Incentive payments rewarded participants for chart-documented use of guideline-recommended antihypertensive medications, BP control, and appropriate responses to uncontrolled BP during a prior four-month performance period over the 20-month intervention. To identify potential unintended consequences of the incentives, the study team interviewed study participants, as well as non-participant primary care personnel and leadership at study sites. Chart reviews included data collection on quality measures not related to hypertension. To evaluate the persistence of the effect of the incentives, the study design includes a washout period. Discussion We briefly describe the rationale for the interventions being studied, as well as the major design choices. Rigorous research designs such as the one described here are necessary to determine whether performance-based payment arrangements such as financial incentives result in meaningful quality improvements. Trial Registration http://www.clinicaltrials.gov NCT00302718 PMID:21967830

Comparison between self-formulation and compounded-formulation dexamethasone mouth rinse for oral lichen planus: a pilot, randomized, cross-over trial.

PubMed

Hambly, Jessica L; Haywood, Alison; Hattingh, Laetitia; Nair, Raj G

2017-08-01

There is a lack of appropriate, commercially-available topical corticosteroid formulations for use in oral lichen planus (OLP) and oral lichenoid reaction. Current therapy includes crushing a dexamethasone tablet and mixing it with water for use as a mouth rinse. This formulation is unpleasant esthetically and to use in the mouth, as it is a bitter and gritty suspension, resulting in poor compliance. Thus, the present study was designed to formulate and pilot an effective, esthetically-pleasing formulation. A single-blinded, cross-over trial was designed with two treatment arms. Patients were monitored for 7 weeks. Quantitative and qualitative data was assessed using VAS, numeric pain scales, the Treatment Satisfaction Questionnaire for Medication-9, and thematic analysis to determine primary patient-reported outcomes, including satisfaction, compliance, quality of life, and symptom relief. Nine patients completed the pilot trial. Data analysis revealed the new compounded formulation to be superior to existing therapy due to its convenience, positive contribution to compliance, patient-perceived faster onset of action, and improved symptom relief. Topical dexamethasone is useful in the treatment of OLP. When carefully formulated into a compounded mouth rinse, it improves patient outcomes. © 2016 John Wiley & Sons Australia, Ltd.

Data management in clinical research: An overview

PubMed Central

Krishnankutty, Binny; Bellary, Shantala; Kumar, Naveen B.R.; Moodahadu, Latha S.

2012-01-01

Clinical Data Management (CDM) is a critical phase in clinical research, which leads to generation of high-quality, reliable, and statistically sound data from clinical trials. This helps to produce a drastic reduction in time from drug development to marketing. Team members of CDM are actively involved in all stages of clinical trial right from inception to completion. They should have adequate process knowledge that helps maintain the quality standards of CDM processes. Various procedures in CDM including Case Report Form (CRF) designing, CRF annotation, database designing, data-entry, data validation, discrepancy management, medical coding, data extraction, and database locking are assessed for quality at regular intervals during a trial. In the present scenario, there is an increased demand to improve the CDM standards to meet the regulatory requirements and stay ahead of the competition by means of faster commercialization of product. With the implementation of regulatory compliant data management tools, CDM team can meet these demands. Additionally, it is becoming mandatory for companies to submit the data electronically. CDM professionals should meet appropriate expectations and set standards for data quality and also have a drive to adapt to the rapidly changing technology. This article highlights the processes involved and provides the reader an overview of the tools and standards adopted as well as the roles and responsibilities in CDM. PMID:22529469

Should in-line filters be used in peripheral intravenous catheters to prevent infusion-related phlebitis? A systematic review of randomized controlled trials.

PubMed

Niël-Weise, Barbara S; Stijnen, Theo; van den Broek, Peterhans J

2010-06-01

In this systematic review, we assessed the effect of in-line filters on infusion-related phlebitis associated with peripheral IV catheters. The study was designed as a systematic review and meta-analysis of randomized controlled trials. We used MEDLINE and the Cochrane Controlled Trial Register up to August 10, 2009. Two reviewers independently assessed trial quality and extracted data. Data on phlebitis were combined when appropriate, using a random-effects model. The impact of the risk of phlebitis in the control group (baseline risk) on the effect of in-line filters was studied by using meta-regression based on the bivariate meta-analysis model. The quality of the evidence was determined by using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method. Eleven trials (1633 peripheral catheters) were included in this review to compare the effect of in-line filters on the incidence of phlebitis in hospitalized patients. Baseline risks across trials ranged from 23% to 96%. Meta-analysis of all trials showed that in-line filters reduced the risk of infusion-related phlebitis (relative risk, 0.66; 95% confidence interval, 0.43-1.00). This benefit, however, is very uncertain, because the trials had serious methodological shortcomings and meta-analysis revealed marked unexplained statistical heterogeneity (P < 0.0000, I(2) = 90.4%). The estimated benefit did not depend on baseline risk. In-line filters in peripheral IV catheters cannot be recommended routinely, because evidence of their benefit is uncertain.

Fallback level concepts for conventional and by-wire automotive brake systems

NASA Astrophysics Data System (ADS)

Retzer, H.; Mishra, R.; Ball, A.; Schmidt, K.

2012-05-01

Brake-by-wire represents the replacement of traditional brake components such as pumps, hoses, fluids, brake boosters, and master cylinders by electronic sensors and actuators. The different design of these brake concepts poses new challenges for the automotive industry with regard to availability and fallback levels in comparison to standard conventional brake systems. This contribution focuses on the development of appropriate fallback level concepts. Hardware-in-the-loop (HIL) techniques and field trials will be used to investigate the performance and the usability of such systems.

Regulatory Scientific Advice on Non-Inferiority Drug Trials

PubMed Central

Knol, Mirjam J.; Klungel, Olaf H.; Gispen-De Wied, Christine C.; de Boer, Antonius; Hoes, Arno W.; Leufkens, Hubert G.; Mantel-Teeuwisse, Aukje K.

2013-01-01

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions ‘whether’ and ‘how’ to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice. PMID:24040346

An Empirical Investigation of Variance Design Parameters for Planning Cluster-Randomized Trials of Science Achievement.

PubMed

Westine, Carl D; Spybrook, Jessaca; Taylor, Joseph A

2013-12-01

Prior research has focused primarily on empirically estimating design parameters for cluster-randomized trials (CRTs) of mathematics and reading achievement. Little is known about how design parameters compare across other educational outcomes. This article presents empirical estimates of design parameters that can be used to appropriately power CRTs in science education and compares them to estimates using mathematics and reading. Estimates of intraclass correlations (ICCs) are computed for unconditional two-level (students in schools) and three-level (students in schools in districts) hierarchical linear models of science achievement. Relevant student- and school-level pretest and demographic covariates are then considered, and estimates of variance explained are computed. Subjects: Five consecutive years of Texas student-level data for Grades 5, 8, 10, and 11. Science, mathematics, and reading achievement raw scores as measured by the Texas Assessment of Knowledge and Skills. Results: Findings show that ICCs in science range from .172 to .196 across grades and are generally higher than comparable statistics in mathematics, .163-.172, and reading, .099-.156. When available, a 1-year lagged student-level science pretest explains the most variability in the outcome. The 1-year lagged school-level science pretest is the best alternative in the absence of a 1-year lagged student-level science pretest. Science educational researchers should utilize design parameters derived from science achievement outcomes. © The Author(s) 2014.

Protecting intellectual property associated with Canadian academic clinical trials - approaches and impact

PubMed Central

2012-01-01

Intellectual property is associated with the creative work needed to design clinical trials. Two approaches have developed to protect the intellectual property associated with multicentre trial protocols prior to site initiation. The ‘open access’ approach involves publishing the protocol, permitting easy access to the complete protocol. The main advantages of the open access approach are that the protocol is freely available to all stakeholders, permitting them to discuss the protocol widely with colleagues, assess the quality and rigour of the protocol, determine the feasibility of conducting the trial at their centre, and after trial completion, to evaluate the reported findings based on a full understanding of the protocol. The main potential disadvantage of this approach is the potential for plagiarism; however if that occurred, it should be easy to identify because of the open access to the original trial protocol, as well as ensure that appropriate sanctions are used to deal with plagiarism. The ‘restricted access’ approach involves the use of non-disclosure agreements, legal documents that must be signed between the trial lead centre and collaborative sites. Potential sites must guarantee they will not disclose any details of the study before they are permitted to access the protocol. The main advantages of the restricted access approach are for the lead institution and nominated principal investigator, who protect their intellectual property associated with the trial. The main disadvantages are that ownership of the protocol and intellectual property is assigned to the lead institution; defining who ‘needs to know’ about the study protocol is difficult; and the use of non-disclosure agreements involves review by lawyers and institutional representatives at each site before access is permitted to the protocol, significantly delaying study implementation and adding substantial indirect costs to research institutes. This extra step may discourage sites from joining a trial. It is possible that the restricted access approach may contribute to the failure of well-designed trials without any significant benefit in protecting intellectual property. Funding agencies should formalize rules around open versus restricted access to the study protocol just as they have around open access to results. PMID:23270486

Protecting intellectual property associated with Canadian academic clinical trials--approaches and impact.

PubMed

Ross, Sue; Magee, Laura; Walker, Mark; Wood, Stephen

2012-12-27

Intellectual property is associated with the creative work needed to design clinical trials. Two approaches have developed to protect the intellectual property associated with multicentre trial protocols prior to site initiation. The 'open access' approach involves publishing the protocol, permitting easy access to the complete protocol. The main advantages of the open access approach are that the protocol is freely available to all stakeholders, permitting them to discuss the protocol widely with colleagues, assess the quality and rigour of the protocol, determine the feasibility of conducting the trial at their centre, and after trial completion, to evaluate the reported findings based on a full understanding of the protocol. The main potential disadvantage of this approach is the potential for plagiarism; however if that occurred, it should be easy to identify because of the open access to the original trial protocol, as well as ensure that appropriate sanctions are used to deal with plagiarism. The 'restricted access' approach involves the use of non-disclosure agreements, legal documents that must be signed between the trial lead centre and collaborative sites. Potential sites must guarantee they will not disclose any details of the study before they are permitted to access the protocol. The main advantages of the restricted access approach are for the lead institution and nominated principal investigator, who protect their intellectual property associated with the trial. The main disadvantages are that ownership of the protocol and intellectual property is assigned to the lead institution; defining who 'needs to know' about the study protocol is difficult; and the use of non-disclosure agreements involves review by lawyers and institutional representatives at each site before access is permitted to the protocol, significantly delaying study implementation and adding substantial indirect costs to research institutes. This extra step may discourage sites from joining a trial. It is possible that the restricted access approach may contribute to the failure of well-designed trials without any significant benefit in protecting intellectual property. Funding agencies should formalize rules around open versus restricted access to the study protocol just as they have around open access to results.

Funding source and the quality of reports of chronic wounds trials: 2004 to 2011

PubMed Central

2014-01-01

Background Critical commentaries suggest that wound care randomised controlled trials (RCTs) are often poorly reported with many methodological flaws. Furthermore, interventions in chronic wounds, rather than being drugs, are often medical devices for which there are no requirements for RCTs to bring products to market. RCTs in wounds trials therefore potentially represent a form of marketing. This study presents a methodological overview of chronic wound trials published between 2004 and 2011 and investigates the influence of industry funding on methodological quality. Methods A systematic search for RCTs for the treatment of chronic wounds published in the English language between 2004 and 2011 (inclusive) in the Cochrane Wounds Group Specialised Register of Trials was carried out. Data were extracted on aspects of trial design, conduct and quality including sample size, duration of follow-up, specification of a primary outcome, use of surrogate outcomes, and risks of bias. In addition, the prevalence of industry funding was assessed and its influence on the above aspects of trial design, conduct and quality was assessed. Results A total of 167 RCTs met our inclusion criteria. We found chronic wound trials often have short durations of follow-up (median 12 weeks), small sample sizes (median 63), fail to define a primary outcome in 41% of cases, and those that do define a primary outcome, use surrogate measures of healing in 40% of cases. Only 40% of trials used appropriate methods of randomisation, 25% concealed allocation and 34% blinded outcome assessors. Of the included trials, 41% were wholly or partially funded by industry, 33% declared non-commercial funding and 26% did not report a funding source. Industry funding was not statistically significantly associated with any measure of methodological quality, though this analysis was probably underpowered. Conclusions This overview confirms concerns raised about the methodological quality of RCTs in wound care and illustrates that greater efforts must be made to follow international standards for conducting and reporting RCTs. There is currently minimal evidence of an influence of industry funding on methodological quality although analyses had limited power and funding source was not reported for a quarter of studies. PMID:24422753

Funding source and the quality of reports of chronic wounds trials: 2004 to 2011.

PubMed

Hodgson, Robert; Allen, Richard; Broderick, Ellen; Bland, J Martin; Dumville, Jo C; Ashby, Rebecca; Bell-Syer, Sally; Foxlee, Ruth; Hall, Jill; Lamb, Karen; Madden, Mary; O'Meara, Susan; Stubbs, Nikki; Cullum, Nicky

2014-01-14

Critical commentaries suggest that wound care randomised controlled trials (RCTs) are often poorly reported with many methodological flaws. Furthermore, interventions in chronic wounds, rather than being drugs, are often medical devices for which there are no requirements for RCTs to bring products to market. RCTs in wounds trials therefore potentially represent a form of marketing. This study presents a methodological overview of chronic wound trials published between 2004 and 2011 and investigates the influence of industry funding on methodological quality. A systematic search for RCTs for the treatment of chronic wounds published in the English language between 2004 and 2011 (inclusive) in the Cochrane Wounds Group Specialised Register of Trials was carried out.Data were extracted on aspects of trial design, conduct and quality including sample size, duration of follow-up, specification of a primary outcome, use of surrogate outcomes, and risks of bias. In addition, the prevalence of industry funding was assessed and its influence on the above aspects of trial design, conduct and quality was assessed. A total of 167 RCTs met our inclusion criteria. We found chronic wound trials often have short durations of follow-up (median 12 weeks), small sample sizes (median 63), fail to define a primary outcome in 41% of cases, and those that do define a primary outcome, use surrogate measures of healing in 40% of cases. Only 40% of trials used appropriate methods of randomisation, 25% concealed allocation and 34% blinded outcome assessors. Of the included trials, 41% were wholly or partially funded by industry, 33% declared non-commercial funding and 26% did not report a funding source. Industry funding was not statistically significantly associated with any measure of methodological quality, though this analysis was probably underpowered. This overview confirms concerns raised about the methodological quality of RCTs in wound care and illustrates that greater efforts must be made to follow international standards for conducting and reporting RCTs. There is currently minimal evidence of an influence of industry funding on methodological quality although analyses had limited power and funding source was not reported for a quarter of studies.

InsuOnline, a Serious Game to Teach Insulin Therapy to Primary Care Physicians: Design of the Game and a Randomized Controlled Trial for Educational Validation.

PubMed

Diehl, Leandro Arthur; Souza, Rodrigo Martins; Alves, Juliano Barbosa; Gordan, Pedro Alejandro; Esteves, Roberto Zonato; Jorge, Maria Lúcia Silva Germano; Coelho, Izabel Cristina Meister

2013-01-21

Physicians´ lack of knowledge contributes to underuse of insulin and poor glycemic control in adults with diabetes mellitus (DM). Traditional continuing medical education have limited efficacy, and new approaches are required. We report the design of a trial to assess the educational efficacy of InsuOnline, a game for education of primary care physicians (PCPs). The goal of InsuOnline was to improve appropriate initiation and adjustment of insulin for the treatment of DM. InsuOnline was designed to be educationally adequate, self-motivating, and attractive. A multidisciplinary team of endocrinologists, experts in medical education, and programmers, was assembled for the design and development of InsuOnline. Currently, we are conducting usability and playability tests, with PCPs and medical students playing the game on a desktop computer. Adjustments will be made based on these results. An unblinded randomized controlled trial with PCPs who work in the city of Londrina, Brazil, will be conducted to assess the educational validity of InsuOnline on the Web. In this trial, 64 PCPs will play InsuOnline, and 64 PCPs will undergo traditional instructional activities (lecture and group discussion). Knowledge on how to initiate and adjust insulin will be assessed by a Web-based multiple choice questionnaire, and attitudes regarding diabetes/insulin will be assessed by Diabetes Attitude Scale 3 at 3 time points-before, immediately after, and 6 months after the intervention. Subjects´ general impressions on the interventions will be assessed by a questionnaire. Software logs will be reviewed. To our knowledge, this is the first research with the aim of assessing the educational efficacy of a computer game for teaching PCPs about insulin therapy in DM. We describe the development criteria used for creating InsuOnline. Evaluation of the game using a randomized controlled trial design will be done in future studies. We demonstrated that the design and development of a game for PCPs education on insulin is possible with a multidisciplinary team. InsuOnline can be an attractive option for large-scale continuous medical education to help improving PCPs´ knowledge on insulin therapy and potentially improving DM patients´ care. Clinicaltrials.gov: NCT01759953; http://clinicaltrials.gov/show/NCT01759953 (Archived by WebCite at http://www.webcitation.org/6Dq8Vc7a6).

The Brief Pain Inventory and its "pain at its worst in the last 24 hours" item: clinical trial endpoint considerations.

PubMed

Atkinson, Thomas M; Mendoza, Tito R; Sit, Laura; Passik, Steven; Scher, Howard I; Cleeland, Charles; Basch, Ethan

2010-03-01

In 2006, the United States Food and Drug Administration (FDA) released a draft Guidance for Industry on the use of patient-reported outcomes (PRO) Measures in Medical Product Development to Support Labeling Claims. This draft guidance outlines psychometric aspects that should be considered when designing a PRO measure, including conceptual framework, content validity, construct validity, reliability, and the ability to detect clinically meaningful score changes. When finalized, it may provide a blueprint for evaluations of PRO measures that can be considered by sponsors and investigators involved in PRO research and drug registration trials. In this review we examine the short form of the Brief Pain Inventory (BPI) and particularly the "pain at its worst in the last 24 hours" item in the context of the FDA draft guidance, to assess its utility in clinical trials that include pain as a PRO endpoint. After a systematic evaluation of the psychometric aspects of the BPI, we conclude that the BPI and its "pain at its worst in the last 24 hours" item generically satisfy most key recommendations outlined in the draft guidance for assessing a pain-reduction treatment effect. Nonetheless, when the BPI is being considered for assessment of pain endpoints in a registration trial, sponsors and investigators should consult with the appropriate FDA division early during research design to discuss whether there is sufficient precedent to use the instrument in the population of interest or whether additional evaluations of measurement properties are advisable.

Protection of xenon against postoperative oxygen impairment in adults undergoing Stanford Type-A acute aortic dissection surgery

PubMed Central

Jin, Mu; Cheng, Yi; Yang, Yanwei; Pan, Xudong; Lu, Jiakai; Cheng, Weiping

2017-01-01

Abstract Objectives: The available evidence shows that hypoxemia after Stanford Type-A acute aortic dissection (AAD) surgery is a frequent cause of several adverse consequences. The pathogenesis of postoperative hypoxemia after AAD surgery is complex, and ischemia/reperfusion and inflammation are likely to be underlying risk factors. Xenon, recognized as an ideal anesthetic and anti-inflammatory treatment, might be a possible treatment for these adverse effects. Methods/Design: The trial is a prospective, double-blind, 4-group, parallel, randomized controlled, a signal-center clinical trial. We will recruit 160 adult patients undergoing Stanford type-A AAD surgery. Patients will be allocated a study number and will be randomized on a 1:1:1:1 basis to receive 1 of the 3 treatment options (pulmonary inflated with 50% xenon, 75% xenon, or 100% xenon) or no treatment (control group, pulmonary inflated with 50% nitrogen). The aims of this study are to clarify the lung protection capability of xenon and its possible mechanisms in patients undergoing the Stanford type-A AAD surgery. Discussion: This trial uses an innovative design to account for the xenon effects of postoperative oxygen impairment, and it also delineates the mechanism for any benefit from xenon. The investigational xenon group is considered a treatment intervention, as it includes 3 groups of pulmonary static inflation with 50%, 75%, and 100% xenon. It is suggested that future trials might define an appropriate concentration of xenon for the best practice intervention. PMID:28834897

InsuOnline, a Serious Game to Teach Insulin Therapy to Primary Care Physicians: Design of the Game and a Randomized Controlled Trial for Educational Validation

PubMed Central

Souza, Rodrigo Martins; Alves, Juliano Barbosa; Gordan, Pedro Alejandro; Esteves, Roberto Zonato; Jorge, Maria Lúcia Silva Germano; Coelho, Izabel Cristina Meister

2013-01-01

Background Physicians´ lack of knowledge contributes to underuse of insulin and poor glycemic control in adults with diabetes mellitus (DM). Traditional continuing medical education have limited efficacy, and new approaches are required. Objective We report the design of a trial to assess the educational efficacy of InsuOnline, a game for education of primary care physicians (PCPs). The goal of InsuOnline was to improve appropriate initiation and adjustment of insulin for the treatment of DM. InsuOnline was designed to be educationally adequate, self-motivating, and attractive. Methods A multidisciplinary team of endocrinologists, experts in medical education, and programmers, was assembled for the design and development of InsuOnline. Currently, we are conducting usability and playability tests, with PCPs and medical students playing the game on a desktop computer. Adjustments will be made based on these results. An unblinded randomized controlled trial with PCPs who work in the city of Londrina, Brazil, will be conducted to assess the educational validity of InsuOnline on the Web. In this trial, 64 PCPs will play InsuOnline, and 64 PCPs will undergo traditional instructional activities (lecture and group discussion). Knowledge on how to initiate and adjust insulin will be assessed by a Web-based multiple choice questionnaire, and attitudes regarding diabetes/insulin will be assessed by Diabetes Attitude Scale 3 at 3 time points—before, immediately after, and 6 months after the intervention. Subjects´ general impressions on the interventions will be assessed by a questionnaire. Software logs will be reviewed. Results To our knowledge, this is the first research with the aim of assessing the educational efficacy of a computer game for teaching PCPs about insulin therapy in DM. We describe the development criteria used for creating InsuOnline. Evaluation of the game using a randomized controlled trial design will be done in future studies. Conclusions We demonstrated that the design and development of a game for PCPs education on insulin is possible with a multidisciplinary team. InsuOnline can be an attractive option for large-scale continuous medical education to help improving PCPs´ knowledge on insulin therapy and potentially improving DM patients´ care. Trial Registration Clinicaltrials.gov: NCT01759953; http://clinicaltrials.gov/show/NCT01759953 (Archived by WebCite at http://www.webcitation.org/6Dq8Vc7a6). PMID:23612462

A qualitative study exploring the acceptability of the McNulty-Zelen design for randomised controlled trials evaluating educational interventions.

PubMed

McNulty, Cliodna; Ricketts, Ellie J; Rugman, Claire; Hogan, Angela; Charlett, Andre; Campbell, Rona

2015-11-17

Traditional randomised controlled trials evaluating the effect of educational interventions in general practice may produce biased results as participants know they are being evaluated. We aimed to explore the acceptability of a McNulty-Zelen Cluster Randomised Control Trial (CRT) design which conceals from educational participants that they are in a RCT. Consent is obtained from a trusted third party considered appropriate to give consent on participants' behalf, intervention practice staff then choose whether to attend the offered education as would occur with normal continuing professional development. We undertook semi structured telephone interviews in England with 16 general practice (GP) staff involved in a RCT evaluating an educational intervention aimed at increasing chlamydia screening tests in general practice using the McNulty-Zelen design, 4 Primary Care (PC) Research Network officers, 5 Primary Care Trust leads in Public or sexual health, and one Research Ethics committee Chair. Interviews were undertaken by members of the original intervention evaluation McNulty-Zelen design RCT study team. These experienced qualitative interviewers used an agreed semi-structured interview schedule and were careful not to lead the participants. To further mitigate against bias, the data analysis was undertaken by a researcher (CR) not involved in the original RCT. We reached data saturation and found five main themes; Support for the design: All found the McNulty-Zelen design acceptable because they considered that it generated more reliable evidence of the value of new educational interventions in real life GP settings. Lack of familiarity with study design: The design was novel to all. GP staff likened the evaluation using the McNulty-Zelen design to audit of their activities with feedback, which were to them a daily experience and therefore acceptable. Ethical considerations: Research stakeholders considered the consent procedure should be very clear and that these trial designs should go through at least a proportionate ethical review. GP staff were happy for the PCT leads to give consent on their behalf. GP research capacity and trial participation: GP staff considered the design increased generalisability, as staff who would not normally volunteer to participate in research due to perceived time constraints and paperwork might do so. Design 'worth it': All interviewees agreed that the advantages of the "more accurate" or "truer" results and information gained about uptake of workshops within Primary Care Trusts (PCTs) outweighed any disadvantages of the consent procedure. Our RCT was evaluating the effect of an educational intervention to increase chlamydia screening tests in general practices where there was routine monitoring of testing rates; our participants may have been less enthusiastic about the design if it had been evaluating a more controversial educational area, or if data monitoring was not routine. The McNulty-Zelen design should be considered for the evaluation of educational interventions, but these designs should have clear consent protocols and proportionate ethical review. The trial was registered on the UK Clinical Research Network Study Portfolio database. UKCRN9722 .

Low-cost failure sensor design and development for water pipeline distribution systems.

PubMed

Khan, K; Widdop, P D; Day, A J; Wood, A S; Mounce, S R; Machell, J

2002-01-01

This paper describes the design and development of a new sensor which is low cost to manufacture and install and is reliable in operation with sufficient accuracy, resolution and repeatability for use in newly developed systems for pipeline monitoring and leakage detection. To provide an appropriate signal, the concept of a "failure" sensor is introduced, in which the output is not necessarily proportional to the input, but is unmistakably affected when an unusual event occurs. The design of this failure sensor is based on the water opacity which can be indicative of an unusual event in a water distribution network. The laboratory work and field trials necessary to design and prove out this type of failure sensor are described here. It is concluded that a low-cost failure sensor of this type has good potential for use in a comprehensive water monitoring and management system based on Artificial Neural Networks (ANN).

The Severity, Frequency, and Variety of Crime in Heroin-Dependent Prisoners Enrolled in a Buprenorphine Clinical Trial

PubMed Central

Gordon, Michael S.; Kinlock, Timothy W.; Schwartz, Robert P.; Couvillion, Kathryn A.; O’Grady, Kevin E.

2014-01-01

Data were obtained on four dimensions of criminal activity (frequency, variety, severity, and income) from male and female prisoners (N = 200) with preincarceration heroin dependence who participated in a randomized clinical trial of buprenorphine treatment. The article examines the above-mentioned dimensions of crime and their relationships with demographic characteristics, substance use, legitimate employment, drug treatment episodes, and psychological problems. Results largely show several important similarities to results on previous prison inmate cohorts with histories of heroin addiction, although the present sample may have more of a tendency toward violent crime than earlier cohorts of heroin-dependent offenders. This study’s findings may have implications for the design of appropriate treatment interventions for prisoners with preincarceration heroin dependence that address not only substance use but also criminal activity. PMID:25392564

Selective elimination of breast cancer surgery in exceptional responders: historical perspective and current trials.

PubMed

van la Parra, Raquel F D; Kuerer, Henry M

2016-03-08

With improvements in chemotherapy regimens, targeted therapies, and our fundamental understanding of the relationship of tumor subtype and pathologic complete response (pCR), there has been dramatic improvement in pCR rates in the past decade, especially among triple-negative and human epidermal growth factor receptor 2-positive breast cancers. Rates of pCR in these groups of patients can be in the 60 % range and thus question the paradigm for the necessity of breast and nodal surgery in all cases, particularly when the patient will be receiving adjuvant local therapy with radiotherapy. Current practice for patients who respond well to neoadjuvant chemotherapy (NCT) is often to proceed with the same breast and axillary procedures as would have been offered women who had not received NCT, regardless of the apparent clinical response. Given these high response rates in defined subgroups among exceptional responders it is appropriate to question whether surgery is now a redundant procedure in their overall management. Further, definitive radiation without surgical resection with or without systemic therapy has been proven effective for several other malignant disease sites including some stages of esophageal, anal, laryngeal, prostate, cervical, and lung carcinoma. The main impediments for potential elimination of surgery have been the fact that prior and current standard and functional breast imaging methods are incapable of accurate prediction of residual disease and that integrating percutaneous biopsy of the breast primary and nodes following NCT may circumvent this issue. This article highlights historical attempts at omission of surgery following NCT in an earlier era, the current status of breast and nodal imaging to predict residual carcinoma, and ongoing and planned trials designed to identify appropriate patients who might be selected for clinical trials designed to test the safety of selected elimination of breast cancer surgery in percutaneous image-guided biopsy-proven exceptional responders to NCT.

MIDSHIPS: Multicentre Intervention Designed for Self-Harm using Interpersonal Problem-Solving: protocol for a randomised controlled feasibility study

PubMed Central

2014-01-01

Background Around 150,000 people each year attend hospitals in England due to self-harm, many of them more than once. Over 5,000 people die by suicide each year in the UK, a quarter of them having attended hospital in the previous year because of self-harm. Self-harm is a major identifiable risk factor for suicide. People receive variable care at hospital; many are not assessed for their psychological needs and little psychological therapy is offered. Despite its frequent occurrence, we have no clear research evidence about how to reduce the repetition of self-harm. Some people who have self-harmed show less active ways of solving problems, and brief problem-solving therapies are considered the most promising psychological treatments. Methods/Design This is a pragmatic, individually randomised, controlled, feasibility study comparing interpersonal problem-solving therapy plus treatment-as-usual with treatment-as-usual alone, for adults attending a general hospital following self-harm. A total of 60 participants will be randomised equally between the treatment arms, which will be balanced with respect to the type of most recent self-harm event, number of previous self-harm events, gender and age. Feasibility objectives are as follows: a) To establish and field test procedures for implementing the problem-solving intervention; b) To determine the feasibility and best method of participant recruitment and follow up; c) To assess therapeutic delivery; d) To assess the feasibility of obtaining the definitive trial’s primary and secondary outcomes; e) To assess the perceived burden and acceptability of obtaining the trial’s self-reported outcome data; f) To inform the sample size calculation for the definitive trial. Discussion The results of this feasibility study will be used to determine the appropriateness of proceeding to a definitive trial and will allow us to design an achievable trial of interpersonal problem-solving therapy for adults who self-harm. Trial registration Current Controlled Trials (ISRCTN54036115) PMID:24886683

Facilitating mental health help-seeking by young adults with a dedicated online program: a feasibility study of Link

PubMed Central

Kauer, Sylvia D; Buhagiar, Kerrie; Blake, Victoria; Cotton, Sue; Sanci, Lena

2017-01-01

Objective To explore the feasibility of a dedicated online youth mental health help-seeking intervention and to evaluate using a randomised controlled trial (RCT) study design in order to identify any modifications needed before commencement of the full-scale RCT. Design A pilot RCT with 1:1 randomisation to either the intervention or comparison arm. Setting An online study conducted Australia-wide. Participants 18–25 year olds living in Australia were recruited via social media. Intervention Link is a dedicated online mental health help-seeking navigation tool that matches user’s mental health issues, severity and service-type preferences (online, phone and face-to-face) with appropriate youth-friendly services. The comparison arm was usual help-seeking strategies with a link to Google.com. Main outcome measures The primary outcome was the number of acceptability and feasibility criteria successfully met. Intervention and study design acceptability and feasibility were assessed by nine criteria. Secondary outcomes, via online surveys (at baseline, 1 week and 1 month) measured service use, help-seeking intentions, psychological distress, barriers to help-seeking, attitudes towards mental health help-seeking, mental health literacy, satisfaction and trust. Results Fifty-one participants were randomised (intervention: n=24; comparison: n=27). Three out of four of the intervention and two out of five of the study design criteria were met. Unmet criteria could be addressed by modifications to the study design. Qualitative analysis demonstrated that Link was useful to participants and may have increased their positive experiences towards help-seeking. There were no observable differences between arms in any outcome measures and no harms were detected. Conclusion Generally, the Link intervention and study design were acceptable and feasible with modifications suggested for the four out of nine unmet criteria. The main trial will hence have shorter surveys and a simpler recruitment process, use positive affect as the primary outcome and will not link to Google.com for the comparison arm. Trial registration number Australian New Zealand Clinical Trials Registry, ACTRN12614000386639. PMID:28694345

Global health trials methodological research agenda: results from a priority setting exercise.

PubMed

Rosala-Hallas, Anna; Bhangu, Aneel; Blazeby, Jane; Bowman, Louise; Clarke, Mike; Lang, Trudie; Nasser, Mona; Siegfried, Nandi; Soares-Weiser, Karla; Sydes, Matt R; Wang, Duolao; Zhang, Junhua; Williamson, Paula R

2018-02-05

Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Modeling and Simulation of Pivotal Clinical Trials Using Linked Models for Multiple Endpoints in Chronic Obstructive Pulmonary Disease With Roflumilast.

PubMed

Facius, Axel; Krause, Andreas; Claret, Laurent; Bruno, Rene; Lahu, Gezim

2017-08-01

Roflumilast is a selective phosphodiesterase 4 inhibitor (PDE4i) for the treatment of severe chronic obstructive pulmonary disease (COPD). In 2 large phase 3 trials in a broader population of COPD patients (BY217/M2-111, ClinicalTrials.gov: NCT00076089 and BY217/M2-112, ClinicalTrials.gov: NCT00430729), treatment with roflumilast reduced the rate of exacerbations; however, the reduction did not reach statistical significance. Two linked dose-response models for the primary (annualized COPD exacerbation counts) and secondary (change from baseline in forced expiratory volume in 1 second [FEV 1 ]) end points were therefore developed to characterize and quantify effect sizes and the patient characteristics influencing them. The models showed that disease severity and bronchitis, particularly the severity of bronchitis expressed in cough-and-sputum scores, were good predictors of exacerbation rates and differential benefit of roflumilast in exacerbation reduction. The models were used to support the rational design of 2 phase 3 randomized, placebo-controlled clinical trials (BY217/M2-124, ClinicalTrials.gov: NCT00297102 and BY217/M2-125, ClinicalTrials.gov: NCT00297115) by identifying the most appropriate patient population using clinical trial simulations. Model predictions for both end points were found to be highly accurate - as confirmed by the results from these trials, which led to the approval of roflumilast as the first oral PDE4i for the treatment of COPD in patients associated with chronic bronchitis and a history of exacerbations. © 2017, The American College of Clinical Pharmacology.

Parent satisfaction in a multi-site acute trial of risperidone in children with autism: a social validity study.

PubMed

Tierney, Elaine; Aman, Michael; Stout, David; Pappas, Krista; Arnold, L Eugene; Vitiello, Benedetto; Scahill, Lawrence; McDougle, Christopher; McCracken, James; Wheeler, Courtney; Martin, Andres; Posey, David; Shah, Bhavik

2007-03-01

Subjects who view experimental procedures as worthwhile are more likely to participate in clinical trials and comply with study procedures. Designing studies that consider the consumer's perspective will help to forge a better alliance between participants and researchers. Participant satisfaction is seldom assessed in pharmacological research. In this paper, we report on parent satisfaction in a randomized clinical trial in children with autistic disorder and severely disruptive behavior. Parents of 101 children with autism who had participated in a multi-site 8-week double-blind clinical trial of risperidone were given a questionnaire at the end to elicit their perceptions of the appropriateness and acceptability of clinical trial procedures. Ninety-six (95.0%) parents returned the questionnaire. Of these, 80.0 to 96.8%, depending on the question, expressed satisfaction with their child's research participation regardless of treatment outcome or assignment to active drug or placebo. In all, 90.5% of parents indicated that they would "definitely" recommend the clinical trial to other families with similar children. A total of 92.7% indicated that they would rejoin the clinical trial if they had to do it all over again. Ethnic minority subjects were more satisfied than white participants with the use of "learning tests". Parents of children participating in this trial were highly satisfied and supportive of the clinical trial procedures. Random assignment to drug or placebo and the clinical response of their children did not appear to influence their views. Further satisfaction studies of this sort are encouraged.

A feasibility study investigating the acceptability and design of a multicentre randomised controlled trial of needle fasciotomy versus limited fasciectomy for the treatment of Dupuytren's contractures of the fingers (HAND-1): study protocol for a randomised controlled trial.

PubMed

Harrison, Eleanor; Tan, Wei; Mills, Nicola; Karantana, Alexia; Sprange, Kirsty; Duley, Lelia; Elliott, Daisy; Blazeby, Jane; Hollingworth, William; Montgomery, Alan A; Davis, Tim

2017-08-25

Dupuytren's contractures are fibrous cords under the skin of the palm of the hand. The contractures are painless but cause one or more fingers to curl into the palm, resulting in loss of function. Standard treatment within the NHS is surgery to remove (fasciectomy) or divide (fasciotomy) the contractures, and the treatment offered is frequently determined by surgeon preference. This study aims to determine the feasibility of conducting a large, multicentre randomised controlled trial to assess the clinical and cost-effectiveness of needle fasciotomy versus limited fasciectomy for the treatment of Dupuytren's contracture. HAND-1 is a parallel, two-arm, multicentre, randomised feasibility trial. Eligible patients aged 18 years or over who have one or more fingers with a Dupuytren's contracture of more than 30° in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints, well-defined cord(s) causing contracture, and have not undergone previous surgery for Dupuytren's on the same hand will be randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy. Participants will be followed-up for up to 6 months post surgery. Feasibility outcomes include number of patients screened, consented and randomised, adherence with treatment, completion of follow-up and identification of an appropriate patient-reported outcome measure (PROM) to use as primary outcome for a main trial. Embedded qualitative research, incorporating a QuinteT Recruitment Intervention, will focus on understanding and optimising the recruitment process, and exploring patients' experiences of trial participation and the interventions. This study will assess whether a large multicentre trial comparing the clinical and cost-effectiveness of needle fasciotomy and limited fasciectomy for the treatment of Dupuytren's contractures is feasible, and if so will provide data to inform its design and successful conduct. International Standard Registered Clinical/soCial sTudy Number: ISRCTN11164292 . Registered on 28 August 2015.

Industry and Patient Perspectives on Child Participation in Clinical Trials: The Pediatric Assent Initiative Survey Report.

PubMed

Lombardi, Donald; Squires, Liza; Sjostedt, Philip; Eichler, Irmgard; Turner, Mark A; Thompson, Charles

2018-01-01

Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment-allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials. Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations' experience and policies regarding pediatric assent. Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients. An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients.

Appendectomy versus non-operative treatment for acute uncomplicated appendicitis in children: study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

PubMed Central

Eaton, Simon; Abbo, Olivier; Arnaud, Alexis P; Beaudin, Marianne; Brindle, Mary; Bütter, Andreana; Davies, Dafydd; Jancelewicz, Tim; Johnson, Kathy; Keijzer, Richard; Lapidus-Krol, Eveline; Offringa, Martin; Piché, Nelson; Rintala, Risto; Skarsgard, Erik; Svensson, Jan F; Ungar, Wendy J; Wester, Tomas; Willan, Andrew R; Zani, Augusto; St Peter, Shawn D; Pierro, Agostino

2017-01-01

Background Appendectomy is considered the gold standard treatment for acute appendicitis. Recently the need for surgery has been challenged in both adults and children. In children there is growing clinician, patient and parental interest in non-operative treatment of acute appendicitis with antibiotics as opposed to surgery. To date no multicentre randomised controlled trials that are appropriately powered to determine efficacy of non-operative treatment (antibiotics) for acute appendicitis in children compared with surgery (appendectomy) have been performed. Methods Multicentre, international, randomised controlled trial with a non-inferiority design. Children (age 5–16 years) with a clinical and/or radiological diagnosis of acute uncomplicated appendicitis will be randomised (1:1 ratio) to receive either laparoscopic appendectomy or treatment with intravenous (minimum 12 hours) followed by oral antibiotics (total course 10 days). Allocation to groups will be stratified by gender, duration of symptoms (> or <48 hours) and centre. Children in both treatment groups will follow a standardised treatment pathway. Primary outcome is treatment failure defined as additional intervention related to appendicitis requiring general anaesthesia within 1 year of randomisation (including recurrent appendicitis) or negative appendectomy. Important secondary outcomes will be reported and a cost-effectiveness analysis will be performed. The primary outcome will be analysed on a non-inferiority basis using a 20% non-inferiority margin. Planned sample size is 978 children. Discussion The APPY trial will be the first multicentre randomised trial comparing non-operative treatment with appendectomy for acute uncomplicated appendicitis in children. The results of this trial have the potential to revolutionise the treatment of this common gastrointestinal emergency. The randomised design will limit the effect of bias on outcomes seen in other studies. Trial registration number clinicaltrials.gov: NCT02687464. Registered on Jan 13th 2016. PMID:29637088

Designing an intervention to prevent suicide: PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial)

PubMed Central

Bruce, Martha L.; Pearson, Jane L.

1999-01-01

Suicide is a major public health problem with greatest risk in the very old. This paper describes an approach to reducing the risk of suicide by intervening on depression in elderly primary care patients. Depression is an appropriate target for an intervention as it is highly prevalent in primary care, is a strong risk factor for suicide, and is more often than not inadequately treated. PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial) is a National institute of Mental Health (NIMH)-funded collaborative study that is testing this approach to suicide risk prevention in 18 primary care practices in the United States. PROSPECT'S intervention of “guideline management” introduces a health specialist into the primary care setting to help physicians provide “on-time, on-target” treatment and long-term management of late-life depression following structured clinical guidelines. The effectiveness of the intervention in reducing suicidal risk and depression is evaluated by following a representative sample of older patients identified using a 2-stage design. PMID:22033641

Designing exercise clinical trials for older adults with cancer: Recommendations from 2015 Cancer and Aging Research Group NCI U13 Meeting

PubMed Central

Kilari, Deepak; Soto-Perez-de-Celis, Enrique; Mohile, Supriya Gupta; Alibhai, Shabbir M.H.; Presley, Carolyn J.; Wildes, Tanya M.; Klepin, Heidi D.; Demark-Wahnefried, Wendy; Jatoi, Amina; Harrison, Robert; Won, Elizabeth; Mustian, Karen M.

2016-01-01

Cancer and its treatment can lead to a myriad of adverse events and negatively impact quality of life of older cancer patients and survivors. Unmet physical activity needs vary across the cancer continuum and remain an important yet understudied area of research in this population. Exercise interventions have been shown to be effective in treating both the physical and psychological declines associated with cancer and its treatment, with a potential to improve cancer-related outcomes. Despite the current evidence, exercise is clearly underutilized due to several barriers and knowledge gaps in existing trials that include appropriate population identification, design, and outcome measures selection. The benefits of regular exercise in both the primary and secondary prevention of chronic conditions are well established in the non-cancer population. In older cancer patients and survivors, further research is needed before exercise gains widespread acceptance. The Cancer and Aging Research Group convened experts in exercise, aging and cancer to evaluate current scientific evidence and knowledge gaps in geriatric exercise oncology. This report summarizes these findings and provides future research directions. PMID:27197916

Using Minitel Network and New Software Engineering Techniques for Randomized Clinical Trials Management

PubMed Central

Lepage, E.; Tavernier, H.; Bouhaddou, O.; Jais, JP.; Gisselbrecht, C.; Aurengo, A.; Boiron, M.

1989-01-01

The usual Randomized Clinical Trials (RCT) management using an anachronic procedure involving a flowsheet exchange between the remote centers and the coordinating center presents a number of inadequacies. Eligibility criteria are not always verified by the coordinating center before inclusion in the trial and randomization. Laboratory tests and therapeutic adjustments are frequently decided from memory by the clinician which often leads to data oversight and variability of therapeutic decisions. This results in protocol deviations and alteration of the efficiency of the RCT. HICREN is a medical consultation system designed to take into account the different difficulties encountered during RCT driving. The system integrates a clinical database with artificial intelligence technics to manage clinical trial data on non-expensive and widely available Minitel® terminals. Randomization is then possible, after eligibility criteria are satisfied, anytime and anywhere in France through the national telematic network. HICREN also includes an intuitive graphic interface to increase physician's compliance: a user friendly dialogue manager supports on line data entry with multi-windowing facilities and pull down menus. Interactive data validation is achieved through an interface to dedicated C programs. Patient follow up is achieved by an expert system that proposes appropriate dose of treatment according to the rules defined in the trial. At present, HICREN is implemented on the CISARC system for conducting three randomized clinical trials and one epidemiologic study.

Life- and person-centred help in Mecklenburg-Western Pomerania, Germany (DelpHi): study protocol for a randomised controlled trial

PubMed Central

2012-01-01

Background The provision of appropriate medical and nursing care for people with dementia is a major challenge for the healthcare system in Germany. New models of healthcare provision need to be developed, tested and implemented on the population level. Trials in which collaborative care for dementia in the primary care setting were studied have demonstrated its effectiveness. These studies have been conducted in different healthcare systems, however, so it is unclear whether these results extend to the specific context of the German healthcare system. The objective of this population-based intervention trial in the primary care setting is to test the efficacy and efficiency of implementing a subsidiary support system on a population level for persons with dementia who live at home. Methods and study design The study was designed to assemble a general physician-based epidemiological cohort of people above the age of 70 who live at home (DelpHi cohort). These people are screened for eligibility to participate in a trial of dementia care management (DelpHi trial). The trial is a cluster-randomised, controlled intervention trial with two arms (intervention and control) designed to test the efficacy and efficiency of implementing a subsidiary support system for persons with dementia who live at home. This subsidiary support system is initiated and coordinated by a dementia care manager: a nurse with dementia-specific qualifications who delivers the intervention according to a systematic, detailed protocol. The primary outcome is quality of life and healthcare for patients with dementia and their caregivers. This is a multidimensional outcome with a focus on four dimensions: (1) quality of life, (2) caregiver burden, (3) behavioural and psychological symptoms of dementia and (4) pharmacotherapy with an antidementia drug and prevention or suspension of potentially inappropriate medication. Secondary outcomes include the assessment of dementia syndromes, activities of daily living, social support health status, utilisation of health care resources and medication. Discussion The results will provide evidence for specific needs in ambulatory care for persons with dementia and will show effective ways to meet those needs. Qualification requirements will be evaluated, and the results will help to modify existing guidelines and treatment paths. Trial registration NCT01401582 PMID:22575023

The CORONIS Trial. International study of caesarean section surgical techniques: a randomised fractional, factorial trial

PubMed Central

2007-01-01

Background Caesarean section is one of the most commonly performed operations on women throughout the world. Rates have increased in recent years – about 20–25% in many developed countries. Rates in other parts of the world vary widely. A variety of surgical techniques for all elements of the caesarean section operation are in use. Many have not yet been rigorously evaluated in randomised controlled trials, and it is not known whether any are associated with better outcomes for women and babies. Because huge numbers of women undergo caesarean section, even small differences in post-operative morbidity rates between techniques could translate into improved health for substantial numbers of women, and significant cost savings. Design CORONIS is a multicentre, fractional, factorial randomised controlled trial and will be conducted in centres in Argentina, Ghana, India, Kenya, Pakistan and Sudan. Women are eligible if they are undergoing their first or second caesarean section through a transverse abdominal incision. Five comparisons will be carried out in one trial, using a 2 × 2 × 2 × 2 × 2 fractional factorial design. This design has rarely been used, but is appropriate for the evaluation of several procedures which will be used together in clinical practice. The interventions are: • Blunt versus sharp abdominal entry • Exteriorisation of the uterus for repair versus intra-abdominal repair • Single versus double layer closure of the uterus • Closure versus non-closure of the peritoneum (pelvic and parietal) • Chromic catgut versus Polyglactin-910 for uterine repair The primary outcome is death or maternal infectious morbidity (one or more of the following: antibiotic use for maternal febrile morbidity during postnatal hospital stay, antibiotic use for endometritis, wound infection or peritonitis) or further operative procedures; or blood transfusion. The sample size required is 15,000 women in total; at least 7,586 women in each comparison. Discussion Improvements in health from optimising caesarean section techniques are likely to be more significant in developing countries, because the rates of postoperative morbidity in these countries tend to be higher. More women could therefore benefit from improvements in techniques. Trial registration The CORONIS Trial is registered in the Current Controlled Trials registry. ISCRTN31089967. PMID:18336721

Mental health first aid for eating disorders: pilot evaluation of a training program for the public.

PubMed

Hart, Laura M; Jorm, Anthony F; Paxton, Susan J

2012-08-02

Eating disorders cause significant burden that may be reduced by early and appropriate help-seeking. However, despite the availability of effective treatments, very few individuals with eating disorders seek treatment. Training in mental health first aid is known to be effective in increasing mental health literacy and supportive behaviours, in the social networks of individuals with mental health problems. Increases in these domains are thought to improve the likelihood that effective help is sought. However, the efficacy of mental health first aid for eating disorders has not been evaluated. The aim of this research was to examine whether specific training in mental health first aid for eating disorders was effective in changing knowledge, attitudes and behaviours towards people with eating disorders. A repeated measures, uncontrolled trial was conducted to establish proof of concept and provide guidance on the future design of a randomised controlled trial. Self-report questionnaires, administered at baseline, post-training and 6-month follow-up, assessed the effectiveness of the 4-hour, single session, mental health first aid training. 73 participants completed the training and all questionnaires. The training intervention was associated with statistically significant increases in problem recognition and knowledge of appropriate mental health first aid strategies, which were maintained at 6-month follow-up. Sustained significant changes in attitudes and behaviours were less clear. 20 participants reported providing assistance to someone with a suspected eating disorder, seven of whom sought professional help as a result of the first aid interaction. Results provided no evidence of a negative impact on participants or the individuals they provided assistance to. This research provides preliminary evidence for the use of training in mental health first aid as a suitable intervention for increasing community knowledge of and support for people with eating disorders to seek appropriate help. Australian New Zealand Clinical Trials Registry ACTRN12611001181998.

Building Networks for Global Clinical Research: The Basics.

PubMed

Shearer, David W; Volberding, Paul A; Schemitsch, Emil H; Cook, Gillian E; Slobogean, Gerard P; Morshed, Saam

2015-12-01

Over the last several decades, interest in global health across all fields of medicine, including orthopaedic surgery, has grown markedly. Cross-national collaborations are an effective means of conducting high-quality clinical research and offer many advantages over single-center investigations. Successful collaboration requires a well-designed research protocol, development of an effective team structure, and the funding to ensure the project is sustained to completion. Equally important, investigators must consider the social, linguistic, and cultural context in which the study is being undertaken. Although randomized clinical trials are the highest level of evidence, study designs may have to be adapted to accommodate available resources, expertise, and local contextual factors. With appropriate planning, these collaborative endeavors can generate changes in clinical practice and positively impact health policy.

Efficacy of paracetamol, diclofenac and advice for acute low back pain in general practice: design of a randomized controlled trial (PACE Plus).

PubMed

Schreijenberg, M; Luijsterburg, P A J; Van Trier, Y D M; Rizopoulos, D; Koopmanschap, M A; Voogt, L; Maher, C G; Koes, B W

2017-02-01

Low back pain is common and associated with a considerable burden to patients and society. There is uncertainty regarding the relative benefit of paracetamol and diclofenac and regarding the additional effect of pain medication compared with advice only in patients with acute low back pain. This trial will assess the effectiveness of paracetamol, diclofenac and placebo for acute low back pain over a period of 4 weeks. Furthermore, this trial will assess the additional effectiveness of paracetamol, diclofenac and placebo compared with advice only for acute low back pain over a period of 4 weeks. The PACE Plus trial is a multi-center, placebo-blinded, superiority randomized controlled trial in primary care, with a follow-up of 12 weeks. Patients with acute low back pain aged 18-60 years presenting in general practice will be included. Patients are randomized into four groups: 1) Advice only (usual care conforming with the clinical guideline of the Dutch College of General Practitioners); 2) Advice and paracetamol; 3) Advice and diclofenac; 4) Advice and placebo. The primary outcome is low back pain intensity measured with a numerical rating scale (0-10). Secondary outcomes include compliance to treatment, disability, perceived recovery, costs, adverse reactions, satisfaction, sleep quality, co-interventions and adequacy of blinding. Between group differences for low back pain intensity will be evaluated using a repeated measurements analysis with linear effects models. An economic evaluation will be performed using a cost-effectiveness analysis with low back pain intensity and a cost-utility analysis with quality of life. Explorative analyses will be performed to assess effect modification by predefined variables. Ethical approval has been granted. Trial results will be released to an appropriate peer-viewed journal. This paper presents the design of the PACE Plus trial: a multi-center, placebo-blinded, superiority randomized controlled trial in primary care that will assess the effectiveness of advice only, paracetamol, diclofenac and placebo for acute low back pain. Dutch Trial Registration NTR6089 , registered September 14th, 2016. Version 4, June 2016.

Protocol for a multicentre randomised feasibility STUdy evaluating the impact of a prognostic model for Management of BLunt chest wall trauma patients: STUMBL trial.

PubMed

Battle, Ceri; Abbott, Zoe; Hutchings, Hayley A; O'Neill, Claire; Groves, Sam; Watkins, Alan; Lecky, Fiona E; Jones, Sally; Gagg, James; Body, Richard; Evans, Philip A

2017-07-10

A new prognostic model has been developed and externally validated, the aim of which is to assist in the management of the blunt chest wall trauma patient in the emergency department (ED). A definitive randomised controlled trial (impact trial) is required to assess the clinical and cost effectiveness of the new model before it can be accepted in clinical practice. The purpose of this trial is to assess the feasibility and acceptability of such a definitive trial and inform its design. This feasibility trial is designed to test the methods of a multicentre, cluster-randomised (stepped- wedge) trial, with a substantial qualitative component. Four EDs in England and Wales will collect data for all blunt chest wall trauma patients over a 5-month period; in the initial period acting as the controls (normal care), and in the second period acting as the interventions (in which the new model will be used). Baseline measurements including completion of the SF-12v2 will be obtained on initial assessment in the ED. Patient outcome data will then be collected for any subsequent hospitalisations. Data collection will conclude with a 6-week follow-up completion of two surveys (SF-12v2 and Client Services Receipt Inventory). Analysis of outcomes will focus on feasibility, acceptability and trial processes and will include recruitment and retention rates, attendance at clinician training rates and use of model in the ED. Qualitative feedback will be obtained through clinician interviews and a research nurse focus group. An evaluation of the feasibility of health economics outcomes data will be completed. Wales Research Ethics Committee 6 granted approval for the trial in September 2016. Patient recruitment will commence in February 2017. Planned dissemination is through publication in a peer-reviewed Emergency Medicine Journal , presentation at appropriate conferences and to stakeholders at professional meetings. ISRCTN95571506; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

12 A multi-centre randomised feasibility study evaluating the impact of a prognostic model for management of blunt chest wall trauma patients: stumbl trial.

PubMed

Battle, Ceri; Hutchings, Hayley; Abbott, Zoe; O'neill, Claire; Groves, Sam; Watkins, Alan; Lecky, Fiona; Jones, Sally; Gagg, James; Body, Rick; Evans, Phillip

2017-12-01

A new prognostic model has been developed and externally validated, the aim of which is to assist in the management of the blunt chest wall trauma patient in the Emergency Department (ED). A definitive randomised controlled trial (impact trial), is required to assess the clinical and cost effectiveness of the new model, before it can be accepted in clinical practice. The purpose of this trial is to assess the feasibility and acceptability of such a definitive trial and inform its design. This feasibility trial is designed to test the methods of a multi-centre, cluster-randomised (stepped wedge) trial, with a substantial qualitative component. Four EDs in England and Wales will collect data for all blunt chest wall trauma patients over a five month period; in the initial period acting as the controls (normal care) and the second period, acting as the interventions (in which the new model will be used). Baseline measurements including completion of the SF-12v2 will be obtained on initial assessment in the ED. Patient outcome data will then be collected for any subsequent hospitalisations. Data collection will conclude with a six week follow-up completion of two surveys (SF-12v2 and Client Services Receipt Inventory).Analysis of outcomes will focus on feasibility, acceptability and trial processes and will include recruitment and retention rates, attendance at clinician training rates and use of model in the ED. Qualitative feedback will be obtained through clinician interviews and a research nurse focus group. An evaluation of the feasibility of health economics outcomes data will be completed. Wales Research Ethics Committee 6 granted approval for the trial in September 2016. Health Care Research Wales Research Permissions and the HRA have granted approval for the study. Patient recruitment commenced in February 2017. Planned dissemination is through publication in a peer-reviewed Emergency Medicine Journal, presentation at appropriate conferences and to stakeholders at Professional Meetings. © 2017, 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.

Clinical Knowledge from Observational Studies: Everything You Wanted to Know but Were Afraid to Ask.

PubMed

Gershon, Andrea S; Jafarzadeh, S Reza; Wilson, Kevin C; Walkey, Allan J

2018-05-07

Well-done randomized trials provide accurate estimates of treatment effect by producing groups that are similar on all measures except for the intervention of interest. However, inferences of efficacy in tightly-controlled experimental settings may not translate into similar effectiveness in real-world settings. Observational studies generally enable inferences over a wider range of patient characteristics and evaluation of a broader range of outcomes over a longer period than randomized trials. However, clinicians are often reluctant to incorporate the findings of observational studies into clinical practice. Reason for uncertainty regarding observational studies include a lack of familiarity with observational research methods, occasional disagreements between results of observational studies and randomized trials, the perceived risk of spurious results from systematic bias, and prior teaching that randomized trials are the most reliable source of medical evidence. We propose that a better understanding of observational research will enhance clinicians' ability to distinguish reliable observational studies from those that are subjected to biases and, therefore, provide more confidence to apply observational research results into clinical practice when appropriate. Herein, we explain why observational studies may be perceived as less conclusive than randomized trials, address situations in which observational research and randomized trials produced different findings, and provide information on observational study design so that quality can be evaluated. We conclude that observational research is a valuable source of medical evidence and that clinical action is strongest when supported by both high quality observational studies and randomized trials.

Rationale and design of the Tanzania Vitamin and HIV Infection Trial.

PubMed

Fawzi, W W; Msamanga, G I; Spiegelman, D; Urassa, E J; Hunter, D J

1999-02-01

We present the rationale and design of a randomized, double-blind, placebo-controlled trial of vitamin supplements among HIV-positive pregnant women in Dar es Salaam, Tanzania. Higher levels of intake of vitamins A, B, C, and E may decrease the risk of vertical transmission and progression of HIV infection by enhancing maternal and infant immune function; by reducing viral load in the blood, breast milk, or lower genital tract secretions; and/or by strengthening the placental barrier to infection. Eligible pregnant women were randomized to receive vitamin A, multivitamins excluding A, vitamin A and multivitamins, or placebo. The main endpoints include vertical transmission of HIV infection, as assessed by examination of infection in infants using polymerase chain reaction (PCR), and progression of HIV disease as measured by the WHO clinical staging system. Over a period of 2 years, 13,876 women were tested for HIV infection, with appropriate pre- and posttest counseling, to enroll 1085 consenting HIV-positive women. The trial assesses women and their children once a month for a minimum of 18 months after delivery or up to the end of this 5-year study. We examine recruitment strategies and means of enhancing cohort retention in long-term follow-up. We assess compliance with the use of supplements by direct questioning, by counting pills, and biochemically by using serum beta-carotene and urine riboflavin levels. Briefly, we discuss ethical issues related to the conduct of AIDS prevention trials in this setting. In sub-Saharan Africa, most HIV-infected persons lack access to the relevant antiretroviral and prophylactic drugs, and the region urgently needs low-cost treatments and preventive strategies. The Tanzania trial should provide valuable data to address the effect of vitamin supplements in the transmission and progression of HIV infection.

Oral paracetamol versus oral ibuprofen for closure of haemodynamically significant patent ductus arteriosus in preterm neonates (<32 weeks): a blinded, randomised, active-controlled, non-inferiority trial

PubMed Central

Kumar, Ashutosh; Sundaram, Venkataseshan; Yadav, Rahul; Oleti, Tejo Pratap; Murki, Srinivas; Krishna, Arun; Sundaram, Mangalabharathi; Saini, Shiv Sajan; Dutta, Sourabh

2017-01-01

Introduction Haemodynamically significant patent ductus arteriosus (hsPDA) is a common cause of mortality and morbidity in preterm infants. Existing medical therapies with ibuprofen or indomethacin have multiple adverse effects. Hence, an alternative drug like paracetamol given through oral route with less side effects need to be tested in an appropriate study design with least risk of bias to arrive at a conclusion. Methods and analysis Multisite, randomised, active-controlled, non-inferiority design. The primary objective is to study the efficacy of oral paracetamol for closure of hsPDA in comparison to oral ibuprofen in preterm neonates of <32 weeks’ gestation. Randomisation web-based and allocation concealment would be done; the treating team, investigators, outcome assessors and laboratory personnel would be blinded from the intervention. Echocardiography images would be coded for independent review. Closure of PDA by the end of last dose of study drug or earlier would be the study endpoint. A sample size of 196 neonates would be enrolled with a non-inferiority margin of 15%. Both intention-to-treat and per-protocol analysis will be done to assess the effect of contamination and protocol violations in the primary outcome. Ethics and dissemination The trial would follow international code of ethics for clinical trial. The trial protocol was approved by the Institute Ethics Committee of all three centres. All serious adverse events would be reported in detail to the Institute Ethics Committee. A written informed consent would be obtained from one of the parents. No plan has been made for dissemination. Trial registration number CTRI/2014/08/004805. PMID:29637155

Assessment of Suicidal Ideation and Behavior: Report of the International Society for CNS Clinical Trials and Methodology Consensus Meeting.

PubMed

Chappell, Phillip B; Stewart, Michelle; Alphs, Larry; DiCesare, Franco; DuBrava, Sarah; Harkavy-Friedman, Jill; Lim, Pilar; Ratcliffe, Sian; Silverman, Morton M; Targum, Steven D; Marder, Stephen R

2017-06-01

To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials. Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17-18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting. Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting. Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded. All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions. © Copyright 2017 Physicians Postgraduate Press, Inc.

Progressive Staging of Pilot Studies to Improve Phase III Trials for Motor Interventions

PubMed Central

Dobkin, Bruce H.

2014-01-01

Based on the suboptimal research pathways that finally led to multicenter randomized clinical trials (MRCTs) of treadmill training with partial body weight support and of robotic assistive devices, strategically planned successive stages are proposed for pilot studies of novel rehabilitation interventions Stage 1, consideration-of-concept studies, drawn from animal experiments, theories, and observations, delineate the experimental intervention in a small convenience sample of participants, so the results must be interpreted with caution. Stage 2, development-of-concept pilots, should optimize the components of the intervention, settle on most appropriate outcome measures, and examine dose-response effects. A well-designed study that reveals no efficacy should be published to counterweight the confirmation bias of positive trials. Stage 3, demonstration-of-concept pilots, can build out from what has been learned to test at least 15 participants in each arm, using random assignment and blinded outcome measures. A control group should receive an active practice intervention aimed at the same primary outcome. A third arm could receive a substantially larger dose of the experimental therapy or a combinational intervention. If only 1 site performed this trial, a different investigative group should aim to reproduce positive outcomes based on the optimal dose of motor training. Stage 3 studies ought to suggest an effect size of 0.4 or higher, so that approximately 50 participants in each arm will be the number required to test for efficacy in a stage 4, proof-of-concept MRCT. By developing a consensus around acceptable and necessary practices for each stage, similar to CONSORT recommendations for the publication of phase III clinical trials, better quality pilot studies may move quickly into better designed and more successful MRCTs of experimental interventions. PMID:19240197

Focus on Function – a randomized controlled trial comparing two rehabilitation interventions for young children with cerebral palsy

PubMed Central

Law, Mary; Darrah, Johanna; Pollock, Nancy; Rosenbaum, Peter; Russell, Dianne; Walter, Stephen D; Petrenchik, Theresa; Wilson, Brenda; Wright, Virginia

2007-01-01

Background Children with cerebral palsy receive a variety of long-term physical and occupational therapy interventions to facilitate development and to enhance functional independence in movement, self-care, play, school activities and leisure. Considerable human and financial resources are directed at the "intervention" of the problems of cerebral palsy, although the available evidence supporting current interventions is inconclusive. A considerable degree of uncertainty remains about the appropriate therapeutic approaches to manage the habilitation of children with cerebral palsy. The primary objective of this project is to conduct a multi-site randomized clinical trial to evaluate the efficacy of a task/context-focused approach compared to a child-focused remediation approach in improving performance of functional tasks and mobility, increasing participation in everyday activities, and improving quality of life in children 12 months to 5 years of age who have cerebral palsy. Method/Design A multi-centred randomized controlled trial research design will be used. Children will be recruited from a representative sample of children attending publicly-funded regional children's rehabilitation centers serving children with disabilities in Ontario and Alberta in Canada. Target sample size is 220 children with cerebral palsy aged 12 months to 5 years at recruitment date. Therapists are randomly assigned to deliver either a context-focused approach or a child-focused approach. Children follow their therapist into their treatment arm. Outcomes will be evaluated at baseline, after 6 months of treatment and at a 3-month follow-up period. Outcomes represent the components of the International Classification of Functioning, Disability and Health, including body function and structure (range of motion), activities (performance of functional tasks, motor function), participation (involvement in formal and informal activities), and environment (parent perceptions of care, parental empowerment). Discussion This paper presents the background information, design and protocol for a randomized controlled trial comparing a task/context-focused approach to a child-focused remediation approach in improving functional outcomes for young children with cerebral palsy. Trial registration [clinical trial registration #: NCT00469872] PMID:17900362

Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

PubMed Central

Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

2017-01-01

Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery, particularly in the TMJ field, by proposing a rigorous design in black Merino sheep. The authors also intend to test the feasibility of pilot outcomes. The authors expect to increase the quality of further studies in this field and to progress in future treatment options for patients undergoing surgery for TMJ disk replacement. Conclusions The study has commenced, but it is too early to provide results or conclusions. PMID:28254733

Systems analysis and improvement to optimize pMTCT (SAIA): a cluster randomized trial

PubMed Central

2014-01-01

Background Despite significant increases in global health investment and the availability of low-cost, efficacious interventions to prevent mother-to-child HIV transmission (pMTCT) in low- and middle-income countries with high HIV burden, the translation of scientific advances into effective delivery strategies has been slow, uneven and incomplete. As a result, pediatric HIV infection remains largely uncontrolled. A five-step, facility-level systems analysis and improvement intervention (SAIA) was designed to maximize effectiveness of pMTCT service provision by improving understanding of inefficiencies (step one: cascade analysis), guiding identification and prioritization of low-cost workflow modifications (step two: value stream mapping), and iteratively testing and redesigning these modifications (steps three through five). This protocol describes the SAIA intervention and methods to evaluate the intervention’s impact on reducing drop-offs along the pMTCT cascade. Methods This study employs a two-arm, longitudinal cluster randomized trial design. The unit of randomization is the health facility. A total of 90 facilities were identified in Côte d’Ivoire, Kenya and Mozambique (30 per country). A subset was randomly selected and assigned to intervention and comparison arms, stratified by country and service volume, resulting in 18 intervention and 18 comparison facilities across all three countries, with six intervention and six comparison facilities per country. The SAIA intervention will be implemented for six months in the 18 intervention facilities. Primary trial outcomes are designed to assess improvements in the pMTCT service cascade, and include the percentage of pregnant women being tested for HIV at the first antenatal care visit, the percentage of HIV-infected pregnant women receiving adequate prophylaxis or combination antiretroviral therapy in pregnancy, and the percentage of newborns exposed to HIV in pregnancy receiving an HIV diagnosis eight weeks postpartum. The Consolidated Framework for Implementation Research (CFIR) will guide collection and analysis of qualitative data on implementation process. Discussion This study is a pragmatic trial that has the potential benefit of improving maternal and infant outcomes by reducing drop-offs along the pMTCT cascade. The SAIA intervention is designed to provide simple tools to guide decision-making for pMTCT program staff at the facility level, and to identify low cost, contextually appropriate pMTCT improvement strategies. Trial registration ClinicalTrials.gov NCT02023658 PMID:24885976

A methodology for assessing the effect of correlations among muscle synergy activations on task-discriminating information.

PubMed

Delis, Ioannis; Berret, Bastien; Pozzo, Thierry; Panzeri, Stefano

2013-01-01

Muscle synergies have been hypothesized to be the building blocks used by the central nervous system to generate movement. According to this hypothesis, the accomplishment of various motor tasks relies on the ability of the motor system to recruit a small set of synergies on a single-trial basis and combine them in a task-dependent manner. It is conceivable that this requires a fine tuning of the trial-to-trial relationships between the synergy activations. Here we develop an analytical methodology to address the nature and functional role of trial-to-trial correlations between synergy activations, which is designed to help to better understand how these correlations may contribute to generating appropriate motor behavior. The algorithm we propose first divides correlations between muscle synergies into types (noise correlations, quantifying the trial-to-trial covariations of synergy activations at fixed task, and signal correlations, quantifying the similarity of task tuning of the trial-averaged activation coefficients of different synergies), and then uses single-trial methods (task-decoding and information theory) to quantify their overall effect on the task-discriminating information carried by muscle synergy activations. We apply the method to both synchronous and time-varying synergies and exemplify it on electromyographic data recorded during performance of reaching movements in different directions. Our method reveals the robust presence of information-enhancing patterns of signal and noise correlations among pairs of synchronous synergies, and shows that they enhance by 9-15% (depending on the set of tasks) the task-discriminating information provided by the synergy decompositions. We suggest that the proposed methodology could be useful for assessing whether single-trial activations of one synergy depend on activations of other synergies and quantifying the effect of such dependences on the task-to-task differences in muscle activation patterns.

Narrative review of yoga intervention clinical trials including weight-related outcomes.

PubMed

Rioux, Jennifer Grace; Ritenbaugh, Cheryl

2013-01-01

Medical authorities have identified obesity as a causal factor in the development of diabetes, hypertension, and cardiovascular disease (CVD), and more broadly, of metabolic syndrome/insulin resistance syndrome. To provide solutions that can modify this risk factor, researchers need to identify methods of effective risk reduction and primary prevention of obesity. Research on the effectiveness of yoga as a treatment for obesity is limited, and studies vary in overall quality and methodological rigor. This narrative review assessed the quantity and quality of clinical trials of yoga as an intervention for weight loss or as a means of risk reduction or treatment for obesity and diseases in which obesity is a causal factor. This review summarized the studies' research designs and evaluated the efficacy of yoga for weight loss via the current evidence base. The research team evaluated published studies to determine the appropriateness of research designs, comparability of programs' intervention elements, and standardization of outcome measures. The research team's literature search used the key terms yoga and obesity or yoga and weight loss in three primary medical-literature databases (PubMed, PsychInfo, and Web of Science). The study excluded clinical trials with no quantitative obesity related measure. Extracted data included each study's (1) design; (2) setting and population; (3) nature, duration, and frequency of interventions; (4) comparison groups; (5) recruitment strategies; (6) outcome measures; (7) data analysis and presentation; and (8) results and conclusions. The research team developed an overall evaluation parameter to compare disparate trials. The research team reviewed each study to determine its key features, each worth a specified number of points, with a maximum total of 20 points. The features included a study's (1) duration, (2) frequency of yoga practice, (3) intensity of (length of) each practice, (4) number of yogic elements, (5) inclusion of dietary modification, (6) inclusion of a residential component, (7) the number of weight-related outcome measures, and (8) a discussion of the details of the yogic elements. Overall, therapeutic yoga programs are frequently effective in promoting weight loss and/or improvements in body composition. The effectiveness of yoga for weight loss is related to the following key features: (1) an increased frequency of practice; (2) a longer intervention duration (3) a yogic dietary component; (4) a residential component; (5) the comprehensive inclusion of yogic components; (5) and a home-practice component. Yoga appears to be an appropriate and potentially successful intervention for weight maintenance, prevention of obesity, and risk reduction for diseases in which obesity plays a significant causal role.

Antitumor Efficacy Testing in Rodents

PubMed Central

2008-01-01

The preclinical research and human clinical trials necessary for developing anticancer therapeutics are costly. One contributor to these costs is preclinical rodent efficacy studies, which, in addition to the costs associated with conducting them, often guide the selection of agents for clinical development. If inappropriate or inaccurate recommendations are made on the basis of these preclinical studies, then additional costs are incurred. In this commentary, I discuss the issues associated with preclinical rodent efficacy studies. These include the identification of proper preclinical efficacy models, the selection of appropriate experimental endpoints, and the correct statistical evaluation of the resulting data. I also describe important experimental design considerations, such as selecting the drug vehicle, optimizing the therapeutic treatment plan, properly powering the experiment by defining appropriate numbers of replicates in each treatment arm, and proper randomization. Improved preclinical selection criteria can aid in reducing unnecessary human studies, thus reducing the overall costs of anticancer drug development. PMID:18957675

The impact of drugs for multiple sclerosis on sleep.

PubMed

Lanza, Giuseppe; Ferri, Raffaele; Bella, Rita; Ferini-Strambi, Luigi

2017-01-01

Although there is a growing literature on the presence of sleep disorders in multiple sclerosis (MS), few studies have specifically addressed the impact of drugs on sleep of these patients. Moreover, even when sleep is considered, quantitative assessment by standardized questionnaires or polysomnography is lacking. The studies that have been done highlight that interferon-beta and some symptomatic medications may affect sleep, thus contributing to fatigue, depression, and poor quality of life; conversely, natalizumab and cannabinoids may improve sleep. Common limitations of the literature reviewed here are small sample size, selection bias, and often a lack of objective outcome measures. Clinicians need to remember to ask about sleep in all MS patients and intervene when appropriate. A systematic approach that takes sleep into account is recommended to enhance recognition and appropriate management of sleep disruption, including disorders related to medication. Consideration of the impact on sleep should also be part of the design of trials of new therapies.

Resource implications of preparing individual participant data from a clinical trial to share with external researchers.

PubMed

Tudur Smith, Catrin; Nevitt, Sarah; Appelbe, Duncan; Appleton, Richard; Dixon, Pete; Harrison, Janet; Marson, Anthony; Williamson, Paula; Tremain, Elizabeth

2017-07-17

Demands are increasingly being made for clinical trialists to actively share individual participant data (IPD) collected from clinical trials using responsible methods that protect the confidentiality and privacy of clinical trial participants. Clinical trialists, particularly those receiving public funding, are often concerned about the additional time and money that data-sharing activities will require, but few published empirical data are available to help inform these decisions. We sought to evaluate the activity and resources required to prepare anonymised IPD from a clinical trial in anticipation of a future data-sharing request. Data from two UK publicly funded clinical trials were used for this exercise: 2437 participants with epilepsy recruited from 90 hospital outpatient clinics in the SANAD trial and 146 children with neuro-developmental problems recruited from 18 hospitals in the MENDS trial. We calculated the time and resources required to prepare each anonymised dataset and assemble a data pack ready for sharing. The older SANAD trial (published 2007) required 50 hours of staff time with a total estimated associated cost of £3185 whilst the more recently completed MENDS trial (published 2012) required 39.5 hours of staff time with total estimated associated cost of £2540. Clinical trial researchers, funders and sponsors should consider appropriate resourcing and allow reasonable time for preparing IPD ready for subsequent sharing. This process would be most efficient if prospectively built into the standard operational design and conduct of a clinical trial. Further empirical examples exploring the resource requirements in other settings is recommended. SANAD: International Standard Randomised Controlled Trials Registry: ISRCTN38354748 . Registered on 25 April 2003. EU Clinical Trials Register Eudract 2006-004025-28 . Registered on 16 May 2007. International Standard Randomised Controlled Trials Registry: ISRCTN05534585 /MREC 07/MRE08/43. Registered on 26 January 2007.

Oral Antibacterial Therapy for Acne Vulgaris: An Evidence-Based Review.

PubMed

Bienenfeld, Amanda; Nagler, Arielle R; Orlow, Seth J

2017-08-01

To some degree, acne vulgaris affects nearly every individual worldwide. Oral antibiotic therapy is routinely prescribed for the treatment of moderate to severe inflammatory acne; however, long-term use of oral antibiotics for acne may have unintended consequences. The aim of this study was to provide a systematic evaluation of the scientific evidence on the efficacy and appropriate use of oral antibiotics in the treatment of acne. A systematic search of MEDLINE was conducted to identify randomized controlled clinical trials, systematic reviews, and meta-analyses evaluating the efficacy of oral antibiotics for acne. Overall, 41 articles that examined oral antibiotics compared with placebo, another oral therapy, topical therapy, alternate dose, or duration were included in this study. Tetracyclines, macrolides, and trimethoprim/sulfamethoxazole are effective and safe in the treatment of moderate to severe inflammatory acne. Superior efficacy of one type or class of antibiotic could not be determined, therefore the choice of antibiotic is generally based on the side-effect profile. Although different dosing regimens have been studied, there is a lack of standardized comparator trials to determine optimal dosing and duration of each oral antibiotic used in acne. The combination of oral antibiotics with a topical therapy is superior to oral antibiotics alone. This article provides a systematic evaluation of the scientific evidence of the efficacy of oral antibiotics for acne. Due to heterogeneity in the design of the trials, there is insufficient evidence to support one type, dose, or duration of oral antibiotic over another in terms of efficacy; however, due to increasing resistance to antibiotics, dermatologists should heed consensus guidelines for their appropriate use.

Methodologic issues in assessing the quality of life of cancer patients.

PubMed

Aaronson, N K

1991-02-01

Although quality of life assessments have been employed successfully in descriptive and evaluative studies in oncology, their use in cancer clinical trials has, to date, been limited. A range of issues have impeded the conduct of clinical trial-based quality of life investigations. These include: the absence of theoretical models to guide the development of quality of life measures; over-reliance on ad hoc approaches to quality of life assessment; and insufficient attention to the practical constraints operating in clinical research settings. Of primary importance is the need to develop multidimensional quality of life instruments that are brief and psychometrically robust. It is suggested that future work on instrument development focus on refining currently available generic or cancer-specific measures, and on developing new diagnostic-specific questionnaire modules. This psychometric work should be guided by appropriate theoretical models of the relationship among health-related quality of life domains. Although it is widely accepted that the patient represents the most appropriate source of quality of life data, it is suggested that efforts also be directed toward improving the validity and reliability of physician-generated assessments of patients' performance status and of treatment toxicities, and toward determining the feasibility of employing family members as proxy raters of the psychologic and social health status of patients who are unwilling or unable to provide such information. Additional attention should be paid to the many logistical problems that arise in clinical trial-based quality of life investigations. In particular, research designs and data collection procedures should be selected that minimize patient, medical staff, and institutional burden.

Rationale and design of a randomized trial to evaluate an evidence-based prescription drug label on actual medication use.

PubMed

Shrank, William H; Parker, Ruth; Davis, Terry; Pandit, Anjali U; Knox, Joann P; Moraras, Pear; Rademaker, Alfred; Wolf, Michael S

2010-11-01

Medication errors are an important public health concern, and poor understanding of medication labels are a root cause. Research shows that labels are variable, of poor quality, and not patient-centered. No real-world trials have evaluated whether improved medication labels can affect appropriate medication use, adherence or health outcomes. We developed an evidence-based prescription label that addresses both content and format. The enhanced label includes a universal medication schedule (UMS) that standardizes the directions for use incorporating 1) standard time periods for administration (morning, noon, evening, and bedtime), 2) numeric vs. alpha characters, 3) 'carriage returns' to separate daily dose and 4) a graphic aid to visually depict dose and frequency. We will evaluate the effect of providing this label to randomly sampled patients who receive their care from free clinics, mobile vans and federally qualified health centers (FQHCs) in Northern Virginia. We will recruit patients with diabetes or hypertension; these patients will be randomly assigned to receive all of their medications with improved labels or to receive prescriptions with standard labels. The primary outcome will be the patient's ability to correctly demonstrate dosing instructions. Other outcomes include adherence, error rates and health outcomes. To our knowledge, this trial is the first to evaluate the effect of prescription label improvement on understanding, medication use and outcomes in a clinical setting. If successful, these findings could be implemented broadly to promote safe and appropriate medication use and to support evidence-based standards in the development of labels. Copyright © 2010 Elsevier Inc. All rights reserved.

Structuring communication relationships for interprofessional teamwork (SCRIPT): a cluster randomized controlled trial

PubMed Central

Zwarenstein, Merrick; Reeves, Scott; Russell, Ann; Kenaszchuk, Chris; Conn, Lesley Gotlib; Miller, Karen-Lee; Lingard, Lorelei; Thorpe, Kevin E

2007-01-01

Background Despite a burgeoning interest in using interprofessional approaches to promote effective collaboration in health care, systematic reviews find scant evidence of benefit. This protocol describes the first cluster randomized controlled trial (RCT) to design and evaluate an intervention intended to improve interprofessional collaborative communication and patient-centred care. Objectives The objective is to evaluate the effects of a four-component, hospital-based staff communication protocol designed to promote collaborative communication between healthcare professionals and enhance patient-centred care. Methods The study is a multi-centre mixed-methods cluster randomized controlled trial involving twenty clinical teaching teams (CTTs) in general internal medicine (GIM) divisions of five Toronto tertiary-care hospitals. CTTs will be randomly assigned either to receive an intervention designed to improve interprofessional collaborative communication, or to continue usual communication practices. Non-participant naturalistic observation, shadowing, and semi-structured, qualitative interviews were conducted to explore existing patterns of interprofessional collaboration in the CTTs, and to support intervention development. Interviews and shadowing will continue during intervention delivery in order to document interactions between the intervention settings and adopters, and changes in interprofessional communication. The primary outcome is the rate of unplanned hospital readmission. Secondary outcomes are length of stay (LOS); adherence to evidence-based prescription drug therapy; patients' satisfaction with care; self-report surveys of CTT staff perceptions of interprofessional collaboration; and frequency of calls to paging devices. Outcomes will be compared on an intention-to-treat basis using adjustment methods appropriate for data from a cluster randomized design. Discussion Pre-intervention qualitative analysis revealed that a substantial amount of interprofessional interaction lacks key core elements of collaborative communication such as self-introduction, description of professional role, and solicitation of other professional perspectives. Incorporating these findings, a four-component intervention was designed with a goal of creating a culture of communication in which the fundamentals of collaboration become a routine part of interprofessional interactions during unstructured work periods on GIM wards. Trial registration Registered with National Institutes of Health as NCT00466297. PMID:17877830

Rationale, design and methods for a randomised and controlled trial to evaluate "Animal Fun"--a program designed to enhance physical and mental health in young children.

PubMed

Piek, Jan P; Straker, Leon M; Jensen, Lynn; Dender, Alma; Barrett, Nicholas C; McLaren, Sue; Roberts, Clare; Reid, Carly; Rooney, Rosie; Packer, Tanya; Bradbury, Greer; Elsley, Sharon

2010-11-04

Children with poor motor ability have been found to engage less in physical activities than other children, and a lack of physical activity has been linked to problems such as obesity, lowered bone mineral density and cardiovascular risk factors. Furthermore, if children are confident with their fine and gross motor skills, they are more likely to engage in physical activities such as sports, crafts, dancing and other physical activity programs outside of the school curriculum which are important activities for psychosocial development. The primary objective of this project is to comprehensively evaluate a whole of class physical activity program called Animal Fun designed for Pre-Primary children. This program was designed to improve the child's movement skills, both fine and gross, and their perceptions of their movement ability, promote appropriate social skills and improve social-emotional development. The proposed randomized and controlled trial uses a multivariate nested cohort design to examine the physical (motor coordination) and psychosocial (self perceptions, anxiety, social competence) outcomes of the program. The Animal Fun program is a teacher delivered universal program incorporating animal actions to facilitate motor skill and social skill acquisition and practice. Pre-intervention scores on motor and psychosocial variables for six control schools and six intervention schools will be compared with post-intervention scores (end of Pre-Primary year) and scores taken 12 months later after the children's transition to primary school Year 1. 520 children aged 4.5 to 6 years will be recruited and it is anticipated that 360 children will be retained to the 1 year follow-up. There will be equal numbers of boys and girls. If this program is found to improve the child's motor and psychosocial skills, this will assist in the child's transition into the first year of school. As a result of these changes, it is anticipated that children will have greater enjoyment participating in physical activities which will further promote long term physical and mental health. This trial is registered in the Australian and New Zealand Clinical trials Registry (ACTRN12609000869279).

Pharmacologic studies in vulnerable populations: Using the pediatric experience.

PubMed

Zimmerman, Kanecia; Gonzalez, Daniel; Swamy, Geeta K; Cohen-Wolkowiez, Michael

2015-11-01

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, pediatric thought leadership, and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women. Copyright © 2015 Elsevier Inc. All rights reserved.

A critical appraisal of the reporting quality of published randomized controlled trials in the fall injuries.

PubMed

Asghari Jafarabadi, Mohammad; Sadeghi-Bazrgani, Homayoun; Dianat, Iman

2018-06-01

To evaluate the quality of reporting in published randomized controlled trials (RTCs) in the field of fall injuries. The 188 RTCs published between 2001 and 2011, indexed in EMBASE and Medline databases were extracted through searching by appropriate keywords and EMTree classification terms. The evaluation trustworthiness was assured through parallel evaluations of two experts in epidemiology and biostatistics. About 40%-75% of papers had problems in reporting random allocation method, allocation concealment, random allocation implementation, blinding and similarity among groups, intention to treat and balancing benefits and harms. Moreover, at least 10% of papers inappropriately/not reported the design, protocol violations, sample size justification, subgroup/adjusted analyses, presenting flow diagram, drop outs, recruitment time, baseline data, suitable effect size on outcome, ancillary analyses, limitations and generalizability. Considering the shortcomings found and due to the importance of the RCTs for fall injury prevention programmes, their reporting quality should be improved.

Comparing strategies to assess multiple behavior change in behavioral intervention studies.

PubMed

Drake, Bettina F; Quintiliani, Lisa M; Sapp, Amy L; Li, Yi; Harley, Amy E; Emmons, Karen M; Sorensen, Glorian

2013-03-01

Alternatives to individual behavior change methods have been proposed, however, little has been done to investigate how these methods compare. To explore four methods that quantify change in multiple risk behaviors targeting four common behaviors. We utilized data from two cluster-randomized, multiple behavior change trials conducted in two settings: small businesses and health centers. Methods used were: (1) summative; (2) z-score; (3) optimal linear combination; and (4) impact score. In the Small Business study, methods 2 and 3 revealed similar outcomes. However, physical activity did not contribute to method 3. In the Health Centers study, similar results were found with each of the methods. Multivitamin intake contributed significantly more to each of the summary measures than other behaviors. Selection of methods to assess multiple behavior change in intervention trials must consider study design, and the targeted population when determining the appropriate method/s to use.

Innovations in design and technology. The story of hip arthroplasty.

PubMed

Amstutz, H C

2000-09-01

The current study reviews the early history of surgeon-initiated trial and error development in hip joint arthroplasty and the subsequent methodological evolution to proper criteria for hypothesis testing using bioengineers and other research scientists. The interplay and relationships to industry, universities, scientific organizations, and the Food and Drug Administration with respect to device development in hip arthroplasty are reviewed. The ethics of and responsibilities to involved parties are outlined, citing the history of many contemporary developments. Examples are provided from the evolution and introduction of unsuccessful innovations, and the problems inherent in the current methodology of the approval process from the Food and Drug Administration using the 5-10K, Investigative Device Exemption, and the Pre-Market Approval protocols. The pros and cons of randomized trials for devices are outlined with the conclusion that they are not appropriate for device introduction. The proper, rational methodology for introduction of new devices is a phased-in clinical trial process after pertinent bench testing. Finally, the ethical dilemmas created by managed care are addressed. Industry involvements of the surgeon-spokesmen are cited.

Use of microbial cultures and antibiotics in the prevention of infection-associated preterm birth.

PubMed

Klein, Laura L; Gibbs, Ronald S

2004-06-01

The purpose of this study was to summarize recent evidence regarding infection-associated preterm birth and to make appropriate recommendations. Antepartum treatment of lower genital tract infection or bacterial colonization has been found to reduce the incidence of preterm birth in the case of asymptomatic bacteriuria and bacterial vaginosis in selected patients but has been proved to be ineffective for vaginal colonization with organisms such as Ureaplasma urealyticum and group B streptococcus. This is a clinical opinion based on a review of recent data related to 1) the association between lower genital tract infection and preterm birth and 2) antibiotic trials to prevent preterm birth. Antepartum treatment of lower genital tract infection or bacterial colonization has been found to reduce the incidence of preterm birth in the case of asymptomatic bacteriuria and bacterial vaginosis in selected patients, but has been proven to be ineffective for vaginal colonization with organisms such as Ureaplasma urealyticum and group B streptococcus. Large well-designed trials have shown that the routine administration of antibiotics to women with preterm labor and intact membranes is not beneficial; however, antibiotic regimens including macrolides are recommended for preterm premature rupture of the membranes. Large well-designed trials have shown that the routine administration of antibiotics to women with preterm labor and intact membranes is not beneficial; however, antibiotic regimens that include macrolides are recommended for preterm premature rupture of the membranes.

Platelet-rich plasma and other cellular strategies in orthopedic surgery.

PubMed

Williams, Phillip N; Moran, George; Bradley, James P; S ElAttrache, Neal; Dines, Joshua S

2015-03-01

The use of biologics in the treatment of musculoskeletal disease has become increasingly more common as research studies continue to provide further elucidation of their mechanisms in healing. Platelet-rich plasma, patches, growth factors, and stem cells are among the many biologics under active investigation and have varying levels of success in augmenting surgical or nonoperative interventions. However, the limitations of these treatments exist, and clear guidelines for their indications and application have yet to be established. Well-designed clinical trials will help determine the appropriate future use of biologics to ensure consistent outcomes.

Assessment and Management of Hypertension in Patients on Dialysis

PubMed Central

Flynn, Joseph; Pogue, Velvie; Rahman, Mahboob; Reisin, Efrain; Weir, Matthew R.

2014-01-01

Hypertension is common, difficult to diagnose, and poorly controlled among patients with ESRD. However, controversy surrounds the diagnosis and treatment of hypertension. Here, we describe the diagnosis, epidemiology, and management of hypertension in dialysis patients, and examine the data sparking debate over appropriate methods for diagnosing and treating hypertension. Furthermore, we consider the issues uniquely related to hypertension in pediatric dialysis patients. Future clinical trials designed to clarify the controversial results discussed here should lead to the implementation of diagnostic and therapeutic techniques that improve long-term cardiovascular outcomes in patients with ESRD. PMID:24700870

Prepare, a randomized trial to promote and evaluate weight loss among overweight and obese women planning pregnancy: Study design and rationale

PubMed Central

Vesco, Kimberly K.; Funk, Kristine L.; Karanja, Njeri; Smith, Ning; Stevens, Victor J.

2017-01-01

Background Women who are overweight or have obesity at pregnancy onset, and those who gain excessive weight during pregnancy, are at increased risk of pregnancy-related complications and large for gestational age infants. Objective This report describes methodology for the Prepare study, a randomized, controlled clinical trial testing a preconception and pregnancy weight management program for women who are overweight or have obesity (BMI ≥ 27 kg/m2). Outcomes This trial examines multiple pregnancy and neonatal outcomes, with the primary outcome being gestational weight gain (GWG). Secondary outcomes include change in weight before conception, offspring birth weight adjusted for gestational age, offspring weight for length, and pregnancy diet quality and physical activity level. Methods Nonpregnant women who anticipate becoming pregnant in the next 2 years are randomly assigned to an intervention program or a usual care control condition. Intervention participants receive weight management counseling by telephone before and during pregnancy, with weekly contacts during the first 6 months and monthly contacts for the next 18 months. Intervention participants also have unlimited access to a study website that provides self-management tools. All participants who become pregnant are contacted at 20 weeks' gestation to assess physical activity levels and dietary habits. All other outcome data are obtained from medical records. Intervention satisfaction is assessed via questionnaire. Summary This clinical trial tests the efficacy of an intervention program designed to help overweight and obese women achieve healthy lifestyle changes that will result in a healthy weight prior to pregnancy and appropriate weight gain during pregnancy. PMID:27394386

Fundamental movement skill interventions in youth: a systematic review and meta-analysis.

PubMed

Morgan, Philip J; Barnett, Lisa M; Cliff, Dylan P; Okely, Anthony D; Scott, Hayley A; Cohen, Kristen E; Lubans, David R

2013-11-01

Fundamental movement skill (FMS) proficiency is positively associated with physical activity and fitness levels. The objective of this study was to systematically review evidence for the benefits of FMS interventions targeting youth. A search with no date restrictions was conducted across 7 databases. Studies included any school-, home-, or community-based intervention for typically developing youth with clear intent to improve FMS proficiency and that reported statistical analysis of FMS competence at both preintervention and at least 1 other postintervention time point. Study designs included randomized controlled trials (RCTs) using experimental and quasi-experimental designs and single group pre-post trials. Risk of bias was independently assessed by 2 reviewers. Twenty-two articles (6 RCTs, 13 quasi-experimental trials, 3 pre-post trials) describing 19 interventions were included. All but 1 intervention were evaluated in primary/elementary schools. All studies reported significant intervention effects for ≥ 1 FMS. Meta-analyses revealed large effect sizes for overall gross motor proficiency (standardized mean difference [SMD] = 1.42, 95% confidence interval [CI] 0.68-2.16, Z = 3.77, P < .0002) and locomotor skill competency (SMD = 1.42, 95% CI 0.56-2.27, Z = 3.25, P = .001). A medium effect size for object control skill competency was observed (SMD = 0.63, 95% CI 0.28-0.98, Z = 3.53, P = .0004). Many studies scored poorly for risk of bias items. School- and community-based programs that include developmentally appropriate FMS learning experiences delivered by physical education specialists or highly trained classroom teachers significantly improve FMS proficiency in youth.

Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer’s Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force

PubMed Central

Soto, M.; Abushakra, S.; Cummings, J.; Siffert, J.; Robert, P.; Vellas, B.; Lyketsos, C.G.

2015-01-01

BACKGROUND The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes. PMID:26413494

A proof of concept phase II non-inferiority criterion.

PubMed

Neuenschwander, Beat; Rouyrre, Nicolas; Hollaender, Norbert; Zuber, Emmanuel; Branson, Michael

2011-06-15

Traditional phase III non-inferiority trials require compelling evidence that the treatment vs control effect bfθ is better than a pre-specified non-inferiority margin θ(NI) . The standard approach compares this margin to the 95 per cent confidence interval of the effect parameter. In the phase II setting, in order to declare Proof of Concept (PoC) for non-inferiority and proceed in the development of the drug, different criteria that are specifically tailored toward company internal decision making may be more appropriate. For example, less evidence may be needed as long as the effect estimate is reasonably convincing. We propose a non-inferiority design that addresses the specifics of the phase II setting. The requirements are that (1) the effect estimate be better than a critical threshold θ(C), and (2) the type I error with regard to θ(NI) is controlled at a pre-specified level. This design is compared with the traditional design from a frequentist as well as a Bayesian perspective, where the latter relies on the Level of Proof (LoP) metric, i.e. the probability that the true effect is better than effect values of interest. Clinical input is required to establish the value θ(C), which makes the design transparent and improves interactions within clinical teams. The proposed design is illustrated for a non-inferiority trial for a time-to-event endpoint in oncology. Copyright © 2011 John Wiley & Sons, Ltd.

Methodology for a trial of brain-centered versus anticholinergic therapy in women with urgency urinary incontinence.

PubMed

Komesu, Yuko M; Rogers, Rebecca G; Sapien, Robert E; Schrader, Ronald M; Simmerman-Sierra, Timothy; Mayer, Andrew R; Ketai, Loren H

2017-06-01

We describe the rationale and methodology for a study comparing mind-body treatment and pharmacotherapy in women with urgency urinary incontinence (UUI). To explore brain associations in UUI, a subset of patients will also undergo functional magnetic resonance imaging (fMRI). We hypothesize that hypnotherapy, a mind-body intervention, will be at least as effective as pharmacotherapy in treating UUI. We also hypothesize that fMRI findings will change following treatment, with changes potentially differing between groups. We describe the development and design challenges of a study comparing the efficacy of hypnotherapy and conventional pharmacotherapy in the treatment of UUI. The study randomizes women to either of these treatments, and outcome measures include bladder diaries and validated questionnaires. Sample size estimates, based on a noninferiority test (alpha = 0.025, beta = 0.20), after considering dropout subjects and subjects lost to follow-up, indicated that approximately 150 woman would be required to test the hypothesis that hypnotherapy is not inferior to pharmacotherapy within a 5 % noninferiority margin. The study will also evaluate fMRI changes in a subset of participants before and after therapy. Challenges included designing a study with a mind-body therapy and a comparison treatment equally acceptable to participants, standardizing the interventions, and confronting the reality that trials are time-consuming for participants who have to make appropriate accommodations in their schedule. Study enrollment began in March 2013 and is ongoing. We describe the design of a randomized controlled trial comparing mind-body therapy and pharmacotherapy in the treatment of UUI and the challenges encountered in its implementation.

Feedback GAP: study protocol for a cluster-randomized trial of goal setting and action plans to increase the effectiveness of audit and feedback interventions in primary care

PubMed Central

2010-01-01

Background Audit and feedback to physicians is commonly used alone or as part of multifaceted interventions. While it can play an important role in quality improvement, the optimal design of audit and feedback is unknown. This study explores how feedback can be improved to increase acceptability and usability in primary care. The trial seeks to determine whether a theory-informed worksheet appended to feedback reports can help family physicians improve quality of care for their patients with diabetes and/or ischemic heart disease. Methods Two-arm cluster trial was conducted with participating primary care practices allocated using minimization to simple feedback or enhanced feedback group. The simple feedback group receives performance feedback reports every six months for two years regarding the proportion of their patients with diabetes and/or ischemic heart disease who are meeting quality targets. The enhanced feedback group receives these same reports as well as a theory-informed worksheet designed to facilitate goal setting and action plan development in response to the feedback reports. Participants are family physicians from across Ontario who use electronic medical records; data for rostered patients are used to produce the feedback reports and for analysis. Outcomes The primary disease outcomes are the blood pressure (BP), and low-density lipoprotein cholesterol (LDL) levels. The primary process measure is a composite score indicating the number of recommended activities (e.g., tests and prescriptions) conducted by the family physicians for their patients with diabetes and/or ischemic heart disease within the appropriate timeframe. Secondary outcomes are the proportion of patients whose results meet targets for glucose, LDL, and BP as well as the percent of patients receiving relevant prescriptions. A qualitative process evaluation using semi-structured interviews will explore perceived barriers to behaviour change in response to feedback reports and preferences with regard to feedback design. Analysis Intention-to-treat approach will be used to analyze the trial. Analysis will be performed on patient-level variables using generalized estimating equation models to adjust for covariates and account for the clustered nature of the data. The trial is powered to show small, but clinically important differences of 7 mmHG in systolic BP and 0.32 mmol/L in LDL. Trial Registration ClinicalTrials.gov NCT00996645 PMID:21167034

Maternal adverse effects of different antenatal magnesium sulphate regimens for improving maternal and infant outcomes: a systematic review

PubMed Central

2013-01-01

Background Antenatal magnesium sulphate, widely used in obstetrics to improve maternal and infant outcomes, may be associated with adverse effects for the mother sufficient for treatment cessation. This systematic review aimed to quantify maternal adverse effects attributed to treatment, assess how adverse effects vary according to different regimens, and explore women’s experiences with this treatment. Methods Bibliographic databases were searched from their inceptions to July 2012 for studies of any design that reported on maternal adverse effects associated with antenatal magnesium sulphate given to improve maternal or infant outcomes. Primary outcomes were life-threatening adverse effects of treatment (death, cardiac arrest, respiratory arrest). For randomised controlled trials, data were meta-analysed, and risk ratios (RR) pooled using fixed-effects or random-effects models. For non-randomised studies, data were tabulated by design, and presented as RR, odds ratios or percentages, and summarised narratively. Results A total of 143 publications were included (21 randomised trials, 15 non-randomised comparative studies, 32 case series and 75 reports of individual cases), of mixed methodological quality. Compared with placebo or no treatment, magnesium sulphate was not associated with an increased risk of maternal death, cardiac arrest or respiratory arrest. Magnesium sulphate significantly increased the risk of 'any adverse effects’ overall (RR 4.62, 95% CI 2.42-8.83; 4 trials, 13,322 women), and treatment cessation due to adverse effects (RR 2.77; 95% CI 2.32-3.30; 5 trials, 13,666 women). Few subgroup differences were observed (between indications for use and treatment regimens). In one trial, a lower dose regimen (2 g/3 hours) compared with a higher dose regimen (5 g/4 hours) significantly reduced treatment cessation (RR 0.05; 95% CI 0.01-0.39, 126 women). Adverse effect estimates from studies of other designs largely supported data from randomised trials. Case reports supported an association between iatrogenic overdose of magnesium sulphate and life-threatening consequences. Conclusions Appropriate administration of antenatal magnesium sulphate was not shown to be associated with serious maternal adverse effects, though an increase in 'minor’ adverse effects and treatment cessation was shown. Larger trials are needed to determine optimal regimens, achieving maximal effectiveness with minimal adverse effects, for each antenatal indication for use. Vigilance in the use of magnesium sulphate is essential for women’s safety. PMID:24139447

Reporting of sample size calculations in analgesic clinical trials: ACTTION systematic review.

PubMed

McKeown, Andrew; Gewandter, Jennifer S; McDermott, Michael P; Pawlowski, Joseph R; Poli, Joseph J; Rothstein, Daniel; Farrar, John T; Gilron, Ian; Katz, Nathaniel P; Lin, Allison H; Rappaport, Bob A; Rowbotham, Michael C; Turk, Dennis C; Dworkin, Robert H; Smith, Shannon M

2015-03-01

Sample size calculations determine the number of participants required to have sufficiently high power to detect a given treatment effect. In this review, we examined the reporting quality of sample size calculations in 172 publications of double-blind randomized controlled trials of noninvasive pharmacologic or interventional (ie, invasive) pain treatments published in European Journal of Pain, Journal of Pain, and Pain from January 2006 through June 2013. Sixty-five percent of publications reported a sample size calculation but only 38% provided all elements required to replicate the calculated sample size. In publications reporting at least 1 element, 54% provided a justification for the treatment effect used to calculate sample size, and 24% of studies with continuous outcome variables justified the variability estimate. Publications of clinical pain condition trials reported a sample size calculation more frequently than experimental pain model trials (77% vs 33%, P < .001) but did not differ in the frequency of reporting all required elements. No significant differences in reporting of any or all elements were detected between publications of trials with industry and nonindustry sponsorship. Twenty-eight percent included a discrepancy between the reported number of planned and randomized participants. This study suggests that sample size calculation reporting in analgesic trial publications is usually incomplete. Investigators should provide detailed accounts of sample size calculations in publications of clinical trials of pain treatments, which is necessary for reporting transparency and communication of pre-trial design decisions. In this systematic review of analgesic clinical trials, sample size calculations and the required elements (eg, treatment effect to be detected; power level) were incompletely reported. A lack of transparency regarding sample size calculations may raise questions about the appropriateness of the calculated sample size. Copyright © 2015 American Pain Society. All rights reserved.

Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation.

PubMed

Patel, Hitesh C; Hayward, Carl; Ozdemir, Baris Ata; Rosen, Stuart D; Krum, Henry; Lyon, Alexander R; Francis, Darrel P; di Mario, Carlo

2015-02-01

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration-related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14-6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83-12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=-0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=-2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design. © 2014 American Heart Association, Inc.

Evaluation of a prototype interactive consent program for pediatric clinical trials: a pilot study

PubMed Central

Voepel-Lewis, Terri; McGonegal, Maureen; Levine, Robert

2011-01-01

Standard written methods of presenting research information may be difficult for many parents and children to understand. This pilot study was designed to examine the use of a novel prototype interactive consent program for describing a hypothetical pediatric asthma trial to parents and children. Parents and children were interviewed to examine their baseline understanding of key elements of a clinical trial, eg, randomization, placebo, and blinding. Subjects then reviewed age-appropriate versions of an interactive computer program describing an asthma trial, and their understanding of key research concepts was again tested along with their understanding of the details of the trial. Parents and children also completed surveys to examine their perceptions and satisfaction with the program. Both parents and children demonstrated improved understanding of key research concepts following administration of the consent program. For example, the percentage of parents and children who could correctly define the terms clinical trials and placebo improved from 60% to 80%, and 80% to 100% among parents and 25% to 50% and 0% to 50% among children, respectively, following review of the interactive programs. Parents and children's overall understanding of the details of the asthma trial were 14.2±0.84 and 9.25±4.9 (0–15 scale, where 15 is complete understanding), respectively. Results also suggest that the interactive programs were easy to use and facilitated understanding of the clinical trial among parents and children. Interactive media may offer an effective means of presenting understandable information to parents and children regarding participation in clinical trials. Further work to examine this novel approach appears warranted. PMID:21803924

Reminder packaging for improving adherence to self-administered long-term medications.

PubMed

Heneghan, C J; Glasziou, P; Perera, R

2006-01-25

Current methods of improving medication adherence for health problems are mostly complex, labour-intensive, and not reliably effective. Medication 'reminder packaging' which incorporates a date or time for a medication to be taken in the packaging, can act as a reminder system to improve adherence. The objective of this review was to determine the effects of reminder packaging to enhance patient adherence with self-administered medications taken for one month or more. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library Issue 3, 2004), MEDLINE, EMBASE, CINAHL and PsycINFO from the start of the databases to 1 September 2004. We also searched the internet, contacted packaging manufacturers, and checked abstracts from the Pharm-line database and reference lists from relevant articles. We did not apply any language restrictions. We selected randomised controlled trials with at least 80% follow up, comparing a reminder packaging device with no device in participants taking self-administered medications for a minimum of one month. Two reviewers independently assessed studies for inclusion, assessed quality, and extracted data from included studies. Where considered appropriate, data were combined for meta-analysis, or were reported and discussed in a narrative. Eight studies containing data on 1,137 participants were included. Six intervention groups in four trials provided data on the percentage of pills taken. Reminder packaging showed a significant increase in the percentage of pills taken, weighted mean difference 11% (95% confidence interval (CI) 6% to 17%). Notable heterogeneity occurred among these trials I(2 )= 96.3%. Two trials provided data for the proportion of self-reported adherent patients, reporting a reduction in the intervention group which was not statistically significant, odds ratio = 0.89 (95% CI 0.56 to 1.40). No appropriate data were available for meta-analysis of different clinical outcomes, the most common of these being blood pressure (three out of eight trials). Other clinical outcomes reported were glycated haemoglobin, serum Vitamin C and E levels, and self-reported psychological symptoms (one trial each). Reminder packing may represent a simple method for improving adherence for patients with selected conditions examined to date. Further research is warranted to improve the design and targeting of these devices.

MIDSHIPS: multicentre intervention designed for self-harm using interpersonal problem-solving: protocol for a randomised controlled feasibility study.

PubMed

Collinson, Michelle; Owens, David; Blenkiron, Paul; Burton, Kayleigh; Graham, Liz; Hatcher, Simon; House, Allan; Martin, Katie; Pembroke, Louise; Protheroe, David; Tubeuf, Sandy; Farrin, Amanda

2014-05-10

Around 150,000 people each year attend hospitals in England due to self-harm, many of them more than once. Over 5,000 people die by suicide each year in the UK, a quarter of them having attended hospital in the previous year because of self-harm. Self-harm is a major identifiable risk factor for suicide. People receive variable care at hospital; many are not assessed for their psychological needs and little psychological therapy is offered. Despite its frequent occurrence, we have no clear research evidence about how to reduce the repetition of self-harm. Some people who have self-harmed show less active ways of solving problems, and brief problem-solving therapies are considered the most promising psychological treatments. This is a pragmatic, individually randomised, controlled, feasibility study comparing interpersonal problem-solving therapy plus treatment-as-usual with treatment-as-usual alone, for adults attending a general hospital following self-harm. A total of 60 participants will be randomised equally between the treatment arms, which will be balanced with respect to the type of most recent self-harm event, number of previous self-harm events, gender and age. Feasibility objectives are as follows: a) To establish and field test procedures for implementing the problem-solving intervention; b) To determine the feasibility and best method of participant recruitment and follow up; c) To assess therapeutic delivery; d) To assess the feasibility of obtaining the definitive trial's primary and secondary outcomes; e) To assess the perceived burden and acceptability of obtaining the trial's self-reported outcome data; f) To inform the sample size calculation for the definitive trial. The results of this feasibility study will be used to determine the appropriateness of proceeding to a definitive trial and will allow us to design an achievable trial of interpersonal problem-solving therapy for adults who self-harm. Current Controlled Trials (ISRCTN54036115).

Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): A prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

PubMed Central

Ripley, David P.; Brown, Julia M.; Everett, Colin C.; Bijsterveld, Petra; Walker, Simon; Sculpher, Mark; McCann, Gerry P.; Berry, Colin; Plein, Sven; Greenwood, John P.

2015-01-01

Background A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. Trial Design CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. Conclusions The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation. PMID:25497243

Protocol for a feasibility study and randomised pilot trial of a low-intensity psychological intervention for depression in adults with autism: the Autism Depression Trial (ADEPT)

PubMed Central

Russell, Ailsa; Cooper, Kate; Barton, Stephen; Ensum, Ian; Gaunt, Daisy; Horwood, Jeremy; Ingham, Barry; Kessler, David; Metcalfe, Chris; Parr, Jeremy; Rai, Dheeraj; Wiles, Nicola

2017-01-01

Introduction High rates of co-occurring depression are reported in autism spectrum disorder (ASD), a neurodevelopmental condition characterised by social communication impairments and repetitive behaviours. Cognitive-behavioural interventions adapted for ASD have been effective for anxiety problems. There have been evaluation studies of group cognitive-behavioural therapy for co-occurring depression, but no randomised trials investigating low-intensity psychological interventions as recommended in clinical guidelines for mild-moderate depression. Methods and analysis A feasibility study comprising a randomised controlled trial (RCT) and nested qualitative evaluation is under way as preparation for a definitive RCT. Participants (n=70) will be randomised to Guided Self-Help: a low-intensity psychological intervention based on behavioural activation adapted for ASD or treatment as usual. Outcomes including depression symptoms, anxiety, social function and service use will be measured at 10, 16 and 24 weeks postrandomisation and will be blind to group allocation for measures that are not self-administered. The analysis will aim to establish the rates of recruitment and retention for a larger-scale RCT as well as the most appropriate measure of depression to serve as primary outcome. The qualitative study will purposively sample up to 24 participants from each treatment group to consider the acceptability and feasibility of the intervention and the trial design. Ethics and dissemination Ethical approval has been received from WALES REC 3 (IRAS project ID: 191558) and the Health Research Authority with R&D approval from Avon and Wiltshire Mental Health Partnership and Northumberland, Tyne and Wear Foundation NHS Trusts. To our knowledge, this is the first study of a low-intensity intervention for depression in adults with autism. The results will inform the design of a definitive RCT. Dissemination will include peer-reviewed journal publications reporting the quantitative and qualitative research findings of the study and presentations at national and international conferences. Trial registration number ISRCTN54650760; Pre-results. PMID:29203509

Screen-and-treat program by point-of-care of Atopobium vaginae and Gardnerella vaginalis in preventing preterm birth (AuTop trial): study protocol for a randomized controlled trial.

PubMed

Bretelle, Florence; Fenollar, Florence; Baumstarck, Karine; Fortanier, Cécile; Cocallemen, Jean François; Serazin, Valérie; Raoult, Didier; Auquier, Pascal; Loubière, Sandrine

2015-10-19

International recommendations in favor of screening for vaginal infection in pregnancy are based on heterogeneous criteria. In most developed countries, the diagnosis of bacterial vaginosis is only recommended for women with high-risk of preterm birth. The Nugent score is currently used, but molecular quantification tools have recently been reported with a high sensitivity and specificity. Their value for reducing preterm birth rates and related complications remains unexplored. This trial was designed to assess the cost-effectiveness of a systematic screen-and-treat program based on a point-of-care technique for rapid molecular diagnosis, immediately followed by an appropriate antibiotic treatment, to detect the presence of abnormal vaginal flora (specifically, Atopobium vaginae and Gardnerella vaginalis) before 20 weeks of gestation in pregnant women in France. We hypothesized that this program would translate into significant reductions in both the rate of preterm births and the medical costs associated with preterm birth. A multicenter, open-label randomized controlled trial (RCT) will be conducted in which 20 French obstetrics and gynecology centers will recruit eligible pregnant women at less than 20 weeks gestation with singleton pregnancy and with a low-risk factor for preterm birth. Interventions will include a) an experimental group that will receive a systematic rapid screen-and-treat program from a point-of-care analysis using a molecular quantification method and b) a control group that will receive usual care management. Randomization will be in a 1:1 allocation ratio. The primary endpoint that will be assessed over a period of 12 months will be the incremental cost-effectiveness ratio (ICER) expressed as cost per avoided preterm birth before 37 weeks. Secondary endpoints will include ICER per avoided preterm birth before 24, 28 and 32 weeks, obstetrical outcomes, neonatal outcomes, rates of treatment failure and recurrence episodes for positive women. Uncertainty surrounding these estimates will be addressed using nonparametric bootstrapping and represented using cost-effectiveness acceptability curves. A total of 6,800 pregnant women will be included. This appropriate randomized controlled design will provide insight into the cost-effectiveness and therefore the potential cost savings of a rapid screen-and-treat strategy for molecular abnormal vaginal flora in pregnant women. National and international recommendations could be updated based on the findings of this study. ClinicalTrials.gov: NCT02288832 (registration date: 30 October 2014); Eudract: 2014-001559-22.

An investigator-blinded, randomized study to compare the efficacy of combined CBT for alcohol use disorders and social anxiety disorder versus CBT focused on alcohol alone in adults with comorbid disorders: the Combined Alcohol Social Phobia (CASP) trial protocol

PubMed Central

2013-01-01

Background Alcohol use disorders and social anxiety disorder are common and disabling conditions that frequently co-exist. Although there are efficacious treatments for each disorder, only two randomized controlled trials of interventions for these combined problems have been published. We developed a new integrated treatment for comorbid Social Anxiety Disorder and Alcohol Use Disorder based on established Motivational Interviewing (MI) and Cognitive Behaviour Therapy (CBT) interventions for the separate disorders. Compared to established MI/CBT for alcohol use disorders this new intervention is hypothesised to lead to greater reductions in symptoms of social anxiety and alcohol use disorder and to produce greater improvements in quality of life. Higher levels of alcohol dependence will result in relatively poorer outcomes for the new integrated treatment. Methods/design A randomised controlled trial comparing 9 sessions of individual integrated treatment for alcohol and social phobia with 9 sessions of treatment for alcohol use problems alone is proposed. Randomisation will be stratified for stable antidepressant use. Post treatment clinical assessments of alcohol consumption and diagnostic status at 3 and 6 month follow-up will be blind to allocation. Discussion The proposed trial addresses a serious gap in treatment evidence and could potentially define the appropriate treatment for a large proportion of adults affected by these problems. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12608000228381. PMID:23895258

[Economic analysis of multinational clinical trials in oncology].

PubMed

Lejeune, Catherine; Lueza, Béranger; Bonastre, Julia

2018-02-01

In oncology, as in other fields of medicine, international multicentre clinical trials came into being so as to include a sufficient number of subjects to investigate a clinical situation. The existence of tight budgetary constraints and the desire to make the best use of the resources available have resulted in the development of economic evaluations associated with these trials, which, thanks to their level of evidence and their size, provide particularly relevant material. Nonetheless, economic evaluations alongside international clinical trials raise specific questions of methodology with regard to both the design and the analysis of the results. Indeed, the costs of goods and services consumed, the types and quantities of resources, and medical practices vary from one country to another and within an individual country. Economic data from the different countries involved must be available so as to study and to take into account this variability, and appropriate techniques for cost estimations and analysis must be implemented to aggregate the results from several countries. From a review of the literature, the aim of this work was to provide an overview of the specific methodological features of economic evaluations alongside international clinical trials: analysis of efficacy data from several countries, collection of resources and real costs, methods to establish the monetary value of resources, methods to aggregate results accounting for the trial effect. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Dressing wear time after breast reconstruction: study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background One of the major risk variables for surgical site infection is wound management. Understanding infection risk factors for breast operations is essential in order to develop infection-prevention strategies and improve surgical outcomes. The aim of this trial is to assess the influence of dressing wear time on surgical site infection rates and skin colonization. Patients’ perception at self-assessment will also be analyzed. Methods/Design This is a two-arm randomized controlled trial. Two hundred breast cancer patients undergoing immediate or delayed breast reconstruction will be prospectively enrolled. Patients will be randomly allocated to group I (dressing removed on postoperative day one) or group II (dressing removed on postoperative day six). Surgical site infections will be defined by standard criteria from the Centers for Disease Control and Prevention (CDC). Skin colonization will be assessed by culture of samples collected at predefined time points. Patients will score dressing wear time with regard to safety, comfort and convenience. Discussion The evidence to support dressing standards for breast surgery wounds is empiric and scarce. CDC recommends protecting, with a sterile dressing for 24 to 48 hours postoperatively, a primarily closed incision, but there is no recommendation to cover this kind of incision beyond 48 hours, or on the appropriate time to shower or bathe with an uncovered incision. The results of the ongoing trial may support standard recommendations regarding dressing wear time after breast reconstruction. Trial registration ClinicalTrials.gov identifier: http://NCT01148823. PMID:23432779

Guidelines for the conduct of pharmacological clinical trials in hand osteoarthritis: Consensus of a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

PubMed

Reginster, Jean-Yves L; Arden, Nigel K; Haugen, Ida K; Rannou, Francois; Cavalier, Etienne; Bruyère, Olivier; Branco, Jaime; Chapurlat, Roland; Collaud Basset, Sabine; Al-Daghri, Nasser M; Dennison, Elaine M; Herrero-Beaumont, Gabriel; Laslop, Andrea; Leeb, Burkhard F; Maggi, Stefania; Mkinsi, Ouafa; Povzun, Anton S; Prieto-Alhambra, Daniel; Thomas, Thierry; Uebelhart, Daniel; Veronese, Nicola; Cooper, Cyrus

2017-12-07

To gather expert opinion on the conduct of clinical trials that will facilitate regulatory review and approval of appropriate efficacious pharmacological treatments for hand osteoarthritis (OA), an area of high unmet clinical need. The European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) organized a working group under the auspices of the International Osteoporosis Foundation (IOF) and the World Health Organization (WHO). This consensus guideline is intended to provide a reference tool for practice, and should allow for better standardization of the conduct of clinical trials in hand OA. Hand OA is a heterogeneous disease affecting different, and often multiple, joints of the thumb and fingers. It was recognized that the various phenotypes and limitations of diagnostic criteria may make the results of hand OA trials difficult to interpret. Nonetheless, practical recommendations for the conduct of clinical trials of both symptom and structure modifying drugs are outlined in this consensus statement, including guidance on study design, execution, and analysis. While the working group acknowledges that the methodology for performing clinical trials in hand OA will evolve as knowledge of the disease increases, it is hoped that this guidance will support the development of new pharmacological treatments targeting hand OA. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cognitive and memory training in adults at risk of dementia: A Systematic Review

PubMed Central

2011-01-01

Background Effective non-pharmacological cognitive interventions to prevent Alzheimer's dementia or slow its progression are an urgent international priority. The aim of this review was to evaluate cognitive training trials in individuals with mild cognitive impairment (MCI), and evaluate the efficacy of training in memory strategies or cognitive exercises to determine if cognitive training could benefit individuals at risk of developing dementia. Methods A systematic review of eligible trials was undertaken, followed by effect size analysis. Cognitive training was differentiated from other cognitive interventions not meeting generally accepted definitions, and included both cognitive exercises and memory strategies. Results Ten studies enrolling a total of 305 subjects met criteria for cognitive training in MCI. Only five of the studies were randomized controlled trials. Meta-analysis was not considered appropriate due to the heterogeneity of interventions. Moderate effects on memory outcomes were identified in seven trials. Cognitive exercises (relative effect sizes ranged from .10 to 1.21) may lead to greater benefits than memory strategies (.88 to -1.18) on memory. Conclusions Previous conclusions of a lack of efficacy for cognitive training in MCI may have been influenced by not clearly defining the intervention. Our systematic review found that cognitive exercises can produce moderate-to-large beneficial effects on memory-related outcomes. However, the number of high quality RCTs remains low, and so further trials must be a priority. Several suggestions for the better design of cognitive training trials are provided. PMID:21942932

The extended Infant Feeding, Activity and Nutrition Trial (InFANT Extend) Program: a cluster-randomized controlled trial of an early intervention to prevent childhood obesity.

PubMed

Campbell, Karen J; Hesketh, Kylie D; McNaughton, Sarah A; Ball, Kylie; McCallum, Zoë; Lynch, John; Crawford, David A

2016-02-18

Understanding how we can prevent childhood obesity in scalable and sustainable ways is imperative. Early RCT interventions focused on the first two years of life have shown promise however, differences in Body Mass Index between intervention and control groups diminish once the interventions cease. Innovative and cost-effective strategies seeking to continue to support parents to engender appropriate energy balance behaviours in young children need to be explored. The Infant Feeding Activity and Nutrition Trial (InFANT) Extend Program builds on the early outcomes of the Melbourne InFANT Program. This cluster randomized controlled trial will test the efficacy of an extended (33 versus 15 month) and enhanced (use of web-based materials, and Facebook® engagement), version of the original Melbourne InFANT Program intervention in a new cohort. Outcomes at 36 months of age will be compared against the control group. This trial will provide important information regarding capacity and opportunities to maximize early childhood intervention effectiveness over the first three years of life. This study continues to build the evidence base regarding the design of cost-effective, scalable interventions to promote protective energy balance behaviors in early childhood, and in turn, promote improved child weight and health across the life course. ACTRN12611000386932. Registered 13 April 2011.

Current status of pharmacokinetic and safety studies of multidrug-resistant tuberculosis treatment in children.

PubMed

Garcia-Prats, A J; Svensson, E M; Weld, E D; Schaaf, H S; Hesseling, A C

2018-05-01

After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB. There is international consensus that an efficacy trial of a novel, all-oral, shortened MDR-TB treatment trial in children is both needed and feasible. Key novel and repurposed second-line anti-tuberculosis drugs include BDQ, DLM, PTM, MFX, LVX, CFZ and LZD. The rapidly emerging PK and safety data on these medications in children with MDR-TB from studies that are underway, completed or planned, will be critical in supporting such an efficacy trial. Commitment to addressing the remaining knowledge gaps, developing child-friendly formulations of key medications, improving the design of paediatric PK and safety studies, and development of international trial capacity in children with MDR-TB are important priorities.

Cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants.

PubMed

Hyttel-Sorensen, Simon; Greisen, Gorm; Als-Nielsen, Bodil; Gluud, Christian

2017-09-04

Cerebral injury and long-term neurodevelopmental impairment is common in extremely preterm infants. Cerebral near-infrared spectroscopy (NIRS) enables continuous estimation of cerebral oxygenation. This diagnostic method coupled with appropriate interventions if NIRS is out of normal range (that is cerebral oxygenation within the 55% to 85% range) may offer benefits without causing more harms. Therefore, NIRS coupled with appropriate responses to abnormal findings on NIRS needs assessment in a systematic review of randomised clinical trials and quasi-randomised studies. To evaluate the benefits and harms of interventions that attempt to alter cerebral oxygenation guided by cerebral NIRS monitoring in order to prevent cerebral injury, improve neurological outcome, and increase survival in preterm infants born more than 8 weeks preterm. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 8), MEDLINE via PubMed (1966 to 10 September 2016), Embase (1980 to 10 September 2016), and CINAHL (1982 to 10 September 2016). We also searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised clinical trials and quasi-randomised studies. Randomised clinical trials and quasi-randomised clinical studies comparing continuous cerebral NIRS monitoring for at least 24 hours versus blinded NIRS or versus no NIRS monitoring. Two review authors independently selected, assessed the quality of, and extracted data from the included trials and studies. If necessary, we contacted authors for further information. We conducted assessments of risks of bias; risks of design errors; and controlled the risks of random errors with Trial Sequential Analysis. We assessed the quality of the evidence with GRADE. One randomised clinical trial met inclusion criteria, including infants born more than 12 weeks preterm. The trial employed adequate methodologies and was assessed at low risk of bias. One hundred and sixty-six infants were randomised to start continuous cerebral NIRS monitoring less than 3 hours after birth until 72 hours after birth plus appropriate interventions if NIRS was out of normal range according to a guideline versus conventional monitoring with blinded NIRS. There was no effect of NIRS plus guideline of mortality until term-equivalent age (RR 0.50, 95% CI 0.29 to 1.00; one trial; 166 participants). There were no effects of NIRS plus guideline on intraventricular haemorrhages: all grades (RR 0.93, 95% CI 0.65 to 1.34; one trial; 166 participants); grade III/IV (RR 0.57, 95% CI 0.25 to 1.31; one trial; 166 participants); and cystic periventricular leukomalacia (which did not occur in either group). Likewise, there was no effect of NIRS plus guideline on the occurrence of a patent ductus arteriosus (RR 1.96, 95% CI 0.94 to 4.08; one trial; 166 participants); chronic lung disease (RR 1.27, 95% CI 0.94 to 1.50; one trial; 166 participants); necrotising enterocolitis (RR 0.83, 95% CI 0.33 to 1.94; one trial; 166 participants); and retinopathy of prematurity (RR 1.64, 95% CI 0.75 to 3.00; one trial; 166 participants). There were no serious adverse events in any of the intervention groups. NIRS plus guideline caused more skin marks from the NIRS sensor in the control group than in the experimental group (unadjusted RR 0.31, 95% CI 0.10 to 0.92; one trial; 166 participants). There are no data regarding neurodevelopmental outcome, renal impairment or air leaks.The quality of evidence for all comparisons discussed above was assessed as very low apart from all-cause mortality and adverse events: these were assessed as low and moderate, respectively. The validity of all comparisons is hampered by a small sample of randomised infants, risk of bias due to lack of blinding, and indirectness of outcomes. The only eligible randomised clinical trial did not demonstrate any consistent effects of NIRS plus a guideline on the assessed clinical outcomes. The trial was, however, only powered to detect difference in cerebral oxygenation, not morbidities or mortality. Our systematic review did not reach sufficient power to prove or disprove effects on clinical outcomes. Further randomised clinical trials with low risks of bias and low risks of random errors are needed.

Appropriate and inappropriate use of dronedarone in 2013.

PubMed

Naccarelli, Gerald V

2013-08-01

Dronedarone is a multichannel blocking antiarrhythmic agent that has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In the ANDROMEDA trial, dronedarone treatment increased mortality and cardiovascular hospitalizations patients with decompensated heart failure. In the ATHENA trial, dronedarone was used in elderly high risk patients with paroxysmal or persistent AF/AFl, excluding those with advanced heart failure, cardiovascular hospitalizations were significantly reduced. Dronedarone increased mortality and cardiovascular hospitalizations in a different patient group with permanent AF/AFl. Although organic toxicity from the drug is very rare, post-marketing data has reported rare hepatic toxicity associated with dronedarone use. Current guidelines position dronedarone as a front-line antiarrhythmic in many patients with AF/Fl. However, dronedarone should not be used in patients with advanced heart failure or in permanent AF. Clinical trial results have helped us define appropriate and inappropriate candidates for dronedarone.

Appropriate and inappropriate methods for investigating the "gateway" hypothesis, with a review of the evidence linking prior snus use to later cigarette smoking.

PubMed

Lee, Peter N

2015-03-20

The "gateway hypothesis" usually refers to the possibility that the taking up of habit A, which is considered harmless (or less harmful), may lead to the subsequent taking up of another habit, B, which is considered harmful (or more harmful). Possible approaches to designing and analysing studies to test the hypothesis are discussed. Evidence relating to the use of snus (A) as a gateway for smoking (B) is then evaluated in detail. The importance of having appropriate data available on the sequence of use of A and B and on other potential confounding factors that may lead to the taking up of B is emphasised. Where randomised trials are impractical, the preferred designs include the prospective cohort study in which ever use of A and of B is recorded at regular intervals, and the cross-sectional survey in which time of starting to use A and B is recorded. Both approaches allow time-stratified analytical methods to be used, in which, in each time period, risk of initiating B among never users of B at the start of the interval is compared according to prior use of A. Adjustment in analysis for the potential confounding factors is essential. Of 11 studies of possible relevance conducted in Sweden, Finland or Norway, only one seriously addresses potential confounding by those other factors involved in the initiation of smoking. Furthermore, 5 of the 11 studies are of a design that does not allow proper testing of the gateway hypothesis for various reasons, and the analysis is unsatisfactory, sometimes seriously, in all the remaining six. While better analyses could be attempted for some of the six studies identified as having appropriate design, the issues of confounding remain, and more studies are clearly needed. To obtain a rapid answer, a properly designed cross-sectional survey is recommended.

Testing of Hypothesis in Equivalence and Non Inferiority Trials-A Concept.

PubMed

Juneja, Atul; Aggarwal, Abha R; Adhikari, Tulsi; Pandey, Arvind

2016-04-01

Establishing the appropriate hypothesis is one of the important steps for carrying out the statistical tests/analysis. Its understanding is important for interpreting the results of statistical analysis. The current communication attempts to provide the concept of testing of hypothesis in non inferiority and equivalence trials, where the null hypothesis is just reverse of what is set up for conventional superiority trials. It is similarly looked for rejection for establishing the fact the researcher is intending to prove. It is important to mention that equivalence or non inferiority cannot be proved by accepting the null hypothesis of no difference. Hence, establishing the appropriate statistical hypothesis is extremely important to arrive at meaningful conclusion for the set objectives in research.

Globally optimal trial design for local decision making.

PubMed

Eckermann, Simon; Willan, Andrew R

2009-02-01

Value of information methods allows decision makers to identify efficient trial design following a principle of maximizing the expected value to decision makers of information from potential trial designs relative to their expected cost. However, in health technology assessment (HTA) the restrictive assumption has been made that, prospectively, there is only expected value of sample information from research commissioned within jurisdiction. This paper extends the framework for optimal trial design and decision making within jurisdiction to allow for optimal trial design across jurisdictions. This is illustrated in identifying an optimal trial design for decision making across the US, the UK and Australia for early versus late external cephalic version for pregnant women presenting in the breech position. The expected net gain from locally optimal trial designs of US$0.72M is shown to increase to US$1.14M with a globally optimal trial design. In general, the proposed method of globally optimal trial design improves on optimal trial design within jurisdictions by: (i) reflecting the global value of non-rival information; (ii) allowing optimal allocation of trial sample across jurisdictions; (iii) avoiding market failure associated with free-rider effects, sub-optimal spreading of fixed costs and heterogeneity of trial information with multiple trials. Copyright (c) 2008 John Wiley & Sons, Ltd.

European Union. Ethical considerations for clinical trials on medicinal products conducted with the paediatric population.

PubMed

2008-07-01

This document has been developed by the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, chaired by the European Commission. The document provides recommendations on various ethical aspects of clinical trials performed in children from birth up to the legal age of adulthood. This will contribute to the protection of all children who are the subject of clinical trials. As the approval of clinical trials, including ethical approval, is performed by the Member States, any recommendations on ethical aspects of clinical trials in children will also facilitate a harmonised approach to the application of the clinical trials directive across the EU, thereby facilitating the conduct of clinical trials in the EU and in whichever country the paediatric trial occurs. The protection against the risks of research in such a vulnerable population is paramount whilst this should not lead to denying them the benefits of research. Children are not small adults and there is a need to carry out specific trials that cannot be performed in adults. In general, children (minors) are unable to consent (in the legal sense) but their assent should be sought using age appropriate information. Ethics Committees need paediatric expertise to balance the benefits and risks of research in children. The lack of legal ability to consent has implications on the design, analysis and the choice of comparators used in trials, which should only be performed by trained investigators with paediatric experience. Pain, fear, distress and parental separation should be prevented and minimised when unavoidable. The neonate represents the most vulnerable of all paediatric age groups and requires even more careful review. Finally, various other aspects relating to the performance of trials in children are discussed.

Staged diabetes management: computerizing a disease state management program.

PubMed

Ginsberg, B H; Tan, M H; Mazze, R; Bergelson, A

1998-04-01

Recently, the Diabetes Control and Complication Trial (DCCT) and other similar studies have demonstrated that near-normalization of blood glucose in diabetes will reduce complications up to 75% but translation of these results into practice has been difficult. In an attempt to help provide the best possible control of patients with diabetes, we have produced an attempt to help provide the best possible control of patients with diabetes, we have produced a new disease state management system for diabetes, called "Staged Diabetes Management" (SDM), implemented it in over 100 sites worldwide, and developed a computer program to simplify its use. SDM, designed to change the way we deal with patients with diabetes, is based upon five principles: (1) community involvement in setting care guidelines; (2) negotiation of goals with patients; (3) appropriate timelines for therapeutic success; (4) use of flowcharts for medical decisions; and (5) evaluation of the program. SDM is designed to be altered by a community to meet its needs and resources. It encourages primary care physicians to deliver better diabetes care using a team approach and to refer patients with diabetes to specialists when appropriate. It has a complete set of materials for communities, individual health care providers and patients. SDM has been tested for changes in structure, process and outcomes. A meta-analysis of seven clinical trials with over 500 patients has shown a time-weighted average fall in hemoglobin A1c of 1.7 points (equivalent to a drop in mean blood glucose of about 3.5 mM or 60 mg/dL). Preliminary pharmacoeconomic analysis demonstrates a lifetime cost saving of over $27,000 per patient. A computer program has been developed for the Microsoft Windows environment that contains a client-server database, based upon DiabCare, for the data file structure.

Structuring Communication Relationships for Interprofessional Teamwork (SCRIPT): a cluster randomized controlled trial.

PubMed

Zwarenstein, Merrick; Reeves, Scott; Russell, Ann; Kenaszchuk, Chris; Conn, Lesley Gotlib; Miller, Karen-Lee; Lingard, Lorelei; Thorpe, Kevin E

2007-09-18

Despite a burgeoning interest in using interprofessional approaches to promote effective collaboration in health care, systematic reviews find scant evidence of benefit. This protocol describes the first cluster randomized controlled trial (RCT) to design and evaluate an intervention intended to improve interprofessional collaborative communication and patient-centred care. The objective is to evaluate the effects of a four-component, hospital-based staff communication protocol designed to promote collaborative communication between healthcare professionals and enhance patient-centred care. The study is a multi-centre mixed-methods cluster randomized controlled trial involving twenty clinical teaching teams (CTTs) in general internal medicine (GIM) divisions of five Toronto tertiary-care hospitals. CTTs will be randomly assigned either to receive an intervention designed to improve interprofessional collaborative communication, or to continue usual communication practices. Non-participant naturalistic observation, shadowing, and semi-structured, qualitative interviews were conducted to explore existing patterns of interprofessional collaboration in the CTTs, and to support intervention development. Interviews and shadowing will continue during intervention delivery in order to document interactions between the intervention settings and adopters, and changes in interprofessional communication. The primary outcome is the rate of unplanned hospital readmission. Secondary outcomes are length of stay (LOS); adherence to evidence-based prescription drug therapy; patients' satisfaction with care; self-report surveys of CTT staff perceptions of interprofessional collaboration; and frequency of calls to paging devices. Outcomes will be compared on an intention-to-treat basis using adjustment methods appropriate for data from a cluster randomized design. Pre-intervention qualitative analysis revealed that a substantial amount of interprofessional interaction lacks key core elements of collaborative communication such as self-introduction, description of professional role, and solicitation of other professional perspectives. Incorporating these findings, a four-component intervention was designed with a goal of creating a culture of communication in which the fundamentals of collaboration become a routine part of interprofessional interactions during unstructured work periods on GIM wards. Registered with National Institutes of Health as NCT00466297.

A systematic review of evaluated suicide prevention programs targeting indigenous youth.

PubMed

Harlow, Alyssa F; Bohanna, India; Clough, Alan

2014-01-01

Indigenous young people have significantly higher suicide rates than their non-indigenous counterparts. There is a need for culturally appropriate and effective suicide prevention programs for this demographic. This review assesses suicide prevention programs that have been evaluated for indigenous youth in Australia, Canada, New Zealand, and the United States. The databases MEDLINE and PsycINFO were searched for publications on suicide prevention programs targeting indigenous youth that include reports on evaluations and outcomes. Program content, indigenous involvement, evaluation design, program implementation, and outcomes were assessed for each article. The search yielded 229 articles; 90 abstracts were assessed, and 11 articles describing nine programs were reviewed. Two Australian programs and seven American programs were included. Programs were culturally tailored, flexible, and incorporated multiple-levels of prevention. No randomized controlled trials were found, and many programs employed ad hoc evaluations, poor program description, and no process evaluation. Despite culturally appropriate content, the results of the review indicate that more controlled study designs using planned evaluations and valid outcome measures are needed in research on indigenous youth suicide prevention. Such changes may positively influence the future of research on indigenous youth suicide prevention as the outcomes and efficacy will be more reliable.

The risk of elevated prolactin levels in pediatric patients exposed to antipsychotics for the treatment of schizophrenia and schizophrenia spectrum disorders: protocol for a systematic review and meta-analysis

PubMed Central

2014-01-01

Background Antipsychotic medications, particularly second-generation antipsychotics, are increasingly being used to alleviate the symptoms of schizophrenia and other severe mental disorders in the pediatric population. While evidence-based approaches examining efficacy and safety outcomes have been reported, no review has evaluated prolactin-based adverse events for antipsychotic treatments in schizophrenia and schizophrenia spectrum disorders. Methods/design Searches involving MEDLINE, EMBASE, CENTRAL, PsycINFO, and clinical trial registries (ClinicalTrials.gov, Drug Industry Document Archive [DIDA], International Clinical Trials Registry Platform [ICTRP]) will be used to identify relevant studies. Two reviewers will independently screen abstracts and relevant full-text articles of the papers identified by the initial search according to the prospectively defined eligibility criteria. Data extraction will be conducted in duplicate independently. Pairwise random effects meta-analyses and network meta-analyses will be conducted on individual drug and class effects where appropriate. Discussion This systematic review will evaluate prolactin-based adverse events of first- and second-generation antipsychotics in the pediatric population with schizophrenia and schizophrenia spectrum disorders. It will also seek to strengthen the evidence base of the safety of antipsychotics by incorporating both randomized controlled trials and observational studies. Systematic review registration PROSPERO CRD42014009506 PMID:25312992

Parental Attitudes About Placebo Use in Children.

PubMed

Faria, Vanda; Kossowsky, Joe; Petkov, Mike P; Kaptchuk, Ted J; Kirsch, Irving; Lebel, Alyssa; Borsook, David

2017-02-01

To assess parental attitudes regarding placebo use in pediatric randomized controlled trials and clinical care. Parents with children under age 18 years living in the US completed and submitted an online survey between September and November 2014. Among all 1300 participants, 1000 (76.9%; 538 mothers and 462 fathers) met the study inclusion criteria. The majority of surveyed parents considered the use of placebos acceptable in some pediatric care situations (86%) and some pediatric trials (91.5%), whereas only 5.7% of parents found the use of placebos in children always unacceptable. The clinical use of placebo was considered acceptable by a majority of parents for only 7 (mostly psychological) of the 17 conditions presented. Respondents' judgment about acceptability was influenced by the doctors' opinions about the therapeutic benefits of placebo treatment, the conditions for pediatric placebo use, transparency, safety, and purity of placebos. Most surveyed parents accepted the idea of using placebos in pediatric trials and within the clinic for some conditions without the practice of deception and with the creation of guidelines for ethical and safe use. This study suggests a need to reconsider pediatric trial design and clinical therapy in the light of generally positive parental support of appropriate placebo use. Copyright © 2016 Elsevier Inc. All rights reserved.

Gestational Weight Gain: Results from the Delta Healthy Sprouts Comparative Impact Trial.

PubMed

Thomson, Jessica L; Tussing-Humphreys, Lisa M; Goodman, Melissa H; Olender, Sarah E

2016-01-01

Introduction. Delta Healthy Sprouts trial was designed to test the comparative impact of two home visiting programs on weight status, dietary intake, and health behaviors of Southern African American women and their infants. Results pertaining to the primary outcome, gestational weight gain, are reported. Methods. Participants (n = 82), enrolled early in their second trimester of pregnancy, were randomly assigned to one of two treatment arms. Gestational weight gain, measured at six monthly home visits, was calculated by subtracting measured weight at each visit from self-reported prepregnancy weight. Weight gain was classified as under, within, or exceeding the Institute of Medicine recommendations based on prepregnancy body mass index. Chi-square tests and generalized linear mixed models were used to test for significant differences in percentages of participants within recommended weight gain ranges. Results. Differences in percentages of participants within the gestational weight gain guidelines were not significant between treatment arms across all visits. Conclusions. Enhancing the gestational nutrition and physical activity components of an existing home visiting program is feasible in a high risk population of primarily low income African American women. The impact of these enhancements on appropriate gestational weight gain is questionable given the more basic living needs of such women. This trial is registered with ClinicalTrials.gov NCT01746394, registered 4 December 2012.

Randomised controlled trial of educational package on management of menorrhagia in primary care: the Anglia menorrhagia education study

PubMed Central

Fender, Guy R K; Prentice, Andrew; Gorst, Tess; Nixon, Richard M; Duffy, Stephen W; Day, Nicholas E; Smith, Stephen K

1999-01-01

Objective To determine whether an educational package could influence the management of menorrhagia, increase the appropriateness of choice of non-hormonal treatment, and reduce referral rates from primary to secondary care. Design Randomised controlled trial. Setting General practices in East Anglia. Subjects 100 practices (348 doctors) in primary care were recruited and randomised to intervention (54) and control (46). Interventions An educational package based on principles of “academic detailing” with independent academics was given in small practice based interactive groups with a visual presentation, a printed evidence based summary, a graphic management flow chart, and a follow up meeting at 6 months. Outcome measures All practices recorded consultation details, treatments offered, and outcomes for women with regular heavy menstrual loss (menorrhagia) over 1 year. Results 1001 consultation data sheets for menorrhagia were returned. There were significantly fewer referrals (20% v 29%; odds ratio 0.64; 95% confidence interval 0.41 to 0.99) and a significantly higher use of tranexamic acid (odds ratio 2.38; 1.61 to 3.49) in the intervention group but no overall difference in norethisterone treatment compared with controls. There were more referrals when tranexamic acid was given with norethisterone than when it was given alone. Those practices reporting fewer than 10 cases showed the highest increase in prescribing of tranexamic acid. Conclusions The educational package positively influenced referral for menorrhagia and treatment with appropriate non-hormonal drugs. Key messagesMenorrhagia (regular excessive menstruation) affects many women and treatment is a considerable use of resourcesAppropriate non-hormonal treatments are not always offered before referral, which often results in therapeutic surgeryAn educational package with independent academics in small informal groups presenting visual, graphic, and written material can positively influence doctors’ behaviourIncreasing appropriate non-hormonal treatments for menorrhagia results in fewer referrals PMID:10231255

A cluster randomized trial for the implementation of an antibiotic checklist based on validated quality indicators: the AB-checklist.

PubMed

van Daalen, Frederike V; Prins, Jan M; Opmeer, Brent C; Boermeester, Marja A; Visser, Caroline E; van Hest, Reinier M; Hulscher, Marlies E J L; Geerlings, Suzanne E

2015-03-19

Recently we developed and validated generic quality indicators that define 'appropriate antibiotic use' in hospitalized adults treated for a (suspected) bacterial infection. Previous studies have shown that with appropriate antibiotic use a reduction of 13% of length of hospital stay can be achieved. Our main objective in this project is to provide hospitals with an antibiotic checklist based on these quality indicators, and to evaluate the introduction of this checklist in terms of (cost-) effectiveness. The checklist applies to hospitalized adults with a suspected bacterial infection for whom antibiotic therapy is initiated, at first via the intravenous route. A stepped wedge study design will be used, comparing outcomes before and after introduction of the checklist in nine hospitals in the Netherlands. At least 810 patients will be included in both the control and the intervention group. The primary endpoint is length of hospital stay. Secondary endpoints are appropriate antibiotic use measured by the quality indicators, admission to and duration of intensive care unit stay, readmission within 30 days, mortality, total antibiotic use, and costs associated with implementation and hospital stay. Differences in numerical endpoints between the two periods will be evaluated with mixed linear models; for dichotomous outcomes generalized estimating equation models will be used. A process evaluation will be performed to evaluate the professionals' compliance with use of the checklist. The key question for the economic evaluation is whether the benefits of the checklist, which include reduced antibiotic use, reduced length of stay and associated costs, justify the costs associated with implementation activities as well as daily use of the checklist. If (cost-) effective, the AB-checklist will provide physicians with a tool to support appropriate antibiotic use in adult hospitalized patients who start with intravenous antibiotics. Dutch trial registry: NTR4872.

Cluster randomised crossover trials with binary data and unbalanced cluster sizes: application to studies of near-universal interventions in intensive care.

PubMed

Forbes, Andrew B; Akram, Muhammad; Pilcher, David; Cooper, Jamie; Bellomo, Rinaldo

2015-02-01

Cluster randomised crossover trials have been utilised in recent years in the health and social sciences. Methods for analysis have been proposed; however, for binary outcomes, these have received little assessment of their appropriateness. In addition, methods for determination of sample size are currently limited to balanced cluster sizes both between clusters and between periods within clusters. This article aims to extend this work to unbalanced situations and to evaluate the properties of a variety of methods for analysis of binary data, with a particular focus on the setting of potential trials of near-universal interventions in intensive care to reduce in-hospital mortality. We derive a formula for sample size estimation for unbalanced cluster sizes, and apply it to the intensive care setting to demonstrate the utility of the cluster crossover design. We conduct a numerical simulation of the design in the intensive care setting and for more general configurations, and we assess the performance of three cluster summary estimators and an individual-data estimator based on binomial-identity-link regression. For settings similar to the intensive care scenario involving large cluster sizes and small intra-cluster correlations, the sample size formulae developed and analysis methods investigated are found to be appropriate, with the unweighted cluster summary method performing well relative to the more optimal but more complex inverse-variance weighted method. More generally, we find that the unweighted and cluster-size-weighted summary methods perform well, with the relative efficiency of each largely determined systematically from the study design parameters. Performance of individual-data regression is adequate with small cluster sizes but becomes inefficient for large, unbalanced cluster sizes. When outcome prevalences are 6% or less and the within-cluster-within-period correlation is 0.05 or larger, all methods display sub-nominal confidence interval coverage, with the less prevalent the outcome the worse the coverage. As with all simulation studies, conclusions are limited to the configurations studied. We confined attention to detecting intervention effects on an absolute risk scale using marginal models and did not explore properties of binary random effects models. Cluster crossover designs with binary outcomes can be analysed using simple cluster summary methods, and sample size in unbalanced cluster size settings can be determined using relatively straightforward formulae. However, caution needs to be applied in situations with low prevalence outcomes and moderate to high intra-cluster correlations. © The Author(s) 2014.

Control treatments in biologics trials of rheumatoid arthritis were often not deemed acceptable in the context of care.

PubMed

Estellat, Candice; Tubach, Florence; Seror, Raphaèle; Alfaiate, Toni; Hajage, David; De Rycke, Yann; Ravaud, Philippe

2016-01-01

Control treatments in randomized controlled trials (RCTs) should not deliberately disadvantage patients. The objectives of the study were to compare (1) willingness to include vs. (2) willingness to prescribe control treatment among physicians randomized to assess, respectively, either (1) enrollment in a trial or (2) appropriateness of control treatment in a care context for the same fictional patient. Physicians were authors of articles about rheumatoid arthritis (RA), involved in RA patient care, and used to enrolling patients in trials. The outcomes were willingness to give control treatment: trial enrollment or control-treatment appropriateness in care context. We derived three case vignettes of fictional standard eligible patients for each of 30 RCTs assessing biologics in RA. Physicians were randomly allocated to the "trial" or "care" arm. For each of the 90 fictional patients, physicians assigned to the trial arm were asked if they would enroll the patient in the RCT the patient was derived from. For the same 90 fictional patients, physicians assigned to the care arm were asked if the control treatment of the RCT was appropriate in a context of usual care. Of the 1,779 physicians invited to participate, 151 were randomized. Half of the fictional patients {41/90; 45% [95% confidence interval (CI): 37%, 53%]} would be enrolled in the RCT although the control-arm treatment of the RCT was not considered appropriate for them in the context of care. This rate differed by type of comparator [55% for non-head-to-head RCTs vs. 6% for head-to-head RCTs; adjusted odds ratio (aOR), 23.9 (95% CI: 5.5, 92.7)] and duration of trial control treatment [56% for ≤24 weeks and 15% for >24 weeks; aOR, 10.7 (95% CI: 2.8, 63.9)] but not patient RA activity [aOR, 2.5 (95% CI: 1.0, 6.6)]. The limitation of this study was that physicians gave their opinion on fictional patients with only RA. Control treatments in RCTs of biologics in RA are often deemed not acceptable in the context of usual care, especially those for non-head-to-head RCTs. These findings raise ethical concerns and challenge the choice of the comparator in RCTs. Copyright © 2016 Elsevier Inc. All rights reserved.

Tobacco and alcohol-related interventions for people with mild/moderate intellectual disabilities: a systematic review of the literature.

PubMed

Kerr, S; Lawrence, M; Darbyshire, C; Middleton, A R; Fitzsimmons, L

2013-05-01

The behavioural determinants of health among people with mild/moderate intellectual disabilities (ID) are of increasing concern. With the closure of long-stay institutions, more people with ID are living in the community. As they lead more ordinary and less restricted lives, people with ID may be exposed to social and environmental pressures that encourage them to adopt behaviours that impact negatively on their health. Levels of smoking and alcohol consumption in this client group are of particular concern. We undertook a mixed method review of the literature, aiming to assess the Feasibility, Appropriateness, Meaningfulness and Effectiveness (FAME) of interventions designed to address the use of tobacco and/or alcohol in people with mild/moderate ID. Key electronic databases were searched (e.g., Medline, Cochrane Register of Controlled Trials, PsycINFO) from 1996 to 2011. The search was developed using appropriate subject headings and key words (e.g., intellectual disability, tobacco use, alcohol drinking, health promotion). On completion of the database searches, inclusion/exclusion criteria, based on an adaptation of the PICO framework (Population, Intervention, Comparison, Outcomes), were applied. Methodological quality was assessed using a seven-point rating scale. Database searches identified 501 unique records, of which nine satisfied the inclusion criteria. Four focused on tobacco, three on alcohol and two on both tobacco and alcohol. Located in the U.K., the U.S.A. and Australia, the studies aimed to increase knowledge levels and/or change behaviour (e.g., to encourage smoking cessation). One was a randomised controlled trial, one a quasi-experiment and the others were before and after studies and/or case studies. Methodological quality was poor or moderate. The combined studies had a sample size of 341, with ages ranging from 14 to 54 years. The interventions were delivered by professionals (e.g., in health, social care, education) during sessions that spanned a period of three weeks to one academic year. The studies highlighted a number of important issues linked to the appropriateness of interventions for this client group (e.g., use of pictures, quizzes, role play, incentives); however, in the majority of cases the interventions appeared to lack a theoretical framework (e.g., behaviour change theory). The appropriateness of the outcome measures for use with this client group was not tested. One study discussed feasibility (teachers delivering lessons on alcohol and tobacco) and only one was informative in terms of effectiveness, i.e., increasing knowledge of the health and social dangers of smoking and excessive alcohol consumption. This review is the first to systematically collate evidence on tobacco and alcohol-related interventions for people with ID. While there is currently little evidence to guide practice, the review delivers clear insights for the development of interventions and presents a strong case for more robust research methods. In particular there is a need to test the effectiveness of interventions in large-scale, well-designed trials and to ensure that outcome measures are developed/tailored appropriately for this client group. © 2012 The Authors. Journal of Intellectual Disability Research © 2012 Blackwell Publishing Ltd.

[Quantitative and qualitative research methods, can they coexist yet?].

PubMed

Hunt, Elena; Lavoie, Anne-Marise

2011-06-01

Qualitative design is gaining ground in Nursing research. In spite of a relative progress however, the evidence based practice movement continues to dominate and to underline the exclusive value of quantitative design (particularly that of randomized clinical trials) for clinical decision making. In the actual context convenient to those in power making utilitarian decisions on one hand, and facing nursing criticism of the establishment in favor of qualitative research on the other hand, it is difficult to chose a practical and ethical path that values the nursing role within the health care system, keeping us committed to quality care and maintaining researcher's integrity. Both qualitative and quantitative methods have advantages and disadvantages, and clearly, none of them can, by itself, capture, describe and explain reality adequately. Therefore, a balance between the two methods is needed. Researchers bare responsibility to society and science, and they should opt for the appropriate design susceptible to answering the research question, not promote the design favored by the research funding distributors.

The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.

PubMed

Guetterman, Timothy C; Fetters, Michael D; Mawocha, Samkeliso; Legocki, Laurie J; Barsan, William G; Lewis, Roger J; Berry, Donald A; Meurer, William J

2017-01-01

Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development.

Pareto Design of State Feedback Tracking Control of a Biped Robot via Multiobjective PSO in Comparison with Sigma Method and Genetic Algorithms: Modified NSGAII and MATLAB's Toolbox

PubMed Central

Mahmoodabadi, M. J.; Taherkhorsandi, M.; Bagheri, A.

2014-01-01

An optimal robust state feedback tracking controller is introduced to control a biped robot. In the literature, the parameters of the controller are usually determined by a tedious trial and error process. To eliminate this process and design the parameters of the proposed controller, the multiobjective evolutionary algorithms, that is, the proposed method, modified NSGAII, Sigma method, and MATLAB's Toolbox MOGA, are employed in this study. Among the used evolutionary optimization algorithms to design the controller for biped robots, the proposed method operates better in the aspect of designing the controller since it provides ample opportunities for designers to choose the most appropriate point based upon the design criteria. Three points are chosen from the nondominated solutions of the obtained Pareto front based on two conflicting objective functions, that is, the normalized summation of angle errors and normalized summation of control effort. Obtained results elucidate the efficiency of the proposed controller in order to control a biped robot. PMID:24616619

Control group design: enhancing rigor in research of mind-body therapies for depression.

PubMed

Kinser, Patricia Anne; Robins, Jo Lynne

2013-01-01

Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research about mind-body therapies, we suggest that researchers should consider 4 key questions: whether the study design matches the research question; whether the control group addresses performance, expectation, and detection bias; whether the control group is ethical, feasible, and attractive; and whether the control group is designed to adequately control for nonspecific intervention effects. Based on these questions, we provide specific recommendations about control group design with the goal of minimizing bias and maximizing validity in future research.

Control Group Design: Enhancing Rigor in Research of Mind-Body Therapies for Depression

PubMed Central

Kinser, Patricia Anne; Robins, Jo Lynne

2013-01-01

Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research about mind-body therapies, we suggest that researchers should consider 4 key questions: whether the study design matches the research question; whether the control group addresses performance, expectation, and detection bias; whether the control group is ethical, feasible, and attractive; and whether the control group is designed to adequately control for nonspecific intervention effects. Based on these questions, we provide specific recommendations about control group design with the goal of minimizing bias and maximizing validity in future research. PMID:23662111

Nurse case-manager vs multifaceted intervention to improve quality of osteoporosis care after wrist fracture: randomized controlled pilot study.

PubMed

Majumdar, S R; Johnson, J A; Bellerose, D; McAlister, F A; Russell, A S; Hanley, D A; Garg, S; Lier, D A; Maksymowych, W P; Morrish, D W; Rowe, B H

2011-01-01

Few outpatients with fractures are treated for osteoporosis in the years following fracture. In a randomized pilot study, we found a nurse case-manager could double rates of osteoporosis testing and treatment compared with a proven efficacious quality improvement strategy directed at patients and physicians (57% vs 28% rates of appropriate care). Few patients with fractures are treated for osteoporosis. An intervention directed at wrist fracture patients (education) and physicians (guidelines, reminders) tripled osteoporosis treatment rates compared to controls (22% vs 7% within 6 months of fracture). More effective strategies are needed. We undertook a pilot study that compared a nurse case-manager to the multifaceted intervention using a randomized trial design. The case-manager counseled patients, arranged bone mineral density (BMD) tests, and prescribed treatments. We included controls from our first trial who remained untreated for osteoporosis 1-year post-fracture. Primary outcome was bisphosphonate treatment and secondary outcomes were BMD testing, appropriate care (BMD test-treatment if bone mass low), and costs. Forty six patients untreated 1-year after wrist fracture were randomized to case-manager (n = 21) or multifaceted intervention (n = 25). Median age was 60 years and 68% were female. Six months post-randomization, 9 (43%) case-managed patients were treated with bisphosphonates compared with 3 (12%) multifaceted intervention patients (relative risk [RR] 3.6, 95% confidence intervals [CI] 1.1-11.5, p = 0.019). Case-managed patients were more likely than multifaceted intervention patients to undergo BMD tests (81% vs 52%, RR 1.6, 95%CI 1.1-2.4, p = 0.042) and receive appropriate care (57% vs 28%, RR 2.0, 95%CI 1.0-4.2, p = 0.048). Case-management cost was $44 (CDN) per patient vs $12 for the multifaceted intervention. A nurse case-manager substantially increased rates of appropriate testing and treatment for osteoporosis in patients at high-risk of future fracture when compared with a multifaceted quality improvement intervention aimed at patients and physicians. Even with case-management, nearly half of patients did not receive appropriate care. clinicaltrials.gov identifier: NCT00152321.

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

PubMed

Bautista, Francisco; Moreno, Lucas; Marshall, Lynley; Pearson, Andrew D J; Geoerger, Birgit; Paoletti, Xavier

2017-11-01

Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Improving Memory and Cognition in Individuals with Down Syndrome.

PubMed

Rafii, Michael S

2016-07-01

Down syndrome (DS), often due to trisomy 21, is the most common genetic cause of intellectual disability (ID). In addition, virtually all individuals with DS develop the neuropathology of Alzheimer's disease (AD) by the age of 40 years and almost 60 % will manifest symptoms of AD dementia by the age of 65 years. Currently, there are no pharmacological treatments available for ID in individuals with DS and only limited symptomatic treatments for AD dementia. Advances in our understanding in both the molecular basis of ID and the pathogenesis of AD have created opportunities to study potential therapeutic targets. Recent studies in animal models of DS continue to provide a rational basis for translating specific compounds into human clinical trials. However, target and compound selection are only initial steps in the drug development pathway. Other necessary considerations include appropriate study designs to assess efficacy in the DS population, as well as operational aspects specifically tailored to assess cognition in this population. We discuss recent progress in the development of compounds for both ID and AD in individuals with DS, as well as concepts for the design and conduct of clinical trials with such compounds.

Designing exercise clinical trials for older adults with cancer: Recommendations from 2015 Cancer and Aging Research Group NCI U13 Meeting.

PubMed

Kilari, Deepak; Soto-Perez-de-Celis, Enrique; Mohile, Supriya Gupta; Alibhai, Shabbir M H; Presley, Carolyn J; Wildes, Tanya M; Klepin, Heidi D; Demark-Wahnefried, Wendy; Jatoi, Amina; Harrison, Robert; Won, Elizabeth; Mustian, Karen M

2016-07-01

Cancer and its treatment can lead to a myriad of adverse events and negatively impact quality of life of older cancer patients and survivors. Unmet physical activity needs vary across the cancer continuum and remain an important yet understudied area of research in this population. Exercise interventions have been shown to be effective in treating both the physical and psychological declines associated with cancer and its treatment, with a potential to improve cancer-related outcomes. Despite the current evidence, exercise is clearly underutilized due to several barriers and knowledge gaps in existing trials that include appropriate population identification, design, and outcome measures selection. The benefits of regular exercise in both the primary and secondary prevention of chronic conditions are well established in the non-cancer population. In older cancer patients and survivors, further research is needed before exercise gains widespread acceptance. The Cancer and Aging Research Group convened experts in exercise, aging and cancer to evaluate current scientific evidence and knowledge gaps in geriatric exercise oncology. This report summarizes these findings and provides future research directions. Published by Elsevier Ltd.

Heritable strategies for controlling insect vectors of disease.

PubMed

Burt, Austin

2014-01-01

Mosquito-borne diseases are causing a substantial burden of mortality, morbidity and economic loss in many parts of the world, despite current control efforts, and new complementary approaches to controlling these diseases are needed. One promising class of new interventions under development involves the heritable modification of the mosquito by insertion of novel genes into the nucleus or of Wolbachia endosymbionts into the cytoplasm. Once released into a target population, these modifications can act to reduce one or more components of the mosquito population's vectorial capacity (e.g. the number of female mosquitoes, their longevity or their ability to support development and transmission of the pathogen). Some of the modifications under development are designed to be self-limiting, in that they will tend to disappear over time in the absence of recurrent releases (and hence are similar to the sterile insect technique, SIT), whereas other modifications are designed to be self-sustaining, spreading through populations even after releases stop (and hence are similar to traditional biological control). Several successful field trials have now been performed with Aedes mosquitoes, and such trials are helping to define the appropriate developmental pathway for this new class of intervention.

Randomised comparison of the effectiveness of the laryngeal mask airway supreme, i-gel and current practice in the initial airway management of prehospital cardiac arrest (REVIVE-Airways): a feasibility study research protocol

PubMed Central

Benger, Jonathan Richard; Voss, Sarah; Coates, David; Greenwood, Rosemary; Nolan, Jerry; Rawstorne, Steven; Rhys, Megan; Thomas, Matthew

2013-01-01

Introduction Effective cardiopulmonary resuscitation with appropriate airway management improves outcomes following out-of-hospital cardiac arrest (OHCA). Historically, tracheal intubation has been accepted as the optimal form of OHCA airway management in the UK. The Joint Royal Colleges Ambulance Liaison Committee recently concluded that newer supraglottic airway devices (SADs) are safe and effective devices for hospital procedures and that their use in OHCA should be investigated. This study will address an identified gap in current knowledge by assessing whether it is feasible to use a cluster randomised design to compare SADs with current practice, and also to each other, during OHCA. Methods and analysis The primary objective of this study is to assess the feasibility of a cluster randomised trial to compare the ventilation success of two newer SADs: the i-gel and the laryngeal mask airway supreme to usual practice during the initial airway management of OHCA. The secondary objectives are to collect data on ventilation success, further airway interventions required, loss of a previously established airway during transport, airway management on arrival at hospital (or termination of the resuscitation attempt), initial resuscitation success, survival to intensive care admission, survival to hospital discharge and patient outcome at 3 months. Ambulance paramedics will be randomly allocated to one of the three methods of airway management. Adults in medical OHCA attended by a trial paramedic will be eligible for the study. Ethics and dissemination Approval for the study has been obtained from a National Health Service Research Ethics Committee with authority to review proposals for trials of a medical device in incapacitated adults. The results will be made publicly available on an open access website, and we will publish the findings in appropriate journals and present them at national and international conferences relevant to the subject field. Trial registration ISRCTN: 18528625. PMID:23408081

Using Bayesian Adaptive Trial Designs for Comparative Effectiveness Research: A Virtual Trial Execution.

PubMed

Luce, Bryan R; Connor, Jason T; Broglio, Kristine R; Mullins, C Daniel; Ishak, K Jack; Saunders, Elijah; Davis, Barry R

2016-09-20

Bayesian and adaptive clinical trial designs offer the potential for more efficient processes that result in lower sample sizes and shorter trial durations than traditional designs. To explore the use and potential benefits of Bayesian adaptive clinical trial designs in comparative effectiveness research. Virtual execution of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) as if it had been done according to a Bayesian adaptive trial design. Comparative effectiveness trial of antihypertensive medications. Patient data sampled from the more than 42 000 patients enrolled in ALLHAT with publicly available data. Number of patients randomly assigned between groups, trial duration, observed numbers of events, and overall trial results and conclusions. The Bayesian adaptive approach and original design yielded similar overall trial conclusions. The Bayesian adaptive trial randomly assigned more patients to the better-performing group and would probably have ended slightly earlier. This virtual trial execution required limited resampling of ALLHAT patients for inclusion in RE-ADAPT (REsearch in ADAptive methods for Pragmatic Trials). Involvement of a data monitoring committee and other trial logistics were not considered. In a comparative effectiveness research trial, Bayesian adaptive trial designs are a feasible approach and potentially generate earlier results and allocate more patients to better-performing groups. National Heart, Lung, and Blood Institute.

Support and assessment for fall emergency referrals (SAFER 2) research protocol: cluster randomised trial of the clinical and cost effectiveness of new protocols for emergency ambulance paramedics to assess and refer to appropriate community-based care

PubMed Central

Snooks, Helen; Anthony, Rebecca; Chatters, Robin; Cheung, Wai-Yee; Dale, Jeremy; Donohoe, Rachael; Gaze, Sarah; Halter, Mary; Koniotou, Marina; Logan, Phillippa; Lyons, Ronan; Mason, Suzanne; Nicholl, Jon; Phillips, Ceri; Phillips, Judith; Russell, Ian; Siriwardena, A Niroshan; Wani, Mushtaq; Watkins, Alan; Whitfield, Richard; Wilson, Lynsey

2012-01-01

Introduction Emergency calls to ambulance services are frequent for older people who have fallen, but ambulance crews often leave patients at the scene without ongoing care. Evidence shows that when left at home with no further support older people often experience subsequent falls which result in injury and emergency-department attendances. SAFER 2 is an evaluation of a new clinical protocol which allows paramedics to assess and refer older people who have fallen, and do not need hospital care, to community-based falls services. In this protocol paper, we report methods and progress during trial implementation. SAFER 2 is recruiting patients through three ambulance services. A successful trial will provide robust evidence about the value of this new model of care, and enable ambulance services to use resources efficiently. Design Pragmatic cluster randomised trial. Methods and analysis We randomly allocated 25 participating ambulance stations (clusters) in three services to intervention or control group. Intervention paramedics received training and clinical protocols for assessing and referring older people who have fallen to community-based falls services when appropriate, while control paramedics deliver care as usual. Patients are eligible for the trial if they are aged 65 or over; resident in a participating falls service catchment area; and attended by a trial paramedic following an emergency call coded as a fall without priority symptoms. The principal outcome is the rate of further emergency contacts (or death), for any cause and for falls. Secondary outcomes include further falls, health-related quality of life, ‘fear of falling’, patient satisfaction reported by participants through postal questionnaires at 1 and 6 months, and quality and pathways of care at the index incident. We shall compare National Health Service (NHS) and patient/carer costs between intervention and control groups and estimate quality-adjusted life years (QALYs) gained from the intervention and thus incremental cost per QALY. We shall estimate wider system effects on key-performance indicators. We shall interview 60 intervention patients, and conduct focus groups with contributing NHS staff to explore their experiences of the assessment and referral service. We shall analyse quantitative trial data by ‘treatment allocated’; and qualitative data using content analysis. Ethics and dissemination The Research Ethics Committee for Wales gave ethical approval and each participating centre gave NHS Research and Development approval. We shall disseminate study findings through peer-reviewed publications and conference presentations. Trial Registration: ISRCTN 60481756 PMID:23148348

Practical characteristics of adaptive design in phase 2 and 3 clinical trials.

PubMed

Sato, A; Shimura, M; Gosho, M

2018-04-01

Adaptive design methods are expected to be ethical, reflect real medical practice, increase the likelihood of research and development success and reduce the allocation of patients into ineffective treatment groups by the early termination of clinical trials. However, the comprehensive details regarding which types of clinical trials will include adaptive designs remain unclear. We examined the practical characteristics of adaptive design used in clinical trials. We conducted a literature search of adaptive design clinical trials published from 2012 to 2015 using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, with common search terms related to adaptive design. We systematically assessed the types and characteristics of adaptive designs and disease areas employed in the adaptive design trials. Our survey identified 245 adaptive design clinical trials. The number of trials by the publication year increased from 2012 to 2013 and did not greatly change afterwards. The most frequently used adaptive design was group sequential design (n = 222, 90.6%), especially for neoplasm or cardiovascular disease trials. Among the other types of adaptive design, adaptive dose/treatment group selection (n = 21, 8.6%) and adaptive sample-size adjustment (n = 19, 7.8%) were frequently used. The adaptive randomization (n = 8, 3.3%) and adaptive seamless design (n = 6, 2.4%) were less frequent. Adaptive dose/treatment group selection and adaptive sample-size adjustment were frequently used (up to 23%) in "certain infectious and parasitic diseases," "diseases of nervous system," and "mental and behavioural disorders" in comparison with "neoplasms" (<6.6%). For "mental and behavioural disorders," adaptive randomization was used in two trials of eight trials in total (25%). Group sequential design and adaptive sample-size adjustment were used frequently in phase 3 trials or in trials where study phase was not specified, whereas the other types of adaptive designs were used more in phase 2 trials. Approximately 82% (202 of 245 trials) resulted in early termination at the interim analysis. Among the 202 trials, 132 (54% of 245 trials) had fewer randomized patients than initially planned. This result supports the motive to use adaptive design to make study durations shorter and include a smaller number of subjects. We found that adaptive designs have been applied to clinical trials in various therapeutic areas and interventions. The applications were frequently reported in neoplasm or cardiovascular clinical trials. The adaptive dose/treatment group selection and sample-size adjustment are increasingly common, and these adaptations generally follow the Food and Drug Administration's (FDA's) recommendations. © 2017 John Wiley & Sons Ltd.

Barriers and facilitators to the implementation of antenatal syphilis screening and treatment for the prevention of congenital syphilis in the Democratic Republic of Congo and Zambia: results of qualitative formative research.

PubMed

Nkamba, Dalau; Mwenechanya, Musaku; Kilonga, Arlette Mavila; Cafferata, Maria Luisa; Berrueta, Amanda Mabel; Mazzoni, Agustina; Althabe, Fernando; Garcia-Elorrio, Ezequiel; Tshefu, Antoniette K; Chomba, Elwyn; Buekens, Pierre M; Belizan, Maria

2017-08-14

The impact of untreated syphilis during pregnancy on neonatal health remains a major public health threat worldwide. Given the high prevalence of syphilis during pregnancy in Zambia and Democratic Republic of Congo (DRC), the Preventive Congenital Syphilis Trial (PCS Trial), a cluster randomized trial, was proposed to increase same-day screening and treatment of syphilis during antenatal care visits. To design an accepted and feasible intervention, we conducted a qualitative  formative research. Our objective was to identify context-specific  barriers and facilitators to the implementation of antenatal screening and treatment during pregnancy. Qualitative research included in-depth semi-structured interviews with clinic administrators, group interviews with health care providers, and focus groups with pregnant women in primary care clinics (PCCs) in Kinshasa (DRC) and Lusaka (Zambia). A total of 112 individuals participated in the interviews and focus groups. Barriers for the implementation of syphilis testing and treatment were identified at the a) system level: fragmentation of the health system, existence of ANC guidelines in conflict with proposed intervention, poor accessibility of clinics (geographical and functional), staff and product shortages at the PCCs; b) healthcare providers' level: lack of knowledge and training about evolving best practices, reservations regarding same-day screening and treatment; c) Pregnant women level: late enrollment in ANC, lack of knowledge about consequences and treatment of syphilis, and stigma. Based on these results, we developed recommendations for the design of the PCS Trial intervention. This research allowed us to identify barriers and facilitators to improve the feasibility and acceptability of a behavioral intervention. Formative research is a critical step in designing appropriate and effective interventions by closing the "know-do gap".

Knowledge translation strategies for enhancing nurses' evidence-informed decision making: a scoping review.

PubMed

Yost, Jennifer; Thompson, David; Ganann, Rebecca; Aloweni, Fazila; Newman, Kristine; McKibbon, Ann; Dobbins, Maureen; Ciliska, Donna

2014-06-01

Nurses are increasingly expected to engage in evidence-informed decision making (EIDM); the use of research evidence with information about patient preferences, clinical context and resources, and their clinical expertise in decision making. Strategies for enhancing EIDM have been synthesized in high-quality systematic reviews, yet most relate to physicians or mixed disciplines. Existing reviews, specific to nursing, have not captured a broad range of strategies for promoting the knowledge and skills for EIDM, patient outcomes as a result of EIDM, or contextual information for why these strategies "work." To conduct a scoping review to identify and map the literature related to strategies implemented among nurses in tertiary care for promoting EIDM knowledge, skills, and behaviours, as well as patient outcomes and contextual implementation details. A search strategy was developed and executed to identify relevant research evidence. Participants included registered nurses, clinical nurse specialists, nurse practitioners, and advanced practice nurses. Strategies were those enhancing nurses' EIDM knowledge, skills, or behaviours, as well as patient outcomes. Relevant studies included systematic reviews, randomized controlled trials, cluster randomized controlled trials, non-randomized trials (including controlled before and after studies), cluster non-randomized trials, interrupted time series designs, prospective cohort studies, mixed-method studies, and qualitative studies. Two reviewers performed study selection and data extraction using standardized forms. Disagreements were resolved through discussion or third party adjudication. Using a narrative synthesis, the body of research was mapped by design, clinical areas, strategies, and provider and patient outcomes to determine areas appropriate for a systematic review. There are a sufficiently high number of studies to conduct a more focused systematic review by care settings, study design, implementation strategies, or outcomes. A focused review could assist in determining which strategies can be recommended for enhancing EIDM knowledge, skills, and behaviours among nurses in tertiary care. © 2014 The Authors. Worldviews on Evidence-Based Nursing published by Wiley Periodicals, Inc. on behalf of Sigma Theta Tau International.

Physical therapy vs. internet-based exercise training (PATH-IN) for patients with knee osteoarthritis: study protocol of a randomized controlled trial.

PubMed

Williams, Quinn I; Gunn, Alexander H; Beaulieu, John E; Benas, Bernadette C; Buley, Bruce; Callahan, Leigh F; Cantrell, John; Genova, Andrew P; Golightly, Yvonne M; Goode, Adam P; Gridley, Christopher I; Gross, Michael T; Heiderscheit, Bryan C; Hill, Carla H; Huffman, Kim M; Kline, Aaron; Schwartz, Todd A; Allen, Kelli D

2015-09-28

Physical activity improves pain and function among individuals with knee osteoarthritis (OA), but most people with this condition are inactive. Physical therapists play a key role in helping people with knee OA to increase appropriate physical activity. However, health care access issues, financial constraints, and other factors impede some patients from receiving physical therapy (PT) for knee OA. A need exists to develop and evaluate other methods to provide physical activity instruction and support to people with knee OA. This study is examining the effectiveness of an internet-based exercise training (IBET) program designed for knee OA, designed by physical therapists and other clinicians. This is a randomized controlled trial of 350 participants with symptomatic knee OA, allocated to three groups: IBET, standard PT, and a wait list (WL) control group (in a 2:2:1 ratio, respectively). The study was funded by the Patient Centered Outcomes Research Institute, which conducted a peer review of the proposal. The IBET program provides patients with a tailored exercise program (based on functional level, symptoms, and current activity), video demonstrations of exercises, and guidance for appropriate exercise progression. The PT group receives up to 8 individual visits with a physical therapist, mirroring standard practice for knee OA and with an emphasis on a home exercise program. Outcomes are assessed at baseline, 4 months (primary time point) and 12 months (to assess maintenance of treatment effects). The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index, and secondary outcomes include objective physical function, satisfaction with physical function, physical activity, depressive symptoms and global assessment of change. Linear mixed models will be used to compare both the IBET and standard PT groups to the WL control group, examine whether IBET is non-inferior to PT (a treatment that has an established evidence base for knee OA), and explore whether participant characteristics are associated with differential effects of IBET and/or standard PT. This research is in compliance with the Helsinki Declaration and was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill. The IBET program could be disseminated widely at relatively low cost and could be an important resource for helping patients with knee OA to adopt and maintain appropriate physical activity. This trial will provide an important evaluation of the effectiveness of this IBET program for knee OA. NCT02312713.

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.

Randomization in clinical trials: stratification or minimization? The HERMES free simulation software.

PubMed

Fron Chabouis, Hélène; Chabouis, Francis; Gillaizeau, Florence; Durieux, Pierre; Chatellier, Gilles; Ruse, N Dorin; Attal, Jean-Pierre

2014-01-01

Operative clinical trials are often small and open-label. Randomization is therefore very important. Stratification and minimization are two randomization options in such trials. The first aim of this study was to compare stratification and minimization in terms of predictability and balance in order to help investigators choose the most appropriate allocation method. Our second aim was to evaluate the influence of various parameters on the performance of these techniques. The created software generated patients according to chosen trial parameters (e.g., number of important prognostic factors, number of operators or centers, etc.) and computed predictability and balance indicators for several stratification and minimization methods over a given number of simulations. Block size and proportion of random allocations could be chosen. A reference trial was chosen (50 patients, 1 prognostic factor, and 2 operators) and eight other trials derived from this reference trial were modeled. Predictability and balance indicators were calculated from 10,000 simulations per trial. Minimization performed better with complex trials (e.g., smaller sample size, increasing number of prognostic factors, and operators); stratification imbalance increased when the number of strata increased. An inverse correlation between imbalance and predictability was observed. A compromise between predictability and imbalance still has to be found by the investigator but our software (HERMES) gives concrete reasons for choosing between stratification and minimization; it can be downloaded free of charge. This software will help investigators choose the appropriate randomization method in future two-arm trials.

Mobile access to virtual randomization for investigator-initiated trials.

PubMed

Deserno, Thomas M; Keszei, András P

2017-08-01

Background/aims Randomization is indispensable in clinical trials in order to provide unbiased treatment allocation and a valid statistical inference. Improper handling of allocation lists can be avoided using central systems, for example, human-based services. However, central systems are unaffordable for investigator-initiated trials and might be inaccessible from some places, where study subjects need allocations. We propose mobile access to virtual randomization, where the randomization lists are non-existent and the appropriate allocation is computed on demand. Methods The core of the system architecture is an electronic data capture system or a clinical trial management system, which is extended by an R interface connecting the R server using the Java R Interface. Mobile devices communicate via the representational state transfer web services. Furthermore, a simple web-based setup allows configuring the appropriate statistics by non-statisticians. Our comprehensive R script supports simple randomization, restricted randomization using a random allocation rule, block randomization, and stratified randomization for un-blinded, single-blinded, and double-blinded trials. For each trial, the electronic data capture system or the clinical trial management system stores the randomization parameters and the subject assignments. Results Apps are provided for iOS and Android and subjects are randomized using smartphones. After logging onto the system, the user selects the trial and the subject, and the allocation number and treatment arm are displayed instantaneously and stored in the core system. So far, 156 subjects have been allocated from mobile devices serving five investigator-initiated trials. Conclusion Transforming pre-printed allocation lists into virtual ones ensures the correct conduct of trials and guarantees a strictly sequential processing in all trial sites. Covering 88% of all randomization models that are used in recent trials, virtual randomization becomes available for investigator-initiated trials and potentially for large multi-center trials.

ACR Appropriateness Criteria® Ovarian Cancer Screening.

PubMed

Pandharipande, Pari V; Lowry, Kathryn P; Reinhold, Caroline; Atri, Mostafa; Benson, Carol B; Bhosale, Priyadarshani R; Green, Edward D; Kang, Stella K; Lakhman, Yulia; Maturen, Katherine E; Nicola, Refky; Salazar, Gloria M; Shipp, Thomas D; Simpson, Lynn; Sussman, Betsy L; Uyeda, Jennifer; Wall, Darci J; Whitcomb, Bradford; Zelop, Carolyn M; Glanc, Phyllis

2017-11-01

There has been much interest in the identification of a successful ovarian cancer screening test, in particular, one that can detect ovarian cancer at an early stage and improve survival. We reviewed the currently available data from randomized and observational trials that examine the role of imaging for ovarian cancer screening in average-risk and high-risk women. We found insufficient evidence to recommend ovarian cancer screening, when considering the imaging modality (pelvic ultrasound) and population (average-risk postmenopausal women) for which there is the greatest available published evidence; randomized controlled trials have not demonstrated a mortality benefit in this setting. Screening high-risk women using pelvic ultrasound may be appropriate in some clinical situations; however, related data are limited because large, randomized trials have not been performed in this setting. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Copyright © 2017 American College of Radiology. Published by Elsevier Inc. All rights reserved.

The evaluation of enhanced feedback interventions to reduce unnecessary blood transfusions (AFFINITIE): protocol for two linked cluster randomised factorial controlled trials.

PubMed

Hartley, Suzanne; Foy, Robbie; Walwyn, Rebecca E A; Cicero, Robert; Farrin, Amanda J; Francis, Jill J; Lorencatto, Fabiana; Gould, Natalie J; Grant-Casey, John; Grimshaw, Jeremy M; Glidewell, Liz; Michie, Susan; Morris, Stephen; Stanworth, Simon J

2017-07-03

Blood for transfusion is a frequently used clinical intervention, and is also a costly and limited resource with risks. Many transfusions are given to stable and non-bleeding patients despite no clear evidence of benefit from clinical studies. Audit and feedback (A&F) is widely used to improve the quality of healthcare, including appropriate use of blood. However, its effects are often inconsistent, indicating the need for coordinated research including more head-to-head trials comparing different ways of delivering feedback. A programmatic series of research projects, termed the 'Audit and Feedback INterventions to Increase evidence-based Transfusion practIcE' (AFFINITIE) programme, aims to test different ways of developing and delivering feedback within an existing national audit structure. The evaluation will comprise two linked 2×2 factorial, cross-sectional cluster-randomised controlled trials. Each trial will estimate the effects of two feedback interventions, 'enhanced content' and 'enhanced follow-on support', designed in earlier stages of the AFFINITIE programme, compared to current practice. The interventions will be embedded within two rounds of the UK National Comparative Audit of Blood Transfusion (NCABT) focusing on patient blood management in surgery and use of blood transfusions in patients with haematological malignancies. The unit of randomisation will be National Health Service (NHS) trust or health board. Clusters providing care relevant to the audit topics will be randomised following each baseline audit (separately for each trial), with stratification for size (volume of blood transfusions) and region (Regional Transfusion Committee). The primary outcome for each topic will be the proportion of patients receiving a transfusion coded as unnecessary. For each audit topic a linked, mixed-method fidelity assessment and cost-effectiveness analysis will be conducted in parallel to the trial. AFFINITIE involves a series of studies to explore how A&F may be refined to change practice including two cluster randomised trials linked to national audits of transfusion practice. The methodology represents a step-wise increment in study design to more fully evaluate the effects of two enhanced feedback interventions on patient- and trust-level clinical, cost, safety and process outcomes. http://www.isrctn.com/ISRCTN15490813.

Screening uptake rates and the clinical and cost effectiveness of screening for gestational diabetes mellitus in primary versus secondary care: study protocol for a randomised controlled trial

PubMed Central

2014-01-01

Background The risks associated with gestational diabetes mellitus (GDM) are well recognized, and there is increasing evidence to support treatment of the condition. However, clear guidance on the ideal approach to screening for GDM is lacking. Professional groups continue to debate whether selective screening (based on risk factors) or universal screening is the most appropriate approach. Additionally, there is ongoing debate about what levels of glucose abnormalities during pregnancy respond best to treatment and which maternal and neonatal outcomes benefit most from treatment. Furthermore, the implications of possible screening options on health care costs are not well established. In response to this uncertainty there have been repeated calls for well-designed, randomised trials to determine the efficacy of screening, diagnosis, and management plans for GDM. We describe a randomised controlled trial to investigate screening uptake rates and the clinical and cost effectiveness of screening in primary versus secondary care settings. Methods/Design This will be an unblinded, two-group, parallel randomised controlled trial (RCT). The target population includes 784 women presenting for their first antenatal visit at 12 to 18 weeks gestation at two hospitals in the west of Ireland: Galway University Hospital and Mayo General Hospital. Participants will be offered universal screening for GDM at 24 to 28 weeks gestation in either primary care (n = 392) or secondary care (n = 392) locations. The primary outcome variable is the uptake rate of screening. Secondary outcomes include indicators of clinical effectiveness of screening at each screening site (primary and secondary) including gestational week at time of screening, time to access antenatal diabetes services for women diagnosed with GDM, and pregnancy and neonatal outcomes for women with GDM. In addition, parallel economic and qualitative evaluations will be conducted. The trial will cover the period from the woman’s first hospital antenatal visit at 12 to 18 weeks gestation, until the completion of the pregnancy. Trial registration Current Controlled Trials: ISRCTN02232125 PMID:24438478

Clinical Impact Research – how to choose experimental or observational intervention study?

PubMed Central

Malmivaara, Antti

2016-01-01

Abstract Background: Interventions directed to individuals by health and social care systems should increase health and welfare of patients and customers. Aims: This paper aims to present and define a new concept Clinical Impact Research (CIR) and suggest which study design, either randomized controlled trial (RCT) (experimental) or benchmarking controlled trial (BCT) (observational) is recommendable and to consider the feasibility, validity, and generalizability issues in CIR. Methods: The new concept is based on a narrative review of the literature and on author’s idea that in intervention studies, there is a need to cover comprehensively all the main impact categories and their respective outcomes. The considerations on how to choose the most appropriate study design (RCT or BCT) were based on previous methodological studies on RCTs and BCTs and on author’s previous work on the concepts benchmarking controlled trial and system impact research (SIR). Results: The CIR covers all studies aiming to assess the impact for health and welfare of any health (and integrated social) care or public health intervention directed to an individual. The impact categories are accessibility, quality, equality, effectiveness, safety, and efficiency. Impact is the main concept, and within each impact category, both generic- and context-specific outcome measures are needed. CIR uses RCTs and BCTs. Conclusions: CIR should be given a high priority in medical, health care, and health economic research. Clinicians and leaders at all levels of health care can exploit the evidence from CIR. Key messagesThe new concept of Clinical Impact Research (CIR) is defined as a research field aiming to assess what are the impacts of healthcare and public health interventions targeted to patients or individuals.The term impact refers to all effects caused by the interventions, with particular emphasis on accessibility, quality, equality, effectiveness, safety, and efficiency. CIR uses two study designs: randomized controlled trials (RCTs) (experimental) and benchmarking controlled trials (BCTs) (observational). Suggestions on how to choose between RCT and BCT as the most suitable study design are presented.Simple way of determining the study question in CIR based on the PICO (patient, intervention, control intervention, outcome) framework is presented.CIR creates the scientific basis for clinical decisions. Clinicians and leaders at all levels of health care and those working for public health can use the evidence from CIR for the benefit of patients and the population. PMID:27494394

Clinical Impact Research - how to choose experimental or observational intervention study?

PubMed

Malmivaara, Antti

2016-11-01

Interventions directed to individuals by health and social care systems should increase health and welfare of patients and customers. This paper aims to present and define a new concept Clinical Impact Research (CIR) and suggest which study design, either randomized controlled trial (RCT) (experimental) or benchmarking controlled trial (BCT) (observational) is recommendable and to consider the feasibility, validity, and generalizability issues in CIR. The new concept is based on a narrative review of the literature and on author's idea that in intervention studies, there is a need to cover comprehensively all the main impact categories and their respective outcomes. The considerations on how to choose the most appropriate study design (RCT or BCT) were based on previous methodological studies on RCTs and BCTs and on author's previous work on the concepts benchmarking controlled trial and system impact research (SIR). The CIR covers all studies aiming to assess the impact for health and welfare of any health (and integrated social) care or public health intervention directed to an individual. The impact categories are accessibility, quality, equality, effectiveness, safety, and efficiency. Impact is the main concept, and within each impact category, both generic- and context-specific outcome measures are needed. CIR uses RCTs and BCTs. CIR should be given a high priority in medical, health care, and health economic research. Clinicians and leaders at all levels of health care can exploit the evidence from CIR. Key messages The new concept of Clinical Impact Research (CIR) is defined as a research field aiming to assess what are the impacts of healthcare and public health interventions targeted to patients or individuals. The term impact refers to all effects caused by the interventions, with particular emphasis on accessibility, quality, equality, effectiveness, safety, and efficiency. CIR uses two study designs: randomized controlled trials (RCTs) (experimental) and benchmarking controlled trials (BCTs) (observational). Suggestions on how to choose between RCT and BCT as the most suitable study design are presented. Simple way of determining the study question in CIR based on the PICO (patient, intervention, control intervention, outcome) framework is presented. CIR creates the scientific basis for clinical decisions. Clinicians and leaders at all levels of health care and those working for public health can use the evidence from CIR for the benefit of patients and the population.

Systems analysis and improvement to optimize pMTCT (SAIA): a cluster randomized trial.

PubMed

Sherr, Kenneth; Gimbel, Sarah; Rustagi, Alison; Nduati, Ruth; Cuembelo, Fatima; Farquhar, Carey; Wasserheit, Judith; Gloyd, Stephen

2014-05-08

Despite significant increases in global health investment and the availability of low-cost, efficacious interventions to prevent mother-to-child HIV transmission (pMTCT) in low- and middle-income countries with high HIV burden, the translation of scientific advances into effective delivery strategies has been slow, uneven and incomplete. As a result, pediatric HIV infection remains largely uncontrolled. A five-step, facility-level systems analysis and improvement intervention (SAIA) was designed to maximize effectiveness of pMTCT service provision by improving understanding of inefficiencies (step one: cascade analysis), guiding identification and prioritization of low-cost workflow modifications (step two: value stream mapping), and iteratively testing and redesigning these modifications (steps three through five). This protocol describes the SAIA intervention and methods to evaluate the intervention's impact on reducing drop-offs along the pMTCT cascade. This study employs a two-arm, longitudinal cluster randomized trial design. The unit of randomization is the health facility. A total of 90 facilities were identified in Côte d'Ivoire, Kenya and Mozambique (30 per country). A subset was randomly selected and assigned to intervention and comparison arms, stratified by country and service volume, resulting in 18 intervention and 18 comparison facilities across all three countries, with six intervention and six comparison facilities per country. The SAIA intervention will be implemented for six months in the 18 intervention facilities. Primary trial outcomes are designed to assess improvements in the pMTCT service cascade, and include the percentage of pregnant women being tested for HIV at the first antenatal care visit, the percentage of HIV-infected pregnant women receiving adequate prophylaxis or combination antiretroviral therapy in pregnancy, and the percentage of newborns exposed to HIV in pregnancy receiving an HIV diagnosis eight weeks postpartum. The Consolidated Framework for Implementation Research (CFIR) will guide collection and analysis of qualitative data on implementation process. This study is a pragmatic trial that has the potential benefit of improving maternal and infant outcomes by reducing drop-offs along the pMTCT cascade. The SAIA intervention is designed to provide simple tools to guide decision-making for pMTCT program staff at the facility level, and to identify low cost, contextually appropriate pMTCT improvement strategies. ClinicalTrials.gov NCT02023658.

The Impact of an Antimicrobial Utilization Program on Antimicrobial Use at a Large Teaching Hospital: A Randomized Controlled Trial

PubMed Central

Camins, Bernard C.; King, Mark D.; Wells, Jane B.; Googe, Heidi L.; Patel, Manish; Kourbatova, Ekaterina V.; Blumberg, Henry M.

2009-01-01

Background Multidisciplinary antimicrobial utilization teams (AUT) have been proposed as a mechanism for improving antimicrobial use, but data on their efficacy remain limited. Objective To determine the impact of an AUT on antimicrobial use at a teaching hospital. Design Randomized controlled intervention trial. Setting A 953-bed public university-affiliated urban teaching hospital. Patients Patients who were prescribed selected antimicrobial agents (piperacillin-tazobactam, levofloxacin, or vancomycin) by internal medicine ward teams. Intervention Twelve internal medicine teams were randomized monthly: 6 teams to intervention group (academic detailing by the AUT), and 6 teams to a control group given indication-based guidelines for prescription of broad spectrum antimicrobials (standard of care) during a 10-month study period. Measurements Proportion of appropriate empiric, definitive (therapeutic), and end antimicrobial (overall) usage. Results A total of 784 new prescriptions of piperacillin-tazobactam, levofloxacin, and vancomycin were reviewed. The proportion of appropriate antimicrobial prescriptions written by the intervention teams was significantly higher than prescribed by the control teams: 82% vs. 73% for empiric (RR=1.14, 95% CI 1.04–1.24), 82% vs. 43% for definitive (RR=1.89, 95% CI 1.53–2.33), and 94% vs. 70% for end antimicrobial usage (RR=1.34, 95% CI 1.25–1.43). In a multivariate analysis, teams that received feedback from the AUT alone (aRR=1.37, 95% CI 1.27–1.48) or from both the AUT and the ID consult service (aRR=2.28, 95% CI 1.64–3.19) were significantly more likely to prescribe end antimicrobial usage appropriately compared to control teams. Conclusions A multidisciplinary AUT which provides feedback to prescribing physicians was an effective method in improving antimicrobial use. PMID:19712032

Have Clinical Trials Properly Assessed c-Met Inhibitors?

PubMed

Hughes, Veronica S; Siemann, Dietmar W

2018-02-01

The c-Met/HGF pathway is implicated in cancer progression and dissemination. Many inhibitors have been developed to target this pathway. Unfortunately, most trials have failed to demonstrate efficacy. However, clinical trials have not adequately tested the concept of c-Met pathway inhibition due to the lack of appropriate patient selection criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov

PubMed Central

Bothwell, Laura E; Avorn, Jerry; Khan, Nazleen F; Kesselheim, Aaron S

2018-01-01

Objectives This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials. Design Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs. Results 142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs. Conclusions Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis. PMID:29440155

78 FR 58318 - Clinical Trial Design for Intravenous Fat Emulsion Products; Public Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-23

...] Clinical Trial Design for Intravenous Fat Emulsion Products; Public Workshop AGENCY: Food and Drug... announcing a 1-day public workshop entitled ``Clinical Trial Design for Intravenous Fat Emulsion Products.'' This workshop will provide a forum to discuss trial design of clinical trials intended to support...

Cost-effectiveness analysis using data from multinational trials: The use of bivariate hierarchical modelling

PubMed Central

Manca, Andrea; Lambert, Paul C; Sculpher, Mark; Rice, Nigel

2008-01-01

Healthcare cost-effectiveness analysis (CEA) often uses individual patient data (IPD) from multinational randomised controlled trials. Although designed to account for between-patient sampling variability in the clinical and economic data, standard analytical approaches to CEA ignore the presence of between-location variability in the study results. This is a restrictive limitation given that countries often differ in factors that could affect the results of CEAs, such as the availability of healthcare resources, their unit costs, clinical practice, and patient case-mix. We advocate the use of Bayesian bivariate hierarchical modelling to analyse multinational cost-effectiveness data. This analytical framework explicitly recognises that patient-level costs and outcomes are nested within countries. Using real life data, we illustrate how the proposed methods can be applied to obtain (a) more appropriate estimates of overall cost-effectiveness and associated measure of sampling uncertainty compared to standard CEA; and (b) country-specific cost-effectiveness estimates which can be used to assess the between-location variability of the study results, while controlling for differences in country-specific and patient-specific characteristics. It is demonstrated that results from standard CEA using IPD from multinational trials display a large degree of variability across the 17 countries included in the analysis, producing potentially misleading results. In contrast, ‘shrinkage estimates’ obtained from the modelling approach proposed here facilitate the appropriate quantification of country-specific cost-effectiveness estimates, while weighting the results based on the level of information available within each country. We suggest that the methods presented here represent a general framework for the analysis of economic data collected from different locations. PMID:17641141

A model for assessment and referral of clients with bowel symptoms in community pharmacies.

PubMed

Sriram, Deepa; McManus, Alexandra; Emmerton, Lynne M; Parsons, Richard W; Jiwa, Moyez

2016-01-01

To expedite diagnosis of serious bowel disease, efforts are required to signpost patients with high-risk symptoms to appropriate care. Community pharmacies are a recognized source of health advice regarding bowel symptoms. This study aimed to examine the effectiveness of a validated self-administered questionnaire, Jodi Lee Test (JLT), for detection, triage, and referral of bowel symptoms suggestive of carcinoma, in pharmacies. 'Usual Practice' was monitored for 12 weeks in 21 pharmacies in Western Australia, documenting outcomes for 84 clients presenting with bowel symptoms. Outcome measures were: acceptance of verbal advice from the pharmacist; general practitioner consultation; and diagnosis. Trial of the JLT involved staff training in the research protocol and monitoring of outcomes for 80 recruited clients over 20 weeks. Utility of the JLT was assessed by post-trial survey of pharmacy staff. Significantly more referrals were made by staff using the JLT than during Usual Practice: 30 (38%) vs 17 (20%). Clients' acceptance of referrals was also higher for the intervention group (40% vs 6%). Two-thirds of pharmacy staff agreed that the JLT could be incorporated into pharmacy practice, and 70% indicated they would use the JLT in the future. A pre-post design was considered more appropriate than a randomized control trial due to an inability to match pharmacies. Limitations of this study were: lack of control over adherence to the study protocol by pharmacy staff; no direct measure of client feedback on the JLT; and loss to follow-up. The JLT was effective in prompting decision-making by pharmacy staff and inter-professional care between pharmacies and general practice, in triage of clients at risk of bowel cancer.

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial.

PubMed

Hayek, Adina; Joshi, Rohina; Usherwood, Tim; Webster, Ruth; Kaur, Baldeep; Saini, Bandana; Armour, Carol; Krass, Ines; Laba, Tracey-Lea; Reid, Christopher; Shiel, Louise; Hespe, Charlotte; Hersch, Fred; Jan, Stephen; Lo, Serigne; Peiris, David; Rodgers, Anthony; Patel, Anushka

2016-09-23

Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Australian New Zealand Clinical Trials Registry ACTRN12616000233426.

Ensuring respect for persons in COMPASS: a cluster randomised pragmatic clinical trial.

PubMed

Andrews, Joseph E; Moore, J Brian; Weinberg, Richard B; Sissine, Mysha; Gesell, Sabina; Halladay, Jacquie; Rosamond, Wayne; Bushnell, Cheryl; Jones, Sara; Means, Paula; King, Nancy M P; Omoyeni, Diana; Duncan, Pamela W

2018-05-02

Cluster randomised clinical trials present unique challenges in meeting ethical obligations to those who are treated at a randomised site. Obtaining informed consent for research within the context of clinical care is one such challenge. In order to solve this problem it is important that an informed consent process be effective and efficient, and that it does not impede the research or the healthcare. The innovative approach to informed consent employed in the COMPASS study demonstrates the feasibility of upholding ethical standards without imposing undue burden on clinical workflows, staff members or patients who may participate in the research by virtue of their presence in a cluster randomised facility. The COMPASS study included 40 randomised sites and compared the effectiveness of a postacute stroke intervention with standard care. Each site provided either the comprehensive postacute stroke intervention or standard care according to the randomisation assignment. Working together, the study team, institutional review board and members of the community designed an ethically appropriate and operationally reasonable consent process which was carried out successfully at all randomised sites. This achievement is noteworthy because it demonstrates how to effectively conduct appropriate informed consent in cluster randomised trials, and because it provides a model that can easily be adapted for other pragmatic studies. With this innovative approach to informed consent, patients have access to the information they need about research occurring where they are seeking care, and medical researchers can conduct their studies without ethical concerns or unreasonable logistical impediments. NCT02588664, recruiting. This article covers the development of consent process that is currentlty being employed in the study. © 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.

Identification of crop cultivars with consistently high lignocellulosic sugar release requires the use of appropriate statistical design and modelling

PubMed Central

2013-01-01

Background In this study, a multi-parent population of barley cultivars was grown in the field for two consecutive years and then straw saccharification (sugar release by enzymes) was subsequently analysed in the laboratory to identify the cultivars with the highest consistent sugar yield. This experiment was used to assess the benefit of accounting for both the multi-phase and multi-environment aspects of large-scale phenotyping experiments with field-grown germplasm through sound statistical design and analysis. Results Complementary designs at both the field and laboratory phases of the experiment ensured that non-genetic sources of variation could be separated from the genetic variation of cultivars, which was the main target of the study. The field phase included biological replication and plot randomisation. The laboratory phase employed re-randomisation and technical replication of samples within a batch, with a subset of cultivars chosen as duplicates that were randomly allocated across batches. The resulting data was analysed using a linear mixed model that incorporated field and laboratory variation and a cultivar by trial interaction, and ensured that the cultivar means were more accurately represented than if the non-genetic variation was ignored. The heritability detected was more than doubled in each year of the trial by accounting for the non-genetic variation in the analysis, clearly showing the benefit of this design and approach. Conclusions The importance of accounting for both field and laboratory variation, as well as the cultivar by trial interaction, by fitting a single statistical model (multi-environment trial, MET, model), was evidenced by the changes in list of the top 40 cultivars showing the highest sugar yields. Failure to account for this interaction resulted in only eight cultivars that were consistently in the top 40 in different years. The correspondence between the rankings of cultivars was much higher at 25 in the MET model. This approach is suited to any multi-phase and multi-environment population-based genetic experiment. PMID:24359577

Computer-delivered indirect screening and brief intervention for drug use in the perinatal period: A randomized trial.

PubMed

Ondersma, Steven J; Svikis, Dace S; Thacker, Casey; Resnicow, Ken; Beatty, Jessica R; Janisse, James; Puder, Karoline

2018-04-01

Under-reporting of drug use in the perinatal period is well-documented, and significantly limits the reach of proactive intervention approaches. The Wayne Indirect Drug Use Screener (WIDUS) focuses on correlates of drug use rather than use itself. This trial tested a computer-delivered, brief intervention designed for use with indirect screen-positive cases, seeking to motivate reductions in drug use without presuming its presence. Randomized clinical trial with 500 WIDUS-positive postpartum women recruited between August 14, 2012 and November 19, 2014. Participants were randomly assigned to either a time control condition or a single-session, tailored, indirect brief intervention. The primary outcome was days of drug use over the 6-month follow-up period; secondary outcomes included urine and hair analyses results at 3- and 6-month follow-up. All outcomes were measured by blinded evaluators. Of the 500 participants (252 intervention and 248 control), 36.1% of participants acknowledged drug use in the 3 months prior to pregnancy, but 89% tested positive at the 6-month follow-up. Participants rated the intervention as easy to use (4.9/5) and helpful (4.4/5). Analyses revealed no between-group differences in drug use (52% in the intervention group, vs. 53% among controls; OR 1.03). Exploratory analyses also showed that intervention effects were not moderated by baseline severity, WIDUS score, or readiness to change. The present trial showed no evidence of efficacy for an indirect, single-session, computer-delivered, brief intervention designed as a complement to indirect screening. More direct approaches that still do not presume active drug use may be possible and appropriate. Copyright © 2018 Elsevier B.V. All rights reserved.

Field-Theoretic Simulations

NASA Astrophysics Data System (ADS)

Ganesan, Venkat; Fredrickson, Glenn H.

The science and engineering of materials is entering a new era of so-called "designer materials", wherein, based upon the properties required for a particular application, a material is designed by exploiting the self-assembly of appropriately chosen molecular constituents [1]. The desirable and marketable properties of such materials, which include plastic alloys, block and graft copolymers, and polyelectrolyte solutions, complexes, and gels, depend critically on the ability to control and manipulate morphology by adjusting a combination of molecular and macroscopic variables. For example, styrenebutadiene block copolymers can be devised that serve either as rigid, tough, transparent thermoplastics or as soft, flexible, thermoplastic elastomers, by appropriate control of copolymer architecture and styrene/butadiene ratio. In this case, the property profiles are intimately connected to the extent and type of nanoscale self-assembly that is established within the material. One of the main challenges confronting the successful design of nano-structured polymers is the development of a basic understanding of the relationship between the molecular details of the polymer formulation and the morphology that is achieved. Unfortunately, such relationships are still mainly determined by trial and error experimentation. A purely experimental-based program in pursuit of this objective proves cumbersome — primarily, due to the broad parameter space accessible at the time of synthesis and formulation. Consequently, there is a significant motivation for the development of computational tools that can enable a rational exploration of the parameter space.

[Pay attention to the complexity of cataract surgery of no vitreous eyes].

PubMed

Bao, Y Z

2017-04-11

With wide-spread performance of pars plana vitrectomy, cataract surgeries with no vitreous are getting more and more. This kind of surgery has great difference between individuals and it lacks randomized large sample clinical trial. Surgical strategy decision was basically relied on the surgeon's personal experience. We should fully aware the individual and common characteristics of no vitreous cataract surgery. Surgical time should be carefully decided. Complete ocular examination, evaluation, design of cataract surgical procedure and appropriate intra-ocular lens selection are needed. We must pay highly attention on the cataract surgery of no vitreous eyes. (Chin J Ophthalmol, 2017, 53: 241-243) .

Genetic and Environmental Pathways in Type 1 Diabetes Complications

DTIC Science & Technology

2010-09-26

setting? In the event that the project identifies a set of strongly predictive biomarkers an appropriate next step would be to approach TrialNet (see...http://www.diabetestrialnet.org). The TrialNet organization is a multi center study with the goal of identifying subjects for T1D prevention and...intervention trials. Children’s Hospital of Pittsburgh (CHP) is already acting as a clinical center for the TrialNet natural history study (Mahon et al

Rationale and design of the SERVE-HF study: treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure.

PubMed

Cowie, Martin R; Woehrle, Holger; Wegscheider, Karl; Angermann, Christiane; d'Ortho, Marie-Pia; Erdmann, Erland; Levy, Patrick; Simonds, Anita; Somers, Virend K; Zannad, Faiez; Teschler, Helmut

2013-08-01

Central sleep apnoea/Cheyne-Stokes respiration (CSA/CSR) is a risk factor for increased mortality and morbidity in heart failure (HF). Adaptive servo-ventilation (ASV) is a non-invasive ventilation modality for the treatment of CSA/CSR in patients with HF. SERVE-HF is a multinational, multicentre, randomized, parallel trial designed to assess the effects of addition of ASV (PaceWave, AutoSet CS; ResMed) to optimal medical management compared with medical management alone (control group) in patients with symptomatic chronic HF, LVEF ≤45%, and predominant CSA. The trial is based on an event-driven group sequential design, and the final analysis will be performed when 651 events have been observed or the study is terminated at one of the two interim analyses. The aim is to randomize ∼1200 patients to be followed for a minimum of 2 years. Patients are to stay in the trial up to study termination. The first patient was randomized in February 2008 and the study is expected to end mid 2015. The primary combined endpoint is the time to first event of all-cause death, unplanned hospitalization (or unplanned prolongation of a planned hospitalization) for worsening (chronic) HF, cardiac transplantation, resuscitation of sudden cardiac arrest, or appropriate life-saving shock for ventricular fibrillation or fast ventricular tachycardia in implantable cardioverter defibrillator patients. The SERVE-HF study is a randomized study that will provide important data on the effect of treatment with ASV on morbidity and mortality, as well as the cost-effectiveness of this therapy, in patients with chronic HF and predominantly CSA/CSR. ISRCTN19572887.

Methodology for a Trial of Brain-Centered versus Anti-cholinergic Therapy for Women with Urgency Urinary Incontinence

PubMed Central

Komesu, Yuko M.; Ketai, Loren H.; Sapien, Robert E.; Rogers, Rebecca G.; Schrader, Ronald M.; Simmerman-Sierra, Timothy; Mayer, Andrew R.

2016-01-01

Introduction This paper describes the rationale and methodology a study which investigates mind-body treatment versus pharmacotherapy for women with urgency urinary incontinence (UUI). To explore brain associations in UUI, a subset of patients will also undergo functional magnetic resonance imaging (fMRI). We hypothesize that hypnotherapy a mind-body intervention, will be at least as effective pharmacotherapy in treating UUI. We also hypothesize that fMRI findings will change following treatment, with changes potentially differing between groups. Methods The purpose of this manuscript is to recount the development and design challenges of a study evaluating the efficacy of hypnotherapy compared to conventional pharmacotherapy in UUI treatment. The study randomizes women to either of these treatments and outcome measures include bladder diaries and validated questionnaires. Sample size estimates, based on a non-inferiority test (alpha=.025, beta=0.20), after considering drop-out/loss to follow-up, indicated approximately 150 woman would be required to test the hypothesis that hypnotherapy is non-inferior to pharmacotherapy within a 5% non-inferiority margin. The study will also evaluate fMRI change in a subset of participants before and after therapy. Study challenges included designing a study with a mind-body therapy and a comparison treatment equally acceptable to participants, standardizing the interventions, confronting the reality that trials are time-consuming for participants and making appropriate accommodations. Results Study enrollment began March 2013 and is ongoing. Conclusions This manuscript details the design a of randomized controlled trial (RCT) comparing mind-body therapy to medications in treatment of UUI and describes the challenges encountered in its planning. PMID:27752750

The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project

PubMed Central

Guetterman, Timothy C; Fetters, Michael D; Mawocha, Samkeliso; Legocki, Laurie J; Barsan, William G; Lewis, Roger J; Berry, Donald A; Meurer, William J

2017-01-01

Objectives: Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. Methods: To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. Results: The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. Conclusion: Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development. PMID:29085638

Feedback GAP: study protocol for a cluster-randomized trial of goal setting and action plans to increase the effectiveness of audit and feedback interventions in primary care.

PubMed

Ivers, Noah M; Tu, Karen; Francis, Jill; Barnsley, Jan; Shah, Baiju; Upshur, Ross; Kiss, Alex; Grimshaw, Jeremy M; Zwarenstein, Merrick

2010-12-17

Audit and feedback to physicians is commonly used alone or as part of multifaceted interventions. While it can play an important role in quality improvement, the optimal design of audit and feedback is unknown. This study explores how feedback can be improved to increase acceptability and usability in primary care. The trial seeks to determine whether a theory-informed worksheet appended to feedback reports can help family physicians improve quality of care for their patients with diabetes and/or ischemic heart disease. Two-arm cluster trial was conducted with participating primary care practices allocated using minimization to simple feedback or enhanced feedback group. The simple feedback group receives performance feedback reports every six months for two years regarding the proportion of their patients with diabetes and/or ischemic heart disease who are meeting quality targets. The enhanced feedback group receives these same reports as well as a theory-informed worksheet designed to facilitate goal setting and action plan development in response to the feedback reports. Participants are family physicians from across Ontario who use electronic medical records; data for rostered patients are used to produce the feedback reports and for analysis. The primary disease outcomes are the blood pressure (BP), and low-density lipoprotein cholesterol (LDL) levels. The primary process measure is a composite score indicating the number of recommended activities (e.g., tests and prescriptions) conducted by the family physicians for their patients with diabetes and/or ischemic heart disease within the appropriate timeframe. Secondary outcomes are the proportion of patients whose results meet targets for glucose, LDL, and BP as well as the percent of patients receiving relevant prescriptions. A qualitative process evaluation using semi-structured interviews will explore perceived barriers to behaviour change in response to feedback reports and preferences with regard to feedback design. Intention-to-treat approach will be used to analyze the trial. Analysis will be performed on patient-level variables using generalized estimating equation models to adjust for covariates and account for the clustered nature of the data. The trial is powered to show small, but clinically important differences of 7 mmHG in systolic BP and 0.32 mmol/L in LDL. ClinicalTrials.gov NCT00996645.

The impact of active stakeholder involvement on recruitment, retention and engagement of schools, children and their families in the cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP): a school-based intervention to prevent obesity.

PubMed

Lloyd, J; McHugh, C; Minton, J; Eke, H; Wyatt, K

2017-08-14

Recruitment and retention of participants is crucial for statistical power and internal and external validity and participant engagement is essential for behaviour change. However, many school-based interventions focus on programme content rather than the building of supportive relationships with all participants and tend to employ specific standalone strategies, such as incentives, to improve retention. We believe that actively involving stakeholders in both intervention and trial design improves recruitment and retention and increases the chances of creating an effective intervention. The Healthy Lifestyles Programme, HeLP (an obesity prevention programme for children 9-10 years old) was developed using intervention mapping and involved extensive stakeholder involvement in both the design of the trial and the intervention to ensure that: (i) delivery methods were suitably engaging, (ii) deliverers had the necessary skills and qualities to build relationships and (iii) the intervention dovetailed with the National Curriculum. HeLP was a year-long intervention consisting of 4 multi-component phases using a range of delivery methods. We recruited 1324 children from 32 schools from the South West of England to a cluster-randomised controlled trial to determine the effectiveness of HeLP in preventing obesity. The primary outcome was change in body mass index standard deviation score (BMI SDS) at 24 months post randomisation. Secondary outcomes included additional anthropometric and behavioural (physical activity and diet) measures at 18 and 24 months. Anthropometric and behavioural measures were taken in 99%, 96% and 94% of children at baseline, 18 and 24 months, respectively, with no differential follow up between the control and intervention groups at each time point. All children participated in the programme and 92% of children and 77% of parents across the socio-economic spectrum were considered to have actively engaged with HeLP. We attribute our excellent retention and engagement results to the high level of stakeholder involvement in both trial and intervention design, the building of relationships using appropriate personnel and creative delivery methods that are accessible to children and their families across the social spectrum. International Standard Randomised Controlled Trials Register, ISRCTN15811706 . Registered on 1 May 2012.

HANDBOOK: QUALITY ASSURANCE/QUALITY CONTROL (QA/QC) PROCEDURES FOR HAZARDOUS WASTE INCINERATION

EPA Science Inventory

Resource Conservation and Recovery Act regulations for hazardous waste incineration require trial burns by permit applicants. uality Assurance Project Plan (QAPjP) must accompany a trial burn plan with appropriate quality assurance/quality control procedures. uidance on the prepa...

Statins reduce appropriate implantable cardioverter-defibrillator shocks in ischemic cardiomyopathy with no benefit in nonischemic cardiomyopathy.

PubMed

Contractor, Tahmeed; Beri, Abhimanyu; Gardiner, Joseph; Ardhanari, Sivakumar; Thakur, Ranjan

2012-11-01

Statins have been hypothesized to decrease ventricular arrhythmias through a direct antiarrhythmic effect. Clinical studies have demonstrated a clear reduction only in populations with underlying ischemic heart disease. This study was designed to compare the effect of statins on appropriate shocks between ischemic and nonischemic cardiomyopathy. Patients with an ejection fraction 35% or less who received an implantable cardioverter-defibrillator and had follow-up for at least 1 month were included. The ischemic and nonischemic groups were divided into statin treatment and control subgroups and the occurrence of appropriate shocks was compared. The frequency of shocks was analyzed using negative binomial models to account for overdispersion of the "count" data (number of appropriate shocks) and an adjusted intensity rate ratio was calculated for statin use. A total of 676 patients were included, of which statins were used by 65% (329 of 506) of the ischemic and 42% (72 of 170) of the nonischemic groups. Occurrence of appropriate shocks was significantly reduced with statins in ischemic (13.4% vs 20.9%; relative risk 0.64, P = 0.028), but not in the patients with nonischemic cardiomyopathy. Similarly, although use of statins lowered the intensity rate of appropriate shocks in ischemic patients (intensity rate ratio, 0.23; 95% confidence interval, 0.12-0.47), no such benefit was noted in the nonischemic group (intensity rate ratio, 1.27; 95% confidence interval, 0.37-4.40). In conclusion, statins reduced the occurrence and frequency of appropriate shocks for ventricular arrhythmias in ischemic but not in nonischemic cardiomyopathy. Larger, randomized controlled trials are needed to confirm these findings.

Reporting outcomes of definitive radiation-based treatment for esophageal cancer: a review of the literature.

PubMed

Main, B G; Strong, S; McNair, A G; Falk, S J; Crosby, T; Blazeby, J M

2015-01-01

Accurate evaluation of radical radiotherapy requires well designed research with valid and appropriate outcomes. This study reviewed standards of outcome reporting and study design in randomized controlled trials (RCTs) of radiation-based therapy for esophageal cancer and made recommendations for future work. Randomized controlled trials reporting outcomes of definitive radiation-based treatment alone or in combination with chemotherapy were systematically identified and summarized. The types, frequency, and definitions of all clinical and patient-reported outcomes (PROs) reported in the methods and results sections of papers were examined. Studies providing a definition for at least one outcome and presenting all outcomes reported in the methods were classified as high quality. From 1425 abstracts, 16 RCTs including 1803 patients were identified. The primary outcome was overall survival in 13 studies, but five different definitions were reported. Outcomes for treatment failure included local, regional, and distant failures, and inconsistent definitions were applied. An observer assessment of dysphagia was reported in seven RCTs but PROs were reported in only one. Only three RCTs were at low risk of bias, with all lacking reports of sequence generation and only a minority reporting allocation concealment. The quality of outcome reporting in RCTs was inconsistent and risked bias. A core outcome set including clinical and PROs is needed to improve reporting of trials of definitive radiation-based treatment for esophageal cancer. © 2014 International Society for Diseases of the Esophagus.

Appropriate prescribing in nursing homes demonstration project (APDP) study protocol: pragmatic, cluster-randomized trial and mixed methods process evaluation of an Ontario policy-maker initiative to improve appropriate prescribing of antipsychotics.

PubMed

Desveaux, Laura; Gomes, Tara; Tadrous, Mina; Jeffs, Lianne; Taljaard, Monica; Rogers, Jess; Bell, Chaim M; Ivers, Noah M

2016-03-29

Antipsychotic medications are routinely prescribed in nursing homes to address the behavioral and psychological symptoms of dementia. Unfortunately, inappropriate prescribing of antipsychotic medications is common and associated with increased morbidity, adverse drug events, and hospitalizations. Multifaceted interventions can achieve a 12-20 % reduction in antipsychotic prescribing levels in nursing homes. Effective interventions have featured educational outreach and ongoing performance feedback. This pragmatic, cluster-randomized control trial and embedded process evaluation seeks to determine the effect of adding academic detailing to audit and feedback on prescribing of antipsychotic medications in nursing homes, compared with audit and feedback alone. Nursing homes within pre-determined regions of Ontario, Canada, are eligible if they express an interest in the intervention. The academic detailing intervention will be delivered by registered health professionals following an intensive training program including relevant clinical issues and techniques to support health professional behavior change. Physicians in both groups will have the opportunity to access confidential reports summarizing their prescribing patterns for antipsychotics in comparison to the local and provincial average. Participating homes will be allocated to one of the two arms of the study (active/full intervention versus standard audit and feedback) in two waves, with a 2:1 allocation ratio. Homes will be randomized after stratifying for geography, baseline antipsychotic prescription rates, and size, to ensure a balance of characteristics. The primary outcome is antipsychotic dispensing in nursing homes, measured 6 months after allocation; secondary outcomes include clinical outcomes and healthcare utilization. Policy-makers and the public have taken note that antipsychotics are used in nursing homes in Ontario far more than other jurisdictions. Academic detailing can be an effective technique to address challenges in appropriate prescribing in nursing homes, but effect sizes vary widely. This opportunistic, policy-driven evaluation, embedded within a government-initiated demonstration project, was designed to ensure policy-makers receive the best evidence possible regarding whether and how to scale up the intervention. ClinicalTrials.gov NLM Identifier: NCT02604056 .

Can emergency medicine research benefit from adaptive design clinical trials?

PubMed

Flight, Laura; Julious, Steven A; Goodacre, Steve

2017-04-01

Adaptive design clinical trials use preplanned interim analyses to determine whether studies should be stopped or modified before recruitment is complete. Emergency medicine trials are well suited to these designs as many have a short time to primary outcome relative to the length of recruitment. We hypothesised that the majority of published emergency medicine trials have the potential to use a simple adaptive trial design. We reviewed clinical trials published in three emergency medicine journals between January 2003 and December 2013. We determined the proportion that used an adaptive design as well as the proportion that could have used a simple adaptive design based on the time to primary outcome and length of recruitment. Only 19 of 188 trials included in the review were considered to have used an adaptive trial design. A total of 154/165 trials that were fixed in design had the potential to use an adaptive design. Currently, there seems to be limited uptake in the use of adaptive trial designs in emergency medicine despite their potential benefits to save time and resources. Failing to take advantage of adaptive designs could be costly to patients and research. It is recommended that where practical and logistical considerations allow, adaptive designs should be used for all emergency medicine clinical trials. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Creation of a core outcome set for clinical trials of people with shoulder pain: a study protocol.

PubMed

Gagnier, Joel J; Page, Matthew J; Huang, Hsiaomin; Verhagen, Arianne P; Buchbinder, Rachelle

2017-07-20

The selection of appropriate outcomes or domains is crucial when designing clinical trials, to appreciate the effects of different interventions, pool results, and make valid comparisons between trials. If the findings are to influence policy and practice, then the chosen outcomes need to be relevant and important to key stakeholders, including patients and the public, healthcare professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. Recent reviews of the measurement properties of patient-reported outcome measures for shoulder disorders revealed a large selection of diverse measures, many with questionable validity, reliability, and responsiveness. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set (COS), which should be measured and reported in all trials of shoulder disorders. The purpose of the present project is to develop and disseminate a COS for clinical trials in shoulder disorders. The methods for the COS development will include 3 phases: (1) a comprehensive review of the core domains used in shoulder disorder trials; (2) an international Delphi study involving relevant stakeholders (patients, clinicians, scientists) to define which domains should be core; and (3) an international focus group informed by the evidence identified in phases 1 and 2, to determine which measurement instruments best measure the core domains and identification of any evidence gaps that require further empiric evidence. The aim of the current proposal is to convene several meetings of international experts and patients to develop a COS for clinical trials of shoulder disorders and to develop an implementation strategy to ensure rapid uptake of the core set of outcomes in clinical trials. There would be an expectation that the core set of outcomes would always be collected and reported, but it would not preclude use of additional outcomes in a particular trial.

General Analytical Schemes for the Characterization of Pectin-Based Edible Gelled Systems

PubMed Central

Haghighi, Maryam; Rezaei, Karamatollah

2012-01-01

Pectin-based gelled systems have gained increasing attention for the design of newly developed food products. For this reason, the characterization of such formulas is a necessity in order to present scientific data and to introduce an appropriate finished product to the industry. Various analytical techniques are available for the evaluation of the systems formulated on the basis of pectin and the designed gel. In this paper, general analytical approaches for the characterization of pectin-based gelled systems were categorized into several subsections including physicochemical analysis, visual observation, textural/rheological measurement, microstructural image characterization, and psychorheological evaluation. Three-dimensional trials to assess correlations among microstructure, texture, and taste were also discussed. Practical examples of advanced objective techniques including experimental setups for small and large deformation rheological measurements and microstructural image analysis were presented in more details. PMID:22645484

Critical appraisal of arguments for the delayed-start design proposed as alternative to the parallel-group randomized clinical trial design in the field of rare disease.

PubMed

Spineli, Loukia M; Jenz, Eva; Großhennig, Anika; Koch, Armin

2017-08-17

A number of papers have proposed or evaluated the delayed-start design as an alternative to the standard two-arm parallel group randomized clinical trial (RCT) design in the field of rare disease. However the discussion is felt to lack a sufficient degree of consideration devoted to the true virtues of the delayed start design and the implications either in terms of required sample-size, overall information, or interpretation of the estimate in the context of small populations. To evaluate whether there are real advantages of the delayed-start design particularly in terms of overall efficacy and sample size requirements as a proposed alternative to the standard parallel group RCT in the field of rare disease. We used a real-life example to compare the delayed-start design with the standard RCT in terms of sample size requirements. Then, based on three scenarios regarding the development of the treatment effect over time, the advantages, limitations and potential costs of the delayed-start design are discussed. We clarify that delayed-start design is not suitable for drugs that establish an immediate treatment effect, but for drugs with effects developing over time, instead. In addition, the sample size will always increase as an implication for a reduced time on placebo resulting in a decreased treatment effect. A number of papers have repeated well-known arguments to justify the delayed-start design as appropriate alternative to the standard parallel group RCT in the field of rare disease and do not discuss the specific needs of research methodology in this field. The main point is that a limited time on placebo will result in an underestimated treatment effect and, in consequence, in larger sample size requirements compared to those expected under a standard parallel-group design. This also impacts on benefit-risk assessment.

A prognostic factor index for overall survival in patients receiving first-line chemotherapy for HER2-negative advanced breast cancer: an analysis of the ATHENA trial.

PubMed

Llombart-Cussac, Antonio; Pivot, Xavier; Biganzoli, Laura; Cortes-Funes, Hernan; Pritchard, Kathleen I; Pierga, Jean-Yves; Smith, Ian; Thomssen, Christoph; Srock, Stefanie; Sampayo, Miguel; Cortes, Javier

2014-10-01

Evidence-based definitions of 'poor-prognosis' or 'aggressive' advanced breast cancer are lacking. We developed a prognostic factor index using data from 2203 patients treated with first-line chemotherapy plus bevacizumab for HER2-negative advanced breast cancer. The risk factors most closely associated with worse OS were: disease-free interval ≤24 months; liver metastases or ≥3 involved organ sites; prior anthracycline and/or taxane therapy; triple-negative breast cancer (TNBC); and performance status 2 or prior analgesic/corticosteroid treatment. Risk of death was increased threefold in patients with ≥3 versus ≤1 risk factors (hazard ratio 3.0 [95% CI 2.6-3.4; p < 0.001]; median 16.0 vs 38.8 months, respectively). This prognostic index may enable identification of patients with a poorer prognosis in whom more intensive systemic regimens may be appropriate. The index may also be considered in designing new trials, although it requires validation in other datasets before extrapolation to non-bevacizumab-containing therapy. ClinicalTrials.gov identifier: NCT00448591. Copyright © 2014 Elsevier Ltd. All rights reserved.

Unique Study Designs in Nephrology: N-of-1 Trials and Other Designs.

PubMed

Samuel, Joyce P; Bell, Cynthia S

2016-11-01

Alternatives to the traditional parallel-group trial design may be required to answer clinical questions in special populations, rare conditions, or with limited resources. N-of-1 trials are a unique trial design which can inform personalized evidence-based decisions for the patient when data from traditional clinical trials are lacking or not generalizable. A concise overview of factorial design, cluster randomization, adaptive designs, crossover studies, and n-of-1 trials will be provided along with pertinent examples in nephrology. The indication for analysis strategies such as equivalence and noninferiority trials will be discussed, as well as analytic pitfalls. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Who's really hypertensive?--Quality control issues in the assessment of blood pressure for randomized trials.

PubMed

Reid, Christopher M; Ryan, Philip; Miles, Helen; Willson, Kristyn; Beilin, Laurence J; Brown, Mark A; Jennings, Garry L; Johnston, Colin I; Macdonald, Graham J; Marley, John E; McNeil, John J; Morgan, Trefor O; West, Malcolm J; Wing, Lindon M H

2005-01-01

The characterization of blood pressure in treatment trials assessing the benefits of blood pressure lowering regimens is a critical factor for the appropriate interpretation of study results. With numerous operators involved in the measurement of blood pressure in many thousands of patients being screened for entry into clinical trials, it is essential that operators follow pre-defined measurement protocols involving multiple measurements and standardized techniques. Blood pressure measurement protocols have been developed by international societies and emphasize the importance of appropriate choice of cuff size, identification of Korotkoff sounds, and digit preference. Training of operators and auditing of blood pressure measurement may assist in reducing the operator-related errors in measurement. This paper describes the quality control activities adopted for the screening stage of the 2nd Australian National Blood Pressure Study (ANBP2). ANBP2 is cardiovascular outcome trial of the treatment of hypertension in the elderly that was conducted entirely in general practices in Australia. A total of 54 288 subjects were screened; 3688 previously untreated subjects were identified as having blood pressure >140/90 mmHg at the initial screening visit, 898 (24%) were not eligible for study entry after two further visits due to the elevated reading not being sustained. For both systolic and diastolic blood pressure recording, observed digit preference fell within 7 percentage points of the expected frequency. Protocol adherence, in terms of the required minimum blood pressure difference between the last two successive recordings, was 99.8%. These data suggest that adherence to blood pressure recording protocols and elimination of digit preferences can be achieved through appropriate training programs and quality control activities in large multi-centre community-based trials in general practice. Repeated blood pressure measurement prior to initial diagnosis and study entry is essential to appropriately characterize hypertension in these elderly patients.

Standardising the reporting of outcomes in gastric cancer surgery trials: protocol for the development of a core outcome set and accompanying outcome measurement instrument set (the GASTROS study).

PubMed

Alkhaffaf, Bilal; Glenny, Anne-Marie; Blazeby, Jane M; Williamson, Paula; Bruce, Iain A

2017-08-09

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Whilst surgery is the mainstay of curative treatment, it is associated with significant risks. Surgical strategies for treating gastric cancer should be based on evidence from systematic reviews of well-designed randomised controlled trials. However, inconsistencies in the reporting of outcomes from these trials makes evidence synthesis unreliable. We present a protocol for an international consensus study to develop a standardised set of outcomes and measurement tools - a 'core outcome set' (COS) - to be used by all future trials examining therapeutic surgical interventions for gastric cancer. The GASTROS study aims to standardise the reporting of outcomes in gastric cancer surgery trials through an international consensus process of key stakeholders including health care professionals and patients. The first of three stages in the study will identify a 'long-list' of potentially important outcomes to be prioritised. These will be extracted from a systematic review of relevant academic literature and patient interviews. Stage 2 will comprise an eDelphi survey which will consider the views of patients, nurse specialists and surgeons to prioritise the most important outcomes. A meeting of stakeholder representatives will ratify the COS. Stage 3 will focus on identifying appropriate instruments to measure the prioritised outcomes by means of quality assessment of available measurement instruments and stakeholder consultation. This study aims to standardise the reporting of outcomes in future trials examining therapeutic surgical interventions for gastric cancer. It is anticipated that standardisation of outcome reporting in these surgical effectiveness trials will enhance the evidence base for clinical practice. Highlighting outcomes of greatest importance to patients will ensure that their perspectives are central to research in this field.

MRC ORACLE Children Study. Long term outcomes following prescription of antibiotics to pregnant women with either spontaneous preterm labour or preterm rupture of the membranes

PubMed Central

Kenyon, Sara; Brocklehurst, Peter; Jones, David; Marlow, Neil; Salt, Alison; Taylor, David

2008-01-01

Background The Medical Research Council (MRC) ORACLE trial evaluated the use of co-amoxiclav 375 mg and/or erythromycin 250 mg in women presenting with preterm rupture of membranes (PROM) ORACLE I or in spontaneous preterm labour (SPL) ORACLE II using a factorial design. The results showed that for women with a singleton baby with PROM the prescription of erythromycin is associated with improvements in short term neonatal outcomes, although co-amoxiclav is associated with prolongation of pregnancy, a significantly higher rate of neonatal necrotising enterocolitis was found in these babies. Prescription of erythromycin is now established practice for women with PROM. For women with SPL antibiotics demonstrated no improvements in short term neonatal outcomes and are not recommended treatment. There is evidence that both these conditions are associated with subclinical infection so perinatal antibiotic administration may reduce the risk of later disabilities, including cerebral palsy, although the risk may be increased through exposure to inflammatory cytokines, so assessment of longer term functional and educational outcomes is appropriate. Methods The MRC ORACLE Children's Study will follow up UK children at age 7 years born to 4809 women with PROM and the 4266 women with SPL enrolled in the earlier ORACLE trials. We will use a parental questionnaire including validated tools to assess disability and behaviour. We will collect the frequency of specific medical conditions: cerebral palsy, epilepsy, respiratory illness including asthma, diabetes, admission to hospital in last year and other diseases, as reported by parents. National standard test results will be collected to assess educational attainment at Key Stage 1 for children in England. Discussion This study is designed to investigate whether or not peripartum antibiotics improve health and disability for children at 7 years of age. Trial registration The ORACLE Trial and Children Study is registered in the Current Controlled Trials registry. ISCRTN 52995660 PMID:18435833

An imbalance in cluster sizes does not lead to notable loss of power in cross-sectional, stepped-wedge cluster randomised trials with a continuous outcome.

PubMed

Kristunas, Caroline A; Smith, Karen L; Gray, Laura J

2017-03-07

The current methodology for sample size calculations for stepped-wedge cluster randomised trials (SW-CRTs) is based on the assumption of equal cluster sizes. However, as is often the case in cluster randomised trials (CRTs), the clusters in SW-CRTs are likely to vary in size, which in other designs of CRT leads to a reduction in power. The effect of an imbalance in cluster size on the power of SW-CRTs has not previously been reported, nor what an appropriate adjustment to the sample size calculation should be to allow for any imbalance. We aimed to assess the impact of an imbalance in cluster size on the power of a cross-sectional SW-CRT and recommend a method for calculating the sample size of a SW-CRT when there is an imbalance in cluster size. The effect of varying degrees of imbalance in cluster size on the power of SW-CRTs was investigated using simulations. The sample size was calculated using both the standard method and two proposed adjusted design effects (DEs), based on those suggested for CRTs with unequal cluster sizes. The data were analysed using generalised estimating equations with an exchangeable correlation matrix and robust standard errors. An imbalance in cluster size was not found to have a notable effect on the power of SW-CRTs. The two proposed adjusted DEs resulted in trials that were generally considerably over-powered. We recommend that the standard method of sample size calculation for SW-CRTs be used, provided that the assumptions of the method hold. However, it would be beneficial to investigate, through simulation, what effect the maximum likely amount of inequality in cluster sizes would be on the power of the trial and whether any inflation of the sample size would be required.

Cycling Time Trial Performance 4 Hours After Glycogen-Lowering Exercise Is Similarly Enhanced by Recovery Nondairy Chocolate Beverages Versus Chocolate Milk.

PubMed

Upshaw, Adam U; Wong, Tiffany S; Bandegan, Arash; Lemon, Peter W

2016-02-01

Postexercise chocolate milk ingestion has been shown to enhance both glycogen resynthesis and subsequent exercise performance. To assess whether nondairy chocolate beverage ingestion post-glycogen-lowering exercise can enhance 20-km cycling time trial performance 4 hr later, eight healthy trained male cyclists (21.8 ± 2.3y, VO2max = 61.2 ± 1.4 ml·kg-1·min-1; M ± SD) completed a series of intense cycling intervals designed to lower muscle glycogen (Jentjens & Jeukendrup, 2003) followed by 4 hr of recovery and a subsequent 20-km cycling time trial. During the first 2 hr of recovery, participants ingested chocolate dairy milk (DAIRYCHOC), chocolate soy beverage (SOYCHOC), chocolate hemp beverage (HEMPCHOC), low-fat dairy milk (MILK), or a low-energy artificially sweetened, flavored beverage (PLACEBO) at 30-min intervals in a double-blind, counterbalanced repeated-measures design. All drinks, except the PLACEBO (247 kJ) were isoenergetic (2,107 kJ), and all chocolate-flavored drinks provided 1-g CHO·kg body mass-1·h-1. Fluid intake across treatments was equalized (2,262 ± 148 ml) by ingesting appropriate quantities of water based on drink intake. The CHO:PRO ratio was 4:1, 1.5:1, 4:1, and 6:1 for DAIRYCHOC, MILK, SOYCHOC, and HEMPCHOC, respectively. One-way analysis of variance with repeated measures showed time trial performance (DAIRYCHOC = 34.58 ± 2.5 min, SOYCHOC = 34.83 ± 2.2 min, HEMPCHOC = 34.88 ± 1.1 min, MILK = 34.47 ± 1.7 min) was enhanced similarly vs PLACEBO (37.85 ± 2.1) for all treatments (p = .019) These data suggest that postexercise macronutrient and total energy intake are more important for same-day 20-km cycling time trial performance after glycogen-lowering exercise than protein type or protein-to-carbohydrate ratio.

Microbicides Development Programme: Engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania

PubMed Central

Vallely, Andrew; Shagi, Charles; Lees, Shelley; Shapiro, Katherine; Masanja, Joseph; Nikolau, Lawi; Kazimoto, Johari; Soteli, Selephina; Moffat, Claire; Changalucha, John; McCormack, Sheena; Hayes, Richard J

2009-01-01

Background HIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania. Methods A mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders' Advisory Group (SAG), which includes two CAC representatives. Results Key recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative. Conclusion Participatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting. Trial registration Current Controlled Trials ISRCTN64716212 PMID:19814830

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

Protection of xenon against postoperative oxygen impairment in adults undergoing Stanford Type-A acute aortic dissection surgery: Study protocol for a prospective, randomized controlled clinical trial.

PubMed

Jin, Mu; Cheng, Yi; Yang, Yanwei; Pan, Xudong; Lu, Jiakai; Cheng, Weiping

2017-08-01

The available evidence shows that hypoxemia after Stanford Type-A acute aortic dissection (AAD) surgery is a frequent cause of several adverse consequences. The pathogenesis of postoperative hypoxemia after AAD surgery is complex, and ischemia/reperfusion and inflammation are likely to be underlying risk factors. Xenon, recognized as an ideal anesthetic and anti-inflammatory treatment, might be a possible treatment for these adverse effects. The trial is a prospective, double-blind, 4-group, parallel, randomized controlled, a signal-center clinical trial. We will recruit 160 adult patients undergoing Stanford type-A AAD surgery. Patients will be allocated a study number and will be randomized on a 1:1:1:1 basis to receive 1 of the 3 treatment options (pulmonary inflated with 50% xenon, 75% xenon, or 100% xenon) or no treatment (control group, pulmonary inflated with 50% nitrogen). The aims of this study are to clarify the lung protection capability of xenon and its possible mechanisms in patients undergoing the Stanford type-A AAD surgery. This trial uses an innovative design to account for the xenon effects of postoperative oxygen impairment, and it also delineates the mechanism for any benefit from xenon. The investigational xenon group is considered a treatment intervention, as it includes 3 groups of pulmonary static inflation with 50%, 75%, and 100% xenon. It is suggested that future trials might define an appropriate concentration of xenon for the best practice intervention.

Study protocol for prevention of falls: A randomized controlled trial of effects of vitamin D and exercise on falls prevention

PubMed Central

2012-01-01

Background Falls are the leading cause of unintentional injury and injury-related death among older people. In addition to physical activity, vitamin D also may affect balance and neuromuscular function. Low serum 25-hydroksivitamin D level increases the risk of bone loss, falls and fractures. Thus, an appropriate exercise program and sufficient vitamin D intake may significantly improve not only functional balance, but also balance confidence. Balance represents a complex motor skill determined by reaction time, muscle strength, and speed and coordination of movement. Methods/Design A 2-year randomized double-blind placebo-controlled vitamin D and open exercise trial of 409 home-dwelling women 70 to 80 years of age comprising four study arms: 1) exercise + vitamin D (800 IU/d), 2) exercise + placebo, 3) no exercise + vitamin D (800 IU/d), 4) no exercise + placebo. In addition to monthly fall diaries, general health status, life style, bone health, physical functioning, and vitamin D metabolism will be assessed. The primary outcomes are the rate of falls and fall-related injuries. Secondary outcomes include changes in neuromuscular functioning (e.g. body balance, muscle strength), ADL- and mobility functions, bone density and structure, cardiovascular risk factors, quality of life and fear of falling. Discussion The successful completion of this trial will provide evidence on the effectiveness of exercise and vitamin D for falls reduction. Trial Registration ClinicalTrial.gov -register (NCT00986466). PMID:22448872

Design of Phase II Non-inferiority Trials.

PubMed

Jung, Sin-Ho

2017-09-01

With the development of inexpensive treatment regimens and less invasive surgical procedures, we are confronted with non-inferiority study objectives. A non-inferiority phase III trial requires a roughly four times larger sample size than that of a similar standard superiority trial. Because of the large required sample size, we often face feasibility issues to open a non-inferiority trial. Furthermore, due to lack of phase II non-inferiority trial design methods, we do not have an opportunity to investigate the efficacy of the experimental therapy through a phase II trial. As a result, we often fail to open a non-inferiority phase III trial and a large number of non-inferiority clinical questions still remain unanswered. In this paper, we want to develop some designs for non-inferiority randomized phase II trials with feasible sample sizes. At first, we review a design method for non-inferiority phase III trials. Subsequently, we propose three different designs for non-inferiority phase II trials that can be used under different settings. Each method is demonstrated with examples. Each of the proposed design methods is shown to require a reasonable sample size for non-inferiority phase II trials. The three different non-inferiority phase II trial designs are used under different settings, but require similar sample sizes that are typical for phase II trials.

The optimal design of stepped wedge trials with equal allocation to sequences and a comparison to other trial designs.

PubMed

Thompson, Jennifer A; Fielding, Katherine; Hargreaves, James; Copas, Andrew

2017-12-01

Background/Aims We sought to optimise the design of stepped wedge trials with an equal allocation of clusters to sequences and explored sample size comparisons with alternative trial designs. Methods We developed a new expression for the design effect for a stepped wedge trial, assuming that observations are equally correlated within clusters and an equal number of observations in each period between sequences switching to the intervention. We minimised the design effect with respect to (1) the fraction of observations before the first and after the final sequence switches (the periods with all clusters in the control or intervention condition, respectively) and (2) the number of sequences. We compared the design effect of this optimised stepped wedge trial to the design effects of a parallel cluster-randomised trial, a cluster-randomised trial with baseline observations, and a hybrid trial design (a mixture of cluster-randomised trial and stepped wedge trial) with the same total cluster size for all designs. Results We found that a stepped wedge trial with an equal allocation to sequences is optimised by obtaining all observations after the first sequence switches and before the final sequence switches to the intervention; this means that the first sequence remains in the control condition and the last sequence remains in the intervention condition for the duration of the trial. With this design, the optimal number of sequences is [Formula: see text], where [Formula: see text] is the cluster-mean correlation, [Formula: see text] is the intracluster correlation coefficient, and m is the total cluster size. The optimal number of sequences is small when the intracluster correlation coefficient and cluster size are small and large when the intracluster correlation coefficient or cluster size is large. A cluster-randomised trial remains more efficient than the optimised stepped wedge trial when the intracluster correlation coefficient or cluster size is small. A cluster-randomised trial with baseline observations always requires a larger sample size than the optimised stepped wedge trial. The hybrid design can always give an equally or more efficient design, but will be at most 5% more efficient. We provide a strategy for selecting a design if the optimal number of sequences is unfeasible. For a non-optimal number of sequences, the sample size may be reduced by allowing a proportion of observations before the first or after the final sequence has switched. Conclusion The standard stepped wedge trial is inefficient. To reduce sample sizes when a hybrid design is unfeasible, stepped wedge trial designs should have no observations before the first sequence switches or after the final sequence switches.

Using GRADE as a framework to guide research on the sexual and reproductive health and rights (SRHR) of women living with HIV - methodological opportunities and challenges.

PubMed

Siegfried, Nandi; Narasimhan, Manjulaa; Kennedy, Caitlin E; Welbourn, Alice; Yuvraj, Anandi

2017-09-01

In March 2016, WHO reviewed evidence to develop global recommendations on the sexual and reproductive health and rights (SRHR) of women living with HIV. Systematic reviews and a global survey of women living with HIV informed the guideline development decision-making process. New recommendations covered abortion, Caesarean section, safe disclosure, and empowerment and self-efficacy interventions. Identification of key research gaps is part of the WHO guidelines development process, but consistent methods to do so are lacking. Our method aimed to ensure consistency and comprised the systematic application of a framework based on GRADE (Grading of Recommendations, Assessment, Development and Evaluation) to the process. The framework incorporates the strength and quality rating of recommendations and the priorities reported by women in the survey to inform research prioritisation. For each gap, we also articulated: (1) the most appropriate and robust study design to answer the question; (2) alternative pragmatic designs if the ideal design is not feasible; and (3) the methodological challenges facing researchers through identifying potential biases. We found 12 research gaps and identified five appropriate study designs to address the related questions: (1) Cross-sectional surveys; (2) Qualitative interview-driven studies; (3) Registries; (4) Randomised controlled trials; and (5) Medical record audit. Methodological challenges included selection, recruitment, misclassification, measurement and contextual biases, and confounding. In conclusion, a framework based on GRADE can provide a systematic approach to identifying research gaps from a WHO guideline. Incorporation of the priorities of women living with HIV into the framework systematically ensures that women living with HIV can shape future policy decisions affecting their lives. Implementation science and participatory research are appropriate over-arching approaches to enhance uptake of interventions and to ensure inclusion of women living with HIV at all stages of the research process.

Quality and Utility: The 1994 Trial State Assessment in Reading. The Fourth Report of the National Academy of Education Panel on the Evaluation of the NAEP Trial State Assessment: 1994 Trial State Assessment in Reading.

ERIC Educational Resources Information Center

National Academy of Education, Stanford, CA.

This report evaluates the conduct, validity, and uses of the National Assessment of Educational Progress (NAEP) Trial State Assessment (TSA). The report addresses such pressing problems as how participation in NAEP can be maintained and appropriate samples can be achieved; how errors can be minimized in the complex process of scaling and analyzing…

Plasminogen Activators and Ischemic Stroke: Conditions for Acute Delivery

PubMed Central

del Zoppo, Gregory J

2013-01-01

Appropriate acute treatment with plasminogen activators (PAs) can significantly increase the probability of minimal or no disability in selected ischemic stroke patients. There is a great deal of evidence showing that intravenous recombinant tissue PAs (rt-PA) infusion accomplishes this goal, recanalization with other PAs has also been demonstrated in the development of this treatment. Recanalization of symptomatic, documented carotid or vertebrobasilar arterial territory occlusions have also been achieved by local intra-arterial PA delivery, although only a single prospective double-blinded randomized placebo-controlled study has been reported. The increase in intracerebral hemorrhage with these agents by either delivery approach underscores the need for careful patient selection, dose-appropriate safety and efficacy, proper clinical trial design, and an understanding of the evolution of cerebral tissue injury due to focal ischemia. Principles underlying the evolution of focal ischemia have been expanded by experience with acute PA intervention. Several questions remain open that concern the manner in which PAs can be applied acutely in ischemic stroke and how injury development can be limited. PMID:23539414

Lymphedema following treatment for breast cancer: a new approach to an old problem.

PubMed

O'Toole, Jean; Jammallo, Lauren S; Skolny, Melissa N; Miller, Cynthia L; Elliott, Krista; Specht, Michelle C; Taghian, Alphonse G

2013-11-01

Lymphedema following treatment for breast cancer can be an irreversible condition with a profound negative impact on quality of life. The lack of consensus regarding standard definitions of clinically significant lymphedema and optimal methods of measurement and quantification are unresolved problems. Inconsistencies persist regarding the appropriate timing of intervention and what forms of treatment should be the standard of care. There are reports that early detection and intervention can prevent progression, however,the Level 1 evidence to support this hypothesis has yet to be generated. To assess these controversies, we propose the implementation of a screening program to detect early lymphedema in conjunction with a randomized, prospective trial designed to generate Level 1 evidence regarding the efficacy of early intervention and appropriate treatment strategies. Collaboration among institutions that manage breast cancer patients is essential to establish a standardized approach to lymphedema and to establish guidelines for best practice. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Evaluating Data Abstraction Assistant, a novel software application for data abstraction during systematic reviews: protocol for a randomized controlled trial.

PubMed

Saldanha, Ian J; Schmid, Christopher H; Lau, Joseph; Dickersin, Kay; Berlin, Jesse A; Jap, Jens; Smith, Bryant T; Carini, Simona; Chan, Wiley; De Bruijn, Berry; Wallace, Byron C; Hutfless, Susan M; Sim, Ida; Murad, M Hassan; Walsh, Sandra A; Whamond, Elizabeth J; Li, Tianjing

2016-11-22

Data abstraction, a critical systematic review step, is time-consuming and prone to errors. Current standards for approaches to data abstraction rest on a weak evidence base. We developed the Data Abstraction Assistant (DAA), a novel software application designed to facilitate the abstraction process by allowing users to (1) view study article PDFs juxtaposed to electronic data abstraction forms linked to a data abstraction system, (2) highlight (or "pin") the location of the text in the PDF, and (3) copy relevant text from the PDF into the form. We describe the design of a randomized controlled trial (RCT) that compares the relative effectiveness of (A) DAA-facilitated single abstraction plus verification by a second person, (B) traditional (non-DAA-facilitated) single abstraction plus verification by a second person, and (C) traditional independent dual abstraction plus adjudication to ascertain the accuracy and efficiency of abstraction. This is an online, randomized, three-arm, crossover trial. We will enroll 24 pairs of abstractors (i.e., sample size is 48 participants), each pair comprising one less and one more experienced abstractor. Pairs will be randomized to abstract data from six articles, two under each of the three approaches. Abstractors will complete pre-tested data abstraction forms using the Systematic Review Data Repository (SRDR), an online data abstraction system. The primary outcomes are (1) proportion of data items abstracted that constitute an error (compared with an answer key) and (2) total time taken to complete abstraction (by two abstractors in the pair, including verification and/or adjudication). The DAA trial uses a practical design to test a novel software application as a tool to help improve the accuracy and efficiency of the data abstraction process during systematic reviews. Findings from the DAA trial will provide much-needed evidence to strengthen current recommendations for data abstraction approaches. The trial is registered at National Information Center on Health Services Research and Health Care Technology (NICHSR) under Registration # HSRP20152269: https://wwwcf.nlm.nih.gov/hsr_project/view_hsrproj_record.cfm?NLMUNIQUE_ID=20152269&SEARCH_FOR=Tianjing%20Li . All items from the World Health Organization Trial Registration Data Set are covered at various locations in this protocol. Protocol version and date: This is version 2.0 of the protocol, dated September 6, 2016. As needed, we will communicate any protocol amendments to the Institutional Review Boards (IRBs) of Johns Hopkins Bloomberg School of Public Health (JHBSPH) and Brown University. We also will make appropriate as-needed modifications to the NICHSR website in a timely fashion.

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

PubMed Central

2010-01-01

Background Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen. Trial Registration ISRCTN10538608 PMID:20102616

Patient Engagement in Neurological Clinical Trials Design: A Conference Summary.

PubMed

Cobb, Enesha M; Meurer, William; Harney, Deneil; Silbergleit, Robert; Lake, Bray Patrick; Clark, Christina; Gipson, Debbie; Barsan, William

2015-12-01

The conference objectives included educating patients and advocates about clinical trials, educating the clinical research community about patient perspectives on participating in clinical trial design, and identifying strategies to increase participation in clinical trial design for neurological disorders. Observations were noted during a 1-day conference attended by patients, patient advocates, clinical trial staff, and investigators. The conference offered didactic sessions, small, and large group discussions. Conference participants were patients, patient advocates, clinical trial staff, students, and investigators interested in engaging patients in clinical trial design for neurological disorders. Conference participants were asked to consider lessons learned that could increase patient engagement in clinical trial design. We found that there is growing interest in including patients in the design of clinical trials for neurological disorders. Several themes emerged on how to move forward: networking; the multifaceted roles of advocates in research; training and education; creating patient-researcher partnerships; and clinical trials regulation issues. The conference provided a forum for dialogue regarding stakeholder engagement in the design of clinical trials for neurological disorders. This experience provides a template for replication and dissemination of this conference and informs next steps to accelerate the pathway from dialogue to action. © 2015 Wiley Periodicals, Inc.

Modifying attitude and intention toward regular physical activity using protection motivation theory: a randomized controlled trial.

PubMed

Mirkarimi, Kamal; Eri, Maryam; Ghanbari, Mohammad R; Kabir, Mohammad J; Raeisi, Mojtaba; Ozouni-Davaji, Rahman B; Aryaie, Mohammad; Charkazi, Abdurrahman

2017-10-30

We were guided by the Protection Motivation Theory to test the motivational interviewing effects on attitude and intention of obese and overweight women to do regular physical activity. In a randomized controlled trial, we selected using convenience sampling 60 overweight and obese women attending health centres. The women were allocated to 2 groups of 30 receiving a standard weight-control programme or motivational interviewing. All constructs of the theory (perceived susceptibility, severity, self-efficacy and response efficacy) and all anthropometric characteristics (except body mass index) were significantly different between the groups at 3 study times. The strongest predictors of intention to do regular physical exercise were perceived response efficacy and attitude at 2- and 6-months follow-up. We showed that targeting motivational interviewing with an emphasis on Protection Motivation Theory constructs appeared to be beneficial for designing and developing appropriate intervention to improve physical activity status among women with overweight and obesity.

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

A randomized controlled trial of a brief self-help coping intervention designed to reduce distress when awaiting genetic risk information.

PubMed

Bennett, Paul; Phelps, Ceri; Brain, Kate; Hood, Kerenza; Gray, Jonathon

2007-07-01

The aim of this study was to evaluate the effectiveness of a distraction-based coping leaflet in reducing distress in women undergoing genetic risk assessment for breast/ovarian cancer. One hundred sixty-two women participated in a randomized controlled trial, receiving either the intervention or standard information. Data were collected through a postal questionnaire at entry into a genetic risk assessment programme and 1 month later. Analysis of covariance revealed a nonsignificant reduction in distress in all women, and a significant reduction of distress among those with high baseline stress, who received the intervention. No gains were found among the control group. Measures of emotional response while thinking about cancer genetic assessment suggested these benefits were achieved in the absence of any rebound emotional response. The intervention offers a low-cost effective coping intervention, which could be integrated into existing services with minimal disruption and may also be appropriate for other periods of waiting and uncertainty.

Conceptualizing the multidimensional nature of self-efficacy: assessment of situational context and level of behavioral challenge to maintain safer sex. National Institute of Mental Health Multisite HIV Prevention Trial Group.

PubMed

Murphy, D A; Stein, J A; Schlenger, W; Maibach, E

2001-07-01

A. Bandura (1991) argued that self-efficacy measurement should be specific both to the situation in which the behavior occurs and level of challenge in that situation. Measures consistent with the 2 dimensions were developed with graded challenge levels and differing gender-appropriate situations. Participants were 1,496 controls in the National Institute of Mental Health Multisite HIV Prevention Trial recruited from STD clinics and health service centers (925 women and 571 men). The authors tested 4 separate-sex confirmatory factor analysis models as follows: (a) Condom negotiation efficacy as a unitary construct across situations and gradation of difficulty; (b) situation as preeminent, which transfers across skills whatever the gradation of difficulty; (c) skill as predominant, irrespective of situation; and (d) a multidimensional design that simultaneously accounts for both situation and graded difficulty. Consistent with Bandura's theory, the multidimensional model provided the best fit for both samples.

Effect of training and structured medication review on medication appropriateness in nursing home residents and on cooperation between health care professionals: the InTherAKT study protocol.

PubMed

Mahlknecht, Angelika; Nestler, Nadja; Bauer, Ulrike; Schüßler, Nadine; Schuler, Jochen; Scharer, Sebastian; Becker, Ralf; Waltering, Isabel; Hempel, Georg; Schwalbe, Oliver; Flamm, Maria; Osterbrink, Jürgen

2017-01-18

Pharmacotherapy in residents of nursing homes is critical due to the special vulnerability of this population. Medical care and interprofessional communication in nursing homes are often uncoordinated. As a consequence, polypharmacy and inappropriate medication use are common and may lead to hospitalizations and health hazards. The aim of this study is to optimize communication between the involved professional groups by specific training and by establishing a structured medication review process, and to improve medication appropriateness and patient-relevant health outcomes for residents of nursing homes. The trial is designed as single-arm study. It involves 300 nursing home residents aged ≥ 65 years and the members of the different professional groups practising in nursing home care (15-20 general practitioners, nurses, pharmacists). The intervention consists of interprofessional education on safe medication use in geriatric patients, and a systematic interprofessional therapy check (recording, reviewing and adapting the medication of the participating residents by means of a specific online platform). The intervention period is divided into two phases; total project period is 3 years. Primary outcome measure is the change in medication appropriateness according to the Medication Appropriateness Index. Secondary outcomes are cognitive performance, occurrence of delirium, agitation, tendency of falls, total number of drugs, number of potentially dangerous drug-drug interactions and appropriateness of recorded analgesic therapy regimens according to the Medication Appropriateness Index. Data are collected at t 0 (before the start of the intervention), t 1 (after the first intervention period) and t 2 (after the second intervention period). Cooperation and communication between the professional groups are investigated twice by qualitative interviews. The project aims to establish a structured system for monitoring of drug therapy in nursing home residents. The newly developed online platform is designed to systematize and to improve the communication between the professional groups and, thus, to enhance quality and safety of drug therapy. Limitations of the study are the lack of a control group and the non-randomly recruited study sample. DRKS Data Management, DRKS-ID: DRKS00007900.

Lessons learnt from the Bristol Girls Dance Project cluster RCT: implications for designing and implementing after-school physical activity interventions

PubMed Central

Edwards, Mark J; May, Thomas; Kesten, Joanna M; Banfield, Kate; Bird, Emma L; Powell, Jane E; Sebire, Simon J; Jago, Russell

2016-01-01

Objective To consider implementation issues associated with the delivery of Bristol Girls Dance Project (BGDP) and to identify improvements that may aid the design of after-school physical activity (PA) interventions. Design Two-armed cluster randomised control trial. The BGDP was a 20-week school-based intervention, consisting of two 75 min after-school dance sessions per week, which aimed to support Year 7 girls to be more physically active. Setting 18 secondary schools (nine intervention, nine control) in the Greater Bristol area (as an indication of deprivation, children eligible for the pupil premium in participant schools ranged from 6.9 to 53.3%). Participants 571 Year 7 girls. This article reports on qualitative data collected from 59 girls in the intervention arm of the trial, 10 dance instructors and 9 school contacts involved in the delivering of the BGDP. Methods Data were obtained from nine focus groups with girls (one per intervention school), and interviews with dance instructors and school contacts. Focus groups sought views of girls’ motivation to participate, teaching styles and experiences of the intervention. Interviews explored views on implementation and dissemination. Framework analysis was used to analyse data. Results Qualitative data elicited three themes associated with the delivery of BGDP that affected implementation: project design, session content and project organisation. ‘Project design’ found issues associated with recruitment, timetabling and session quantity to influence the effectiveness of BGDP. ‘Session content’ found that dance instructors delivered a range of content and that girls enjoyed a variety of dance. Themes within ‘project organisation’ suggested an ‘open enrolment’ policy and greater parental involvement may facilitate better attendance. Conclusions After-school PA interventions have potential for increasing PA levels among adolescent girls. There is a need to consider the context in which interventions are delivered and implement them in ways that are appropriate to the needs of participants. Trial registration number ISRCTN52882523. PMID:26747038

Ethical Considerations for the Participation of Children of Minor Parents in Clinical Trials.

PubMed

Ott, Mary A; Crawley, Francis P; Sáez-Llorens, Xavier; Owusu-Agyei, Seth; Neubauer, David; Dubin, Gary; Poplazarova, Tatjana; Begg, Norman; Rosenthal, Susan L

2018-06-01

Children of minor parents are under-represented in clinical trials. This is largely because of the ethical, legal, and regulatory complexities in the enrolment, consent, and appropriate access of children of minor parents to clinical research. Using a case-based approach, we examine appropriate access of children of minor parents in an international vaccine trial. We first consider the scientific justification for inclusion of children of minor parents in a vaccine trial. Laws and regulations governing consent generally do not address the issue of minor parents. In their absence, local community and cultural contexts may influence consent processes. Rights of the minor parent include dignity in their role as a parent and respect for their decision-making capacity in that role. Rights of the child include the right to have decisions made in their best interest and the right to the highest attainable standard of health. Children of minor parents may have vulnerabilities related to the age of their parent, such as increased rates of poverty, that have implications for consent. Neuroscience research suggests that, by age 12-14 years, minors have adult-level capacity to make research decisions in situations with low emotion and low distraction. We conclude with a set of recommendations based on these findings to facilitate appropriate access and equity related to the participation of children of minor parents in clinical research.

[Basic considerations during outsourcing of clinical data management services].

PubMed

Shen, Tong; Liu, Yan

2015-11-01

With worldwide improvements in the regulations of international and domestic clinical trial conductions, the quality of clinical trials and trial data management are receiving a great deal of attention. To ensure the quality of clinical trials, maintain business flexibilities and effectively utilize internal and external resources, the outsourcing model is used in the management of clinical data in operation of pharmaceutical companies. The essential criteria of a successful outsourcing mode in clinical trial are selection of qualified contract research organizations (CRO); establishment of appropriate outsourcing model, and generation of effective quality control systems to ensure the authenticity, integrity and accuracy of the clinical trial data.

Biomarker-Guided Non-Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

PubMed Central

Antoniou, Miranta; Kolamunnage-Dona, Ruwanthi; Jorgensen, Andrea L.

2017-01-01

Biomarker-guided treatment is a rapidly developing area of medicine, where treatment choice is personalised according to one or more of an individual’s biomarker measurements. A number of biomarker-guided trial designs have been proposed in the past decade, including both adaptive and non-adaptive trial designs which test the effectiveness of a biomarker-guided approach to treatment with the aim of improving patient health. A better understanding of them is needed as challenges occur both in terms of trial design and analysis. We have undertaken a comprehensive literature review based on an in-depth search strategy with a view to providing the research community with clarity in definition, methodology and terminology of the various biomarker-guided trial designs (both adaptive and non-adaptive designs) from a total of 211 included papers. In the present paper, we focus on non-adaptive biomarker-guided trial designs for which we have identified five distinct main types mentioned in 100 papers. We have graphically displayed each non-adaptive trial design and provided an in-depth overview of their key characteristics. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. Our comprehensive review provides guidance for those designing biomarker-guided trials. PMID:28125057

Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments.

PubMed

Saas, Philippe; Daguindau, Etienne; Perruche, Sylvain

2016-06-01

The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473. © 2016 AlphaMed Press.

'Huang Qi Elixir' for proteinuria in patients with diabetic nephropathy: a study protocol for a randomized controlled pilot trial.

PubMed

Tu, Xiang; Liu, Fang; Jordan, James B; Ye, Xue Feng; Fu, Ping; Wang, Fei; Zhong, Sen

2013-07-18

Diabetic nephropathy (DN) is the major complication of diabetes; proteinuria is the hall mark of DN. Currently, the treatment for proteinuria is mainly limited to angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). According to Traditional Chinese Medicine (TCM) theory, Chinese medicinals 'securing essence and tonifying the kidney' may be appropriate for proteinuria. The most promising Chinese medicinals and formulae are introduced in the present study to form a potent formula for DN proteinuria. To make oral administration convenient, the formula will be processed in the form of granules. A randomized, multi-center pilot trial will be conducted. Forty eight participants with DN will be randomly assigned to one of four treatment groups: 1. A granule group, at 10 grams, three times daily (G10 group, n = 12); 2. A granule group, at 20 grams, three times daily (G20 group, n = 12); 3. A decoction group (D group, n = 12); and 4. An irbesartan group (Aprovel group, n = 12).The following outcome measures will be used: the percentage change of the albumin-to-creatinine ratio; and the changes in serum creatinine, glomerular filtration rate, fasting plasma glucose and hemoglobulin from baseline to the end of the trial. It is notable that most published clinical trials which assessed the efficacy of TCM on DN were of poor methodology and, therefore, their results have been invalidated. It is necessary to carry out well-designed clinical trials to provide sound evidence. The present trial is a study with potentially great value, for it will provide the parameters for future randomized, placebo-controlled, clinical trials with large sample sizes. The trial is registered on the Chinese Clinical Trial Registry: ChiCTR-TRC-12002718 (http://www.chictr.org/cn/proj/show.aspx?proj=3820).

Morita therapy for depression and anxiety (Morita Trial): study protocol for a pilot randomised controlled trial.

PubMed

Sugg, Holly Victoria Rose; Richards, David A; Frost, Julia

2016-03-24

Morita Therapy, a psychological therapy for common mental health problems, is in sharp contrast to established western psychotherapeutic approaches in teaching that undesired symptoms are natural features of human emotion rather than something to control or eliminate. The approach is widely practiced in Japan, but untested and little known in the UK. A clinical trial of Morita Therapy is required to establish the effectiveness of Morita Therapy for a UK population. However, a number of methodological, procedural and clinical uncertainties associated with such a trial first require addressing. The Morita Trial is a mixed methods study addressing the uncertainties associated with an evaluation of Morita Therapy compared with treatment as usual for depression and anxiety. We will undertake a pilot randomised controlled trial with embedded qualitative study. Sixty participants with major depressive disorder, with or without anxiety disorders, will be recruited predominantly from General Practice record searches and randomised to receive Morita Therapy plus treatment as usual or treatment as usual alone. Morita Therapy will be delivered by accredited psychological therapists. We will collect quantitative data on depressive symptoms, general anxiety, attitudes and quality of life at baseline and four month follow-up to inform future sample size calculations; and rates of recruitment, retention and treatment adherence to assess feasibility. We will undertake qualitative interviews in parallel with the trial, to explore people's views of Morita Therapy. We will conduct separate and integrated analyses on the quantitative and qualitative data. The outcomes of this study will prepare the ground for the design and conduct of a fully-powered evaluation of Morita Therapy plus treatment as usual versus treatment as usual alone, or inform a conclusion that such a trial is not feasible and/or appropriate. We will obtain a more comprehensive understanding of these issues than would be possible from either a quantitative or qualitative approach alone. Current Controlled Trials ISRCTN17544090 registered on 23 July 2015.

Clinical trial quality: From supervision to collaboration and beyond.

PubMed

Meeker-O'Connell, Ann; Glessner, Coleen

2018-02-01

Over the past decade, clinical trial quality has evolved from an after-the-fact, reactive activity to one focused on the important work of evidence generation from well-designed trials. This article explores the role the Clinical Trials Transformation Initiative has played in advancing quality as a core element of clinical trial design, through project work that initially focused on monitoring but evolved into a holistic, prospective, and comprehensive quality by design approach to clinical trial design and conduct.

Improving Diabetes care through Examining, Advising, and prescribing (IDEA): protocol for a theory-based cluster randomised controlled trial of a multiple behaviour change intervention aimed at primary healthcare professionals

PubMed Central

2014-01-01

Background New clinical research findings may require clinicians to change their behaviour to provide high-quality care to people with type 2 diabetes, likely requiring them to change multiple different clinical behaviours. The present study builds on findings from a UK-wide study of theory-based behavioural and organisational factors associated with prescribing, advising, and examining consistent with high-quality diabetes care. Aim To develop and evaluate the effectiveness and cost of an intervention to improve multiple behaviours in clinicians involved in delivering high-quality care for type 2 diabetes. Design/methods We will conduct a two-armed cluster randomised controlled trial in 44 general practices in the North East of England to evaluate a theory-based behaviour change intervention. We will target improvement in six underperformed clinical behaviours highlighted in quality standards for type 2 diabetes: prescribing for hypertension; prescribing for glycaemic control; providing physical activity advice; providing nutrition advice; providing on-going education; and ensuring that feet have been examined. The primary outcome will be the proportion of patients appropriately prescribed and examined (using anonymised computer records), and advised (using anonymous patient surveys) at 12 months. We will use behaviour change techniques targeting motivational, volitional, and impulsive factors that we have previously demonstrated to be predictive of multiple health professional behaviours involved in high-quality type 2 diabetes care. We will also investigate whether the intervention was delivered as designed (fidelity) by coding audiotaped workshops and interventionist delivery reports, and operated as hypothesised (process evaluation) by analysing responses to theory-based postal questionnaires. In addition, we will conduct post-trial qualitative interviews with practice teams to further inform the process evaluation, and a post-trial economic analysis to estimate the costs of the intervention and cost of service use. Discussion Consistent with UK Medical Research Council guidance and building on previous development research, this pragmatic cluster randomised trial will evaluate the effectiveness of a theory-based complex intervention focusing on changing multiple clinical behaviours to improve quality of diabetes care. Trial registration ISRCTN66498413. PMID:24886606

Lawyers and Legal Advocacy in Juvenile Courts: An Assessment.

ERIC Educational Resources Information Center

Puritz, Patricia; Burrell, Sue; Schwartz, Robert; Soler, Mark; Warboys, Loren

2000-01-01

Evaluates the juvenile justice system focusing on the barriers children encounter when seeking appropriate counsel and the quality of representation. Includes an assessment of the appointment of counsel, pretrial preparation and trial performance, post-trial maneuvers, and appeals. Finds that the most common obstacle is the overwhelming caseloads…

Statistical power, the Belmont report, and the ethics of clinical trials.

PubMed

Vollmer, Sara H; Howard, George

2010-12-01

Achieving a good clinical trial design increases the likelihood that a trial will take place as planned, including that data will be obtained from a sufficient number of participants, and the total number of participants will be the minimal required to gain the knowledge sought. A good trial design also increases the likelihood that the knowledge sought by the experiment will be forthcoming. Achieving such a design is more than good sense-it is ethically required in experiments when participants are at risk of harm. This paper argues that doing a power analysis effectively contributes to ensuring that a trial design is good. The ethical importance of good trial design has long been recognized for trials in which there is risk of serious harm to participants. However, whether the quality of a trial design, when the risk to participants is only minimal, is an ethical issue is rarely discussed. This paper argues that even in cases when the risk is minimal, the quality of the trial design is an ethical issue, and that this is reflected in the emphasis the Belmont Report places on the importance of the benefit of knowledge gained by society. The paper also argues that good trial design is required for true informed consent.

Development of a Portable Knee Rehabilitation Device That Uses Mechanical Loading.

PubMed

Fitzwater, Daric; Dodge, Todd; Chien, Stanley; Yokota, Hiroki; Anwar, Sohel

2013-12-01

Joint loading is a recently developed mechanical modality, which potentially provides a therapeutic regimen to activate bone formation and prevent degradation of joint tissues. To our knowledge, however, few joint loading devices are available for clinical or point-of-care applications. Using a voice-coil actuator, we developed an electromechanical loading system appropriate for human studies and preclinical trials that should prove both safe and effective. Two specific tasks for this loading system were development of loading conditions (magnitude and frequency) suitable for humans, and provision of a convenient and portable joint loading apparatus. Desktop devices have been previously designed to evaluate the effects of various loading conditions using small and large animals. However, a portable knee loading device is more desirable from a usability point of view. In this paper, we present such a device that is designed to be portable, providing a compact, user-friendly loader. The portable device was employed to evaluate its capabilities using a human knee model. The portable device was characterized for force-pulse width modulation duty cycle and loading frequency properties. The results demonstrate that the device is capable of producing the necessary magnitude of forces at appropriate frequencies to promote the stimulation of bone growth and which can be used in clinical studies for further evaluations.

Co-enrolment of Participants into Multiple Cancer Trials: Benefits and Challenges.

PubMed

Cafferty, F H; Coyle, C; Rowley, S; Berkman, L; MacKensie, M; Langley, R E

2017-07-01

Opportunities to enter patients into more than one clinical trial are not routinely considered in cancer research and experiences with co-enrolment are rarely reported. Potential benefits of allowing appropriate co-enrolment have been identified in other settings but there is a lack of evidence base or guidance to inform these decisions in oncology. Here, we discuss the benefits and challenges associated with co-enrolment based on experiences in the Add-Aspirin trial - a large, multicentre trial recruiting across a number of tumour types, where opportunities to co-enrol patients have been proactively explored and managed. The potential benefits of co-enrolment include: improving recruitment feasibility; increased opportunities for patients to participate in trials; and collection of robust data on combinations of interventions, which will ensure the ongoing relevance of individual trials and provide more cohesive evidence to guide the management of future patients. There are a number of perceived barriers to co-enrolment in terms of scientific, safety and ethical issues, which warrant consideration on a trial-by-trial basis. In many cases, any potential effect on the results of the trials will be negligible - limited by a number of factors, including the overlap in trial cohorts. Participant representatives stress the importance of autonomy to decide about trial enrolment, providing a compelling argument for offering co-enrolment where there are multiple trials that are relevant to a patient and no concerns regarding safety or the integrity of the trials. A number of measures are proposed for managing and monitoring co-enrolment. Ensuring acceptability to (potential) participants is paramount. Opportunities to enter patients into more than one cancer trial should be considered more routinely. Where planned and managed appropriately, co-enrolment can offer a number of benefits in terms of both scientific value and efficiency of study conduct, and will increase the opportunities for patients to participate in, and benefit from, clinical research. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Dose-finding designs for trials of molecularly targeted agents and immunotherapies

PubMed Central

Chiuzan, Cody; Shtaynberger, Jonathan; Manji, Gulam A.; Duong, Jimmy K.; Schwartz, Gary K.; Ivanova, Anastasia; Lee, Shing M.

2017-01-01

Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose-finding trials that met our criteria, 1,591 (92.9%) utilized a rule-based design, and 92 (5.4%; range 2.3% in 2009 to 9.7% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy. Among the MTA and immunotherapy trials, 5.8% used model-based methods, compared to 3.9% and 8.3% of the chemotherapy or radiotherapy trials, respectively. While the percentage of trials using novel dose-finding designs has tripled since 2007, only 7.1% of trials use novel designs. PMID:28166468

Interactions between physicians and the pharmaceutical industry: what does the literature say?

PubMed Central

Lexchin, J

1993-01-01

OBJECTIVE: To determine the effect of three types of interaction between physicians and the pharmaceutical industry--company-funded clinical trials, company-sponsored continuing medical education (CME) and information for physicians supplied by pharmaceutical detailers--on orientation and quality of clinical trials, content of CME courses and physicians' prescribing behaviour. DATA SOURCES: MEDLINE and HEALTH searches for English-language articles published from 1978 to 1993, supplemented by material from the author's personal collection. STUDY SELECTION: A total of 227 papers from the MEDLINE and HEALTH searches and about 2000 items from the author's library were initially reviewed. The following selection criteria were used: studies conducted in Australia, Canada, New Zealand, Britain and the United States; studies conducted after 1977; quantitative surveys containing details of the survey methods; studies on the orientation and quality of company-funded clinical trials and on the content of CME courses giving explicit criteria used in the evaluation; and reports on the outcome of interactions stating how the outcomes were assessed. Thirty-six studies met these criteria. DATA EXTRACTION: Information was extracted on five topics: physicians' attitudes toward drug industry interactions, frequency with which physicians participate in the interactions, orientation and quality of company-funded clinical trials, content of company-sponsored CME courses and changes in physicians' prescribing behaviour as a result of an interaction. DATA SYNTHESIS: Although most physicians participate only occasionally in company-sponsored clinical trials, most see detailers and attend company-sponsored CME courses. However, physicians do not have a very high opinion of the information from detailers or of company-sponsored CME events. Many doctors regard pharmaceutical companies as an important source of funding for clinical trials, but they also have concerns about accepting money from this source. Company funding of clinical trials may affect the quality of the trials and the types of research that physicians undertake. Company-sponsored CME courses may have a commercial bias even if conducted under guidelines designed to ensure the independence of the event. All three types of interactions affect physicians' prescribing behaviour and, in the case of obtaining information from detailers, physicians' prescribing practices are less appropriate as a result of the interaction. CONCLUSIONS: Physicians are affected by their interactions with the pharmaceutical industry. Further research needs to be done in most cases to determine whether such interactions lead to more or less appropriate prescribing practices. The CMA's guidelines on this topic should be evaluated to see whether they are effective in controlling physician-industry interactions. Further measures may be necessary if the guidelines fail to prevent negative effects on prescribing practices. PMID:8221424

Enhancing treatment fidelity in psychotherapy research: novel approach to measure the components of cognitive behavioural therapy for relapse prevention in first-episode psychosis.

PubMed

Alvarez-Jimenez, Mario; Wade, Darryl; Cotton, Sue; Gee, Donna; Pearce, Tracey; Crisp, Kingsley; McGorry, Patrick D; Gleeson, John F

2008-12-01

Establishing treatment fidelity is one of the most important aspects of psychotherapy research. Treatment fidelity refers to the methodological strategies used to examine and enhance the reliability and validity of psychotherapy. This study sought to develop and evaluate a measure specifically designed to assess fidelity to the different therapeutic components (i.e. therapy phases) of the individual intervention of a psychotherapy clinical trial (the EPISODE II trial). A representative sample of sessions stratified by therapy phase was assessed using a specifically developed fidelity measure (Relapse Prevention Therapy-Fidelity Scale, RPT-FS). Each RPT-FS subscale was designed to include a different component/phase of therapy and its major therapeutic ingredients. The measure was found to be reliable and had good internal consistency. The RPT-FS discriminated, almost perfectly, between therapy phases. The analysis of the therapeutic strategies implemented during the intervention indicated that treatment fidelity was good throughout therapy phases. While therapists primarily engaged in interventions from the appropriate therapeutic phase, flexibility in therapy was evident. This study described the development of a brief, reliable and internally consistent measure to determine both treatment fidelity and the therapy components implemented throughout the intervention. This methodology can be potentially useful to determine those components related to therapeutic change.

The evolving landscape of therapeutic drug development for hepatocellular carcinoma.

PubMed

Chong, Dawn Qingqing; Tan, Iain Beehuat; Choo, Su-Pin; Toh, Han Chong

2013-11-01

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. Copyright © 2013 Elsevier Inc. All rights reserved.

Should structural interventions be evaluated using RCTs? The case of HIV prevention.

PubMed

Bonell, Christopher; Hargreaves, James; Strange, Vicki; Pronyk, Paul; Porter, John

2006-09-01

Structural interventions addressing macro-social determinants of risk have been suggested as potentially important adjuncts to biomedical and behavioural interventions for the prevention of HIV and other diseases. A few interventions of this type have been evaluated using randomised controlled trials (RCTs), the most rigorous design to evaluate the effects of biomedical and behavioural interventions. The appropriateness of applying RCTs to structural interventions is however debated. This paper considers whether issues of ethics, feasibility and utility preclude the use of RCTs in evaluations of structural interventions for HIV prevention. We conclude there is nothing particular to this category of interventions prohibiting use of RCTs. However, we suggest that RCTs may prove unacceptable, unfeasible or not useful in certain circumstances, such as where an intervention brings important benefits other than HIV prevention (such as increased income); where leaders of clusters do not allow decisions about macro-social policies to be determined randomly; where the unit of social organization addressed by an intervention is so large that recruitment of adequate numbers of clusters is impossible; and where the period required to trial interventions extends beyond practical decision-making time-scales. In such cases, alternative evaluative designs must be assessed for their ability to provide evidence of intervention effectiveness.

Design of control-group conditions in clinical trials of behavioral interventions.

PubMed

Lindquist, Ruth; Wyman, Jean F; Talley, Kristine M C; Findorff, Mary J; Gross, Cynthia R

2007-01-01

To review considerations in the design of placebo (attention) control conditions for community-based clinical trials of health behavior change interventions and to provide practical strategies for the design of control conditions. A well-designed control condition is an essential component of a clinical trial to foster the unambiguous interpretation of study findings. Pitfalls in the design of control conditions in clinical trials of behavioral interventions are identified and strategies to address them are offered. Types of control conditions that have been used in fall prevention trials are described, along with their strengths and weaknesses. The control condition used in the recent fall evaluation and prevention program (FEPP) was designed to overcome limitations of previous trial designs; it is provided to illustrate how to apply specific design principles. Pitfalls in the design of behavioral intervention studies may be avoided with the application of sound design principles. The FEPP active control condition can be used as a model in the design of future studies.

Randomized clinical trials in pediatric critical care: Rarely done but desperately needed.

PubMed

Randolph, Adrienne G.; Lacroix, Jacques

2002-04-01

OBJECTIVE: To review the benefits and challenges of using the randomized, controlled trial (RCT) study design to evaluate preventive and therapeutic interventions in pediatric critical care medicine. CONCLUSIONS: The RCT design is able to control for many sources of potential bias that other types of study designs cannot. The findings of RCTs often contradict the findings of less rigorous study designs. Before performing an RCT, there must exist a state of clinical equipoise, a sufficient number of eligible patients must be available, and the epidemiology of the disorder in question must be well studied. There are many challenges to performing high-quality RCTs. Studying multiple element support strategies in the critically ill patient population is more complex than studying a single drug therapy. High patient and practice variability and hazy diagnostic definitions can dilute the signal-to-noise ratio. Most interventions in critical care are expected to have a modest or small effect. This markedly increases the requisite sample size. There is a paucity of accepted clinically important measurements of the outcome of critical care, making mortality a common outcome to evaluate with a not-so-common incidence. Developmental issues, the inability to give informed consent, and the failure to perform the appropriate pharmacokinetic and safety studies are additional challenges facing pediatric investigators. Despite these limitations, a good RCT remains the best way to prove that an intervention is working or not. Indeed, RCTs are and will remain the "gold standard" method to estimate the efficacy of a therapeutic or prophylactic intervention.

Design complexity in termite-fishing tools of chimpanzees (Pan troglodytes)

PubMed Central

Sanz, Crickette; Call, Josep; Morgan, David

2009-01-01

Adopting the approach taken with New Caledonian crows (Corvus moneduloides), we present evidence of design complexity in one of the termite-fishing tools of chimpanzees (Pan troglodytes) in the Goualougo Triangle, Republic of Congo. Prior to termite fishing, chimpanzees applied a set of deliberate, distinguishable actions to modify herb stems to fashion a brush-tipped probe, which is different from the form of fishing tools used by chimpanzees in East and West Africa. This means that ‘brush-tipped fishing probes’, unlike ‘brush sticks’, are not a by-product of use but a deliberate design feature absent in other chimpanzee populations. The specialized modifications to prepare the tool for termite fishing, measures taken to repair non-functional brushes and appropriate orientation of the modified end suggest that these wild chimpanzees are attentive to tool modifications. We also conducted experimental trials that showed that a brush-tipped probe is more effective in gathering insects than an unmodified fishing probe. Based on these findings, we suggest that chimpanzees in the Congo Basin have developed an improved fishing probe design. PMID:19324641

A randomized evaluation of a computer-based physician's workstation: design considerations and baseline results.

PubMed Central

Rotman, B. L.; Sullivan, A. N.; McDonald, T.; DeSmedt, P.; Goodnature, D.; Higgins, M.; Suermondt, H. J.; Young, C. Y.; Owens, D. K.

1995-01-01

We are performing a randomized, controlled trial of a Physician's Workstation (PWS), an ambulatory care information system, developed for use in the General Medical Clinic (GMC) of the Palo Alto VA. Goals for the project include selecting appropriate outcome variables and developing a statistically powerful experimental design with a limited number of subjects. As PWS provides real-time drug-ordering advice, we retrospectively examined drug costs and drug-drug interactions in order to select outcome variables sensitive to our short-term intervention as well as to estimate the statistical efficiency of alternative design possibilities. Drug cost data revealed the mean daily cost per physician per patient was 99.3 cents +/- 13.4 cents, with a range from 0.77 cent to 1.37 cents. The rate of major interactions per prescription for each physician was 2.9% +/- 1%, with a range from 1.5% to 4.8%. Based on these baseline analyses, we selected a two-period parallel design for the evaluation, which maximized statistical power while minimizing sources of bias. PMID:8563376

HETEROGENEITY IN TREATMENT EFFECT AND COMPARATIVE EFFECTIVENESS RESEARCH.

PubMed

Luo, Zhehui

2011-10-01

The ultimate goal of comparative effectiveness research (CER) is to develop and disseminate evidence-based information about which interventions are most effective for which patients under what circumstances. To achieve this goal it is crucial that researchers in methodology development find appropriate methods for detecting the presence and sources of heterogeneity in treatment effect (HTE). Comparing with the typically reported average treatment effect (ATE) in randomized controlled trials and non-experimental (i.e., observational) studies, identifying and reporting HTE better reflect the nature and purposes of CER. Methodologies of CER include meta-analysis, systematic review, design of experiments that encompasses HTE, and statistical correction of various types of estimation bias, which is the focus of this review.

Evolution of endovascular stroke therapies and devices.

PubMed

Wallace, Adam N; Kansagra, Akash P; McEachern, James; Moran, Christopher J; Cross, Dewitte T; Derdeyn, Colin P

2016-01-01

Acute ischemic stroke is caused by occlusion of a cerebral artery, resulting in loss of brain tissue and neurologic deficits. However, a portion of the ischemic brain can be salvaged if blood flow is restored within an appropriate time frame. The past year has seen the publication of five positive randomized controlled trials demonstrating substantial benefit of mechanical thrombectomy in select patients with large vessel cerebrovascular occlusion. This progress is related to several factors, but most importantly, dramatic improvements in speed and rates of recanalization with the latest generation devices. In this article, we review the evolution of endovascular acute ischemic stroke therapies and key design features of the most widely used devices.

Fish-like propulsion of an airship with planar membrane dielectric elastomer actuators.

PubMed

Jordi, C; Michel, S; Fink, E

2010-06-01

The goal of our project is to mimic fish-like movement in air, propelling an airship by undulating its hull and a caudal fin. The activation of the fish-like body in air is realized by dielectric elastomers. These actuators are quite unique for their soft light-weight membrane structure and they are therefore very appropriate to the application on inflated structures. The principles of biomimetics for the structural design and movement are discussed and the conception and design of the airship is described. Various development tests, including wind tunnel testing and flight trials, were performed and the results obtained are presented. It can be shown that an 8 m model airship can be propelled in a fish-like manner in air and that the propulsion can be drastically improved by undulating the body as well as the caudal fin contrary to propulsion with only the caudal fin.

Data to Action

PubMed Central

Rohm Young, Deborah; Johnson, Carolyn C.; Steckler, Allan; Gittelsohn, Joel; Saunders, Ruth P.; Saksvig, Brit I.; Ribisl, Kurt M.; Lytle, Leslie A.; McKenzie, Thomas L.

2008-01-01

Formative research is used to inform intervention development, but the processes of transmitting results to intervention planners and incorporating information into intervention designs are not well documented. The authors describe how formative research results from the Trial of Activity for Adolescent Girls (TAAG) were transferred to planners to guide intervention development. Methods included providing oral and written reports, prioritizing recommendations, and cross-checking recommendations with intervention objectives and implementation strategies. Formative work influenced the intervention in many ways. For example, results indicated that middle schools offered only coeducational physical education and health education classes, so the TAAG intervention was designed to be appropriate for both sexes, and intervention strategies were developed to directly address girls’ stated preferences (e.g., enjoyable activities, opportunity to socialize) and barriers (e.g., lack of skills, fear of injury) for physical activity. The challenges of using formative research for intervention development are discussed. PMID:16397162

A review of the efficacy of the picture exchange communication system intervention.

PubMed

Preston, Deborah; Carter, Mark

2009-10-01

The Picture Exchange Communication System (PECS) is a communication program that has become widely used, especially with children with autism. This paper reports the results of a review of the empirical literature on PECS. A descriptive review is provided of the 27 studies identified, which included randomized controlled trials (RCTs), other group designs and single subject studies. For 10 appropriate single subject designs the percentage of nonoverlapping data (PND) and percentage exceeding median (PEM) metrics were examined. While there are few RCTs, on balance, available research provides preliminary evidence that PECS is readily learned by most participants and provides a means of communication for individuals with little or no functional speech. Very limited data suggest some positive effect on both social-communicative and challenging behaviors, while effects on speech development remain unclear. Directions for future research are discussed including the priority need for further well-conducted RCTs.

A Comparison of PECS and iPad to Teach Requesting to Pre-schoolers with Autistic Spectrum Disorders.

PubMed

Agius, May M; Vance, Margaret

2016-01-01

Few studies have compared the efficacy of the Picture Exchange Communication System (PECS) and iPads used as speech generating devices (SGDs), and none have targeted preschoolers. This study compares the relative efficacy of PECS and an iPad/SGD with three preschool-aged children with autism spectrum disorder and limited functional speech who lived in Malta. The study utilized an adapted alternating treatment design embedded in a multiple baseline design, with requesting of reinforcers as the dependent variable. Visual analysis of the results indicated that all participants required more prompted trials and sessions for the iPad/SGD condition. All participants learned a three step navigational sequence on the iPad. Participant preference probes were inconclusive and were not linked to speed of acquisition of requesting skills. Results suggest that both PECS and an iPad could be appropriate for teaching requesting skills to beginning communicators.

Data to action: using formative research to develop intervention programs to increase physical activity in adolescent girls.

PubMed

Young, Deborah Rohm; Johnson, Carolyn C; Steckler, Allan; Gittelsohn, Joel; Saunders, Ruth P; Saksvig, Brit I; Ribisl, Kurt M; Lytle, Leslie A; McKenzie, Thomas L

2006-02-01

Formative research is used to inform intervention development, but the processes of transmitting results to intervention planners and incorporating information into intervention designs are not well documented. The authors describe how formative research results from the Trial of Activity for Adolescent Girls (TAAG) were transferred to planners to guide intervention development. Methods included providing oral and written reports, prioritizing recommendations, and cross-checking recommendations with intervention objectives and implementation strategies. Formative work influenced the intervention in many ways. For example, results indicated that middle schools offered only coeducational physical education and health education classes, so the TAAG intervention was designed to be appropriate for both sexes, and intervention strategies were developed to directly address girls' stated preferences (e.g., enjoyable activities, opportunity to socialize) and barriers (e.g., lack of skills, fear of injury) for physical activity. The challenges of using formative research for intervention development are discussed.

Commentary: considerations for using the 'Trials within Cohorts' design in a clinical trial of an investigational medicinal product.

PubMed

Bibby, Anna C; Torgerson, David J; Leach, Samantha; Lewis-White, Helen; Maskell, Nick A

2018-01-08

The 'trials within cohorts' (TwiC) design is a pragmatic approach to randomised trials in which trial participants are randomly selected from an existing cohort. The design has multiple potential benefits, including the option of conducting multiple trials within the same cohort. To date, the TwiC design methodology been used in numerous clinical settings but has never been applied to a clinical trial of an investigational medicinal product (CTIMP). We have recently secured the necessary approvals to undertake the first CTIMP using the TwiC design. In this paper, we describe some of the considerations and modifications required to ensure such a trial is compliant with Good Clinical Practice and international clinical trials regulations. We advocate using a two-stage consent process and using the consent stages to explicitly differentiate between trial participants and cohort participants who are providing control data. This distinction ensured compliance but had consequences with respect to costings, recruitment and the trial assessment schedule. We have demonstrated that it is possible to secure ethical and regulatory approval for a CTIMP TwiC. By including certain considerations at the trial design stage, we believe this pragmatic and efficient methodology could be utilised in other CTIMPs in future.

Design of sEMG assembly to detect external anal sphincter activity: a proof of concept.

PubMed

Shiraz, Arsam; Leaker, Brian; Mosse, Charles Alexander; Solomon, Eskinder; Craggs, Michael; Demosthenous, Andreas

2017-10-31

Conditional trans-rectal stimulation of the pudendal nerve could provide a viable solution to treat hyperreflexive bladder in spinal cord injury. A set threshold of the amplitude estimate of the external anal sphincter surface electromyography (sEMG) may be used as the trigger signal. The efficacy of such a device should be tested in a large scale clinical trial. As such, a probe should remain in situ for several hours while patients attend to their daily routine; the recording electrodes should be designed to be large enough to maintain good contact while observing design constraints. The objective of this study was to arrive at a design for intra-anal sEMG recording electrodes for the subsequent clinical trials while deriving the possible recording and processing parameters. Having in mind existing solutions and based on theoretical and anatomical considerations, a set of four multi-electrode probes were designed and developed. These were tested in a healthy subject and the measured sEMG traces were recorded and appropriately processed. It was shown that while comparatively large electrodes record sEMG traces that are not sufficiently correlated with the external anal sphincter contractions, smaller electrodes may not maintain a stable electrode tissue contact. It was shown that 3 mm wide and 1 cm long electrodes with 5 mm inter-electrode spacing, in agreement with Nyquist sampling, placed 1 cm from the orifice may intra-anally record a sEMG trace sufficiently correlated with external anal sphincter activity. The outcome of this study can be used in any biofeedback, treatment or diagnostic application where the activity of the external anal sphincter sEMG should be detected for an extended period of time.

A cortical neural prosthesis for restoring and enhancing memory

NASA Astrophysics Data System (ADS)

Berger, Theodore W.; Hampson, Robert E.; Song, Dong; Goonawardena, Anushka; Marmarelis, Vasilis Z.; Deadwyler, Sam A.

2011-08-01

A primary objective in developing a neural prosthesis is to replace neural circuitry in the brain that no longer functions appropriately. Such a goal requires artificial reconstruction of neuron-to-neuron connections in a way that can be recognized by the remaining normal circuitry, and that promotes appropriate interaction. In this study, the application of a specially designed neural prosthesis using a multi-input/multi-output (MIMO) nonlinear model is demonstrated by using trains of electrical stimulation pulses to substitute for MIMO model derived ensemble firing patterns. Ensembles of CA3 and CA1 hippocampal neurons, recorded from rats performing a delayed-nonmatch-to-sample (DNMS) memory task, exhibited successful encoding of trial-specific sample lever information in the form of different spatiotemporal firing patterns. MIMO patterns, identified online and in real-time, were employed within a closed-loop behavioral paradigm. Results showed that the model was able to predict successful performance on the same trial. Also, MIMO model-derived patterns, delivered as electrical stimulation to the same electrodes, improved performance under normal testing conditions and, more importantly, were capable of recovering performance when delivered to animals with ensemble hippocampal activity compromised by pharmacologic blockade of synaptic transmission. These integrated experimental-modeling studies show for the first time that, with sufficient information about the neural coding of memories, a neural prosthesis capable of real-time diagnosis and manipulation of the encoding process can restore and even enhance cognitive, mnemonic processes.

A Randomized Educational Intervention Trial to Determine the Effect of Online Education on the Quality of Resident-Delivered Care.

PubMed

Dolan, Brigid M; Yialamas, Maria A; McMahon, Graham T

2015-09-01

There is limited research on whether online formative self-assessment and learning can change the behavior of medical professionals. We sought to determine if an adaptive longitudinal online curriculum in bone health would improve resident physicians' knowledge, and change their behavior regarding prevention of fragility fractures in women. We used a randomized control trial design in which 50 internal medicine resident physicians at a large academic practice were randomized to either receive a standard curriculum in bone health care alone, or to receive it augmented with an adaptive, longitudinal, online formative self-assessment curriculum delivered via multiple-choice questions. Outcomes were assessed 10 months after the start of the intervention. Knowledge outcomes were measured by a multiple-choice question examination. Clinical outcomes were measured by chart review, including bone density screening rate, calculation of the fracture risk assessment tool (FRAX) score, and rate of appropriate bisphosphonate prescription. Compared to the control group, residents participating in the intervention had higher scores on the knowledge test at the end of the study. Bone density screening rates and appropriate use of bisphosphonates were significantly higher in the intervention group compared with the control group. FRAX score reporting did not differ between the groups. Residents participating in a novel adaptive online curriculum outperformed peers in knowledge of fragility fracture prevention and care practices to prevent fracture. Online adaptive education can change behavior to improve patient care.

A Randomized Educational Intervention Trial to Determine the Effect of Online Education on the Quality of Resident-Delivered Care

PubMed Central

Dolan, Brigid M.; Yialamas, Maria A.; McMahon, Graham T.

2015-01-01

Background There is limited research on whether online formative self-assessment and learning can change the behavior of medical professionals. Objective We sought to determine if an adaptive longitudinal online curriculum in bone health would improve resident physicians' knowledge, and change their behavior regarding prevention of fragility fractures in women. Methods We used a randomized control trial design in which 50 internal medicine resident physicians at a large academic practice were randomized to either receive a standard curriculum in bone health care alone, or to receive it augmented with an adaptive, longitudinal, online formative self-assessment curriculum delivered via multiple-choice questions. Outcomes were assessed 10 months after the start of the intervention. Knowledge outcomes were measured by a multiple-choice question examination. Clinical outcomes were measured by chart review, including bone density screening rate, calculation of the fracture risk assessment tool (FRAX) score, and rate of appropriate bisphosphonate prescription. Results Compared to the control group, residents participating in the intervention had higher scores on the knowledge test at the end of the study. Bone density screening rates and appropriate use of bisphosphonates were significantly higher in the intervention group compared with the control group. FRAX score reporting did not differ between the groups. Conclusions Residents participating in a novel adaptive online curriculum outperformed peers in knowledge of fragility fracture prevention and care practices to prevent fracture. Online adaptive education can change behavior to improve patient care. PMID:26457142

Ethical Considerations in Tissue Engineering Research: Case Studies in Translation

PubMed Central

Baker, Hannah B.; McQuilling, John P.

2016-01-01

Tissue engineering research is a complex process that requires investigators to focus on the relationship between their research and anticipated gains in both knowledge and treatment improvements. The ethical considerations arising from tissue engineering research are similarly complex when addressing the translational progression from bench to bedside, and investigators in the field of tissue engineering act as moral agents at each step of their research along the translational pathway, from early benchwork and preclinical studies to clinical research. This review highlights the ethical considerations and challenges at each stage of research, by comparing issues surrounding two translational tissue engineering technologies: the bioartificial pancreas and a tissue engineered skeletal muscle construct. We present relevant ethical issues and questions to consider at each step along the translational pathway, from the basic science bench to preclinical research to first-in-human clinical trials. Topics at the bench level include maintaining data integrity, appropriate reporting and dissemination of results, and ensuring that studies are designed to yield results suitable for advancing research. Topics in preclinical research include the principle of “modest translational distance” and appropriate animal models. Topics in clinical research include key issues that arise in early-stage clinical trials, including selection of patient-subjects, disclosure of uncertainty, and defining success. The comparison of these two technologies and their ethical issues brings to light many challenges for translational tissue engineering research and provides guidance for investigators engaged in development of any tissue engineering technology. PMID:26282436

Ethical considerations in tissue engineering research: Case studies in translation.

PubMed

Baker, Hannah B; McQuilling, John P; King, Nancy M P

2016-04-15

Tissue engineering research is a complex process that requires investigators to focus on the relationship between their research and anticipated gains in both knowledge and treatment improvements. The ethical considerations arising from tissue engineering research are similarly complex when addressing the translational progression from bench to bedside, and investigators in the field of tissue engineering act as moral agents at each step of their research along the translational pathway, from early benchwork and preclinical studies to clinical research. This review highlights the ethical considerations and challenges at each stage of research, by comparing issues surrounding two translational tissue engineering technologies: the bioartificial pancreas and a tissue engineered skeletal muscle construct. We present relevant ethical issues and questions to consider at each step along the translational pathway, from the basic science bench to preclinical research to first-in-human clinical trials. Topics at the bench level include maintaining data integrity, appropriate reporting and dissemination of results, and ensuring that studies are designed to yield results suitable for advancing research. Topics in preclinical research include the principle of "modest translational distance" and appropriate animal models. Topics in clinical research include key issues that arise in early-stage clinical trials, including selection of patient-subjects, disclosure of uncertainty, and defining success. The comparison of these two technologies and their ethical issues brings to light many challenges for translational tissue engineering research and provides guidance for investigators engaged in development of any tissue engineering technology. Copyright © 2015 Elsevier Inc. All rights reserved.

Case study and case-based research in emergency nursing and care: Theoretical foundations and practical application in paramedic pre-hospital clinical judgment and decision-making of patients with mental illness.

PubMed

Shaban, Ramon Z; Considine, Julie; Fry, Margaret; Curtis, Kate

2017-02-01

Generating knowledge through quality research is fundamental to the advancement of professional practice in emergency nursing and care. There are multiple paradigms, designs and methods available to researchers to respond to challenges in clinical practice. Systematic reviews, randomised control trials and other forms of experimental research are deemed the gold standard of evidence, but there are comparatively few such trials in emergency care. In some instances it is not possible or appropriate to undertake experimental research. When exploring new or emerging problems where there is limited evidence available, non-experimental methods are required and appropriate. This paper provides the theoretical foundations and an exemplar of the use of case study and case-based research to explore a new and emerging problem in the context of emergency care. It examines pre-hospital clinical judgement and decision-making of mental illness by paramedics. Using an exemplar the paper explores the theoretical foundations and conceptual frameworks of case study, it explains how cases are defined and the role researcher in this form of inquiry, it details important principles and the procedures for data gathering and analysis, and it demonstrates techniques to enhance trustworthiness and credibility of the research. Moreover, it provides theoretically and practical insights into using case study in emergency care. Copyright © 2017 College of Emergency Nursing Australasia. Published by Elsevier Ltd. All rights reserved.

Design and rationale for a randomised comparison of everolimus-eluting stents and coronary artery bypass graft surgery in selected patients with left main coronary artery disease: the EXCEL trial.

PubMed

Kappetein, Arie Pieter; Serruys, Patrick W; Sabik, Joseph F; Leon, Martin B; Taggart, David P; Morice, Marie-Claude; Gersh, Bernard J; Pocock, Stuart J; Cohen, David J; Wallentin, Lars; Ben-Yehuda, Ori; van Es, Gerrit-Anne; Simonton, Charles A; Stone, Gregg W

2016-09-18

Coronary artery bypass graft (CABG) surgery is the standard of care for revascularisation of patients with left main coronary artery disease (LMCAD). Recent studies have suggested that percutaneous coronary intervention (PCI) with drug-eluting stents (DES) may provide comparable outcomes in selected patients with LMCAD without extensive CAD. We therefore designed a trial to investigate whether PCI with XIENCE cobalt-chromium everolimus-eluting stents (CoCr-EES) would result in non-inferior or superior clinical outcomes to CABG in selected patients with LMCAD. The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is a prospective, open-label, multicentre, international study of 1,900 randomised subjects. Patients with significant LMCAD with a SYNTAX score ≤32 and local Heart Team consensus that the subject is appropriate for revascularisation by both PCI and CABG are consented and randomised 1:1 to undergo PCI using CoCr-EES or CABG. All patients undergo follow-up for five years. The primary endpoint is the three-year composite rate of death, stroke or myocardial infarction, assessed at a median follow-up of at least three years (with at least two-year follow-up in all patients), powered for sequential non-inferiority and superiority testing. The EXCEL study will define the contemporary roles of CABG and PCI using XIENCE CoCr-EES in patients with LMCAD disease with low and intermediate SYNTAX scores.

Interventions to improve water quality for preventing diarrhoea: systematic review and meta-analysis

PubMed Central

Schmidt, Wolf-Peter; Rabie, Tamer; Roberts, Ian; Cairncross, Sandy

2007-01-01

Objective To assess the effectiveness of interventions to improve the microbial quality of drinking water for preventing diarrhoea. Design Systematic review. Data sources Cochrane Infectious Diseases Group's trials register, CENTRAL, Medline, Embase, LILACS; hand searching; and correspondence with experts and relevant organisations. Study selection Randomised and quasirandomised controlled trials of interventions to improve the microbial quality of drinking water for preventing diarrhoea in adults and in children in settings with endemic disease. Data extraction Allocation concealment, blinding, losses to follow-up, type of intervention, outcome measures, and measures of effect. Pooled effect estimates were calculated within the appropriate subgroups. Data synthesis 33 reports from 21 countries documenting 42 comparisons were included. Variations in design, setting, and type and point of intervention, and variations in defining, assessing, calculating, and reporting outcomes limited the comparability of study results and pooling of results by meta-analysis. In general, interventions to improve the microbial quality of drinking water are effective in preventing diarrhoea. Effectiveness was not conditioned on the presence of improved water supplies or sanitation in the study setting and was not enhanced by combining the intervention with instructions on basic hygiene, a water storage vessel, or improved sanitation or water supplies—other common environmental interventions intended to prevent diarrhoea. Conclusion Interventions to improve water quality are generally effective for preventing diarrhoea in all ages and in under 5s. Significant heterogeneity among the trials suggests that the level of effectiveness may depend on a variety of conditions that research to date cannot fully explain. PMID:17353208

Ophthalmic randomized controlled trials reports: the statement of the hypothesis.

PubMed

Lee, Chun Fan; Cheng, Andy Chi On; Fong, Daniel Yee Tak

2014-01-01

To evaluate whether the ophthalmic randomized controlled trials (RCTs) were designed properly, their hypotheses stated clearly, and their conclusions drawn correctly. A systematic review of 206 ophthalmic RCTs. The objective statement, methods, and results sections and the conclusions of RCTs published in 4 major general clinical ophthalmology journals from 2009 through 2011 were assessed. The clinical objective and specific hypothesis were the main outcome measures. The clinical objective of the trial was presented in 199 (96.6%) studies and the hypothesis was specified explicitly in 56 (27.2%) studies. One hundred ninety (92.2%) studies tested superiority. Among them, 17 (8.3%) studies comparing 2 or more active treatments concluded equal or similar effectiveness between the 2 arms after obtaining insignificant results. There were 5 noninferiority studies and 4 equivalence studies. How the treatments were compared was not mentioned in 1 of the noninferiority studies. Two of the equivalence studies did not specify the equivalence margin and used tests for detecting difference rather than confirming equivalence. The clinical objective commonly was stated, but the prospectively defined hypothesis tended to be understated in ophthalmic RCTs. Superiority was the most common type of comparison. Conclusions made in some of them with negative results were not consistent with the hypothesis, indicating that noninferiority or equivalence may be a more appropriate design. Flaws were common in the noninferiority and equivalence studies. Future ophthalmic researchers should choose the type of comparison carefully, specify the hypothesis clearly, and draw conclusions that are consistent with the hypothesis. Copyright © 2014 Elsevier Inc. All rights reserved.