Ethical considerations in HIV prevention and vaccine research in resource-limited settings.

PubMed

Garner, Samual A; Anude, Chuka J; Adams, Elizabeth; Dawson, Liza

2014-09-01

HIV prevention research has been facing increasing ethical and operational challenges. Factors influencing the design and conduct of HIV prevention trials include a rapidly changing evidence base, new biomedical prevention methods and modalities being tested, a large diversity of countries, sites and populations affected by HIV and participating in trials, and challenges of developing and making available products that will be feasible and affordable for at-risk populations. To discuss these challenges, a meeting, Ethical considerations around novel combination prevention modalities in HIV prevention and vaccine trials in resource-limited settings, was convened by NIH/NIAID/Division of AIDS on April 22-23, 2013. Several themes emerged from the meeting: (1) because of both trial design and ethical complexities, choosing prevention packages and designing combination prevention research trials will need to be evaluated on a case by case basis in different clinical trials, countries, and health systems; (2) multilevel stakeholder engagement from the beginning is vital to a fair and transparent process and also to designing ethical and relevant trials; (3) research should generally be responsive to a host country's needs, and sponsors and stakeholders should work together to address potential barriers to future access; and finally, (4) another meeting including a broader group of stakeholders is needed to address many of the outstanding ethical issues raised by this meeting. We offer an overview of the meeting and the key discussion points and recommendations to help guide the design and conduct of future HIV prevention and vaccine research in resource-limited settings.

14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends.

PubMed

Erkan, Doruk; Aguiar, Cassyanne L; Andrade, Danieli; Cohen, Hannah; Cuadrado, Maria J; Danowski, Adriana; Levy, Roger A; Ortel, Thomas L; Rahman, Anisur; Salmon, Jane E; Tektonidou, Maria G; Willis, Rohan; Lockshin, Michael D

2014-06-01

Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non-warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Redesigning TRACER trial after TRITON.

PubMed

Serebruany, Victor L

2015-10-15

Designing of smart clinical trials is critical for regulatory approval and future drug utilization. Importantly, trial design should be reconsidered if the interim analyses suggest unexpected harm, or conflicting results were yielded from the other trials within the same therapeutic area. With regard to antiplatelet agents, the perfect example is redesigning of the ongoing PRoFESS trial by eliminating aspirin from clopidogrel arm after the earlier MATCH trial results became available. The goal was to aseess the unchanged TRACER trial design in light of the evidence yielded from the earlier completed TRITON trial. TRACER was designed as a triple versus dual antiplatelet trial in NSTEMI patients with no previous long-term outcome data supporting such aggressive strategy. TRITON data represented dual versus dual antiplatelet therapy, and became available before TRACER enrollment starts revealing prasugrel front-loaded early vascular benefit predominantly in STEMI patients with the growing over time bleeding and cancer risks. Moreover, large prasugrel NSTEMI TRITON cohort exhibited trend towards excess mortality in experimental arm warning against aggressive TRACER design. The long-term TRITON results in general, and especially in the NSTEMI patients challenge unchanged TRACER trial design. Applying dual, rather than triple antiplatelet therapy protocol modification should be considered in TRACER to minimize bleeding, cancer, and non-cardiovascular death risks. Copyright © 2015. Published by Elsevier Ireland Ltd.

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.

Designing Clinical Trials of Interventions for Mobility Disability: Results from the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) Trial

PubMed Central

Espeland, Mark A.; Gill, Thomas M.; Guralnik, Jack; Miller, Michael E.; Fielding, Roger; Newman, Anne B.; Pahor, Marco

2008-01-01

Background Clinical trials to assess interventions for mobility disability are critically needed; however, data for efficiently designing such trials are lacking. Methods Results are described from a pilot clinical trial in which 424 volunteers aged 70–89 years were randomly assigned to one of two interventions -- physical activity or a healthy aging education program -- and followed for a planned minimum of 12 months. We evaluated the longitudinal distributions of four standardized outcomes to contrast how they may serve as primary outcomes of future clinical trials: ability to walk 400 meters, ability to walk 4 meters in ≤10 seconds, a physical performance battery, and a questionnaire focused on physical function. Results Changes in all four outcomes were inter-related over time. The ability to walk 400 meters as a dichotomous outcome provided the smallest sample size projections (i.e. appeared to be the most efficient outcome). It loaded most heavily on the underlying latent variable in structural equation modeling with a weight of 80%. A four-year trial based on the outcome of 400 meter walk is projected to require N = 962 to 2,234 to detect an intervention effect of 30% to 20% with 90% power. Conclusions Future clinical trials of interventions designed to influence mobility disability may have greater efficiency if they adopt the ability to complete a 400 meter walk as their primary outcome. PMID:18000143

Conducting a Trial of Web Conferencing Software: Why, How, and Perceptions from the Coalface

ERIC Educational Resources Information Center

Reushle, Shirley; Loch, Birgit

2008-01-01

This paper reports on the trial of web conferencing software conducted at a regional Australian university with a significant distance population. The paper shares preliminary findings, the views of participants and recommendations for future activity. To design and conduct the trial, an action research method was chosen because it is…

Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities

PubMed Central

Baik, Christina S.; Rubin, Eric H.; Forde, Patrick M.; Mehnert, Janice M.; Collyar, Deborah; Butler, Marcus O.; Dixon, Erica L.; Chow, Laura Q.M.

2017-01-01

Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials. PMID:28864727

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

PubMed Central

Antoniou, Miranta; Jorgensen, Andrea L; Kolamunnage-Dona, Ruwanthi

2016-01-01

Background Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient’s biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have been proposed for testing a biomarker’s clinical utility, including Phase II and Phase III clinical trials which aim to test the effectiveness of a biomarker-guided approach to treatment; these designs can be broadly classified into adaptive and non-adaptive. While adaptive designs allow planned modifications based on accumulating information during a trial, non-adaptive designs are typically simpler but less flexible. Methods and Findings We have undertaken a comprehensive review of biomarker-guided adaptive trial designs proposed in the past decade. We have identified eight distinct biomarker-guided adaptive designs and nine variations from 107 studies. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. We have graphically displayed the current biomarker-guided adaptive trial designs and summarised the characteristics of each design. Conclusions Our in-depth overview provides future researchers with clarity in definition, methodology and terminology for biomarker-guided adaptive trial designs. PMID:26910238

Hubble trial: time to stick to basics for treatment of haemorrhoids?

PubMed

Brown, S R

2017-01-01

The results of the Hubble trial, a randomised controlled trial comparing haemorrhoidal artery ligation with rubber band ligation for early-grade prolapsing haemorrhoids, are discussed. The difficulties in defining treatment success are debated along with the trial design highlighting the pitfalls of previous research. A finding that haemorrhoidal artery ligation is not necessarily superior to cheap alternatives has implications for current practice and future commissioning of surgeons.

Future prospects of therapeutic clinical trials in acute myeloid leukemia

PubMed Central

Khan, Maliha; Mansoor, Armaghan-e-Rehman; Kadia, Tapan M

2017-01-01

Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future. PMID:27771959

An Evaluation and Redesign of the Conflict Prediction and Trial Planning Planview Graphical User Interface

NASA Technical Reports Server (NTRS)

Laudeman, Irene V.; Brasil, Connie L.; Stassart, Philippe

1998-01-01

The Planview Graphical User Interface (PGUI) is the primary display of air traffic for the Conflict Prediction and Trial Planning, function of the Center TRACON Automation System. The PGUI displays air traffic information that assists the user in making decisions related to conflict detection, conflict resolution, and traffic flow management. The intent of this document is to outline the human factors issues related to the design of the conflict prediction and trial planning portions of the PGUI, document all human factors related design changes made to the PGUI from December 1996 to September 1997, and outline future plans for the ongoing PGUI design.

Clinical studies in restorative dentistry: New directions and new demands.

PubMed

Opdam, N J M; Collares, K; Hickel, R; Bayne, S C; Loomans, B A; Cenci, M S; Lynch, C D; Correa, M B; Demarco, F; Schwendicke, F; Wilson, N H F

2018-01-01

Clinical research of restorative materials is confounded by problems of study designs, length of trials, type of information collected, and costs for trials, despite increasing numbers and considerable development of trials during the past 50 years. This opinion paper aims to discuss advantages and disadvantages of different study designs and outcomes for evaluating survival of dental restorations and to make recommendations for future study designs. Advantages and disadvantages of randomized trials, prospective and retrospective longitudinal studies, practice-based, pragmatic and cohort studies are addressed and discussed. The recommendations of the paper are that clinical trials should have rational control groups, include confounders such as patient risk factors in the data and analysis and should use outcome parameters relevant for profession and patients. Copyright © 2017 The Academy of Dental Materials. Published by Elsevier Ltd. 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

The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned.

PubMed

Yusen, Roger D; Criner, Gerard J; Sternberg, Alice L; Au, David H; Fuhlbrigge, Anne L; Albert, Richard K; Casaburi, Richard; Stoller, James K; Harrington, Kathleen F; Cooper, J Allen D; Diaz, Philip; Gay, Steven; Kanner, Richard; MacIntyre, Neil; Martinez, Fernando J; Piantadosi, Steven; Sciurba, Frank; Shade, David; Stibolt, Thomas; Tonascia, James; Wise, Robert; Bailey, William C

2018-01-01

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).

New approaches to trials in glomerulonephritis.

PubMed

Craig, Jonathan C; Tong, Allison; Strippoli, Giovanni F M

2017-01-01

Randomized controlled trials are required to reliably identify interventions to improve the outcomes for people with glomerulonephritis (GN). Unfortunately, although easier, observational studies are inherently unreliable even though the findings of both study designs agree most of the time. Currently there are ∼790 trials in GN, but suboptimal design and reporting, together with small sample sizes, mean that they may not be reliable for decision making. If the history is somewhat bleak, the future looks bright, with recent initiatives to improve the quality, size and relevance of clinical trials in nephrology, including greater patient engagement, trial networks, core outcome sets, registry-based trials and adaptive designs. Given the current state of the evidence informing the care of people with GN, disruptive technologies and pervasive culture change is required to ensure that the potential of trials to improve the health of people with this complex condition is to be realized. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Assessing Cognitive Function in Bipolar Disorder: Challenges and Recommendations for Clinical Trial Design

PubMed Central

Burdick, Katherine E.; Ketter, Terence A.; Goldberg, Joseph F.; Calabrese, Joseph R.

2015-01-01

OBJECTIVE Neurocognitive impairment in schizophrenia has been recognized for more than a century. In contrast, only recently have significant neurocognitive deficits been recognized in bipolar disorder. Converging data suggest the importance of cognitive problems in relation to quality of life in bipolar disorder, highlighting the need for treatment and prevention efforts targeting cognition in bipolar patients. Future treatment trials targeting cognitive deficits will be met with methodological challenges due to the inherent complexity and heterogeneity of the disorder, including significant diagnostic comorbidities, the episodic nature of the illness, frequent use of polypharmacy, cognitive heterogeneity, and a lack of consensus regarding measurement of cognition and outcome in bipolar patients. Guidelines for use in designing future trials are needed. PARTICIPANTS The members of the consensus panel (each of the bylined authors) were selected based upon their expertise in bipolar disorder. Dr. Burdick is a neuropsychologist who has studied cognition in this illness for 15 years; Drs. Ketter, Calabrese, and Goldberg each bring considerable expertise in the treatment of bipolar disorder both within and outside of controlled clinical trials. This consensus statement was derived from work together at scientific meetings (e.g. symposium presention at the 2014 Annual meeting of the American Society of Clinical Psychopharmacology, among others) and ongoing discussions by conference call. With the exception of the public presentations on this topic, these meetings were closed to outside participants. EVIDENCE A literature review was undertaken by the authors to identify illness-specific challenges relevant to the design and conduct of treatment trials targeting neurocognition in bipolar disorder. Expert opinion from each of the authors guided the consensus recommendations. CONSENSUS PROCESS Consensus recommendations, reached by unanimous opinion of the authors, are provided here as a preliminary guide for future trial design. Recommendations comprise exclusion of certain syndromal level comorbid diagnoses and current affective instability, restrictions on numbers and types of medications, and use of pre-screening assessment to ensure enrollment of subjects with adequate objective evidence of baseline cognitive impairment. CONCLUSIONS Clinical trials to address cognitive deficits in bipolar disorder face distinctive design challenges. As such trials move from proof-of-concept to confirmation of clinical efficacy, it will be important to incorporate distinctive design modifications to adequately address these challenges and increase the likelihood of demonstrating cognitive remediation effects. The field is now primed to address these challenges and a comprehensive effort to formalize best practice guidelines will be a critically important next step. PMID:25830456

Future vaccination strategies against tuberculosis: thinking outside the box.

PubMed

Kaufmann, Stefan H E

2010-10-29

With almost a dozen vaccine candidates in clinical trials, tuberculosis (TB) research and development is finally reaping the first fruits of its labors. Vaccine candidates in clinical trials may prevent TB disease reactivation by efficiently containing the pathogen Mycobacterium tuberculosis (Mtb). Future research should target vaccines that achieve sterile eradication of Mtb or even prevent stable infection. These are ambitious goals that can be reached only by highly cooperative engagement of basic immunologists, vaccinologists, and clinical researchers--or in other words, by translation from basic immunology to vaccine research and development, as well as reverse translation of insights from clinical trials back to hypothesis-driven research in the basic laboratory. Here, we review current and future strategies toward the rational design of novel vaccines against TB, as well as the progress made thus far, and the hurdles that need to be overcome in the near and distant future. Copyright © 2010 Elsevier Inc. All rights reserved.

Moving the boundaries of international collaboration on clinical trials and QoL: experiences in oncology and legislation within the European Parliament.

PubMed

Bottomley, Andrew; Kirby, Tony; Bean, John; Walker, Julie

2013-02-01

The European Organisation for Research and Treatment of Cancer undertook another successful event with their third annual conference addressing quality of life matters in cancer clinical trials. More than 40 presentations were made over a 3-day period hosted at the European Parliament on 17-20 October 2012, in Brussels. The conference managed to get speakers and policy makers together to debate all the key issues in cancer clinical trials, design and reporting, including future policy and regulatory concerns. This meeting set the stage for future research and policy meetings to give greater visibility to quality of life as an outcome in clinical trials within the world of EU legislators.

Pediatric Cardiovascular Clinical Trials: An Analysis of ClinicalTrials.gov and the Food and Drug Administration Pediatric Drug Labeling Database

PubMed Central

Hill, Kevin D.; Henderson, Heather T.; Hornik, Christoph P.; Li, Jennifer S.

2015-01-01

Recent regulatory initiatives in the United States and Europe have transformed the pediatric clinical trials landscape by significantly increasing capital investment and pediatric trial volume. The purpose of this manuscript is to review the impact of these initiatives on the pediatric cardiovascular trials landscape when compared to other pediatric sub-specialties. We also evaluate factors that may have contributed to the success or failure of recent major pediatric cardiovascular trials so as to inform the optimal design and conduct of future trials in the field. PMID:26377725

Paediatric cardiovascular clinical trials: an analysis of ClinicalTrials.gov and the Food and Drug Administration Pediatric Drug Labeling Database.

PubMed

Hill, Kevin D; Henderson, Heather T; Hornik, Christoph P; Li, Jennifer S

2015-08-01

Recent regulatory initiatives in the United States of America and Europe have transformed the paediatric clinical trials landscape by significantly increasing capital investment and paediatric trial volume. The purpose of this manuscript was to review the impact of these initiatives on the paediatric cardiovascular trials landscape when compared with other paediatric sub-specialties. We also evaluate factors that may have contributed to the success or failure of recent major paediatric cardiovascular trials so as to inform the optimal design and conduct of future trials in the field.

Group sequential designs for stepped-wedge cluster randomised trials.

PubMed

Grayling, Michael J; Wason, James Ms; Mander, Adrian P

2017-10-01

The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs. Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored. We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial's type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate. The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped-wedge cluster randomised trials according to the needs of the particular trial.

Cross-System Evaluation of Clinical Trial Search Engines

PubMed Central

Jiang, Silis Y.; Weng, Chunhua

2014-01-01

Clinical trials are fundamental to the advancement of medicine but constantly face recruitment difficulties. Various clinical trial search engines have been designed to help health consumers identify trials for which they may be eligible. Unfortunately, knowledge of the usefulness and usability of their designs remains scarce. In this study, we used mixed methods, including time-motion analysis, think-aloud protocol, and survey, to evaluate five popular clinical trial search engines with 11 users. Differences in user preferences and time spent on each system were observed and correlated with user characteristics. In general, searching for applicable trials using these systems is a cognitively demanding task. Our results show that user perceptions of these systems are multifactorial. The survey indicated eTACTS being the generally preferred system, but this finding did not persist among all mixed methods. This study confirms the value of mixed-methods for a comprehensive system evaluation. Future system designers must be aware that different users groups expect different functionalities. PMID:25954590

Cross-system evaluation of clinical trial search engines.

PubMed

Jiang, Silis Y; Weng, Chunhua

2014-01-01

Clinical trials are fundamental to the advancement of medicine but constantly face recruitment difficulties. Various clinical trial search engines have been designed to help health consumers identify trials for which they may be eligible. Unfortunately, knowledge of the usefulness and usability of their designs remains scarce. In this study, we used mixed methods, including time-motion analysis, think-aloud protocol, and survey, to evaluate five popular clinical trial search engines with 11 users. Differences in user preferences and time spent on each system were observed and correlated with user characteristics. In general, searching for applicable trials using these systems is a cognitively demanding task. Our results show that user perceptions of these systems are multifactorial. The survey indicated eTACTS being the generally preferred system, but this finding did not persist among all mixed methods. This study confirms the value of mixed-methods for a comprehensive system evaluation. Future system designers must be aware that different users groups expect different functionalities.

Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

PubMed Central

Bogaerts, Jan; Sydes, Matthew R.; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M.; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J.; Law, Kate; Trimble, Ted; Seymour, Matthew

2015-01-01

Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. PMID:25542058

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

PubMed

Bogaerts, Jan; Sydes, Matthew R; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J; Law, Kate; Trimble, Ted; Seymour, Matthew

2015-02-01

The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Immune-directed therapy for type 1 diabetes at the clinical level: the Immune Tolerance Network (ITN) experience.

PubMed

Ehlers, Mario R; Nepom, Gerald T

2012-01-01

Reestablishing immune tolerance in type 1 diabetes (T1D), a chronic autoimmune disease, is a major goal. The Immune Tolerance Network (ITN) has initiated eight clinical trials of immunomodulatory therapies in recent-onset T1D over the past decade. Results have been mixed in terms of clinical efficacy, but the studies have provided valuable mechanistic insight that are enhancing our understanding of the disease and guiding the design of future trials. Trials of non-Fc-binding anti-CD3 mAbs have revealed that modulation of this target leads to partial responses, and ITN's AbATE trial led to identification of a robust responder group that could be distinguished from non-responders by baseline metabolic and immunologic features. A pilot study of the combination of IL-2 and rapamycin gave the first demonstration that frequency and function of regulatory T cells (Tregs) can be enhanced in T1D subjects, although the therapy triggered the activation of effectors with transient β-cell dysfunction. Similarly, therapy with anti-thymocyte globulin led to substantial lymphocyte depletion, but also to the activation of the acute-phase response with no clinical benefit during preliminary analyses. These and other results provide mechanistic tools that can be used as biomarkers for safety and efficacy in future trials. Furthermore, our results, together with those of other organizations, notably TrialNet, delineate the roles of the major components of the immune response in T1D. This information is setting the stage for future combination therapy trials. The development of disease-relevant biomarkers will also enable the implementation of innovative trial designs, notably adaptive trials, which will increase efficiencies in terms of study duration and sample size, and which will expedite the conduct of trials in which there are uncertainties about dose response and effect size.

Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study

PubMed Central

Luce, Bryan R; Broglio, Kristine R; Ishak, K Jack; Mullins, C Daniel; Vanness, David J; Fleurence, Rachael; Saunders, Elijah; Davis, Barry R

2013-01-01

Background Randomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making. Purpose Our prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE-ADAPT) study is a ‘proof of concept’ to stimulate investment in Bayesian adaptive designs for future CER trials. Methods We will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT. Results We prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information-based adaptive randomization. Limitations While the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes. Conclusion This article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data. PMID:23983160

Testing for carryover effects after cessation of treatments: a design approach.

PubMed

Sturdevant, S Gwynn; Lumley, Thomas

2016-08-02

Recently, trials addressing noisy measurements with diagnosis occurring by exceeding thresholds (such as diabetes and hypertension) have been published which attempt to measure carryover - the impact that treatment has on an outcome after cessation. The design of these trials has been criticised and simulations have been conducted which suggest that the parallel-designs used are not adequate to test this hypothesis; two solutions are that either a differing parallel-design or a cross-over design could allow for diagnosis of carryover. We undertook a systematic simulation study to determine the ability of a cross-over or a parallel-group trial design to detect carryover effects on incident hypertension in a population with prehypertension. We simulated blood pressure and focused on varying criteria to diagnose systolic hypertension. Using the difference in cumulative incidence hypertension to analyse parallel-group or cross-over trials resulted in none of the designs having acceptable Type I error rate. Under the null hypothesis of no carryover the difference is well above the nominal 5 % error rate. When a treatment is effective during the intervention period, reliable testing for a carryover effect is difficult. Neither parallel-group nor cross-over designs using the difference in cumulative incidence appear to be a feasible approach. Future trials should ensure their design and analysis is validated by simulation.

Group sequential designs for stepped-wedge cluster randomised trials

PubMed Central

Grayling, Michael J; Wason, James MS; Mander, Adrian P

2017-01-01

Background/Aims: The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs. Methods: Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored. Results: We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial’s type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate. Conclusion: The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped-wedge cluster randomised trials according to the needs of the particular trial. PMID:28653550

Translating Stem Cell Research to Cardiac Disease Therapies: Pitfalls and Prospects for Improvement

PubMed Central

Rosen, Michael R.; Myerburg, Robert J.; Francis, Darrel P.; Cole, Graham D.; Marbán, Eduardo

2014-01-01

Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of articles focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. The first section by Rosen and Myerburg is an independent review that analyzes the basic science and translational strategies supporting the rapid advance of stem cell technology to the clinic, the philosophies behind them, trial designs, and means for going forward that may impact favorably on progress. The second and third sections were collected in response to the initial section of this review. The commentary by Francis and Cole discusses the Rosen and Myerburg review and details how trial outcomes can be affected by noise, poor trial design (particularly the absence of blinding), and normal human tendencies toward optimism and denial. The final, independent article by Marbán takes a different perspective concerning the potential for positive impact of stem cell research applied to heart disease and future prospects for its clinical application. PMID:25169179

Mesh fixation in endoscopic inguinal hernia repair: evaluation of methodology based on a systematic review of randomised clinical trials.

PubMed

Lederhuber, Hans; Stiede, Franziska; Axer, Stephan; Dahlstrand, Ursula

2017-11-01

The issue of mesh fixation in endoscopic inguinal hernia repair is frequently debated and still no conclusive data exist on differences between methods regarding long-term outcome and postoperative complications. The quantity of trials and the simultaneous lack of high-quality evidence raise the question how future trials should be planned. PubMed, EMBASE and the Cochrane Library were searched, using the filters "randomised clinical trials" and "humans". Trials that compared one method of mesh fixation with another fixation method or with non-fixation in endoscopic inguinal hernia repair were eligible. To be included, the trial was required to have assessed at least one of the following primary outcome parameters: recurrence; surgical site infection; chronic pain; or quality-of-life. Fourteen trials assessing 2161 patients and 2562 hernia repairs were included. Only two trials were rated as low risk for bias. Eight trials evaluated recurrence or surgical site infection; none of these could show significant differences between methods of fixation. Two of 11 trials assessing chronic pain described significant differences between methods of fixation. One of two trials evaluating quality-of-life showed significant differences between fixation methods in certain functions. High-quality evidence for differences between the assessed mesh fixation techniques is still lacking. From a socioeconomic and ethical point of view, it is necessary that future trials will be properly designed. As small- and medium-sized single-centre trials have proven unable to find answers, register studies or multi-centre studies with an evident focus on methodology and study design are needed in order to answer questions about mesh fixation in inguinal hernia repair.

Mental Health Smartphone Apps: Review and Evidence-Based Recommendations for Future Developments.

PubMed

Bakker, David; Kazantzis, Nikolaos; Rickwood, Debra; Rickard, Nikki

2016-03-01

The number of mental health apps (MHapps) developed and now available to smartphone users has increased in recent years. MHapps and other technology-based solutions have the potential to play an important part in the future of mental health care; however, there is no single guide for the development of evidence-based MHapps. Many currently available MHapps lack features that would greatly improve their functionality, or include features that are not optimized. Furthermore, MHapp developers rarely conduct or publish trial-based experimental validation of their apps. Indeed, a previous systematic review revealed a complete lack of trial-based evidence for many of the hundreds of MHapps available. To guide future MHapp development, a set of clear, practical, evidence-based recommendations is presented for MHapp developers to create better, more rigorous apps. A literature review was conducted, scrutinizing research across diverse fields, including mental health interventions, preventative health, mobile health, and mobile app design. Sixteen recommendations were formulated. Evidence for each recommendation is discussed, and guidance on how these recommendations might be integrated into the overall design of an MHapp is offered. Each recommendation is rated on the basis of the strength of associated evidence. It is important to design an MHapp using a behavioral plan and interactive framework that encourages the user to engage with the app; thus, it may not be possible to incorporate all 16 recommendations into a single MHapp. Randomized controlled trials are required to validate future MHapps and the principles upon which they are designed, and to further investigate the recommendations presented in this review. Effective MHapps are required to help prevent mental health problems and to ease the burden on health systems.

Mental Health Smartphone Apps: Review and Evidence-Based Recommendations for Future Developments

PubMed Central

Kazantzis, Nikolaos; Rickwood, Debra; Rickard, Nikki

2016-01-01

Background The number of mental health apps (MHapps) developed and now available to smartphone users has increased in recent years. MHapps and other technology-based solutions have the potential to play an important part in the future of mental health care; however, there is no single guide for the development of evidence-based MHapps. Many currently available MHapps lack features that would greatly improve their functionality, or include features that are not optimized. Furthermore, MHapp developers rarely conduct or publish trial-based experimental validation of their apps. Indeed, a previous systematic review revealed a complete lack of trial-based evidence for many of the hundreds of MHapps available. Objective To guide future MHapp development, a set of clear, practical, evidence-based recommendations is presented for MHapp developers to create better, more rigorous apps. Methods A literature review was conducted, scrutinizing research across diverse fields, including mental health interventions, preventative health, mobile health, and mobile app design. Results Sixteen recommendations were formulated. Evidence for each recommendation is discussed, and guidance on how these recommendations might be integrated into the overall design of an MHapp is offered. Each recommendation is rated on the basis of the strength of associated evidence. It is important to design an MHapp using a behavioral plan and interactive framework that encourages the user to engage with the app; thus, it may not be possible to incorporate all 16 recommendations into a single MHapp. Conclusions Randomized controlled trials are required to validate future MHapps and the principles upon which they are designed, and to further investigate the recommendations presented in this review. Effective MHapps are required to help prevent mental health problems and to ease the burden on health systems. PMID:26932350

A Method for Analyzing Commonalities in Clinical Trial Target Populations

PubMed Central

He, Zhe; Carini, Simona; Hao, Tianyong; Sim, Ida; Weng, Chunhua

2014-01-01

ClinicalTrials.gov presents great opportunities for analyzing commonalities in clinical trial target populations to facilitate knowledge reuse when designing eligibility criteria of future trials or to reveal potential systematic biases in selecting population subgroups for clinical research. Towards this goal, this paper presents a novel data resource for enabling such analyses. Our method includes two parts: (1) parsing and indexing eligibility criteria text; and (2) mining common eligibility features and attributes of common numeric features (e.g., A1c). We designed and built a database called “Commonalities in Target Populations of Clinical Trials” (COMPACT), which stores structured eligibility criteria and trial metadata in a readily computable format. We illustrate its use in an example analytic module called CONECT using COMPACT as the backend. Type 2 diabetes is used as an example to analyze commonalities in the target populations of 4,493 clinical trials on this disease. PMID:25954450

Involving seldom-heard groups in a PPI process to inform the design of a proposed trial on the use of probiotics to prevent preterm birth: a case study.

PubMed

Rayment, Juliet; Lanlehin, Rosemary; McCourt, Christine; Husain, Shahid M

2017-01-01

When designing clinical trials it is important to involve members of the public, who can provide a view on what may encourage or prevent people participating and on what matters to them. This is known as Public and Patient Involvement (PPI). People from minority ethnic groups are often less likely to take part in clinical trials, but it is important to ensure they are able to participate fully so that health research and its findings are relevant to a wide population. We are preparing to conduct a randomised controlled trial (RCT) to test whether taking probiotic capsules can play a role in preventing preterm birth. Women from some minority ethnic groups, for example women from West Africa, and those who are from low-income groups are more likely to suffer preterm births. Preterm birth can lead to extra costs to health services and psychosocial costs for families. In this article we describe how we engaged women in discussion about the design of the planned trial, and how we aim to use our findings to ensure the trial is workable and beneficial to women, as well as to further engage service users in the future development of the trial. Four socially and ethnically diverse groups of women in East London took part in discussions about the trial and contributed their ideas and concerns. These discussions have helped to inform and improve the design of a small practice or 'pilot' trial to test the recruitment in a 'real life' setting, as well as encourage further PPI involvement for the future full-scale trial. Background Patient and public involvement (PPI) is an important tool in approaching research challenges. However, involvement of socially and ethnically diverse populations remains limited and practitioners need effective methods of involving a broad section of the population in planning and designing research. Methods In preparation for the development of a pilot randomised controlled trial (RCT) on the use of probiotics to prevent preterm birth, we conducted a public consultation exercise in a socially disadvantaged and ethnically diverse community. The consultation aimed to meet and engage local service users in considering the acceptability of the proposed protocol, and to encourage their participation in future and ongoing patient and public involvement activities. Four discussion groups were held in the community with mothers of young children within the proposed trial region, using an inclusive approach that incorporated a modified version of the Nominal Group Technique (NGT). Bringing the consultation to the community supported the involvement of often seldom-heard participants, such as those from minority ethnic groups. Results The women involved expressed a number of concerns about the proposed protocol, including adherence to the probiotic supplement regimen and randomisation. The proposal for the RCT in itself was perceived as confirmation that probiotic supplements had potentially beneficial effects, but also that they had potentially harmful side-effects. The complexity of the women's responses provided greater insights into the challenges of even quite simple trial designs and enabled the research team to take these concerns into account while planning the pilot trial. Conclusions The use of the NGT method allowed for a consultation of a population traditionally less likely to participate in medical research. A carefully facilitated PPI exercise can allow members to express unanticipated concerns that may not have been elicited by a survey method. Findings from such exercises can be utilised to improve clinical trial design, provide insight into the feasibility of trials, and enable engagement of often excluded population groups.

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

PubMed

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

2018-02-08

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

The Correction of Myopia Evaluation Trial: lessons from the study design.

PubMed

Hyman, L; Gwiazda, J

2004-01-01

The Correction of Myopia Evaluation Trial (COMET), a multicentre clinical trial based in 4 schools of optometry in the United States, evaluated the effect of progressive addition lenses versus single vision lenses on myopia progression in an ethnically diverse group of 469 myopic children aged 6 to 11 years. Completion of the clinical trial phase of the study provides an opportunity to evaluate aspects of the study design that contribute to its success. This article describes aspects of the study design that were influential in ensuring the smooth conduct of COMET. These include a dedicated team of investigators, an organisational structure with strong leadership and an independent Co-ordinating Centre, regular communication among investigators, flexible and creative approaches to recruitment and retention, sensitivity to concerns for child safety and child participation, and methods for enhancing and monitoring data reliability. The experience with COMET has provided a number of valuable lessons for all aspects of the study design that should benefit the development and implementation of future clinical trials, particularly those done in similar populations of children. The use of a carefully designed protocol using standard methods by dedicated members of the study team is essential in ensuring achievement of the study aims.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

Improving recruitment to pharmacological trials for illicit opioid use: findings from a qualitative focus group study

PubMed Central

Tompkins, Charlotte N. E.; McDonald, Rebecca; Strang, John

2018-01-01

Abstract Aim To explore potential study participants’ views on willingness to join clinical trials of pharmacological interventions for illicit opioid use to inform and improve future recruitment strategies. Design Qualitative focus group study [six groups: oral methadone (two groups); buprenorphine tablets (two groups); injectable opioid agonist treatment (one group); and former opioid agonist treatment (one group)]. Settings Drug and alcohol services and a peer support recovery service (London, UK). Participants Forty people with experience of opioid agonist treatment for heroin dependence (26 males, 14 females; aged 33–66 years). Measurements Data collection was facilitated by a topic guide that explored willingness to enrol in clinical pharmacological trials. Groups were audio‐recorded and transcribed. Transcribed data were analysed inductively via Iterative Categorization. Findings Participants’ willingness to join pharmacological trials of medications for opioid dependence was affected by factors relating to study burden, study drug, study design, study population and study relationships. Participants worried that the trial drug might be worse than, or interfere with, their current treatment. They also misunderstood aspects of trial design despite the researchers’ explanations. Conclusions Recruitment of participants for clinical trials of pharmacological interventions for illicit opioid use could be improved if researchers became better at explaining clinical trials to potential participants, dispelling misconceptions about trials and increasing trust in the research process and research establishment. A checklist of issues to consider when designing pharmacological trials for illicit opioid use is proposed. PMID:29356208

Multiple System Atrophy

MedlinePlus

... which can be expected to aid in the design of future trials. Additionally, MSA is one of ... Outcomes Data Training & Career Development High School, Undergraduate, & Post-Baccalaureate Predoctoral Fellows Postdoctoral Fellows Clinician-Scientists Faculty ...

Multisite effectiveness trials of treatments for substance abuse and co-occurring problems: have we chosen the best designs?

PubMed

Nunes, Edward V; Ball, Samuel; Booth, Robert; Brigham, Gregory; Calsyn, Donald A; Carroll, Kathleen; Feaster, Daniel J; Hien, Denise; Hubbard, Robert L; Ling, Walter; Petry, Nancy M; Rotrosen, John; Selzer, Jeffrey; Stitzer, Maxine; Tross, Susan; Wakim, Paul; Winhusen, Theresa; Woody, George

2010-06-01

Multisite effectiveness trials such as those carried out in the National Drug Abuse Treatment Clinical Trials Network (CTN) are a critical step in the development and dissemination of evidence-based treatments because they address how such treatments perform in real-world clinical settings. As Brigham et al. summarized in a recent article (G. S. Brigham, D. J. Feaster, P. G. Wakim, & C. L. Dempsey C. L., 2009), several possible experimental designs may be chosen for such effectiveness trials. These include (a) a new treatment intervention (Tx) is compared to an existing mode of community based treatment as usual (TAU): Tx versus TAU; (b) a new intervention is added to TAU and compared to TAU alone: Tx + TAU versus TAU; or (c) a new intervention is added to TAU and compared to a control condition added to TAU: Tx + TAU versus control + TAU. Each of these designs addresses a different question and has different potential strengths and weaknesses. As of December 2009, the primary outcome paper had been published for 16 of the multisite randomized clinical trials conducted in the CTN, testing various treatments for drug abuse, HIV risk behavior, or related problems. This paper systematically examines, for each of the completed trials, the experimental design type chosen and its original rationale, the main findings of the trial, and the strengths and weaknesses of the design in hindsight. Based on this review, recommendations are generated to inform the design of future effectiveness trials on treatments for substance abuse, HIV risk, and other behavioral health problems.

Framing the conversation: use of PRECIS-2 ratings to advance understanding of pragmatic trial design domains.

PubMed

Lipman, Paula Darby; Loudon, Kirsty; Dluzak, Leanora; Moloney, Rachael; Messner, Donna; Stoney, Catherine M

2017-11-10

There continues to be debate about what constitutes a pragmatic trial and how it is distinguished from more traditional explanatory trials. The NIH Pragmatic Trials Collaborative Project, which includes five trials and a coordinating unit, has adopted the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) instrument. The purpose of the study was to collect PRECIS-2 ratings at two points in time to assess whether the tool was sensitive to change in trial design, and to explore with investigators the rationale for rating shifts. A mixed-methods design included sequential collection and analysis of quantitative data (PRECIS-2 ratings) and qualitative data. Ratings were collected at two annual, in-person project meetings, and subsequent interviews conducted with investigators were recorded, transcribed, and coded using NVivo 11 Pro for Windows. Rating shifts were coded as either (1) actual change (reflects a change in procedure or protocol), (2) primarily a rating shift reflecting rater variability, or (3) themes that reflect important concepts about the tool and/or pragmatic trial design. Based on PRECIS-2 ratings, each trial was highly pragmatic at the planning phase and remained so 1 year later in the early phases of trial implementation. Over half of the 45 paired ratings for the nine PRECIS-2 domains indicated a rating change from Time 1 to Time 2 (N = 24, 53%). Of the 24 rating changes, only three represented a true change in the design of the trial. Analysis of rationales for rating shifts identified critical themes associated with the tool or pragmatic trial design more generally. Each trial contributed one or more relevant comments, with Eligibility, Flexibility of Adherence, and Follow-up each accounting for more than one. PRECIS-2 has proved useful for "framing the conversation" about trial design among members of the Pragmatic Trials Collaborative Project. Our findings suggest that design elements assessed by the PRECIS-2 tool may represent mostly stable decisions. Overall, there has been a positive response to using PRECIS-2 to guide conversations around trial design, and the project's focus on the use of the tool by this group of early adopters has provided valuable feedback to inform future trainings on the tool.

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.

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.

Design and challenges for a randomized, multi-site clinical trial comparing the use of service dogs and emotional support dogs in Veterans with post-traumatic stress disorder (PTSD).

PubMed

Saunders, Gabrielle H; Biswas, Kousick; Serpi, Tracey; McGovern, Stephanie; Groer, Shirley; Stock, Eileen M; Magruder, Kathryn M; Storzbach, Daniel; Skelton, Kelly; Abrams, Thad; McCranie, Mark; Richerson, Joan; Dorn, Patricia A; Huang, Grant D; Fallon, Michael T

2017-11-01

Posttraumatic stress disorder (PTSD) is a leading cause of impairments in quality of life and functioning among Veterans. Service dogs have been promoted as an effective adjunctive intervention for PTSD, however published research is limited and design and implementation flaws in published studies limit validated conclusions. This paper describes the rationale for the study design, a detailed methodological description, and implementation challenges of a multisite randomized clinical trial examining the impact of service dogs on the on the functioning and quality of life of Veterans with PTSD. Trial design considerations prioritized participant and intervention (dog) safety, selection of an intervention comparison group that would optimize enrollment in all treatment arms, pragmatic methods to ensure healthy well-trained dogs, and the selection of outcomes for achieving scientific and clinical validity in a Veteran PTSD population. Since there is no blueprint for conducting a randomized clinical trial examining the impact of dogs on PTSD of this size and scope, it is our primary intent that the successful completion of this trial will set a benchmark for future trial design and scientific rigor, as well as guiding researchers aiming to better understand the role that dogs can have in the management of Veterans experiencing mental health conditions such as PTSD. Published by Elsevier Inc.

Impact of the Patient-Reported Outcomes Management Information System (PROMIS) upon the design and operation of multi-center clinical trials: a qualitative research study.

PubMed

Eisenstein, Eric L; Diener, Lawrence W; Nahm, Meredith; Weinfurt, Kevin P

2011-12-01

New technologies may be required to integrate the National Institutes of Health's Patient Reported Outcome Management Information System (PROMIS) into multi-center clinical trials. To better understand this need, we identified likely PROMIS reporting formats, developed a multi-center clinical trial process model, and identified gaps between current capabilities and those necessary for PROMIS. These results were evaluated by key trial constituencies. Issues reported by principal investigators fell into two categories: acceptance by key regulators and the scientific community, and usability for researchers and clinicians. Issues reported by the coordinating center, participating sites, and study subjects were those faced when integrating new technologies into existing clinical trial systems. We then defined elements of a PROMIS Tool Kit required for integrating PROMIS into a multi-center clinical trial environment. The requirements identified in this study serve as a framework for future investigators in the design, development, implementation, and operation of PROMIS Tool Kit technologies.

Early phase clinical trials with human immunodeficiency virus-1 and malaria vectored vaccines in The Gambia: frontline challenges in study design and implementation.

PubMed

Afolabi, Muhammed O; Adetifa, Jane U; Imoukhuede, Egeruan B; Viebig, Nicola K; Kampmann, Beate; Bojang, Kalifa

2014-05-01

Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria are among the most important infectious diseases in developing countries. Existing control strategies are unlikely to curtail these diseases in the absence of efficacious vaccines. Testing of HIV and malaria vaccines candidates start with early phase trials that are increasingly being conducted in developing countries where the burden of the diseases is high. Unique challenges, which affect planning and implementation of vaccine trials according to internationally accepted standards have thus been identified. In this review, we highlight specific challenges encountered during two early phase trials of novel HIV-1 and malaria vectored vaccine candidates conducted in The Gambia and how some of these issues were pragmatically addressed. We hope our experience will be useful for key study personnel involved in day-to-day running of similar clinical trials. It may also guide future design and implementation of vaccine trials in resource-constrained settings.

Impact of the Patient-Reported Outcomes Management Information System (PROMIS) upon the Design and Operation of Multi-center Clinical Trials: a Qualitative Research Study

PubMed Central

Diener, Lawrence W.; Nahm, Meredith; Weinfurt, Kevin P.

2013-01-01

New technologies may be required to integrate the National Institutes of Health’s Patient Reported Outcome Management Information System (PROMIS) into multi-center clinical trials. To better understand this need, we identified likely PROMIS reporting formats, developed a multi-center clinical trial process model, and identified gaps between current capabilities and those necessary for PROMIS. These results were evaluated by key trial constituencies. Issues reported by principal investigators fell into two categories: acceptance by key regulators and the scientific community, and usability for researchers and clinicians. Issues reported by the coordinating center, participating sites, and study subjects were those faced when integrating new technologies into existing clinical trial systems. We then defined elements of a PROMIS Tool Kit required for integrating PROMIS into a multi-center clinical trial environment. The requirements identified in this study serve as a framework for future investigators in the design, development, implementation, and operation of PROMIS Tool Kit technologies. PMID:20703765

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations

PubMed Central

Butler, Javed; Hamo, Carine E.; Udelson, James E.; O’Connor, Christopher; Sabbah, Hani N.; Metra, Marco; Shah, Sanjiv J.; Kitzman, Dalane W.; Teerlink, John; Bernstein, Harold S.; Brooks, Gabriel; Depre, Christophe; DeSouza, Mary M.; Dinh, Wilfried; Donovan, Mark; Frische-Danielson, Regina; Frost, Robert J.; Garza, Dahlia; Gohring, Udo-Michael; Hellawell, Jennifer; Hsia, Judith; Ishihara, Shiro; Kay-Mugford, Patricia; Koglin, Joerg; Kozinn, Marc; Larson, Christopher J.; Mayo, Martha; Gan, Li-Ming; Mugnier, Pierrre; Mushonga, Sekayi; Roessig, Lothar; Russo, Cesare; Salsali, Afshin; Satler, Carol; Shi, Victor; Ticho, Barry; van der Laan, Michael; Yancy, Clyde; Stockbridge, Norman; Gheorghiade, Mihai

2017-01-01

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue regarding the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17th 2016 represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions. PMID:28356300

New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

PubMed Central

Senni, Michele; Paulus, Walter J.; Gavazzi, Antonello; Fraser, Alan G.; Díez, Javier; Solomon, Scott D.; Smiseth, Otto A.; Guazzi, Marco; Lam, Carolyn S. P.; Maggioni, Aldo P.; Tschöpe, Carsten; Metra, Marco; Hummel, Scott L.; Edelmann, Frank; Ambrosio, Giuseppe; Stewart Coats, Andrew J.; Filippatos, Gerasimos S.; Gheorghiade, Mihai; Anker, Stefan D.; Levy, Daniel; Pfeffer, Marc A.; Stough, Wendy Gattis; Pieske, Burkert M.

2014-01-01

The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed. PMID:25104786

Methodological issues associated with clinical trials in epilepsy.

PubMed

Ferlazzo, Edoardo; Sueri, Chiara; Gasparini, Sara; Russo, Emilio; Cianci, Vittoria; Ascoli, Michele; De Sarro, Giovambattista; Aguglia, Umberto

2017-10-01

despite methodological advances in epilepsy clinical trials, the proportion of patients reaching seizure-freedom has not substantially changed over the years. We review the main methodological limitations of current trials, the possible strategies to overcome these limits, and the issues that need to be addressed in next future. Area covered: references were identified by PubMed search until March 2017 and unpublished literature was searched on ClinicalTrials.gov. Add-on trials mainly involve refractory epilepsy subjects, reducing overall response to the investigational drug. The inclusion of subjects with earlier disease from less developed countries has partially allowed overcoming this limitation, but has introduced more random variability of results. Monotherapy trials rise methodological, economical, and ethical concerns with different regulatory requirements in European Union and in the United States of America. Newer trial designs, such as futility trials or 'time-to-event' design, have been implemented. Moreover, both add-on and monotherapy trials results might be affected by patient's ability to recognize and record seizures, and by randomness of seizures occurrence over time. Possible strategies to achieve more reliable outcomes are detailed. Expert commentary: clinical trial methodology needs to be optimized to better address regulatory agencies requirements and to encounter both patients' and clinicians' needs.

Lessons for Successful Study Enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

PubMed Central

Crowley, Susan T.; Chertow, Glenn M.; Vitale, Joseph; O'Connor, Theresa; Zhang, Jane; Schein, Roland M.H.; Choudhury, Devasmita; Finkel, Kevin; Vijayan, Anitha; Paganini, Emil; Palevsky, Paul M.

2008-01-01

Background and objectives: Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. Design, setting, participants, & measurements: Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. Results: 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. Conclusions: The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury. PMID:18385390

Critical Questions about PARADIGM-HF and the Future

PubMed Central

Chen, Chen-Huan

2016-01-01

Cardiovascular (CV) diseases in general and heart failure (HF) in particular are major contributors to death and morbidity and are also recognized as important drivers of health care expenditure. The PARADIGM-HF trial was a pivotal trial designed to compare the long-term effects of LCZ696 with enalapril in patients with symptomatic HF with reduced ejection fraction (HFrEF). This review article presents an in-depth view of the PARADIGM-HF trial and the implications of the results in the management of patients with HF and is based on peer reviewed manuscripts, editorials, perspectives and opinions written about the PARADIGM-HF trial. The article presents the key safety and efficacy results of the trial with specific emphasis on the clinical implications of these findings. The review highlights the highly statistically significant, 20% reduction in the primary composite endpoint of cardiovascular death or HF hospitalization, and a 16% reduction in the risk of death from any cause. It also provides an overview of the design, clinical findings, limitations and special areas of clinical interest. The review discusses the future of LCZ696 and additional trials that seek to answer questions in other sub-populations of patients with HF. The article reiterates what has been concluded by many experts in the field of HF- the introduction of LCZ696 into routine clinical care, while dependent on the regulatory approvals in various countries as well as acceptance by physicians, payers and patients, will change the treatment landscape for patients with HFrEF. PMID:27471351

The Importance and Role of Intracluster Correlations in Planning Cluster Trials

PubMed Central

Preisser, John S.; Reboussin, Beth A.; Song, Eun-Young; Wolfson, Mark

2008-01-01

There is increasing recognition of the critical role of intracluster correlations of health behavior outcomes in cluster intervention trials. This study examines the estimation, reporting, and use of intracluster correlations in planning cluster trials. We use an estimating equations approach to estimate the intracluster correlations corresponding to the multiple-time-point nested cross-sectional design. Sample size formulae incorporating 2 types of intracluster correlations are examined for the purpose of planning future trials. The traditional intracluster correlation is the correlation among individuals within the same community at a specific time point. A second type is the correlation among individuals within the same community at different time points. For a “time × condition” analysis of a pretest–posttest nested cross-sectional trial design, we show that statistical power considerations based upon a posttest-only design generally are not an adequate substitute for sample size calculations that incorporate both types of intracluster correlations. Estimation, reporting, and use of intracluster correlations are illustrated for several dichotomous measures related to underage drinking collected as part of a large nonrandomized trial to enforce underage drinking laws in the United States from 1998 to 2004. PMID:17879427

Vibrating vaginal balls to improve pelvic floor muscle performance in women after childbirth: a protocol for a randomised controlled feasibility trial.

PubMed

Oblasser, Claudia; McCourt, Christine; Hanzal, Engelbert; Christie, Janice

2016-04-01

This paper presents a feasibility trial protocol the purpose of which is to prepare for a future randomised controlled trial to determine the effectiveness of vibrating vaginal pelvic floor training balls for postpartum pelvic floor muscle rehabilitation. Vibrating vaginal pelvic floor training balls are available in Austria to enhance women's pelvic floor muscles and thus prevent or treat urinary incontinence and other pelvic floor problems following childbirth. Nonetheless, there is currently little empirical knowledge to substantiate their use or assess their relative effectiveness in comparison to current standard care, which involves pelvic floor muscle exercises. Single blind, randomised controlled feasibility trial with two parallel groups. It is planned to recruit 56 postpartum women in Vienna, who will be randomised into one of two intervention groups to use either vibrating vaginal balls or a comparator pelvic floor muscle exercises for 12 weeks. As this is a feasibility study, study design features (recruitment, selection, randomisation, intervention concordance, data collection methods and tools) will be assessed and participants' views and experiences will be surveyed. Tested outcome measures, collected before and after the intervention, will be pelvic floor muscle performance as reported by participants and measured by perineometry. Descriptive and inferential statistics and content analysis will serve the preparation of the future trial. The results of this feasibility trial will inform the design and conduct of a full randomised controlled trial and provide insight into the experiences of women regarding the interventions and study participation. © 2015 John Wiley & Sons Ltd.

Preliminary evaluation of factors associated with premature trial closure and feasibility of accrual benchmarks in phase III oncology trials.

PubMed

Schroen, Anneke T; Petroni, Gina R; Wang, Hongkun; Gray, Robert; Wang, Xiaofei F; Cronin, Walter; Sargent, Daniel J; Benedetti, Jacqueline; Wickerham, Donald L; Djulbegovic, Benjamin; Slingluff, Craig L

2010-08-01

A major challenge for randomized phase III oncology trials is the frequent low rates of patient enrollment, resulting in high rates of premature closure due to insufficient accrual. We conducted a pilot study to determine the extent of trial closure due to poor accrual, feasibility of identifying trial factors associated with sufficient accrual, impact of redesign strategies on trial accrual, and accrual benchmarks designating high failure risk in the clinical trials cooperative group (CTCG) setting. A subset of phase III trials opened by five CTCGs between August 1991 and March 2004 was evaluated. Design elements, experimental agents, redesign strategies, and pretrial accrual assessment supporting accrual predictions were abstracted from CTCG documents. Percent actual/predicted accrual rate averaged per month was calculated. Trials were categorized as having sufficient or insufficient accrual based on reason for trial termination. Analyses included univariate and bivariate summaries to identify potential trial factors associated with accrual sufficiency. Among 40 trials from one CTCG, 21 (52.5%) trials closed due to insufficient accrual. In 82 trials from five CTCGs, therapeutic trials accrued sufficiently more often than nontherapeutic trials (59% vs 27%, p = 0.05). Trials including pretrial accrual assessment more often achieved sufficient accrual than those without (67% vs 47%, p = 0.08). Fewer exclusion criteria, shorter consent forms, other CTCG participation, and trial design simplicity were not associated with achieving sufficient accrual. Trials accruing at a rate much lower than predicted (<35% actual/predicted accrual rate) were consistently closed due to insufficient accrual. This trial subset under-represents certain experimental modalities. Data sources do not allow accounting for all factors potentially related to accrual success. Trial closure due to insufficient accrual is common. Certain trial design factors appear associated with attaining sufficient accrual. Defining accrual benchmarks for early trial termination or redesign is feasible, but better accrual prediction methods are critically needed. Future studies should focus on identifying trial factors that allow more accurate accrual predictions and strategies that can salvage open trials experiencing slow accrual.

Preliminary evaluation of factors associated with premature trial closure and feasibility of accrual benchmarks in phase III oncology trials

PubMed Central

Schroen, Anneke T; Petroni, Gina R; Wang, Hongkun; Gray, Robert; Wang, Xiaofei F; Cronin, Walter; Sargent, Daniel J; Benedetti, Jacqueline; Wickerham, Donald L; Djulbegovic, Benjamin; Slingluff, Craig L

2014-01-01

Background A major challenge for randomized phase III oncology trials is the frequent low rates of patient enrollment, resulting in high rates of premature closure due to insufficient accrual. Purpose We conducted a pilot study to determine the extent of trial closure due to poor accrual, feasibility of identifying trial factors associated with sufficient accrual, impact of redesign strategies on trial accrual, and accrual benchmarks designating high failure risk in the clinical trials cooperative group (CTCG) setting. Methods A subset of phase III trials opened by five CTCGs between August 1991 and March 2004 was evaluated. Design elements, experimental agents, redesign strategies, and pretrial accrual assessment supporting accrual predictions were abstracted from CTCG documents. Percent actual/predicted accrual rate averaged per month was calculated. Trials were categorized as having sufficient or insufficient accrual based on reason for trial termination. Analyses included univariate and bivariate summaries to identify potential trial factors associated with accrual sufficiency. Results Among 40 trials from one CTCG, 21 (52.5%) trials closed due to insufficient accrual. In 82 trials from five CTCGs, therapeutic trials accrued sufficiently more often than nontherapeutic trials (59% vs 27%, p = 0.05). Trials including pretrial accrual assessment more often achieved sufficient accrual than those without (67% vs 47%, p = 0.08). Fewer exclusion criteria, shorter consent forms, other CTCG participation, and trial design simplicity were not associated with achieving sufficient accrual. Trials accruing at a rate much lower than predicted (<35% actual/predicted accrual rate) were consistently closed due to insufficient accrual. Limitations This trial subset under-represents certain experimental modalities. Data sources do not allow accounting for all factors potentially related to accrual success. Conclusion Trial closure due to insufficient accrual is common. Certain trial design factors appear associated with attaining sufficient accrual. Defining accrual benchmarks for early trial termination or redesign is feasible, but better accrual prediction methods are critically needed. Future studies should focus on identifying trial factors that allow more accurate accrual predictions and strategies that can salvage open trials experiencing slow accrual. PMID:20595245

Feasibility of Extracting Key Elements from ClinicalTrials.gov to Support Clinicians' Patient Care Decisions.

PubMed

Kim, Heejun; Bian, Jiantao; Mostafa, Javed; Jonnalagadda, Siddhartha; Del Fiol, Guilherme

2016-01-01

Motivation: Clinicians need up-to-date evidence from high quality clinical trials to support clinical decisions. However, applying evidence from the primary literature requires significant effort. Objective: To examine the feasibility of automatically extracting key clinical trial information from ClinicalTrials.gov. Methods: We assessed the coverage of ClinicalTrials.gov for high quality clinical studies that are indexed in PubMed. Using 140 random ClinicalTrials.gov records, we developed and tested rules for the automatic extraction of key information. Results: The rate of high quality clinical trial registration in ClinicalTrials.gov increased from 0.2% in 2005 to 17% in 2015. Trials reporting results increased from 3% in 2005 to 19% in 2015. The accuracy of the automatic extraction algorithm for 10 trial attributes was 90% on average. Future research is needed to improve the algorithm accuracy and to design information displays to optimally present trial information to clinicians.

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.

Outcomes Research in Cardiovascular Imaging

PubMed Central

Douglas, Pamela S.; Taylor, Allen; Bild, Diane; Bonow, Robert; Greenland, Philip; Lauer, Michael; Peacock, Frank; Udelson, James

2009-01-01

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation. PMID:19560655

A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial

PubMed Central

Deeks, Jonathan J; Griffith, Michael; Lip, Gregory YH; Mehta, Samir; Slinn, Gemma; Stanbury, Mary; Steeds, Richard P; Townend, Jonathan N

2017-01-01

Background and objective Atrial fibrillation (AF) is common and causes impaired quality of life, an increased risk of stroke and death as well as frequent hospital admissions. The majority of patients with AF require control of heart rate. In this article, we summarise the limited evidence from clinical trials that guides prescription, and present the rationale and protocol for a new randomised trial. As rate control has not yet been shown to reduce mortality, there is a clear need to compare the impact of therapy on quality of life, cardiac function and exercise capacity. Such a trial should concentrate on the long-term effects of treatment in the largest proportion of patients with AF, those with symptomatic permanent AF, with the aim of improving patient well-being. Design and intervention The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial will enrol 160 participants with a prospective, randomised, open-label, blinded end point design comparing initial rate control with digoxin or bisoprolol. This will be the first head-to-head randomised trial of digoxin and beta-blockers in AF. Participants Recruited patients will be aged ≥60 years with permanent AF and symptoms of breathlessness (equivalent to New York Heart Association class II or above), with few exclusion criteria to maximise generalisability to routine clinical practice. Outcome measures The primary outcome is patient-reported quality of life, with secondary outcomes including echocardiographic ventricular function, exercise capacity and biomarkers of cellular and clinical response. Follow-up will occur at 6 and 12 months, with feasibility components to inform the design of a future trial powered to detect a difference in hospital admission. The RATE-AF trial will underpin an integrated approach to management including biomarkers, functions and symptoms that will guide future research into optimal, personalised rate control in patients with AF. Ethics and dissemination East Midlands-Derby Research Ethics Committee (16/EM/0178); peer-reviewed publications. Trial registration Clinicaltrials.gov: NCT02391337; ISRCTN: 95259705. Pre-results. PMID:28729311

Materials, Chemistry, and Simulation for Future Energy Technology.

PubMed

Aguey-Zinsou, Kondo-Francois; Wang, Da-Wei; Su, Dang-Sheng

2015-09-07

Special Issue: The Future of Energy. The science and engineering of clean energy now is becoming a multidisciplinary area, typically when new materials, chemistry, or mechanisms are met. "Trial and error" is the past. Exploration of new concepts for future clean energy can be accomplished through computer-aided materials design and reaction simulation, thanks to innovations in information technologies. This special issue, a fruit of the Energy Future Conference organized by UNSW Australia, has compiled some excellent examples of such approaches. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed Central

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

2017-01-01

Objectives 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. Design 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. Results 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. Conclusions 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. PMID:28213598

A response adaptive randomization platform trial for efficient evaluation of Ebola virus treatments: A model for pandemic response.

PubMed

Berry, Scott M; Petzold, Elizabeth A; Dull, Peter; Thielman, Nathan M; Cunningham, Coleen K; Corey, G Ralph; McClain, Micah T; Hoover, David L; Russell, James; Griffiss, J McLeod; Woods, Christopher W

2016-02-01

The outbreak of Ebola virus disease in West Africa is the largest ever recorded. Numerous treatment alternatives for Ebola have been considered, including widely available repurposed drugs, but initiation of enrollment into clinical trials has been limited. The proposed trial is an adaptive platform design. Multiple agents and combinations will be investigated simultaneously. Additionally, new agents may enter the trial as they become available, and failing agents may be removed. In order to accommodate the many possible agents and combinations, a critical feature of this design is the use of response adaptive randomization to assign treatment regimens. As the trial progresses, the randomization ratio evolves to favor the arms that are performing better, making the design also suitable for all-cause pandemic preparedness planning. The study was approved by US and Sierra Leone ethics committees, and reviewed by the US Food and Drug Administration. Additionally, data management, drug supply lines, and local sites were prepared. However, in response to the declining epidemic seen in February 2015, the trial was not initiated. Sierra Leone remains ready to rapidly activate the protocol as an emergency response trial in the event of a resurgence of Ebola. (ClinicalTrials.gov Identifier: NCT02380625.) In summary, we have designed a single controlled trial capable of efficiently identifying highly effective or failing regimens among a rapidly evolving list of proposed therapeutic alternatives for Ebola virus disease and to treat the patients within the trial effectively based on accruing data. Provision of these regimens, if found safe and effective, would have a major impact on future epidemics by providing effective treatment options. © The Author(s) 2016.

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

Lessons learned from lifestyle prevention trials in gestational diabetes mellitus.

PubMed

Egan, A M; Simmons, D

2018-06-25

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse outcomes for mother and infant both at birth and later in life. A large body of evidence is now available relating to antenatal prevention of GDM. Overall, despite some individual trials of a variety of lifestyle interventions revealing benefit, many more have shown no effect from the second trimester onwards, even with significant gestational weight gain limitation. At-risk women often seem reluctant to engage in lifestyle changes and frequently cannot adhere to recommended interventions even within a clinical trial setting. Many trials have not considered the heterogeneity of diabetes first discovered in pregnancy, something of importance into the future. Future work should focus on designing interventions acceptable to the population at risk, whether those taking place before or during the first trimester of pregnancy are effective, and whether greater individualization can identify those women most likely to benefit. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

For the Benefit of Others: Reasons Why Women with Breast Cancer Participate in RCTs.

PubMed

Jenkins, Valerie A; Fallowfield, Lesley J

2015-04-01

Appreciation of the barriers and drivers affecting enrolment in randomised clinical trials (RCTs) is important for future trial design, communication and information provision. As part of an intervention to facilitate UK multidisciplinary team communication about RCTs, women with breast cancer who discussed trials with doctors or research nurses completed questionnaires examining i) clarity of trial information and ii) reasons for their trial decision. 152 women completed the questionnaires; 113/152 (74%) consented to RCT enrolment. Patients' satisfaction with communication about the trial information was very good, irrespective of participation decisions. Acceptors' and decliners' responses to 9/16 statements concerning decisions about trial participation differed significantly. 'Wanting to help with doctor's research' influenced 100% acceptors compared to 57% of decliners (p < 0.001). Decliners were more likely to be 'worried about randomisation' (20 vs. 39%; p < 0.035) and to 'want doctor to choose treatment rather than be randomised' (31 vs. 53%; p < 0.031). Primary reason for trial acceptance was altruism; 'I feel that others with my illness will benefit from the results of the trial', 58/108 (54%). A majority of women accepted RCT entry citing altruistic motivations as the primary driver for participation. Trial design and setting (metastatic or adjuvant) had little impact on participation.

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study.

PubMed

Crowley, Susan T; Chertow, Glenn M; Vitale, Joseph; O'Connor, Theresa; Zhang, Jane; Schein, Roland M H; Choudhury, Devasmita; Finkel, Kevin; Vijayan, Anitha; Paganini, Emil; Palevsky, Paul M

2008-07-01

Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Qualitative research within trials: developing a standard operating procedure for a clinical trials unit

PubMed Central

2013-01-01

Background Qualitative research methods are increasingly used within clinical trials to address broader research questions than can be addressed by quantitative methods alone. These methods enable health professionals, service users, and other stakeholders to contribute their views and experiences to evaluation of healthcare treatments, interventions, or policies, and influence the design of trials. Qualitative data often contribute information that is better able to reform policy or influence design. Methods Health services researchers, including trialists, clinicians, and qualitative researchers, worked collaboratively to develop a comprehensive portfolio of standard operating procedures (SOPs) for the West Wales Organisation for Rigorous Trials in Health (WWORTH), a clinical trials unit (CTU) at Swansea University, which has recently achieved registration with the UK Clinical Research Collaboration (UKCRC). Although the UKCRC requires a total of 25 SOPs from registered CTUs, WWORTH chose to add an additional qualitative-methods SOP (QM-SOP). Results The qualitative methods SOP (QM-SOP) defines good practice in designing and implementing qualitative components of trials, while allowing flexibility of approach and method. Its basic principles are that: qualitative researchers should be contributors from the start of trials with qualitative potential; the qualitative component should have clear aims; and the main study publication should report on the qualitative component. Conclusions We recommend that CTUs consider developing a QM-SOP to enhance the conduct of quantitative trials by adding qualitative data and analysis. We judge that this improves the value of quantitative trials, and contributes to the future development of multi-method trials. PMID:23433341

Renal denervation for the management of resistant hypertension

PubMed Central

Patel, Hitesh C; Hayward, Carl; Vassiliou, Vassilis; Patel, Ketna; Howard, James P; Di Mario, Carlo

2015-01-01

Renal sympathetic denervation (RSD) as a therapy for patients with resistant hypertension has attracted great interest. The majority of studies in this field have demonstrated impressive reductions in blood pressure (BP). However, these trials were not randomized or sham-controlled and hence, the findings may have been overinflated due to trial biases. SYMPLICITY HTN-3 was the first randomized controlled trial to use a blinded sham-control and ambulatory BP monitoring. A surprise to many was that this study was neutral. Possible reasons for this neutrality include the fact that RSD may not be effective at lowering BP in man, RSD was not performed adequately due to limited operator experience, patients’ adherence with their anti-hypertensive drugs may have changed during the trial period, and perhaps the intervention only works in certain subgroups that are yet to be identified. Future studies seeking to demonstrate efficacy of RSD should be designed as randomized blinded sham-controlled trials. The efficacy of RSD is in doubt, but many feel that its safety has been established through the thousands of patients in whom the procedure has been performed. Over 90% of these data, however, are for the Symplicity™ system and rarely extend beyond 12 months of follow-up. Long-term safety cannot be assumed with RSD and nor should it be assumed that if one catheter system is safe then all are. We hope that in the near future, with the benefit of well-designed clinical trials, the role of renal denervation in the management of hypertension will be established. PMID:26672761

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.

Development of an alkaline fuel cell subsystem

NASA Technical Reports Server (NTRS)

1987-01-01

A two task program was initiated to develop advanced fuel cell components which could be assembled into an alkaline power section for the Space Station Prototype (SSP) fuel cell subsystem. The first task was to establish a preliminary SSP power section design to be representative of the 200 cell Space Station power section. The second task was to conduct tooling and fabrication trials and fabrication of selected cell stack components. A lightweight, reliable cell stack design suitable for the SSP regenerative fuel cell power plant was completed. The design meets NASA's preliminary requirements for future multikilowatt Space Station missions. Cell stack component fabrication and tooling trials demonstrated cell components of the SSP stack design of the 1.0 sq ft area can be manufactured using techniques and methods previously evaluated and developed.

Initial Field Trial of a Coach-Supported Web-Based Depression Treatment.

PubMed

Schueller, Stephen M; Mohr, David C

2015-08-01

Early web-based depression treatments were often self-guided and included few interactive elements, instead focusing mostly on delivering informational content online. Newer programs include many more types of features. As such, trials should analyze the ways in which people use these sites in order to inform the design of subsequent sites and models of support. The current study describes of a field trial consisting of 9 patients with major depressive disorder who completed a 12-week program including weekly coach calls. Patients usage varied widely, however, patients who formed regular patterns tended to persist with the program for the longest. Future sites might be able to facilitate user engagement by designing features to support regular use and to use coaches to help establish patterns to increase long-term use and benefit.

Acupuncture/Moxibustion RCT for Distal Sensory Peripheral Neuropathy in HIV/AIDS

PubMed Central

Anastasi, Joyce K.; Capili, Bernadette; Chung, Ann M.; Hammerschlag, Richard

2017-01-01

Distal sensory peripheral neuropathy is a common neurological complication experienced by people living with the human immunodeficiency virus (HIV). Traditional Chinese medicine (TCM) may offer effective interventions in the management of its symptoms. To improve the quality and transparency of reporting acupuncture clinical trials, the Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in 1996 and the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) recommendations were introduced in 2001. Incorporating international guidelines, this paper describes the development of a RCT including rationale, design, methods, procedures and logistics for a pilot study aimed at evaluating acupuncture and moxibustion for neuropathy associated with HIV. Using STRICTA guidelines as a template, aspects of clinical research design are explored to further optimise future studies of TCM. PMID:29756126

HIV Topical Microbicides: Steer the Ship or Run Aground

PubMed Central

Gross, Michael

2004-01-01

Six HIV candidate microbicides are scheduled to enter 6 large-scale effectiveness trials in the next year. The selection of products for testing and the design of this group of trials should be reconsidered to provide an answer to a key question now before the field: Does a sulfonated polyanion, delivered intravaginally as a gel, block HIV attachment to target cells with sufficient potency to protect women from sexually acquired HIV infection? Paradoxically, entering more candidates into more trials may confuse or compromise efforts to identify an effective product. Instead, a single trial of the most promising product(s) best serves the current candidates while also preserving resources needed to promptly advance innovative new protective concepts into future large-scale trials. PMID:15226123

Comprehension of a simplified assent form in a vaccine trial for adolescents.

PubMed

Lee, Sonia; Kapogiannis, Bill G; Flynn, Patricia M; Rudy, Bret J; Bethel, James; Ahmad, Sushma; Tucker, Diane; Abdalian, Sue Ellen; Hoffman, Dannie; Wilson, Craig M; Cunningham, Coleen K

2013-06-01

Future HIV vaccine efficacy trials with adolescents will need to ensure that participants comprehend study concepts in order to confer true informed assent. A Hepatitis B vaccine trial with adolescents offers valuable opportunity to test youth understanding of vaccine trial requirements in general. Youth reviewed a simplified assent form with study investigators and then completed a comprehension questionnaire. Once enrolled, all youth were tested for HIV and confirmed to be HIV-negative. 123 youth completed the questionnaire (mean age=15 years; 63% male; 70% Hispanic). Overall, only 69 (56%) youth answered all six questions correctly. Youth enrolled in a Hepatitis B vaccine trial demonstrated variable comprehension of the study design and various methodological concepts, such as treatment group masking.

A critical review of clinical trials in systemic lupus erythematosus

PubMed Central

Mahieu, Mary A.; Strand, Vibeke; Simon, Lee S.; Lipsky, Peter E.; Ramsey-Goldman, Rosalind

2016-01-01

One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs. PMID:27497257

Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

PubMed Central

Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

2015-01-01

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899

Comprehensive Characterization of Reference Standard Lots of HIV-1 Subtype C Gp120 Proteins for Clinical Trials in Southern African Regions

PubMed Central

Wang, Zihao; Lorin, Clarisse; Koutsoukos, Marguerite; Franco, David; Bayat, Babak; Zhang, Ying; Carfi, Andrea; Barnett, Susan W.; Porter, Frederick

2016-01-01

Two HIV-1 subtype C gp120 protein candidates were the selected antigens for several experimental vaccine regimens now under evaluation in HVTN 100 Phase I/II clinical trial aiming to support the start of the HVTN 702 Phase IIb/III trial in southern Africa, which is designed to confirm and extend the partial protection seen against HIV-1 infection in the RV144 Thai trial. Here, we report the comprehensive physicochemical characterization of the gp120 reference materials that are representative of the clinical trial materials. Gp120 proteins were stably expressed in Chinese Hamster Ovary (CHO) cells and subsequently purified and formulated. A panel of analytical techniques was used to characterize the physicochemical properties of the two protein molecules. When formulated in the AS01 Adjuvant System, the bivalent subtype C gp120 antigens elicited 1086.C- and TV1.C-specific binding antibody and CD4+ T cell responses in mice. All the characteristics were highly representative of the Clinical Trial Materials (CTM). Data from this report demonstrate the immunogenicity of the gp120 antigens, provide comprehensive characterization of the molecules, set the benchmark for assessment of current and future CTM lots, and lay the physicochemical groundwork for interpretation of future clinical trial data. PMID:27187483

Multicenter clinical trials in sepsis: understanding the big picture and building a successful operation at your hospital.

PubMed

Dellinger, R Phillip; Schorr, Christa; Trzeciak, Stephen

2011-03-01

Only through adequately designed and adequately conducted clinical trials can new treatments be found for the benefit of the septic patient. Over the past 20 years, tens of thousands of patients have been enrolled in sepsis clinical trials with little success. These efforts, however, have not been without worth. Much has been learned and the knowledge gained has changed our approach to trial design in this very difficult field. Animal studies are better designed to match the clinical picture of severe sepsis. Phase II studies are more carefully engineered to answer questions about the most suitable target population and end points. Trial conduct likely benefits from use of CROs and a CCC. The future of clinical trials may include more standardization of sepsis management across investigative sites. Before the decision is made to become an investigative site in a multicenter industry-sponsored clinical trial in sepsis or severe sepsis, it is important to recognize what is required to succeed. Once these key-to-success elements are in place, members of the investigative team are more likely to realize the satisfaction and career growth from becoming a successful site. The most professional satisfaction comes from the knowledge of contributing to original science in the field of the sepsis. Copyright © 2011 Elsevier Inc. All rights reserved.

HIV Infection and Health Policy.

ERIC Educational Resources Information Center

Weiss, Robin; Hardy, Leslie M.

1990-01-01

Describes issues facing policymakers dealing with the human immunodeficiency virus (HIV) epidemic. Addresses six challenges for policymakers: (1) protecting people from discrimination; (2) designing testing and screening programs; (3) developing safe and effective antiviral drugs; (4) planning for future vaccine trials; (5) organizing and…

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.

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

PubMed Central

Borghaei, Hossein

2017-01-01

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

Improving recruitment to pharmacological trials for illicit opioid use: findings from a qualitative focus group study.

PubMed

Neale, Joanne; Tompkins, Charlotte N E; McDonald, Rebecca; Strang, John

2018-06-01

To explore potential study participants' views on willingness to join clinical trials of pharmacological interventions for illicit opioid use to inform and improve future recruitment strategies. Qualitative focus group study [six groups: oral methadone (two groups); buprenorphine tablets (two groups); injectable opioid agonist treatment (one group); and former opioid agonist treatment (one group)]. Drug and alcohol services and a peer support recovery service (London, UK). Forty people with experience of opioid agonist treatment for heroin dependence (26 males, 14 females; aged 33-66 years). Data collection was facilitated by a topic guide that explored willingness to enrol in clinical pharmacological trials. Groups were audio-recorded and transcribed. Transcribed data were analysed inductively via Iterative Categorization. Participants' willingness to join pharmacological trials of medications for opioid dependence was affected by factors relating to study burden, study drug, study design, study population and study relationships. Participants worried that the trial drug might be worse than, or interfere with, their current treatment. They also misunderstood aspects of trial design despite the researchers' explanations. Recruitment of participants for clinical trials of pharmacological interventions for illicit opioid use could be improved if researchers became better at explaining clinical trials to potential participants, dispelling misconceptions about trials and increasing trust in the research process and research establishment. A checklist of issues to consider when designing pharmacological trials for illicit opioid use is proposed. © 2018 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Accounting for multiple births in randomised trials: a systematic review.

PubMed

Yelland, Lisa Nicole; Sullivan, Thomas Richard; Makrides, Maria

2015-03-01

Multiple births are an important subgroup to consider in trials aimed at reducing preterm birth or its consequences. Including multiples results in a unique mixture of independent and clustered data, which has implications for the design, analysis and reporting of the trial. We aimed to determine how multiple births were taken into account in the design and analysis of recent trials involving preterm infants, and whether key information relevant to multiple births was reported. We conducted a systematic review of multicentre randomised trials involving preterm infants published between 2008 and 2013. Information relevant to multiple births was extracted. Of the 56 trials included in the review, 6 (11%) excluded multiples and 24 (43%) failed to indicate whether multiples were included. Among the 26 trials that reported multiples were included, only one (4%) accounted for clustering in the sample size calculations and eight (31%) took the clustering into account in the analysis of the primary outcome. Of the 20 trials that randomised infants, 12 (60%) failed to report how infants from the same birth were randomised. Information on multiple births is often poorly reported in trials involving preterm infants, and clustering due to multiple births is rarely taken into account. Since ignoring clustering could result in inappropriate recommendations for clinical practice, clustering should be taken into account in the design and analysis of future neonatal and perinatal trials including infants from a multiple birth. 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.

Motor skill interventions to improve fundamental movement skills of preschoolers with developmental delay.

PubMed

Kirk, Megan A; Rhodes, Ryan E

2011-07-01

Preschoolers with developmental delay (DD) are at risk for poor fundamental movement skills (FMS), but a paucity of early FMS interventions exist. The purpose of this review was to critically appraise the existing interventions to establish direction for future trials targeting preschoolers with DD. A total of 11 studies met the inclusion criteria. Major findings were summarized based on common subtopics of overall intervention effect, locomotor skill outcomes, object-control outcomes, and gender differences. Trials ranged from 8 to 24 weeks and offered 540-1700 min of instruction. The majority of trials (n = 9) significantly improved FMS of preschoolers with DD, with a large intervention effect (η(2) = 0.57-0.85). This review supports the utility of interventions to improve FMS of preschoolers with DD. Future researchers are encouraged to include more robust designs, a theoretical framework, and involvement of parents and teachers in the delivery of the intervention.

Feasibility of Extracting Key Elements from ClinicalTrials.gov to Support Clinicians’ Patient Care Decisions

PubMed Central

Kim, Heejun; Bian, Jiantao; Mostafa, Javed; Jonnalagadda, Siddhartha; Del Fiol, Guilherme

2016-01-01

Motivation: Clinicians need up-to-date evidence from high quality clinical trials to support clinical decisions. However, applying evidence from the primary literature requires significant effort. Objective: To examine the feasibility of automatically extracting key clinical trial information from ClinicalTrials.gov. Methods: We assessed the coverage of ClinicalTrials.gov for high quality clinical studies that are indexed in PubMed. Using 140 random ClinicalTrials.gov records, we developed and tested rules for the automatic extraction of key information. Results: The rate of high quality clinical trial registration in ClinicalTrials.gov increased from 0.2% in 2005 to 17% in 2015. Trials reporting results increased from 3% in 2005 to 19% in 2015. The accuracy of the automatic extraction algorithm for 10 trial attributes was 90% on average. Future research is needed to improve the algorithm accuracy and to design information displays to optimally present trial information to clinicians. PMID:28269867

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

PubMed Central

2011-01-01

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

Planning Future Clinical Trials for Machado-Joseph Disease.

PubMed

Saute, Jonas Alex Morales; Jardim, Laura Bannach

2018-01-01

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant multiple neurological systems degenerative disorder caused by a CAG repeat expansion at ATXN3 gene. Only a few treatments were evaluated in randomized clinical trials (RCT) in SCA3/MJD patients, with a lack of evidence for both disease-modifying and symptomatic therapies. The present chapter discuss in detail major methodological issues for planning future RCT for SCA3/MJD. There are several potential therapies for SCA3/MJD with encouraging preclinical results. Route of treatment, dosage titration and potential therapy biomarkers might differ among candidate drugs; however, the core study design and protocol will be mostly the same. RCT against placebo group is the best study design to test a disease-modifying therapy; the same cannot be stated for some symptomatic treatments. Main outcomes for future RCT are clinical scales: the Scale for the Assessment and Rating of ataxia (SARA) is currently the instrument of choice to prove efficacy of disease-modifying or symptomatic treatments against ataxia, the most important disease feature. Ataxia quantitative scales or its composite scores can be used as primary outcomes to provide preliminary evidence of efficacy in phase 2 RCT, due to a greater sensitivity to change. Details regarding eligibility criteria, randomization, sample size estimation, duration and type of analysis for both disease modifying and symptomatic treatment trials, were also discussed. Finally, a section anticipates the methodological issues for testing novel drugs when an effective treatment is already available. We conclude emphasizing four points, the first being the need of RCT for a number of different aims in the care of SCA3/MJD. Due to large sample sizes needed to warrant power, RCT for disease-modifying therapies should be multicenter enterprises. There is an urge need for surrogate markers validated for several drug classes. Finally, engagement of at risk or presymptomatic individuals in future trials will enable major advances on treatment research for SCA3/MJD.

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

Integrating Comparative Effectiveness Design Elements and Endpoints Into a Phase III, Randomized Clinical Trial (SWOG S1007) Evaluating OncotypeDX-Guided Management for Women With Breast Cancer Involving Lymph Nodes

PubMed Central

Ramsey, Scott D.; Barlow, William E.; Gonzalez-Angulo, Ana M.; Tunis, Sean; Baker, Laurence; Crowley, John; Deverka, Patricia; Veenstra, David; Hortobagyi, Gabriel N.

2012-01-01

Women with breast cancer involving the lymph nodes are typically treated with cytotoxic chemotherapy. Retrospective evaluations of prior studies suggest that the 21-gene test (OncotypeDX®), may allow identification of those who can safely avoid chemotherapy. To better understand the performance of the 21-gene test, the RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer) study was designed, a multicenter Phase III trial randomizing women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay recurrence score (RS) of 25 or less to endocrine therapy alone versus chemotherapy followed by endocrine therapy. As one of the first large-scale comparative-effectiveness studies in oncology, RxPONDER utilized an external stakeholder group to help inform the design of the trial. Stakeholders met with representatives of SWOG over several months through a structured discussion process. The stakeholder engagement process resulted in several changes being made to the trial design. In addition, stakeholder representatives from the health insurance industry provided guidance regarding a mechanism whereby the costs of OncotypeDX® would be paid by the majority of health insurers as part of the trial. The process may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups. PMID:23000081

Methods to Limit Attrition in Longitudinal Comparative Effectiveness Trials: Lessons from the Lithium Use for Bipolar Disorder (LiTMUS) Study

PubMed Central

Sylvia, Louisa G.; Reilly-Harrington, Noreen A.; Leon, Andrew C.; Kansky, Christine I.; Ketter, Terence A.; Calabrese, Joseph R.; Thase, Michael E.; Bowden, Charles L.; Friedman, Edward S.; Ostacher, Michael J.; Iosifescu, Dan V.; Severe, Joanne; Nierenberg, Andrew A.

2013-01-01

Background High attrition rates which occur frequently in longitudinal clinical trials of interventions for bipolar disorder limit the interpretation of results. Purpose The aim of this article is to present design approaches that limited attrition in the Lithium Use for Bipolar Disorder (LiTMUS) Study. Methods LiTMUS was a 6-month randomized, longitudinal multi-site comparative effectiveness trial that examined bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium, in addition to other treatments needed for mood stabilization administered in a guideline-informed, empirically supported, and personalized fashion (N=283). Results Components of the study design that may have contributed to the low attrition rate of the study included use of: (1) an intent-to-treat design; (2) a randomized adjunctive single-blind design; (3) participant reimbursement; (4) intent-to-attend the next study visit (includes a discussion of attendance obstacles when intention is low); (5) quality care with limited participant burden; and (6) target windows for study visits. Limitations Site differences and the effectiveness and tolerability data have not been analyzed yet. Conclusions These components of the LiTMUS study design may have reduced the probability of attrition which would inform the design of future randomized clinical effectiveness trials. PMID:22076437

Outcomes following vaginal prolapse repair and mid urethral sling (OPUS) trial--design and methods.

PubMed

Wei, John; Nygaard, Ingrid; Richter, Holly; Brown, Morton; Barber, Matthew; Xiao Xu; Kenton, Kimberly; Nager, Charles; Schaffer, Joseph; Visco, Anthony; Weber, Anne

2009-04-01

The primary aims of this trial are to determine whether the use of a concomitant prophylactic anti-incontinence procedure may prevent stress urinary incontinence symptom development in women undergoing vaginal prolapse surgery and to evaluate the cost-effectiveness of this prophylactic approach. To present the rationale and design of a randomized controlled surgical trial (RCT), the Outcomes following vaginal Prolapse repair and mid Urethral Sling (OPUS) Trial highlighting the challenges in the design and implementation. The challenges of implementing this surgical trial combined with a cost-effectiveness study and patient preference group are discussed including the study design, ethical issues regarding use of sham incision, maintaining the masking of study staff, and pragmatic difficulties encountered in the collection of cost data. The trial is conducted by the NICHD-funded Pelvic Floor Disorders Network. The ongoing OPUS trial started enrollment in May 2007 with a planned accrual of 350. The use of sham incision was generally well accepted but the collection of cost data using conventional billing forms was found to potentially unmask key study personnel. This necessitated changes in the study forms and planned timing for collection of cost data. To date, the enrollment to the patient preference group has been lower than the limit established by the protocol suggesting a willingness on the part of women to participate in the randomization. Given the invasive nature of surgical intervention trials, potential participants may be reluctant to accept random assignment, potentially impacting generalizability. Findings from the OPUS trial will provide important information that will help surgeons to better counsel women on the benefits and risks of concomitant prophylactic anti-incontinence procedure at the time of vaginal surgery for prolapse. The implementation of the OPUS trial has necessitated that investigators consider ethical issues up front, remain flexible with regards to data collection and be constantly aware of unanticipated opportunities for unmasking. Future surgical trials should be aware of potential challenges in maintaining masking and collection of cost-related information.

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.

An intervention to support stroke survivors and their carers in the longer term (LoTS2Care): study protocol for a cluster randomised controlled feasibility trial.

PubMed

Forster, Anne; Hartley, Suzanne; Barnard, Lorna; Ozer, Seline; Hardicre, Natasha; Crocker, Tom; Fletcher, Marie; Moreau, Lauren; Atkinson, Ross; Hulme, Claire; Holloway, Ivana; Schmitt, Laetitia; House, Allan; Hewison, Jenny; Richardson, Gillian; Farrin, Amanda

2018-06-11

Despite the evidence that many stroke survivors report longer term unmet needs, the provision of longer term care is limited. To address this, we are conducting a programme of research to develop an evidence-based and replicable longer term care strategy. The developed complex intervention (named New Start), which includes needs identification, exploration of social networks and components of problem solving and self-management, was designed to improve quality of life by addressing unmet needs and increasing participation. A multicentre, cluster randomised controlled feasibility trial designed to inform the design of a possible future definitive cluster randomised controlled trial (cRCT) and explore the potential clinical and cost-effectiveness of New Start. Ten stroke services across the UK will be randomised on a 1:1 basis either to implement New Start or continue with usual care only. New Start will be delivered by trained facilitators and will be offered to all stroke survivors within the services allocated to the intervention arm. Stroke survivors will be eligible for the trial if they are 4-6 months post-stroke and residing in the community. Carers (if available) will also be invited to take part. Invitation to participate will be initiated by post and outcome measures will be collected via postal questionnaires at 3, 6 and 9 months after recruitment. Outcome data relating to perceived health and disability, wellbeing and quality of life as well as unmet needs will be collected. A 'study within a trial' (SWAT) is planned to determine the most acceptable format in which to provide the postal questionnaires. Details of health and social care service usage will also be collected to inform the economic evaluation. The feasibility of recruiting services and stroke survivors to the trial and of collecting postal outcomes will be assessed and the potential for effectiveness will be investigated. An embedded process evaluation (reported separately) will assess implementation fidelity and explore and clarify causal assumptions regarding implementation. This feasibility trial with embedded process evaluation will allow us to gather important and detailed data regarding methodological and implementation issues to inform the design of a possible future definitive cRCT of this complex intervention. ISRCTN38920246 . Registered 22 June 2016.

"I didn't really understand it, I just thought it'd help": exploring the motivations, understandings and experiences of patients with advanced lung cancer participating in a non-placebo clinical IMP trial.

PubMed

Harrop, Emily; Noble, Simon; Edwards, Michelle; Sivell, Stephanie; Moore, Barbara; Nelson, Annmarie

2016-07-20

Few studies have explored in depth the experiences of patients with advanced cancer who are participating in clinical investigational medicinal product trials. However, integrated qualitative studies in such trials are needed to enable a broader evaluation of patient experiences in the trial, with important ethical and practical implications for the design and conduct of similar trials and treatment regimes in the future. Ten participants were recruited from the control and intervention arms of FRAGMATIC: a non-placebo trial for patients with advanced lung cancer. Participants were interviewed at up to three time points during their time in the trial. Interviews were analysed using Interpretive Phenomenological Analysis. Patients were motivated to join the trial out of hope of medical benefit and altruism. Understanding of randomisation was mixed and in some cases poor, as was appreciation of trial purpose and equipoise. The trial was acceptable to and evaluated positively by most participants; participants receiving the intervention focused on the potential treatment benefits they hoped they would receive, whilst participants in the control arm found alternative reasons, such as altruism, personal fulfilment and positive attention, to commit to and perceive benefits from the trial. However, whilst experiences were generally very positive, poor understanding, limited engagement with trial information and focus on treatment benefits amongst some participants give cause for concern. By exploring longitudinally the psychological, emotional and cognitive domains of trial participation, we consider potential harms and benefits of participation in non-placebo trials amongst patients with advanced lung cancer and identify several implications for future research with and care for patients with advanced cancer. ISRCTN80812769 . Registered on 8 July 2005.

Oncosurgical Management of Liver Limited Stage IV Colorectal Cancer: Preliminary Data and Protocol for a Randomized Controlled Trial.

PubMed

Sutton, Paul; Vimalachandran, Dale; Poston, Graeme; Fenwick, Stephen; Malik, Hassan

2018-05-09

Colorectal cancer is the fourth commonest cancer and second commonest cause of cancer-related death in the United Kingdom. Almost 15% of patients have metastases on presentation. An increasing number of surgical strategies and better neoadjuvant treatment options are responsible for more patients undergoing resection of liver metastases, with prolonged survival in a select group of patients who present with synchronous disease. It is clear that the optimal strategy for the management of these patients remains unclear, and there is certainly a complete absence of Level 1 evidence in the literature. The objective of this study is to undertake preliminary work and devise an outline trial protocol to inform the future development of clinical studies to investigate the management of patients with liver limited stage IV colorectal cancer. We have undertaken some preliminary work and begun the process of designing a randomized controlled trial and present a draft trial protocol here. This study is at the protocol development stage only, and as such no results are available. There is no funding in place for this study, and no anticipated start date. We have presented preliminary work and an outline trial protocol which we anticipate will inform the future development of clinical studies to investigate the management of patients with liver limited stage IV colorectal cancer. We do not believe that the trial we have designed will answer the most significant clinical questions, nor that it is feasible to be delivered within the United Kingdom's National Health Service at this current time. ©Paul Sutton, Dale Vimalachandran, Graeme Poston, Stephen Fenwick, Hassan Malik. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 09.05.2018.

Designing clinical trials for age-related geographic atrophy of the macula: enrollment data from the geographic atrophy natural history study.

PubMed

Sunness, Janet S; Applegate, Carol A; Bressler, Neil M; Hawkins, Barbara S

2007-02-01

To derive information from the Geographic Atrophy (GA) Natural History Study that is relevant to recruiting patients and designing clinical trials for GA. A prospective natural history study with annual follow-up enrolled patients with GA and no choroidal neovascularization (CNV) in at least one eye. Characteristics of recruited and enrolled patients are analyzed, in the context of progression data from the study. The data show that GA from age-related macular degeneration (AMD) was seen in 82% of the referred patients, there was an attrition rate of 14%, and 60% of the patients with GA from AMD had bilateral GA without CNV. Within the 83 patients in the bilateral GA group with follow-up, 50 patients (60%) met both the proposed visual acuity and the proposed GA area criteria for a treatment trial in one or both eyes. These data should be helpful in planning future treatment trials for GA.

A Bayesian predictive two-stage design for phase II clinical trials.

PubMed

Sambucini, Valeria

2008-04-15

In this paper, we propose a Bayesian two-stage design for phase II clinical trials, which represents a predictive version of the single threshold design (STD) recently introduced by Tan and Machin. The STD two-stage sample sizes are determined specifying a minimum threshold for the posterior probability that the true response rate exceeds a pre-specified target value and assuming that the observed response rate is slightly higher than the target. Unlike the STD, we do not refer to a fixed experimental outcome, but take into account the uncertainty about future data. In both stages, the design aims to control the probability of getting a large posterior probability that the true response rate exceeds the target value. Such a probability is expressed in terms of prior predictive distributions of the data. The performance of the design is based on the distinction between analysis and design priors, recently introduced in the literature. The properties of the method are studied when all the design parameters vary.

Future directions in treatment of brain metastases

PubMed Central

Barani, Igor J.; Larson, David A.; Berger, Mitchel S.

2013-01-01

Background: Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT. Methods: A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text. Results: The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline. Conclusions: Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT. PMID:23717793

Future directions in treatment of brain metastases.

PubMed

Barani, Igor J; Larson, David A; Berger, Mitchel S

2013-01-01

Brain metastases affect up to 30% of patients with cancer. Management of brain metastases continues to evolve with ever increasing focus on cognitive preservation and quality of life. This manuscript reviews current state of brain metastases management and discusses various treatment controversies with focus on future clinical trials. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) are discussed in context of multiple (4+ brain metastases) as well as new approaches combining radiation and targeted agents. A brief discussion of modified WBRT approaches, including hippocampal-avoidance WBRT (HA-WBRT) is included as well as a section on recently presented results of Radiation Therapy Oncology Group (RTOG) 0614, a randomized, double-blind, placebo-controlled trial of menantine for prevention of neurocognitive injury after WBRT. A search of selected studies relevant to management of brain metastases was performed in PubMed as well as in various published meeting abstracts. This data was collated and analyzed in context of contemporary management and future clinical trial plans. This data is presented in tabular form and discussed extensively in the text. The published data demonstrate continued evolution of clinical trials and management strategies designed to minimize and/or prevent cognitive decline following radiation therapy management of brain metastases. Hippocampal avoidance whole-brain radiation therapy (HA-WBRT) and radiosurgery treatments for multiple brain metastases are discussed along with preliminary results of RTOG 0614, a trial of memantine therapy to prevent cognitive decline following WBRT. Trial results appear to support the use of memantine for prevention of cognitive decline. Different management strategies for multiple brain metastases (>4 brain metastases) are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following WBRT.

Systematic Review and Meta-Analysis of Antimicrobial Treatment Effect Estimation in Complicated Urinary Tract Infection

PubMed Central

Li, Gang; Mitrani-Gold, Fanny S.; Kurtinecz, Milena; Wetherington, Jeffrey; Tomayko, John F.; Mundy, Linda M.

2013-01-01

Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations. PMID:23939900

Vaccine testing for emerging infections: the case for individual randomisation

PubMed Central

Eyal, Nir; Lipsitch, Marc

2017-01-01

During the 2014–2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, many opposed the use of individually randomised controlled trials to test candidate Ebola vaccines. For a raging fatal disease, they explained, it is unethical to relegate some study participants to control arms. In Zika and future emerging infections, similar opposition may hinder urgent vaccine research, so it is best to address these questions now. This article lays out the ethical case for individually randomised control in testing vaccines against many emerging infections, including lethal infections in low-income countries, even when at no point in the trial do the controls receive the countermeasures being tested. When individual randomisation is feasible—and it often will be—it tends to save more lives than alternative designs would. And for emerging infections, individual randomisation also tends as such to improve care, access to the experimental vaccine and prospects for all participants relative to their opportunities absent the trial, and no less than alternative designs would. That obtains even under placebo control and without equipoise—requiring which would undermine individual randomisation and the alternative designs that opponents proffered. Our arguments expound four often-neglected factors: benefits to non-participants, benefits to participants once a trial is over including post-trial access to the study intervention, participants’ prospects before randomisation to arms and the near-inevitable disparity between arms in any randomised controlled trial. PMID:28396558

A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).

PubMed

Phillips, Patrick P J; Dooley, Kelly E; Gillespie, Stephen H; Heinrich, Norbert; Stout, Jason E; Nahid, Payam; Diacon, Andreas H; Aarnoutse, Rob E; Kibiki, Gibson S; Boeree, Martin J; Hoelscher, Michael

2016-03-23

The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world's greatest infectious disease killer. We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.

The future of recombinant growth factors in wound healing.

PubMed

Robson, M C; Mustoe, T A; Hunt, T K

1998-08-01

For more than a decade, clinical trials have been conducted of the application of topical exogenous recombinant growth factors in attempts to accelerate the healing of chronic wounds. Although the results of some of these trials have been encouraging, overall the results have been somewhat discouraging. Much of the difficulty lies in the paucity of carefully controlled clinical trials of wound healing. Since wound healing is a complex process that can be influenced, both positively and negatively, by many factors, designing these trials has proved difficult. To date, only a single recombinant growth factor-recombinant human platelet-derived growth factor-BB (rhPDGF-BB)- has been approved by the US Food and Drug Administration; and that only for use in diabetic foot ulcers. It is unlikely, however, that a single growth factor will be able to resolve all issues of repair or strengthen all vulnerabilities of chronic wounds. Our expectation, therefore, is that growth factors, cytokines, and other biologic agents will be used more specifically in the future, for example, by targeting growth factor therapy at those specific components or processes that a given wound uses to heal.

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/.

An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials

PubMed Central

Mi, Michael Y.; Betensky, Rebecca A.

2013-01-01

Background Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD design already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and if we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample size re-estimation, up to 25% power was recovered from underestimated sample size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study’s results are limited to situations described by the parameters that were used, and may not generalize to all possible scenarios. Furthermore, drop-out of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments. PMID:23283576

Sample Size Calculations for Micro-randomized Trials in mHealth

PubMed Central

Liao, Peng; Klasnja, Predrag; Tewari, Ambuj; Murphy, Susan A.

2015-01-01

The use and development of mobile interventions are experiencing rapid growth. In “just-in-time” mobile interventions, treatments are provided via a mobile device and they are intended to help an individual make healthy decisions “in the moment,” and thus have a proximal, near future impact. Currently the development of mobile interventions is proceeding at a much faster pace than that of associated data science methods. A first step toward developing data-based methods is to provide an experimental design for testing the proximal effects of these just-in-time treatments. In this paper, we propose a “micro-randomized” trial design for this purpose. In a micro-randomized trial, treatments are sequentially randomized throughout the conduct of the study, with the result that each participant may be randomized at the 100s or 1000s of occasions at which a treatment might be provided. Further, we develop a test statistic for assessing the proximal effect of a treatment as well as an associated sample size calculator. We conduct simulation evaluations of the sample size calculator in various settings. Rules of thumb that might be used in designing a micro-randomized trial are discussed. This work is motivated by our collaboration on the HeartSteps mobile application designed to increase physical activity. PMID:26707831

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

Health benefit for the child and promotion of the common good were the two most important reasons for participation in the FinIP vaccine trial.

PubMed

Nieminen, Heta; Syrjänen, Ritva K; Puumalainen, Taneli; Sirén, Päivi; Palmu, Arto A

2015-07-17

The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was a nationwide cluster-randomised double-blind trial designed to demonstrate the effectiveness of pneumococcal conjugate vaccine in vaccinated children and indirect effects in unvaccinated populations. Together with the parallel carriage/AOM trial, over 47,000 children were enrolled, 52% of the initial target. We conducted a questionnaire study to find out which factors affected parents' decision on their child's study participation. A questionnaire designed to evaluate parents' attitudes to vaccine trial participation in general and the FinIP trial in particular was mailed after the trial enrolment period had ended to parents of randomly selected children: 1484 who participated in the trial and 1485 who did not participate. Altogether 1438 parents (48%) responded to the questionnaire. The response rate was higher among FinIP participants (65%, 965/1484) than among FinIP non-participants (32%, 473/1485). The two most important reasons for giving consent to the FinIP trial were the potential benefit of immunisation against pneumococcal diseases (75% of consenters) and the promotion of the common good and public health (11%). The reasons reported as most important for declining consent were suspicions of vaccine safety (36%) and the double-blind trial design (12%). Up to 65% of the non-consenters declared that drug and vaccine trials should not be conducted in children at all. The expected health benefit for the child was by far the most important reason for consenting to the vaccine trial. Safety concern was the main reason for decline. Importance and necessity of clinical drug and vaccine trials among children and the rationale of the blinded studies should be thoroughly explained to the public. This may increase participation in future vaccine trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

BORDERLINE RESECTABLE PANCREATIC CANCER: Need for Standardization and Methods for Optimal Clinical Trial Design

PubMed Central

Katz, Matthew HG; Marsh, Robert; Herman, Joseph M.; Shi, Qian; Collison, Eric; Venook, Alan; Kindler, Hedy; Alberts, Steven; Philip, Philip; Lowy, Andrew M.; Pisters, Peter; Posner, Mitchell; Berlin, Jordan; Ahmad, Syed A.

2017-01-01

Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included the absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. In this manuscript, we will review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A0201101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. PMID:23435609

Statistical Considerations of Food Allergy Prevention Studies.

PubMed

Bahnson, Henry T; du Toit, George; Lack, Gideon

Clinical studies to prevent the development of food allergy have recently helped reshape public policy recommendations on the early introduction of allergenic foods. These trials are also prompting new research, and it is therefore important to address the unique design and analysis challenges of prevention trials. We highlight statistical concepts and give recommendations that clinical researchers may wish to adopt when designing future study protocols and analysis plans for prevention studies. Topics include selecting a study sample, addressing internal and external validity, improving statistical power, choosing alpha and beta, analysis innovations to address dilution effects, and analysis methods to deal with poor compliance, dropout, and missing data. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cancer prevention clinical trials.

PubMed

Nixon, D W

1994-01-01

Many kinds of cancer are preventable. Avoidance of tobacco would essentially eliminate lung cancer and most head and neck cancers as well. Other common cancers (breast, colon, prostate) are related to diet and therefore may also be preventable, at least in part. Abundant epidemiologic and laboratory data link specific nutrients including fat, fiber and vitamins to cancer so that appropriate manipulation of these constituents might reduce cancer risk. Determination of appropriate manipulations requires prospective clinical trials in humans. Approximately 40 such trials are in progress. Some have been completed with encouraging results. Future large scale trials will require designs that overcome the barriers of cost, large subject numbers and long study duration. The use of "intermediate markers" rather than cancer end points is a strategy that will help overcome these barriers.

Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity.

PubMed

Choi, Chan-Bum; Liang, Matthew H; Bae, Sang-Cheol

2016-01-06

Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design.

STAR*D: helping to close the gap between science and practice.

PubMed

Shern, David L; Moran, Hazel

2009-11-01

Practical clinical trials, such as STAR*D (Sequenced Treatment Alternatives to Relieve Depression), extend the traditional randomized controlled trial to real-world settings. Consumers and clinicians should be encouraged by STAR*D's 70% remission rate and should realize that for many participants remission required medication switching and augmentation. Policy makers should recognize the importance of easy access to a full range of treatments. Researchers should be sobered by the high attrition rate and the 30% of participants who did not achieve remission. Although more such practical trials are needed, future work must more meaningfully involve consumers in design, analysis, and interpretation.

A conceptual model for the development process of confirmatory adaptive clinical trials within an emergency research network.

PubMed

Mawocha, Samkeliso C; Fetters, Michael D; Legocki, Laurie J; Guetterman, Timothy C; Frederiksen, Shirley; Barsan, William G; Lewis, Roger J; Berry, Donald A; Meurer, William J

2017-06-01

Adaptive clinical trials use accumulating data from enrolled subjects to alter trial conduct in pre-specified ways based on quantitative decision rules. In this research, we sought to characterize the perspectives of key stakeholders during the development process of confirmatory-phase adaptive clinical trials within an emergency clinical trials network and to build a model to guide future development of adaptive clinical trials. We used an ethnographic, qualitative approach to evaluate key stakeholders' views about the adaptive clinical trial development process. Stakeholders participated in a series of multidisciplinary meetings during the development of five adaptive clinical trials and completed a Strengths-Weaknesses-Opportunities-Threats questionnaire. In the analysis, we elucidated overarching themes across the stakeholders' responses to develop a conceptual model. Four major overarching themes emerged during the analysis of stakeholders' responses to questioning: the perceived statistical complexity of adaptive clinical trials and the roles of collaboration, communication, and time during the development process. Frequent and open communication and collaboration were viewed by stakeholders as critical during the development process, as were the careful management of time and logistical issues related to the complexity of planning adaptive clinical trials. The Adaptive Design Development Model illustrates how statistical complexity, time, communication, and collaboration are moderating factors in the adaptive design development process. The intensity and iterative nature of this process underscores the need for funding mechanisms for the development of novel trial proposals in academic settings.

A Randomized Phase II Dose-Response Exercise Trial among Colon Cancer Survivors: Purpose, Study Design, Methods, and Recruitment Results

PubMed Central

Brown, Justin C.; Troxel, Andrea B.; Ky, Bonnie; Damjanov, Nevena; Zemel, Babette S.; Rickels, Michael R.; Rhim, Andrew D.; Rustgi, Anil K.; Courneya, Kerry S.; Schmitz, Kathryn H.

2016-01-01

Background Observational studies indicate that higher volumes of physical activity are associated with improved disease outcomes among colon cancer survivors. The aim of this report is to describe the purpose, study design, methods, and recruitment results of the COURAGE trial, a National Cancer Institute (NCI) sponsored, phase II, randomized, dose-response exercise trial among colon cancer survivors. Methods/Results The primary objective of the COURAGE trial is to quantify the feasibility, safety, and physiologic effects of low-dose (150 min·wk−1) and high-dose (300 min·wk−1) moderate-intensity aerobic exercise compared to usual-care control group over six months. The exercise groups are provided with in-home treadmills and heart rate monitors. Between January and July 2015, 1,433 letters were mailed using a population-based state cancer registry; 126 colon cancer survivors inquired about participation, and 39 were randomized onto the study protocol. Age was associated with inquiry about study participation (P<0.001) and randomization onto the study protocol (P<0.001). No other demographic, clinical, or geographic characteristics were associated with study inquiry or randomization. The final trial participant was randomized in August 2015. Six month endpoint data collection was completed in February 2016. Discussion The recruitment of colon cancer survivors into an exercise trial is feasible. The findings from this trial will inform key design aspects for future phase 2 and phase 3 randomized controlled trials to examine the efficacy of exercise to improve clinical outcomes among colon cancer survivors. PMID:26970181

An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials.

PubMed

Mi, Michael Y; Betensky, Rebecca A

2013-04-01

Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample-size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Because the basic SPCD already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and whether we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample-size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample-size re-estimation, up to 25% power was recovered from underestimated sample-size scenarios. Given the numerous possible test parameters that could have been chosen for the simulations, the study's results are limited to situations described by the parameters that were used and may not generalize to all possible scenarios. Furthermore, dropout of patients is not considered in this study. It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.

PLAYgrounds: Effect of a PE playground program in primary schools on PA levels during recess in 6 to 12 year old children. Design of a prospective controlled trial

PubMed Central

2011-01-01

Background The relative number of children meeting the minimal required dose of daily physical activity remains execrably low. It has been estimated that in 2015 one out of five children will be overweight. Therefore, low levels of physical activity during early childhood may compromise the current and future health and well-being of the population, and promoting physical activity in younger children is a major public health priority. This study is to gain insight into effects of a Physical Education based playground program on the PA levels during recess in primary school children aged 6-12. Methods/design The effectiveness of the intervention program will be evaluated using a prospective controlled trial design in which schools will be matched, with a follow-up of one school year. The research population will consist of 6-12 year old primary school children. The intervention program will be aimed at improving physical activity levels and will consist of a multi-component alteration of the schools' playground. In addition, playground usage will be increased through altered time management of recess times, as well as a modification of the Physical Education content. Discussion The effects of the intervention on physical activity levels during recess (primary outcome measure), overall daily physical activity and changes in physical fitness (secondary outcome measures) will be assessed. Results of this study could possibly lead to changes in the current playground system of primary schools and provide structured health promotion for future public health. Trial registration Netherlands Trial Register (NTR): NTR2386 PMID:21548998

Intraclass correlation estimates for cancer screening outcomes: estimates and applications in the design of group-randomized cancer screening studies.

PubMed

Hade, Erinn M; Murray, David M; Pennell, Michael L; Rhoda, Dale; Paskett, Electra D; Champion, Victoria L; Crabtree, Benjamin F; Dietrich, Allen; Dignan, Mark B; Farmer, Melissa; Fenton, Joshua J; Flocke, Susan; Hiatt, Robert A; Hudson, Shawna V; Mitchell, Michael; Monahan, Patrick; Shariff-Marco, Salma; Slone, Stacey L; Stange, Kurt; Stewart, Susan L; Strickland, Pamela A Ohman

2010-01-01

Screening has become one of our best tools for early detection and prevention of cancer. The group-randomized trial is the most rigorous experimental design for evaluating multilevel interventions. However, identifying the proper sample size for a group-randomized trial requires reliable estimates of intraclass correlation (ICC) for screening outcomes, which are not available to researchers. We present crude and adjusted ICC estimates for cancer screening outcomes for various levels of aggregation (physician, clinic, and county) and provide an example of how these ICC estimates may be used in the design of a future trial. Investigators working in the area of cancer screening were contacted and asked to provide crude and adjusted ICC estimates using the analysis of variance method estimator. Of the 29 investigators identified, estimates were obtained from 10 investigators who had relevant data. ICC estimates were calculated from 13 different studies, with more than half of the studies collecting information on colorectal screening. In the majority of cases, ICC estimates could be adjusted for age, education, and other demographic characteristics, leading to a reduction in the ICC. ICC estimates varied considerably by cancer site and level of aggregation of the groups. Previously, only two articles had published ICCs for cancer screening outcomes. We have complied more than 130 crude and adjusted ICC estimates covering breast, cervical, colon, and prostate screening and have detailed them by level of aggregation, screening measure, and study characteristics. We have also demonstrated their use in planning a future trial and the need for the evaluation of the proposed interval estimator for binary outcomes under conditions typically seen in GRTs.

Designing Comparative Effectiveness Trials of Surgical Ablation for Atrial Fibrillation: Experience of the Cardiothoracic Surgical Trials Network

PubMed Central

Gillinov, A. Marc; Argenziano, Michael; Blackstone, Eugene H.; Iribarne, Alexander; DeRose, Joseph J.; Ailawadi, Gorav; Russo, Mark J.; Ascheim, Deborah D.; Parides, Michael K.; Rodriguez, Evelio; Bouchard, Denis; Taddei-Peters, Wendy C.; Geller, Nancy L.; Acker, Michael A.; Gelijns, Annetine C.

2013-01-01

Background Since the introduction of the cut-and-sew Cox-Maze procedure for atrial fibrillation (AF) there has been substantial innovation in techniques for ablation. Use of alternate energy sources for ablation simplified the procedure and has resulted in dramatic increase in the number of AF patients treated by surgical ablation. Despite its increasingly widespread adoption, there is lack of rigorous clinical evidence to establish this as an effective clinical therapy. Methods and Results This paper describes a comparative effectiveness randomized trial, supported by the Cardiothoracic Surgical Trials Network, of surgical ablation with left atrial appendage (LAA) closure versus LAA closure alone in patients with persistent and longstanding persistent AF undergoing mitral valve surgery. Nested within this trial, is a further randomized comparison of 2 different lesions sets: pulmonary vein isolation and full Maze lesion set. This paper addresses trial design challenges, including how to best characterize the target population, operationalize freedom from AF as a primary endpoint, account for the impact of anti-arrhythmic drugs, and measure and analyze secondary endpoints, such as post-operative AF load. Conclusions This paper concludes by discussing how insights that emerge from this trial may affect surgical practice and guide future research in this area. PMID:21616507

StaR Child Health: developing evidence-based guidance for the design, conduct and reporting of paediatric trials.

PubMed

Van't Hoff, William; Offringa, Martin

2015-02-01

There has been a huge upsurge in clinical research in children in the last decade, stimulated in England by dedicated research infrastructure and support through the National Institute for Health Research. This infrastructure offering research design, expert review, trial management, research nurse, data support and dedicated facilities enables paediatricians to conduct more and better research. The challenge is how to design and conduct trials that will make a real difference to children's health. Standards for Research (StaR) in Child Health was founded in 2009 to address the paucity and shortcomings of paediatric clinical trials. This global initiative involves methodologists, clinicians, patient advocacy groups and policy makers dedicated to developing practical, evidence-based standards for enhancing the reliability and relevance of paediatric clinical research. In this overview, we highlight the contribution of StaR to this agenda, describe the international context, and suggest how StaR's future plans could be integrated with new and existing support for research. 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 trials transparency and the Trial and Experimental Studies Transparency (TEST) act.

PubMed

Logvinov, Ilana

2014-03-01

Clinical trial research is the cornerstone for successful advancement of medicine that provides hope for millions of people in the future. Full transparency in clinical trials may allow independent investigators to evaluate study designs, perform additional analysis of data, and potentially eliminate duplicate studies. Current regulatory system and publishers rely on investigators and pharmaceutical industries for complete and accurate reporting of results from completed clinical trials. Legislation seems to be the only way to enforce mandatory disclosure of results. The Trial and Experimental Studies Transparency (TEST) Act of 2012 was introduced to the legislators in the United States to promote greater transparency in research industry. Public safety and advancement of science are the driving forces for the proposed policy change. The TEST Act may benefit the society and researchers; however, there are major concerns with participants' privacy and intellectual property protection. Copyright © 2014 Elsevier Inc. All rights reserved.

OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma.

PubMed

Kaufman, Howard L; Bines, Steven D

2010-06-01

There are few effective treatment options available for patients with advanced melanoma. An oncolytic herpes simplex virus type 1 encoding granulocyte macrophage colony-stimulating factor (GM-CSF; Oncovex(GM-CSF)) for direct injection into accessible melanoma lesions resulted in a 28% objective response rate in a Phase II clinical trial. Responding patients demonstrated regression of both injected and noninjected lesions highlighting the dual mechanism of action of Oncovex(GM-CSF) that includes both a direct oncolytic effect in injected tumors and a secondary immune-mediated anti-tumor effect on noninjected tumors. Based on these preliminary results a prospective, randomized Phase III clinical trial in patients with unresectable Stage IIIb or c and Stage IV melanoma has been initiated. The rationale, study design, end points and future development of the Oncovex(GM-CSF) Pivotal Trial in Melanoma (OPTIM) trial are discussed in this article.

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.

Why is recruitment to trials difficult? An investigation into recruitment difficulties in an RCT of supported employment in patients with severe mental illness

PubMed Central

Howard, Louise; de Salis, Isabel; Tomlin, Zelda; Thornicroft, Graham; Donovan, Jenny

2009-01-01

Background Under-recruitment to randomised controlled trials (RCTs) is often problematic and there may be particular difficulties in recruiting patients with severe mental illness. Aim To evaluate reasons for under-recruitment in an RCT of patients with severe mental illness Methods Qualitative study during the recruitment phase of an RCT of supported employment. Trial staff and recruiting clinicians were interviewed. Data were analyzed thematically using constant comparative techniques. Results Recruitment rates were low. Five main reasons for recruitment difficulties were found. These included: (i) misconceptions about trials, (ii) lack of equipoise, (iii) misunderstanding of the trial arms, (iv) variable interpretations of eligibility criteria, (v) paternalism. Conclusion Reasons for recruitment difficulties in trials involving patients with severe mental illness include issues that occur in trials in general, but others are more specific to these patients. Clinician and patient involvement in the study design may improve recruitment in future similar trials. PMID:18718555

Patient Selection in Heart Failure With Preserved Ejection Fraction Clinical Trials

PubMed Central

Kelly, Jacob P.; Mentz, Robert J.; Mebazaa, Alexandre; Voors, Adriaan A.; Butler, Javed; Roessig, Lothar; Fiuzat, Mona; Zannad, Faiez; Pitt, Bertram; O’Connor, Christopher M.; Lam, Carolyn S.P.

2015-01-01

Recent clinical trials in patients with heart failure with preserved ejection fraction (HFpEF) have provided important insights into participant selection strategies. Historically, HFpEF trials have included patients with relatively preserved left ventricular ejection fraction ranging from 40% to 55% and a clinical history of heart failure. Contemporary HFpEF trials have also incorporated inclusion criteria such as hospitalization for HFpEF, altered functional capacity, cardiac structural and functional abnormalities, and abnormalities in neurohormonal status (e.g., elevated natriuretic peptide levels). Careful analyses of the impact of these patient selection criteria on outcomes in prior trials provide valuable lessons for future trial design. We review recent and ongoing HFpEF clinical trials from a patient selection perspective and appraise trial patient selection methodologies in relation to outcomes. This review reflects discussions between clinicians, scientists, trialists, regulators, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum in Paris, France on December 6, 2013. PMID:25908073

A survey of facilitators and barriers to recruitment to the MAGNETIC trial.

PubMed

Kaur, Geetinder; Smyth, Rosalind L; Powell, Colin V E; Williamson, Paula

2016-12-23

Recruitment to randomised controlled trials with children is challenging. It is imperative to understand the factors that boost or hinder recruitment of children to clinical trials. We conducted a survey of facilitators and barriers to recruitment to the MAGNETIC trial, using a previously developed web-based tool. MAGNETIC is a multicentre randomised trial of nebulised magnesium in acute severe asthma, recruiting 508 children from 30 UK sites. Recruiters were asked to grade a list of factors from -3 to +3 depending on whether the factor was perceived as a strong, intermediate or weak barrier (-3 to -1) or facilitator (+1 to + 3), and using (0) if it was thought to be not applicable. Free text responses were invited on strategies applied to counter the identified barriers. The commonly identified facilitators were motivation and experience of study teams, effective communication and coordination between teams at site and between sites and the Clinical Trials Unit, the presence of designated research nurses, good trial management, clinical trial publicity, simple inclusion criteria, effective communication with parents and presentation of trial information in a simple and clear manner. The commonly identified barriers were heavy clinical workload, shift patterns of work, Good Clinical Practice (GCP) training, inadequate number of trained staff, time and setting of consent seeking, non-availability of research staff out of hours and parents' concerns about their child taking an experimental medicine. Having a designated research nurse, arranging GCP training and trial-related training sessions for staff were the most commonly reported interventions. This study highlights important generic and trial-specific facilitators and barriers to recruitment to a paediatric trial in the acute setting and provides information on the recruitment strategies or interventions that were applied to overcome these barriers. This information can be very useful in informing the design and conduct of future clinical trials with children, particularly in the acute or emergency setting. ISRCTN, ISRCTN81456894 . Registered on 15 November 2007.

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual

PubMed Central

Massett, Holly A.; Mishkin, Grace; Rubinstein, Larry; Ivy, S. Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, Jennifer; Zwiebel, James A.; Abrams, Jeffrey S.

2016-01-01

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAPs) received for slow-accruing Phase 1 and 2 trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for Phase 1 trials and 66 for Phase 2 trials. Primary reasons cited for slow accrual were safety/toxicity (Phase 1: 48%), design/protocol concerns (Phase 1: 42%, Phase 2: 33%), and eligibility criteria (Phase 1: 41%, Phase 2: 35%). The most commonly proposed corrective actions were adding institutions (Phase 1: 43%, Phase 2: 85%) and amending the trial to change eligibility or design (Phase 1: 55%, Phase 2: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (Phase 1=48; Phase 2=46). Of these, 67% of Phase 1 and 70% of Phase 2 trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial lifecycles, but it may be more beneficial to invest in earlier accrual planning. PMID:27401246

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

PubMed

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

2014-03-20

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

Clinical Predictors of Severe Cetuximab-Induced Rash: Observations from 933 Patients Enrolled in North Central Cancer Treatment Group Study N0147

PubMed Central

Jatoi, Aminah; Green, Erin M.; Rowland, Jr., Kendrith M.; Sargent, Daniel J.; Alberts, Steven R.

2009-01-01

Objective Epidermal growth factor receptor inhibitors can result in a severe rash in 5–10% of patients and can detract from quality of life. The objective of this study was to identify clinical predictors of severe rash in the hope of utilizing such factors in the design of future rash palliative and prevention trials. Methods 933 cetuximab-treated patients enrolled on N0147, an adjuvant chemotherapy trial for colon cancer, were evaluated for clinical risk factors of severe rash. Results Within this cohort, 50 patients (5%) developed a severe rash (grade 3). More men compared to women developed such a rash: 34 (7%) versus 16 (3%) (multivariate odds ratio = 2.12; 95% confidence interval: 1.14–3.88; p = 0.017). A greater number of younger patients (<70 years of age) also developed a rash: 48 (6%) versus 2 (1%) (multivariate odds ratio = 0.21; 95% confidence interval: 0.05–0.88; p = 0.032). Race and performance score were not predictive. Conclusion Men and younger patients are at greater risk for a severe cetuximab-induced rash although overall the risk is low. These observations are particularly important in designing future rash prevention and palliation trials. PMID:19622902

Rationale, conduct, and outcome using hypofractionated radiotherapy in prostate cancer

PubMed Central

Ritter, Mark

2008-01-01

Hypofractionated radiation therapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic ratio with treatments delivered in larger-sized fractions. In addition, the associated reduction in fraction number produces attractive cost and patient convenience advantages as well. A still limited but growing number of hypofractionation trials have reported acceptable short-term levels of toxicity and biochemical control, but most have insufficient follow-up to assure the long-term safety and efficacy of this approach. This situation will improve as many currently active trials mature, particularly several high value randomized trials. In contrast, extreme hypofractionation, with schedules delivering only on the order of 5 fractions, is truly in its infancy for prostate cancer, with extremely limited tolerance and efficacy information currently available. Several uncertainties in the radiobiology of hypofractionation mitigate for an organized, cautious investigational approach. The fractionation response (α/β ratio) of prostate cancers and, for that matter, late responding normal tissues, has yet to be rigorously defined. Additionally, the linear quadratic (LQ) model used in the design of hypofractionation schedules is subject to its own uncertainties, particularly with respect to the upper limit of fraction sizes for which it remains valid. Contemporary dose escalated radiation therapy is already highly effective, making it imperative that ongoing and future studies of hypofractionation be carried out in carefully designed, randomized clinical trials. Clinical validation permitting, the adaptation of hypofractionation as a standard of care could profoundly influence future management of localized prostate cancer. PMID:18725112

Clinical Trials in Head Injury

PubMed Central

NARAYAN, RAJ K.; MICHEL, MARY ELLEN; Ansell, Beth; Baethmann, Alex; Biegon, Anat; Bracken, Michael B.; Bullock, M. Ross; Choi, Sung C.; Clifton, Guy L.; Contant, Charles F.; Coplin, William M.; Dietrich, W. Dalton; Ghajar, Jamshid; Grady, Sean M.; Grossman, Robert G.; Hall, Edward D.; Heetderks, William; Hovda, David A.; Jallo, Jack; Katz, Russell L.; Knoller, Nachshon; Kochanek, Patrick M.; Maas, Andrew I.; Majde, Jeannine; Marion, Donald W.; Marmarou, Anthony; Marshall, Lawrence F.; McIntosh, Tracy K.; Miller, Emmy; Mohberg, Noel; Muizelaar, J. Paul; Pitts, Lawrence H.; Quinn, Peter; Riesenfeld, Gad; Robertson, Claudia S.; Strauss, Kenneth I.; Teasdale, Graham; Temkin, Nancy; Tuma, Ronald; Wade, Charles; Walker, Michael D.; Weinrich, Michael; Whyte, John; Wilberger, Jack; Young, A. Byron; Yurkewicz, Lorraine

2006-01-01

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research. PMID:12042091

Independent data monitoring committees: Preparing a path for the future

PubMed Central

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

2014-01-01

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

Update on B-cell targeted therapies for systemic lupus erythematosus.

PubMed

Mok, Chi Chiu

2014-06-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by flares and remission, leading to accrual of organ damage over time as a result of persistent tissue inflammation and treatment-related complications. Novel therapies aiming at better treatment response and fewer adverse effects are being tested in the pipeline. This review summarizes the B-cell abnormalities observed in patients with SLE, and updates recent data on the efficacy and safety of B-cell targeted therapies in the treatment of SLE. The pitfalls of clinical trial design and future directions of the development of SLE therapeutics are discussed. The variability of clinical response to treatment in SLE reflects the clinical and immunological heterogeneity of the disease. The treatment plan for patients with SLE should be individualized with the aim of eradicating disease activity, preventing flares and minimizing treatment-related complications. Despite the disappointment of recent clinical trials, B-cell remains the promising target of future SLE therapies. Results from ongoing clinical trials on B-cell targeted biological agents are eagerly awaited.

Exploring patients' treatment journeys following randomisation in mental health trials to improve future trial conduct: a synthesis of multiple qualitative data sets.

PubMed

Turner, Katrina M; Percival, John; Kessler, David; Donovan, Jenny

2017-06-15

The way in which pragmatic trials are designed suggests that there are differences between the experiences of participants randomised to usual care and intervention arms. These potential differences relate not only to which treatment participants receive but also how they access and engage with their allocated treatment. Such differences could affect trial results. The aim of this study was to assess whether such differences exist and, if they do, to consider their implications for the design of future trials. Interview transcripts were sampled from data sets gathered during three qualitative studies, all of which had been nested within large, primary care depression trials. Each study had explored trial participants' views and experiences of treatments received following randomisation. Transcripts from 37 participants were purposefully sampled, 20 of which were from interviews held with individuals allocated to receive usual GP care. Data were analysed thematically. There was evidence of differences between trial arms across all three data sets. Intervention participants were willing and able to engage with the treatment to which they had been allocated. Randomisation had led to them embarking upon a clear treatment pathway and receiving care in a context where they felt comfortable discussing their mental health and had sufficient time to do so. Intervention participants also had continuity with and confidence in the practitioners they saw. A few usual-care participants talked about having continuity with and confidence in their GPs. However, most of the usual-care participants reported a reluctance to consult GPs about mental health, difficulties in securing treatment appointments, and little or no changes in care following randomisation. Additionally, most reported a lack of continuity of care and a lack confidence in the treatment available to them. There are important differences between usual-care and intervention arms that go beyond treatment received, and they relate to how participants experience accessing and engaging with their allocated care. As these differences could affect trial results, researchers may want to measure or reduce them in order to fully appreciate or control for the range of factors that might affect treatment outcomes.

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.

Design challenges in transdiagnostic psychotherapy research: Comparing Transdiagnostic Behavior Therapy (TBT) to existing evidence-based psychotherapy in veterans with affective disorders.

PubMed

Gros, Daniel F

2015-07-01

To address the limitations of disorder-specific approaches, newer transdiagnostic approaches to psychotherapy have been developed to provide a single treatment that is capable of addressing several, related disorders. However, the recruitment of multiple diagnoses presents many challenges to the traditional design of psychotherapy randomized controlled trials (RCTs). The goal of the manuscript is to present the challenges and rationale for designing a RCT for transdiagnostic treatment to inform and aid in the development of future investigations. A recently funded and ongoing RCT for Transdiagnostic Behavior Therapy (TBT) is used as an example to discuss the related design challenges. The TBT study involves the recruitment of 96 veteran participants with any of the following eight principal diagnoses: posttraumatic stress disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, generalized anxiety disorder, specific phobia, major depressive disorder, or persistent depressive disorder. Within the TBT study, participants will complete a semi-structured diagnostic interview and a series of transdiagnostic self-report measures to determine eligibility and assess baseline symptomatology. Qualifying participants will be randomized to TBT or control psychotherapy. Additional assessments will be completed at post-treatment and 6-month follow-up. Due to the transdiagnostic nature of the sample, adjustments to the recruitment and randomization procedures, selection of measures, selection of control psychotherapy, and analysis plan were required. These adjustments have implications to future trials on transdiagnostic psychotherapy protocols as well as future research in line with the transdiagnostic focus of the National Institute of Mental Health's Research Domain Criteria (RDoC) funding strategy. Published by Elsevier Inc.

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

Methodological Overview of an African American Couple-Based HIV/STD Prevention Trial

PubMed Central

2010-01-01

Objective To provide an overview of the NIMH Multisite HIV/STD Prevention Trial for African American Couples conducted in four urban areas: Atlanta, Los Angeles, New York, and Philadelphia. The rationale, study design methods, proposed data analyses, and study management are described. Design This is a two arm randomized Trial, implementing a modified randomized block design, to evaluate the efficacy of a couples based intervention designed for HIV serodiscordant African American couples. Methods The study phases consisted of formative work, pilot studies, and a randomized clinical trial. The sample is 535 HIV serodiscordant heterosexual African American couples. There are two theoretically derived behavioral interventions with eight group and individual sessions: the Eban HIV/STD Risk Reduction Intervention (treatment) versus the Eban Health Promotion Intervention (control). The treatment intervention was couples based and focused on HIV/STD risk reduction while the control was individual based and focused on health promotion. The two study conditions were structurally similar in length and types of activities. At baseline, participants completed an Audio Computer-assisted Self Interview (ACASI) interview as well as interviewer-administered questionnaire, and provided biological specimens to assess for STDs. Similar follow-up assessments were conducted immediately after the intervention, at 6 months, and at 12 months. Results The Trial results will be analyzed across the four sites by randomization assignment. Generalized estimating equations (GEE) and mixed effects modeling (MEM) are planned to test: (1) the effects of the intervention on STD incidence and condom use as well as on mediator variables of these outcomes, and (2) whether the effects of the intervention differ depending on key moderator variables (e.g., gender of the HIV-seropositive partners, length of relationship, psychological distress, sexual abuse history, and substance abuse history). Conclusions The lessons learned from the design and conduct of this clinical trial provide guidelines for future couples based clinical trials in HIV/STD risk reduction and can be generalized to other couples based behavioral interventions. PMID:18724188

Design and implementation of a controlled clinical trial to evaluate the effectiveness and efficiency of routine opt-out rapid human immunodeficiency virus screening in the emergency department.

PubMed

Haukoos, Jason S; Hopkins, Emily; Byyny, Richard L; Conroy, Amy A; Silverman, Morgan; Eisert, Sheri; Thrun, Mark; Wilson, Michael; Boyett, Brian; Heffelfinger, James D

2009-08-01

In 2006, the Centers for Disease Control and Prevention (CDC) released revised recommendations for performing human immunodeficiency virus (HIV) testing in health care settings, including implementing routine rapid HIV screening, the use of an integrated opt-out consent, and limited prevention counseling. Emergency departments (EDs) have been a primary focus of these efforts. These revised CDC recommendations were primarily based on feasibility studies and have not been evaluated through the application of rigorous research methods. This article describes the design and implementation of a large prospective controlled clinical trial to evaluate the CDC's recommendations in an ED setting. From April 15, 2007, through April 15, 2009, a prospective quasi-experimental equivalent time-samples clinical trial was performed to compare the clinical effectiveness and efficiency of routine (nontargeted) opt-out rapid HIV screening (intervention) to physician-directed diagnostic rapid HIV testing (control) in a high-volume urban ED. In addition, three nested observational studies were performed to evaluate the cost-effectiveness and patient and staff acceptance of the two rapid HIV testing methods. This article describes the rationale, methodologies, and study design features of this program evaluation clinical trial. It also provides details regarding the integration of the principal clinical trial and its nested observational studies. Such ED-based trials are rare, but serve to provide valid comparisons between testing approaches. Investigators should consider similar methodology when performing future ED-based health services research.

Impact of Availability of Companion Diagnostics on the Clinical Development of Anticancer Drugs.

PubMed

Tibau, Ariadna; Díez-González, Laura; Navarro, Beatriz; Galán-Moya, Eva M; Templeton, Arnoud J; Seruga, Bostjan; Pandiella, Atanasio; Amir, Eitan; Ocana, Alberto

2017-06-01

Companion diagnostics permit the selection of patients likely to respond to targeted anticancer drugs; however, it is unclear if the drug development process differs between drugs developed with or without companion diagnostics. Identification of differences in study design could help future clinical development. Anticancer drugs approved for use in solid tumors between 28 September 2000 and 4 January 2014 were identified using a search of the US FDA website. Phase III trials supporting registration were extracted from the drug label. Each published study was reviewed to obtain information about the phase I and II trials used for the development of the respective drug. We identified 35 drugs and 59 phase III randomized trials supporting regulatory approval. Fifty-three phase I trials and 47 phase II trials were cited in the studies and were used to support the design of these phase III trials. The approval of drugs using a companion diagnostic has increased over time (p for trend 0.01). Expansion cohorts were more frequently observed with drugs developed with a companion diagnostic (62 vs. 20%; p = 0.005). No differences between drugs developed with or without a companion diagnostic were observed for the design of phase I and II studies. The approval of drugs developed with a companion diagnostic has increased over time. The availability of a companion diagnostic was associated with more frequent use of phase I expansion cohorts comprising patients selected by the companion diagnostic.

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

PubMed

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

2010-02-01

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

Invasive Cortical Stimulation to Promote Recovery of Function After Stroke

PubMed Central

Plow, Ela B.; Carey, James R.; Nudo, Randolph J.; Pascual-Leone, Alvaro

2011-01-01

Background and Purpose Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result. Summary of Review Regarding cortical stimulation, it is important to determine the (1) location of peri-infarct representations by integrating multiple neuroanatomical and physiological techniques; (2) role of other mechanisms of stroke recovery; (3) viability of peri-infarct tissue and descending pathways; (4) lesion geometry to ensure no alteration/displacement of current density; and (5) applicability of lessons generated from noninvasive brain stimulation studies in humans. In terms of combining stimulation with rehabilitation, we should understand (1) the principle of homeostatic plasticity; (2) the effect of ongoing cortical activity and phases of learning; and (3) that subject-specific intervention may be necessary. Conclusions Future cortical stimulation trials should consider the factors that may have contributed to the peculiar results of the Phase III trial and address those in future study designs. PMID:19359643

Achieving consensus for clinical trials

PubMed Central

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

2013-01-01

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

Detailed systematic analysis of recruitment strategies in randomised controlled trials in patients with an unscheduled admission to hospital

PubMed Central

Rooshenas, Leila; Fairhurst, Katherine; Rees, Jonathan; Gamble, Carrol; Blazeby, Jane M

2018-01-01

Objectives To examine the design and findings of recruitment studies in randomised controlled trials (RCTs) involving patients with an unscheduled hospital admission (UHA), to consider how to optimise recruitment in future RCTs of this nature. Design Studies within the ORRCA database (Online Resource for Recruitment Research in Clinical TriAls; www.orrca.org.uk) that reported on recruitment to RCTs involving UHAs in patients >18 years were included. Extracted data included trial clinical details, and the rationale and main findings of the recruitment study. Results Of 3114 articles populating ORRCA, 39 recruitment studies were eligible, focusing on 68 real and 13 hypothetical host RCTs. Four studies were prospectively planned investigations of recruitment interventions, one of which was a nested RCT. Most recruitment papers were reports of recruitment experiences from one or more ‘real’ RCTs (n=24) or studies using hypothetical RCTs (n=11). Rationales for conducting recruitment studies included limited time for informed consent (IC) and patients being too unwell to provide IC. Methods to optimise recruitment included providing patients with trial information in the prehospital setting, technology to allow recruiters to cover multiple sites, screening logs to uncover recruitment barriers, and verbal rather than written information and consent. Conclusion There is a paucity of high-quality research into recruitment in RCTs involving UHAs with only one nested randomised study evaluating a recruitment intervention. Among the remaining studies, methods to optimise recruitment focused on how to improve information provision in the prehospital setting and use of screening logs. Future research in this setting should focus on the prospective evaluation of the well-developed interventions to optimise recruitment. PMID:29420230

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

PubMed

Vormoor, B; Veal, G J; Griffin, M J; Boddy, A V; Irving, J; Minto, L; Case, M; Banerji, U; Swales, K E; Tall, J R; Moore, A S; Toguchi, M; Acton, G; Dyer, K; Schwab, C; Harrison, C J; Grainger, J D; Lancaster, D; Kearns, P; Hargrave, D; Vormoor, J

2017-06-01

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies. © 2016 Wiley Periodicals, Inc.

Initial test results from a prototype, 20 kW helium charged Stirling engine

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

Clarke, M.A.; Taylor, D.R.

An alpha-configuration, helium charged Stirling engine with a predicted output of 20 kW indicated power has been developed by a British consortium of universities and industrial companies. The work performed by the Royal Naval Engineering College has been in computer assisted design and component testing, with future plans for full engine trials during 1984/85. The scope of this paper is to outline the data obtained during motoring trials of the engine block and crankcase assembly, together with details of modifications incorporated in the various components.

Leveraging Big Data in Pediatric Development Programs: Proceedings From the 2016 American College of Clinical Pharmacology Annual Meeting Symposium.

PubMed

Mulugeta, Lily Yeruk; Yao, Lynne; Mould, Diane; Jacobs, Brian; Florian, Jeffrey; Smith, Brian; Sinha, Vikram; Barrett, Jeffrey S

2018-01-10

This article discusses the use of big data in pediatric drug development. The article covers key topics discussed at the ACCP annual meeting symposium in 2016 including the extent to which big data or real-world data can inform clinical trial design and substitute for efficacy and safety data typically obtained in clinical trials. The current states of use, opportunities, and challenges with the use of big data in future pediatric drug development are discussed. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Supportive care for men with prostate cancer: why are the trials not working? A systematic review and recommendations for future trials.

PubMed

Moore, Theresa Helen Mazzarello; King, Anna Jyoti Louise; Evans, Maggie; Sharp, Debbie; Persad, Raj; Huntley, Alyson Louise

2015-08-01

Men with prostate cancer are likely to have a long illness and experience psychological distress for which supportive care may be helpful. This systematic review describes the evidence for effectiveness and cost-effectiveness of supportive care for men with prostate cancer, taking into account treatment pathway and components of interventions. MEDLINE, EMBASE, CINAHL, CENTRAL, and Psychinfo were searched from inception--July 2013 for randomized controlled trials and controlled trials. Two authors independently assessed risk of bias and extracted data. Twenty-six studies were included (2740 participants). Interventions were delivered pre and during (n = 12), short-term (n = 8), and longer term (18 months) (n = 5) after primary treatment. No interventions were delivered beyond this time. Few trials recruited ethnic minorities and none recruited men in same sex relationships. Intervention components included information, education, health professional discussion, homework, peer discussion, buddy support, cognitive behavioral therapy, cognitive restructuring, psychoeducation, Reiki and relaxation. Most interventions were delivered for 5-10 weeks. Risk of bias of trials was assessed as unclear for most domains due to lack of information. The majority of trials measuring quality of life and depression found no effect. Relatively few trials measured anxiety, coping skills and self-efficacy, and the majority found no effect. No cost data were available. Trials of supportive care for men with prostate cancer cover a range of interventions but are limited by population diversity, inconsistent measurement and reporting of outcomes, and inability to assess risk of bias. Recommendations on design and conduct of future trials are presented. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design.

PubMed

Reddy, Venkat; Jayne, David; Close, David; Isenberg, David

2013-01-01

B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the tw studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.

Clinical trial resources on the internet must be designed to reach underrepresented minorities.

PubMed

Wilson, John J; Mick, Rosemarie; Wei, S Jack; Rustgi, Anil K; Markowitz, Sanford D; Hampshire, Maggie; Metz, James M

2006-01-01

Internet-based clinical trial information services are being developed to increase recruitment to studies. However, there are limited data that evaluate their ability to reach elderly and underrepresented minority populations. This study was designed to evaluate the ability of an established clinical trials registry to reach these populations based on expected Internet use. This study compares general Internet users to participants who enrolled in an Internet based colorectal cancer clinical trials registry established by OncoLink (www.oncolink.org) and the National Colorectal Cancer Research Alliance. Observed rates of demographic groupings were compared to those established for general Internet users. Two thousand, four hundred and thirty-seven participants from the continental United States used the Internet to register for the database. New England, the Mid-Atlantic region, and the Southeast had the highest relative frequency of participation in the database, whereas the Upper Midwest, California, and the South had the lowest rates. Compared to general Internet users, there was an overrepresentation of women (73% vs. 50%) and participants over 55 years old (27% vs. 14%). However, there was an underrepresentation of minorities (10.3% vs. 22%), particularly African Americans (3.1% vs. 8%) and Hispanics (2.8% vs. 9%). The Internet is a growing medium for registry into clinical trials databases. However, even taking into account the selection bias of Internet accessibility, there are still widely disparate demographics between general Internet users and those registering for clinical trials, particularly the underrepresentation of minorities. Internet-based educational and recruitment services for clinical trials must be designed to reach these underrepresented minorities to avoid selection biases in future clinical trials.

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

Reading and assessing reports of treatment studies in oncology.

PubMed

Simon, R

2000-04-01

Rapid advances in tumor biology, immunology, genomics, and technology give physicians great hopes for providing patients with better chances in the struggle against cancer. The pace of progress will be slowed, however, if we do not have clear answers regarding which treatments work and do not work. Such answers come from carefully designed, randomized, clinical trials. Such trials require infrastructure, commitment, cooperation, time, and money, and they provide little fame. They are, however, an invaluable contribution of the medical profession to their patients, to their next generation of colleagues, and to future patients. Randomized clinical trials that answer important medical questions definitively should be supported, participated in, and demanded by surgeons and oncologists.

Issues related to development of antiepileptogenic therapies.

PubMed

Pitkänen, Asla; Nehlig, Astrid; Brooks-Kayal, Amy R; Dudek, F Edward; Friedman, Daniel; Galanopoulou, Aristea S; Jensen, Frances E; Kaminski, Rafal M; Kapur, Jaideep; Klitgaard, Henrik; Löscher, Wolfgang; Mody, Istvan; Schmidt, Dieter

2013-08-01

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Clinical Trials of Blood Pressure Lowering and Antihypertensive Medication: Is Cognitive Measurement State-of-the-Art?

PubMed

Elias, Merrill F; Torres, Rachael V; Davey, Adam

2018-05-07

Randomized controlled trials of blood pressure (BP) lowering and antihypertensive medication use on cognitive outcomes have often been disappointing, reporting mixed findings and small effect sizes. We evaluate the extent to which cognitive assessment protocols used in these trials approach state-of-the-art. Overall, we find that a primary focus on cognition and the systematic selection of cognitive outcomes across trials take a backseat to other trial goals. Twelve trials investigating change in cognitive functioning were examined and none met criteria for state-of-the-art assessment, including use of at least 4 tests indexing 2 cognitive domains. Four trials investigating incident dementia were also examined. Each trial used state-of-the-art diagnostic criteria to assess dementia, although follow-up periods were relatively short, with only 2 trials lasting for at least 3 years. Weaknesses in each trial may act to obscure or weaken the positive effects of BP lowering on cognitive functioning. Improving trial designs in terms of cognitive outcomes selected and length of follow-up periods employed could lead to more promising findings. We offer logical steps to achieve state-of-the-art assessment protocols, with examples, in hopes of improving future trials.

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.

Progression-free survival as primary endpoint in randomized clinical trials of targeted agents for advanced renal cell carcinoma. Correlation with overall survival, benchmarking and power analysis.

PubMed

Bria, Emilio; Massari, Francesco; Maines, Francesca; Pilotto, Sara; Bonomi, Maria; Porta, Camillo; Bracarda, Sergio; Heng, Daniel; Santini, Daniele; Sperduti, Isabella; Giannarelli, Diana; Cognetti, Francesco; Tortora, Giampaolo; Milella, Michele

2015-01-01

A correlation, power and benchmarking analysis between progression-free and overall survival (PFS, OS) of randomized trials with targeted agents or immunotherapy for advanced renal cell carcinoma (RCC) was performed to provide a practical tool for clinical trial design. For 1st-line of treatment, a significant correlation was observed between 6-month PFS and 12-month OS, between 3-month PFS and 9-month OS and between the distributions of the cumulative PFS and OS estimates. According to the regression equation derived for 1st-line targeted agents, 7859, 2873, 712, and 190 patients would be required to determine a 3%, 5%, 10% and 20% PFS advantage at 6 months, corresponding to an absolute increase in 12-month OS rates of 2%, 3%, 6% and 11%, respectively. These data support PFS as a reliable endpoint for advanced RCC receiving up-front therapies. Benchmarking and power analyses, on the basis of the updated survival expectations, may represent practical tools for future trial' design. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual.

PubMed

Massett, Holly A; Mishkin, Grace; Rubinstein, Larry; Ivy, S Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, Jennifer; Zwiebel, James A; Abrams, Jeffrey S

2016-11-15

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. Clin Cancer Res; 22(22); 5408-16. ©2016 AACRSee related commentary by Mileham and Kim, p. 5397. ©2016 American Association for Cancer Research.

THE COOPERATIVE INTERNATIONAL NEUROMUSCULAR RESEARCH GROUP DUCHENNE NATURAL HISTORY STUDY—A LONGITUDINAL INVESTIGATION IN THE ERA OF GLUCOCORTICOID THERAPY: DESIGN OF PROTOCOL AND THE METHODS USED

PubMed Central

McDonald, Craig M.; Henricson, Erik K.; Abresch, R. Ted; Han, Jay J.; Escolar, Diana M.; Florence, Julaine M.; Duong, Tina; Arrieta, Adrienne; Clemens, Paula R.; Hoffman, Eric P.; Cnaan, Avital

2014-01-01

Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. Methods The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2–28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/ health-related quality-of-life instruments. Results Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). Conclusions Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. PMID:23677550

Accounting for twin births in sample size calculations for randomised trials.

PubMed

Yelland, Lisa N; Sullivan, Thomas R; Collins, Carmel T; Price, David J; McPhee, Andrew J; Lee, Katherine J

2018-05-04

Including twins in randomised trials leads to non-independence or clustering in the data. Clustering has important implications for sample size calculations, yet few trials take this into account. Estimates of the intracluster correlation coefficient (ICC), or the correlation between outcomes of twins, are needed to assist with sample size planning. Our aims were to provide ICC estimates for infant outcomes, describe the information that must be specified in order to account for clustering due to twins in sample size calculations, and develop a simple tool for performing sample size calculations for trials including twins. ICCs were estimated for infant outcomes collected in four randomised trials that included twins. The information required to account for clustering due to twins in sample size calculations is described. A tool that calculates the sample size based on this information was developed in Microsoft Excel and in R as a Shiny web app. ICC estimates ranged between -0.12, indicating a weak negative relationship, and 0.98, indicating a strong positive relationship between outcomes of twins. Example calculations illustrate how the ICC estimates and sample size calculator can be used to determine the target sample size for trials including twins. Clustering among outcomes measured on twins should be taken into account in sample size calculations to obtain the desired power. Our ICC estimates and sample size calculator will be useful for designing future trials that include twins. Publication of additional ICCs is needed to further assist with sample size planning for future trials. © 2018 John Wiley & Sons Ltd.

Cancer survivors' uptake and adherence in diet and exercise intervention trials: an integrative data analysis.

PubMed

Adams, Rebecca N; Mosher, Catherine E; Blair, Cindy K; Snyder, Denise C; Sloane, Richard; Demark-Wahnefried, Wendy

2015-01-01

The health benefits of diet and exercise interventions for cancer survivors are well documented. However, little is known regarding demographic and medical predictors of survivors' willingness to participate in diet and exercise intervention trials, study enrollment, intervention adherence, and study completion. To assist in interpreting the generalizability of trial findings and to improve the design of future trials, this study examined predictors of these process measures. An integrative data analysis was performed on data from 3 of the largest home-based diet and exercise intervention trials for cancer survivors (n = 23,841). Demographic and medical factors (ie, sex, race, age, time since diagnosis, and cancer type) were examined as predictors of willingness to participate, study enrollment, intervention adherence, and study completion in the pooled sample. A 99% confidence interval was used to determine statistical significance. Across trials, 11.1% of contacted survivors were willing to participate, and 5.7% were eligible and enrolled. Among enrollees, 53.4% demonstrated ≥75% adherence to the intervention, and 91.1% completed the study. Race (Caucasian vs others), age, time since diagnosis, and cancer type predicted survivors' willingness to participate (P < .01). All examined predictors were associated with the likelihood of study enrollment (P < .01). No significant predictors of intervention adherence or study completion were found among study enrollees (P ≥ .01). Cancer survivors' demographic and medical characteristics predicted their interest and participation in diet and exercise intervention trials. These findings have implications for the generalizability of results and can help to guide procedures used in future trials to enhance patient representation. © 2014 American Cancer Society.

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

PubMed

Kiluk, Brian D; Carroll, Kathleen M; Duhig, Amy; Falk, Daniel E; Kampman, Kyle; Lai, Shengan; Litten, Raye Z; McCann, David J; Montoya, Ivan D; Preston, Kenzie L; Skolnick, Phil; Weisner, Constance; Woody, George; Chandler, Redonna; Detke, Michael J; Dunn, Kelly; Dworkin, Robert H; Fertig, Joanne; Gewandter, Jennifer; Moeller, F Gerard; Ramey, Tatiana; Ryan, Megan; Silverman, Kenneth; Strain, Eric C

2016-01-01

The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

An exploratory cluster randomised trial of a university halls of residence based social norms intervention in Wales, UK

PubMed Central

2012-01-01

Background Excessive alcohol consumption amongst university students has received increasing attention. A social norms approach to reducing drinking behaviours has met with some success in the USA. Such an approach is based on the assumption that student's perceptions of the norms of their peers are highly influential, but that these perceptions are often incorrect. Social norms interventions therefore aim to correct these inaccurate perceptions, and in turn, to change behaviours. However, UK studies are scarce and it is increasingly recognised that social norm interventions need to be supported by socio ecological approaches that address the wider determinants of behaviour. Objectives To describe the research design for an exploratory trial examining the acceptability, hypothesised process of change and implementation of a social norm marketing campaign designed to correct misperceptions of normative alcohol use and reduce levels of misuse, implemented alongside a university wide alcohol harm reduction toolkit. It also assesses the feasibility of a potential large scale effectiveness trial by providing key trial design parameters including randomisation, recruitment and retention, contamination, data collection methods, outcome measures and intracluster correlations. Methods/design The study adopts an exploratory cluster randomised controlled trial design with halls of residence as the unit of allocation, and a nested mixed methods process evaluation. Four Welsh (UK) universities participated in the study, with residence hall managers consenting to implementation of the trial in 50 university owned campus based halls of residence. Consenting halls were randomised to either a phased multi channel social norm marketing campaign addressing normative discrepancies (n = 25 intervention) or normal practice (n = 25 control). The primary outcome is alcohol consumption (units per week) measured using the Daily Drinking Questionnaire. Secondary outcomes assess frequency of alcohol consumption, higher risk drinking, alcohol related problems and change in perceptions of alcohol-related descriptive and injunctive norms. Data will be collected for all 50 halls at 4 months follow up through a cross-sectional on line and postal survey of approximately 4000 first year students. The process evaluation will explore the acceptability and implementation of the social norms intervention and toolkit and hypothesised process of change including awareness, receptivity and normative changes. Discussion Exploratory trials such as this are essential to inform future definitive trials by providing crucial methodological parameters and guidance on designing and implementing optimum interventions. Trial registration number ISRCTN: ISRCTN48556384 PMID:22414293

Children, parents, and pets exercising together (CPET) randomised controlled trial: study rationale, design, and methods

PubMed Central

2012-01-01

Background Objectively measured physical activity is low in British children, and declines as childhood progresses. Observational studies suggest that dog-walking might be a useful approach to physical activity promotion in children and adults, but there are no published public health interventions based on dog-walking with children. The Children, Parents, and Pets Exercising Together Study aims to develop and evaluate a theory driven, generalisable, family-based, dog walking intervention for 9-11 year olds. Methods/design The Children, Parents, and Pets Exercising Together Study is an exploratory, assessor-blinded, randomised controlled trial as defined in the UK MRC Framework on the development and evaluation of complex interventions in public health. The trial will follow CONSORT guidance. Approximately 40 dog-owning families will be allocated randomly in a ratio of 1.5:1 to receive a simple behavioural intervention lasting for 10 weeks or to a 'waiting list' control group. The primary outcome is change in objectively measured child physical activity using Actigraph accelerometry. Secondary outcomes in the child, included in part to shape a future more definitive randomised controlled trial, are: total time spent sedentary and patterning of sedentary behaviour (Actigraph accelerometry); body composition and bone health from dual energy x-ray absorptiometry; body weight, height and BMI; and finally, health-related quality of life using the PedsQL. Secondary outcomes in parents and dogs are: changes in body weight; changes in Actigraph accelerometry measured physical activity and sedentary behaviour. Process evaluation will consist of assessment of simultaneous child, parent, and dog accelerometry data and brief interviews with participating families. Discussion The Children, Parents, and Pets Exercising Together trial should be the first randomised controlled study to establish and evaluate an intervention aimed at dog-based physical activity promotion in families. It should advance our understanding of whether and how to use pet dogs to promote physical activity and/or to reduce sedentary behaviour in children and adults. The trial is intended to lead to a subsequent more definitive randomised controlled trial, and the work should inform future dog-based public health interventions such as secondary prevention interventions in children or adults. Trial registration number ISRCTN85939423 PMID:22429665

A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial.

PubMed

Kotecha, Dipak; Calvert, Melanie; Deeks, Jonathan J; Griffith, Michael; Kirchhof, Paulus; Lip, Gregory Yh; Mehta, Samir; Slinn, Gemma; Stanbury, Mary; Steeds, Richard P; Townend, Jonathan N

2017-07-20

Atrial fibrillation (AF) is common and causes impaired quality of life, an increased risk of stroke and death as well as frequent hospital admissions. The majority of patients with AF require control of heart rate. In this article , we summarise the limited evidence from clinical trials that guides prescription, and present the rationale and protocol for a new randomised trial. As rate control has not yet been shown to reduce mortality, there is a clear need to compare the impact of therapy on quality of life, cardiac function and exercise capacity. Such a trial should concentrate on the long-term effects of treatment in the largest proportion of patients with AF, those with symptomatic permanent AF, with the aim of improving patient well-being. The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial will enrol 160 participants with a prospective, randomised, open-label, blinded end point design comparing initial rate control with digoxin or bisoprolol. This will be the first head-to-head randomised trial of digoxin and beta-blockers in AF. Recruited patients will be aged ≥60 years with permanent AF and symptoms of breathlessness (equivalent to New York Heart Association class II or above), with few exclusion criteria to maximise generalisability to routine clinical practice. The primary outcome is patient-reported quality of life, with secondary outcomes including echocardiographic ventricular function, exercise capacity and biomarkers of cellular and clinical response. Follow-up will occur at 6 and 12 months, with feasibility components to inform the design of a future trial powered to detect a difference in hospital admission. The RATE-AF trial will underpin an integrated approach to management including biomarkers, functions and symptoms that will guide future research into optimal, personalised rate control in patients with AF. East Midlands-Derby Research Ethics Committee (16/EM/0178); peer-reviewed publications. Clinicaltrials.gov: NCT02391337; ISRCTN: 95259705. 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.

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

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials

PubMed Central

Gilbert, Peter B.; Juraska, Michal; deCamp, Allan C.; Karuna, Shelly; Edupuganti, Srilatha; Mgodi, Nyaradzo; Donnell, Deborah J.; Bentley, Carter; Sista, Nirupama; Andrew, Philip; Isaacs, Abby; Huang, Yunda; Zhang, Lily; Capparelli, Edmund; Kochar, Nidhi; Wang, Jing; Eshleman, Susan H.; Mayer, Kenneth H.; Magaret, Craig A.; Hural, John; Kublin, James G.; Gray, Glenda; Montefiori, David C.; Gomez, Margarita M.; Burns, David N.; McElrath, Julie; Ledgerwood, Julie; Graham, Barney S.; Mascola, John R.; Cohen, Myron; Corey, Lawrence

2017-01-01

Background Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. Methods The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Results Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. Conclusions The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention. PMID:29218117

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials.

PubMed

Gilbert, Peter B; Juraska, Michal; deCamp, Allan C; Karuna, Shelly; Edupuganti, Srilatha; Mgodi, Nyaradzo; Donnell, Deborah J; Bentley, Carter; Sista, Nirupama; Andrew, Philip; Isaacs, Abby; Huang, Yunda; Zhang, Lily; Capparelli, Edmund; Kochar, Nidhi; Wang, Jing; Eshleman, Susan H; Mayer, Kenneth H; Magaret, Craig A; Hural, John; Kublin, James G; Gray, Glenda; Montefiori, David C; Gomez, Margarita M; Burns, David N; McElrath, Julie; Ledgerwood, Julie; Graham, Barney S; Mascola, John R; Cohen, Myron; Corey, Lawrence

2017-01-01

Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

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

PubMed

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

2017-08-01

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

The dry eye assessment and management (DREAM©) study: Study design and baseline characteristics.

PubMed

Asbell, Penny A; Maguire, Maureen G; Peskin, Ellen; Bunya, Vatinee Y; Kuklinski, Eric J

2018-06-05

Describe trial design and baseline characteristics of participants in the DRy Eye Assessment and Management (DREAM©) Study. Prospective, multi-center, randomized, double-masked "real-world" clinical trial assessing efficacy and safety of oral omega-3 (ω3) supplementation for the treatment of dry eye disease (DED). RESULTS: Mean age of participants was 58.0 ± 13.2 years. Mean OSDI score at baseline was 44.4 ± 14.2. Mean conjunctival staining score (scale 0-6) was 3.0 ± 1.4, corneal staining score (scale 0-15) was 3.9 ± 2.7, tear break-up time was 3.1 ± 1.5 s, and Schirmer test was 9.6 ± 6.5 mm/5 min. DREAM© participants mirror real world patients who seek intervention for their DED-related symptoms despite their current treatments. Results regarding the efficacy of omega-3 supplementation will be helpful to clinicians and patients with moderate to severe DED who are considering omega-3 as a treatment. This trial design may be a model for future RCT's on nutritional supplements and DED treatments seeking to provide useful information for clinical practice. ClinicalTrials.gov number NCT02128763. Copyright © 2017. Published by Elsevier Inc.

What can qualitative research do for randomised controlled trials? A systematic mapping review

PubMed Central

O'Cathain, A; Thomas, K J; Drabble, S J; Rudolph, A; Hewison, J

2013-01-01

Objective To develop an empirically based framework of the aspects of randomised controlled trials addressed by qualitative research. Design Systematic mapping review of qualitative research undertaken with randomised controlled trials and published in peer-reviewed journals. Data sources MEDLINE, PreMEDLINE, EMBASE, the Cochrane Library, Health Technology Assessment, PsycINFO, CINAHL, British Nursing Index, Social Sciences Citation Index and ASSIA. Eligibility criteria Articles reporting qualitative research undertaken with trials published between 2008 and September 2010; health research, reported in English. Results 296 articles met the inclusion criteria. Articles focused on 22 aspects of the trial within five broad categories. Some articles focused on more than one aspect of the trial, totalling 356 examples. The qualitative research focused on the intervention being trialled (71%, 254/356); the design, process and conduct of the trial (15%, 54/356); the outcomes of the trial (1%, 5/356); the measures used in the trial (3%, 10/356); and the target condition for the trial (9%, 33/356). A minority of the qualitative research was undertaken at the pretrial stage (28%, 82/296). The value of the qualitative research to the trial itself was not always made explicit within the articles. The potential value included optimising the intervention and trial conduct, facilitating interpretation of the trial findings, helping trialists to be sensitive to the human beings involved in trials, and saving money by steering researchers towards interventions more likely to be effective in future trials. Conclusions A large amount of qualitative research undertaken with specific trials has been published, addressing a wide range of aspects of trials, with the potential to improve the endeavour of generating evidence of effectiveness of health interventions. Researchers can increase the impact of this work on trials by undertaking more of it at the pretrial stage and being explicit within their articles about the learning for trials and evidence-based practice. PMID:23794542

Person mobility in the design and analysis of cluster-randomized cohort prevention trials.

PubMed

Vuchinich, Sam; Flay, Brian R; Aber, Lawrence; Bickman, Leonard

2012-06-01

Person mobility is an inescapable fact of life for most cluster-randomized (e.g., schools, hospitals, clinic, cities, state) cohort prevention trials. Mobility rates are an important substantive consideration in estimating the effects of an intervention. In cluster-randomized trials, mobility rates are often correlated with ethnicity, poverty and other variables associated with disparity. This raises the possibility that estimated intervention effects may generalize to only the least mobile segments of a population and, thus, create a threat to external validity. Such mobility can also create threats to the internal validity of conclusions from randomized trials. Researchers must decide how to deal with persons who leave study clusters during a trial (dropouts), persons and clusters that do not comply with an assigned intervention, and persons who enter clusters during a trial (late entrants), in addition to the persons who remain for the duration of a trial (stayers). Statistical techniques alone cannot solve the key issues of internal and external validity raised by the phenomenon of person mobility. This commentary presents a systematic, Campbellian-type analysis of person mobility in cluster-randomized cohort prevention trials. It describes four approaches for dealing with dropouts, late entrants and stayers with respect to data collection, analysis and generalizability. The questions at issue are: 1) From whom should data be collected at each wave of data collection? 2) Which cases should be included in the analyses of an intervention effect? and 3) To what populations can trial results be generalized? The conclusions lead to recommendations for the design and analysis of future cluster-randomized cohort prevention trials.

Development of custom measurement system for biomechanical evaluation of independent wheelchair transfers.

PubMed

Koontz, Alicia M; Lin, Yen-Sheng; Kankipati, Padmaja; Boninger, Michael L; Cooper, Rory A

2011-01-01

This study describes a new custom measurement system designed to investigate the biomechanics of sitting-pivot wheelchair transfers and assesses the reliability of selected biomechanical variables. Variables assessed include horizontal and vertical reaction forces underneath both hands and three-dimensional trunk, shoulder, and elbow range of motion. We examined the reliability of these measures between 5 consecutive transfer trials for 5 subjects with spinal cord injury and 12 nondisabled subjects while they performed a self-selected sitting pivot transfer from a wheelchair to a level bench. A majority of the biomechanical variables demonstrated moderate to excellent reliability (r > 0.6). The transfer measurement system recorded reliable and valid biomechanical data for future studies of sitting-pivot wheelchair transfers.We recommend a minimum of five transfer trials to obtain a reliable measure of transfer technique for future studies.

Polymer therapeutics at a crossroads? Finding the path for improved translation in the twenty-first century.

PubMed

Duncan, Ruth

Despite the relatively small early investment, first generation 'polymer therapeutics' have been remarkably successful with more than 25 products licenced for human use as polymeric drugs, sequestrants, conjugates, and as an imaging agent. Many exhibit both clinical and commercial success with new concepts already in clinical trials. Nevertheless after four decades of evolution, this field is arriving at an important crossroads. Over the last decade, the landscape has changed rapidly. There are an increasing number of failed clinical trials, the number of 'copy' and 'generic' products is growing (danger of ignoring the biological rationale for design and suppression of innovation), potential drawbacks of PEG are becoming more evident, and the 'nanomedicine' boom has brought danger of loss of scientific focus/hype. Grasping opportunities provided by advances in understanding of the patho-physiology and molecular basis of diseases, new polymer/conjugate synthetic and analytical methods, as well as the large database of clinical experience will surely ensure a successful future for innovative polymer therapeutics. Progress will, however, be in jeopardy if polymer safety is overlooked in respect of the specific route of administration/clinical use, poorly characterised materials/formulations are used to define biological or early clinical properties, and if clinical trial protocols fail to select patients most likely to benefit from these macromolecular therapeutics. Opportunities to improve clinical trial design for polymer-anticancer drug conjugates are discussed. This short personal perspective summarises some of the important challenges facing polymer therapeutics in R&D today, and future opportunities to improve successful translation.

Design of clinical trials of antidepressants: should a placebo control arm be included?

PubMed

Fritze, J; Möller, H J

2001-01-01

There is no doubt that available antidepressants are efficacious and effective. Nevertheless, more effective drugs with improved tolerability are needed. With this need in mind, some protagonists claim that future antidepressants should be proved superior to, or at least as effective as, established antidepressants, making placebo control methodologically dispensable in clinical trials. Moreover, the use of placebo control is criticised as unethical because it might result in effective treatment being withheld. There are, however, a number of methodological reasons why placebo control is indispensable for the proof of efficacy of antidepressants. Comparing investigational antidepressants only with standard antidepressants and not placebo yields ambiguous results that are difficult to interpret, be it in superiority or equivalence testing, and this method of assessment requires larger sample sizes than those required with the use of placebo control. Experimental methodology not adhering to the optimal study design is ethically questionable. Restricting the testing of investigational antidepressants only to superiority over standard antidepressants is an obstacle to therapeutic progress in terms of tolerability and the detection of innovative mechanisms of action from which certain subgroups of future patients might benefit. The use of a methodology that requires larger samples for testing of superiority or equivalence is also ethically questionable. In view of the high placebo response rates in trials of antidepressants, placebo treatment does not mean withholding effective treatment. Accepting the necessity of the clinical evaluation of new, potentially ineffective antidepressants implicitly means accepting placebo control as ethically justified. Three- or multi-arm comparisons including placebo and an active reference represent the optimal study design.

Internet and cardiovascular research: the present and its future potentials and limits.

PubMed

2002-03-01

The Internet and the World Wide Web have been proposed as tools to improve medical and cardiovascular research. These new technologies have been mainly applied to large-scale clinical trials, with the development of clinical-trial websites. They include tools for the management of some aspects of clinical trials, such as the dissemination of information on trial progress; randomisation and the monitoring processes; the distribution and accountability of study drugs; and remote data-entry. Several clinical-trial websites have been developed in the cardiovascular field over the last few years, but few have been designed to conduct trials fully online. Advantages of such systems include greater interaction between the coordinating centre and investigators, availability of a clean database in a short time, and cost reduction. Website developers need to take care of security issues and to use security tools (data encryption, firewalls, passwords and electronic signatures) in order to prevent unauthorised users from accessing the system and patient data.

The Effects of Interactive and Passive Distraction on Cold Pressor Pain in Preschool-aged Children

PubMed Central

Dahlquist, Lynnda M.; Wohlheiter, Karen

2011-01-01

Objective Using a mixed model design, this study examined the effects of interactive versus passive distraction on healthy preschool-aged children’s cold pressor pain tolerance. Methods Sixty-one children aged 3–5 years were randomly assigned to one of the following: interactive distraction, passive distraction, or no distraction control. Participants underwent a baseline cold pressor trial followed by interactive distraction trial, passive distraction trial, or second baseline trial. One or two additional trials followed. Children originally assigned to distraction received the alternate distraction intervention. Controls participated in both interactive and passive distraction trials in counterbalanced order. Results Participants showed significantly higher pain tolerance during both interactive and passive distraction relative to baseline. The two distraction conditions did not differ. Conclusions Interactive and passive video game distraction appear to be effective for preschool-aged children during laboratory pain exposure. Future studies should examine whether more extensive training would enhance effects of interactive video game distraction. PMID:21278378

Co-designing the next generation of home energy management systems with lead-users.

PubMed

Peacock, Andrew D; Chaney, Joel; Goldbach, Kristin; Walker, Guy; Tuohy, Paul; Santonja, Salvador; Todoli, David; Owens, Edward H

2017-04-01

Home energy management systems are widely promoted as essential components of future low carbon economies. It is argued in this paper that assumptions surrounding their deployment, and the methods used to design them, emerge from discredited models of people and energy. This offers an explanation for why their field trial performance is so inconsistent. A first of a kind field trial is reported. Three eco communities took part in a comprehensive participatory design exercise as lead users. The challenge was to help users synchronise their energy use behaviours with the availability of locally generated renewable energy sources. To meet this aim, a set of highly novel Home Energy Management interfaces were co-designed and tested. Not only were the designs radically different to the norm, but they also yielded sustained user engagement over a six-month follow-up period. It is argued that user-centred design holds the key to unlocking the energy saving potential of new domestic technologies, and this study represents a bold step in that direction. Copyright © 2016 Elsevier Ltd. All rights reserved.

A novel cognitive behaviour therapy for bipolar disorders (Think Effectively About Mood Swings or TEAMS): study protocol for a randomized controlled trial.

PubMed

Mansell, Warren; Tai, Sara; Clark, Alexandra; Akgonul, Savas; Dunn, Graham; Davies, Linda; Law, Heather; Morriss, Richard; Tinning, Neil; Morrison, Anthony P

2014-10-24

Existing psychological therapies for bipolar disorders have been found to have mixed results, with a consensus that they provide a significant, but modest, effect on clinical outcomes. Typically, these approaches have focused on promoting strategies to prevent future relapse. An alternative treatment approach, termed 'Think Effectively About Mood Swings' (TEAMS) addresses current symptoms, including subclinical hypomania, depression and anxiety, and promotes long-term recovery. Following the publication of a theoretical model, a range of research studies testing the model and a case series have demonstrated positive results. The current study reports the protocol of a feasibility randomized controlled trial to inform a future multi-centre trial. A target number of 84 patients with a diagnosis of bipolar I or II disorder, or bipolar disorder not-otherwise-specified are screened, allocated to a baseline assessment and randomized to either 16 sessions of TEAMS therapy plus treatment-as-usual (TAU) or TAU. Patients complete self-report inventories of depression, anxiety, recovery status and bipolar cognitions targeted by TEAMS. Assessments of diagnosis, bipolar symptoms, medication, access to services and quality of life are conducted by assessors blind to treatment condition at 3, 6, 12 and 18 months post-randomization. The main aim is to evaluate recruitment and retention of participants into both arms of the study, as well as adherence to therapy, to determine feasibility and acceptability. It is predicted that TEAMS plus TAU will reduce self-reported depression in comparison to TAU alone at six months post-randomization. The secondary hypotheses are that TEAMS will reduce the severity of hypomanic symptoms and anxiety, reduce bipolar cognitions, improve social functioning and promote recovery compared to TAU alone at post-treatment and follow-up. The study also incorporates semi-structured interviews about the experiences of previous treatment and the experience of TEAMS therapy that will be subject to qualitative analyses to inform future developments of the approach. The design will provide preliminary evidence of efficacy, feasibility, acceptability, uptake, attrition and barriers to treatment to design a definitive trial of this novel intervention compared to treatment as usual. This trial was registered with Current Controlled Trials (ISRCTN83928726) on registered 25 July 2014.

Control group design, contamination and drop-out in exercise oncology trials: a systematic review.

PubMed

Steins Bisschop, Charlotte N; Courneya, Kerry S; Velthuis, Miranda J; Monninkhof, Evelyn M; Jones, Lee W; Friedenreich, Christine; van der Wall, Elsken; Peeters, Petra H M; May, Anne M

2015-01-01

Important considerations for exercise trials in cancer patients are contamination and differential drop-out among the control group members that might jeopardize the internal validity. This systematic review provides an overview of different control groups design characteristics of exercise-oncology trials and explores the association with contamination and drop-out rates. Randomized controlled exercise-oncology trials from two Cochrane reviews were included. Additionally, a computer-aided search using Medline (Pubmed), Embase and CINAHL was conducted after completion date of the Cochrane reviews. Eligible studies were classified according to three control group design characteristics: the exercise instruction given to controls before start of the study (exercise allowed or not); and the intervention the control group was offered during (any (e.g., education sessions or telephone contacts) or none) or after (any (e.g., cross-over or exercise instruction) or none) the intervention period. Contamination (yes or no) and excess drop-out rates (i.e., drop-out rate of the control group minus the drop-out rate exercise group) were described according to the three design characteristics of the control group and according to the combinations of these three characteristics; so we additionally made subgroups based on combinations of type and timing of instructions received. 40 exercise-oncology trials were included based on pre-specified eligibility criteria. The lowest contamination (7.1% of studies) and low drop-out rates (excess drop-out rate -4.7±9.2) were found in control groups offered an intervention after the intervention period. When control groups were offered an intervention both during and after the intervention period, contamination (0%) and excess drop-out rates (-10.0±12.8%) were even lower. Control groups receiving an intervention during and after the study intervention period have lower contamination and drop-out rates. The present findings can be considered when designing future exercise-oncology trials.

Vaccine testing for emerging infections: the case for individual randomisation.

PubMed

Eyal, Nir; Lipsitch, Marc

2017-09-01

During the 2014-2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, many opposed the use of individually randomised controlled trials to test candidate Ebola vaccines. For a raging fatal disease, they explained, it is unethical to relegate some study participants to control arms. In Zika and future emerging infections, similar opposition may hinder urgent vaccine research, so it is best to address these questions now. This article lays out the ethical case for individually randomised control in testing vaccines against many emerging infections, including lethal infections in low-income countries, even when at no point in the trial do the controls receive the countermeasures being tested. When individual randomisation is feasible-and it often will be-it tends to save more lives than alternative designs would. And for emerging infections, individual randomisation also tends as such to improve care, access to the experimental vaccine and prospects for all participants relative to their opportunities absent the trial, and no less than alternative designs would. That obtains even under placebo control and without equipoise-requiring which would undermine individual randomisation and the alternative designs that opponents proffered. Our arguments expound four often-neglected factors: benefits to non-participants, benefits to participants once a trial is over including post-trial access to the study intervention, participants' prospects before randomisation to arms and the near-inevitable disparity between arms in any randomised controlled trial. 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/.

On the value of therapeutic interventions targeting the complement system in acute myocardial infarction.

PubMed

Emmens, Reindert W; Wouters, Diana; Zeerleder, Sacha; van Ham, S Marieke; Niessen, Hans W M; Krijnen, Paul A J

2017-04-01

The complement system plays an important role in the inflammatory response subsequent to acute myocardial infarction (AMI). The aim of this study is to create a systematic overview of studies that have investigated therapeutic administration of complement inhibitors in both AMI animal models and human clinical trials. To enable extrapolation of observations from included animal studies toward post-AMI clinical trials, ex vivo studies on isolated hearts and proof-of-principle studies on inhibitor administration before experimental AMI induction were excluded. Positive therapeutic effects in AMI animal models have been described for cobra venom factor, soluble complement receptor 1, C1-esterase inhibitor (C1-inh), FUT-175, C1s-inhibitor, anti-C5, ADC-1004, clusterin, and glycosaminoglycans. Two types of complement inhibitors have been tested in clinical trials, being C1-inh and anti-C5. Pexelizumab (anti-C5) did not result in reproducible beneficial effects for AMI patients. Beneficial effects were reported in AMI patients for C1-inhibitor, albeit in small patient groups. In general, despite the absence of consistent positive effects in clinical trials thus far, the complement system remains a potentially interesting target for therapy in AMI patients. Based on the study designs of previous animal studies and clinical trials, we discuss several issues which require attention in the design of future studies: adjustment of clinical trial design to precise mechanism of action of administered inhibitor, optimizing the duration of therapy, and optimization of time point(s) on which therapeutic effects will be evaluated. Copyright © 2016 Elsevier Inc. All rights reserved.

Analysis of edge density fluctuation measured by trial KSTAR beam emission spectroscopy systema)

NASA Astrophysics Data System (ADS)

Nam, Y. U.; Zoletnik, S.; Lampert, M.; Kovácsik, Á.

2012-10-01

A beam emission spectroscopy (BES) system based on direct imaging avalanche photodiode (APD) camera has been designed for Korea Superconducting Tokamak Advanced Research (KSTAR) and a trial system has been constructed and installed for evaluating feasibility of the design. The system contains two cameras, one is an APD camera for BES measurement and another is a fast visible camera for position calibration. Two pneumatically actuated mirrors were positioned at front and rear of lens optics. The front mirror can switch the measurement between edge and core region of plasma and the rear mirror can switch between the APD and the visible camera. All systems worked properly and the measured photon flux was reasonable as expected from the simulation. While the measurement data from the trial system were limited, it revealed some interesting characteristics of KSTAR plasma suggesting future research works with fully installed BES system. The analysis result and the development plan will be presented in this paper.

Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

PubMed Central

Nicastro, Holly L.; Dunn, Barbara K.

2013-01-01

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention. PMID:23552052

Studying the effects of classic hallucinogens in the treatment of alcoholism: rationale, methodology, and current research with psilocybin.

PubMed

Bogenschutz, Michael P

2013-03-01

Recent developments in the study of classic hallucinogens, combined with a re-appraisal of the older literature, have led to a renewal of interest in possible therapeutic applications for these drugs, notably their application in the treatment of addictions. This article will first provide a brief review of the research literature providing direct and indirect support for the possible therapeutic effects of classic hallucinogens such as psilocybin and lysergic acid diethylamide (LSD) in the treatment of addictions. Having provided a rationale for clinical investigation in this area, we discuss design issues in clinical trials using classic hallucinogens, some of which are unique to this class of drug. We then discuss the current status of this field of research and design considerations in future randomized trials.

Recommendations for imaging tumor response in neurofibromatosis clinical trials

PubMed Central

Ardern-Holmes, Simone L.; Babovic-Vuksanovic, Dusica; Barker, Fred G.; Connor, Steve; Evans, D. Gareth; Fisher, Michael J.; Goutagny, Stephane; Harris, Gordon J.; Jaramillo, Diego; Karajannis, Matthias A.; Korf, Bruce R.; Mautner, Victor; Plotkin, Scott R.; Poussaint, Tina Y.; Robertson, Kent; Shih, Chie-Schin; Widemann, Brigitte C.

2013-01-01

Objective: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. Conclusions: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors. PMID:24249804

Recommendations for imaging tumor response in neurofibromatosis clinical trials.

PubMed

Dombi, Eva; Ardern-Holmes, Simone L; Babovic-Vuksanovic, Dusica; Barker, Fred G; Connor, Steve; Evans, D Gareth; Fisher, Michael J; Goutagny, Stephane; Harris, Gordon J; Jaramillo, Diego; Karajannis, Matthias A; Korf, Bruce R; Mautner, Victor; Plotkin, Scott R; Poussaint, Tina Y; Robertson, Kent; Shih, Chie-Schin; Widemann, Brigitte C

2013-11-19

Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

PubMed

Kloppenburg, M; Maheu, E; Kraus, V B; Cicuttini, F; Doherty, M; Dreiser, R-L; Henrotin, Y; Jiang, G-L; Mandl, L; Martel-Pelletier, J; Nelson, A E; Neogi, T; Pelletier, J-P; Punzi, L; Ramonda, R; Simon, L S; Wang, S

2015-05-01

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders.

PubMed

Karanth, Laxminarayan; Barua, Ankur; Kanagasabai, Sachchithanantham; Nair, Sreekumar

2015-09-09

Congenital bleeding disorders can cause obstetric haemorrhage during pregnancy, labour and following delivery. Desmopressin acetate is found to be an effective drug which can reduce the risk of haemorrhage and can also stop bleeding in certain congenital bleeding disorders. Its use in pregnancy has been controversial. Hence beneficial and adverse effects of desmopressin acetate in these groups of pregnant women should be evaluated.This is an update of a Cochrane review first published in 2013. To determine the efficacy of desmopressin acetate in preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant and abstract books of conferences proceedings. We also searched for any randomised controlled trials in a registry of ongoing trials and the reference lists of relevant articles and reviews.Date of most recent search: 18 June 2015. Randomised and quasi-randomised controlled trials investigating the efficacy of desmopressin acetate versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. The review did not identify any randomised controlled trials investigating the relative effectiveness of desmopressin acetate for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with desmopressin acetate.Given the ethical considerations, future randomised controlled trials are unlikely. However, other high quality controlled studies (such as risk allocation designs, sequential design, parallel cohort design) to investigate the risks and benefits of using desmopressin acetate in this population are needed.

Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders.

PubMed

Karanth, Laxminarayan; Barua, Ankur; Kanagasabai, Sachchithanantham; Nair, N S

2013-04-30

Congenital bleeding disorders can cause obstetric haemorrhage during pregnancy, labour and following delivery. Desmopressin acetate is found to be an effective drug which can reduce the risk of haemorrhage and can also stop bleeding in certain congenital bleeding disorders. Its use in pregnancy has been controversial. Hence beneficial and adverse effects of desmopressin acetate in these groups of pregnant women should be evaluated. To determine the efficacy of desmopressin acetate in preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant and abstract books of conferences proceedings. We also searched for any randomised controlled trials in a registry of ongoing trials and the reference lists of relevant articles and reviews.Date of most recent search: 28 February 2013. Randomised and quasi-randomised controlled trials investigating the efficacy of desmopressin acetate versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. The review did not identify any randomised controlled trials investigating the relative effectiveness of desmopressin acetate for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with desmopressin acetate.Given the ethical considerations, future randomised controlled trials are unlikely. However, other high quality controlled studies (such as risk allocation designs, sequential design, parallel cohort design) to investigate the risks and benefits of using desmopressin acetate in this population are needed.

Retinal Implants for Blind Patients

NASA Astrophysics Data System (ADS)

Rothermel, Albrecht

Recently, very promising results have been obtained in clinical trials with eye-prostheses for the blind. There is a chance that advances in surgical techniques, microelectronics design, and material science may lead to the first really useful applications of retinal implants in the near future. This chapter will focus on the actual status of subretinal surgery and implant technologies. Opportunities and limitations of the different technologies will be discussed in terms of patients benefit and technological challenges. Finally, a vision on how the devices may work and look like in the future will be given.

Nanosystem trends in drug delivery using quality-by-design concept.

PubMed

Li, Jing; Qiao, Yanjiang; Wu, Zhisheng

2017-06-28

Quality by design (QbD) has become an inevitable trend because of its benefits for product quality and process understanding. Trials have been conducted using QbD in nanosystems' optimization. This paper reviews the application of QbD for processing nanosystems and summarizes the application procedure. It provides prospective guidelines for future investigations that apply QbD to nanosystem manufacturing processes. Employing the QbD concept in this way is a novel area in nanosystem quality. Copyright © 2017 Elsevier B.V. All rights reserved.

Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials.

PubMed

Roth, Daniel E; Leung, Michael; Mesfin, Elnathan; Qamar, Huma; Watterworth, Jessica; Papp, Eszter

2017-11-29

Objectives  To estimate the effects of vitamin D supplementation during pregnancy on 11 maternal and 27 neonatal/infant outcomes; to determine frequencies at which trial outcome data were missing, unreported, or inconsistently reported; and to project the potential contributions of registered ongoing or planned trials. Design  Systematic review and meta-analysis of randomised controlled trials; systematic review of registered but unpublished trials. Data sources  Medline, Embase, PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to September 2017; manual searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials. Eligibility criteria for study selection  Trials of prenatal vitamin D supplementation with randomised allocation and control groups administered placebo, no vitamin D, or vitamin D ≤600 IU/day (or its equivalent), and published in a peer reviewed journal. Results  43 trials (8406 participants) were eligible for meta-analyses. Median sample size was 133 participants. Vitamin D increased maternal/cord serum concentration of 25-hydroxyvitamin D, but the dose-response effect was weak. Maternal clinical outcomes were rarely ascertained or reported, but available data did not provide evidence of benefits. Overall, vitamin D increased mean birth weight of 58.33 g (95% confidence interval 18.88 g to 97.78 g; 37 comparisons) and reduced the risk of small for gestational age births (risk ratio 0.60, 95% confidence interval 0.40 to 0.90; seven comparisons), but findings were not robust in sensitivity and subgroup analyses. There was no effect on preterm birth (1.0, 0.77 to 1.30; 15 comparisons). There was strong evidence that prenatal vitamin D reduced the risk of offspring wheeze by age 3 years (0.81, 0.67 to 0.98; two comparisons). For most outcomes, meta-analyses included data from a minority of trials. Only eight of 43 trials (19%) had an overall low risk of bias. Thirty five planned/ongoing randomised controlled trials could contribute 12 530 additional participants to future reviews. Conclusions  Most trials on prenatal vitamin D published by September 2017 were small and of low quality. The evidence to date seems insufficient to guide clinical or policy recommendations. Future trials should be designed and powered to examine clinical endpoints, including maternal conditions related to pregnancy (such as pre-eclampsia), infant growth, and respiratory outcomes. Systematic review registration  PROSPERO CRD42016051292. 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.

Bristol girls dance project feasibility study: using a pilot economic evaluation to inform design of a full trial

PubMed Central

Powell, Jane E; Carroll, Fran E; Sebire, Simon J; Haase, Anne M; Jago, Russell

2013-01-01

Background There is currently little guidance for pilot trial economic evaluation where health outcomes and costs are influenced by a range of wider determinants and factors. Objectives This article presents the findings of a pilot economic evaluation study running alongside the Bristol Girls Dance Project (BGDP) feasibility study. Design 3-arm, cluster randomised, controlled pilot trial and economic evaluation. 7 schools (n=210) from the Bristol and greater Bristol area, UK were randomly allocated to the intervention arm 3 schools (n=90) and the control arm 4 schools (n=120). Intervention Girls aged 11–12 years with parental consent were provided with two, 90 min dance sessions per week for 9 weeks at school facilities. Economic outcome measures Programme costs and girls’ preferences for attributes of dance and preferences for competing leisure time activities were measured. Results The mainstream average cost of the BGDP programme (not including research, control and dance teacher training costs) per school was $2126.40, £1329 and €1555 and per participant was $70.90, £44.31 and €51.84 in 2010–2011 prices. Discrete choice experiment (DCE) methods are acceptable to girls of this age indicating time available for other leisure activities on dance class days is the attribute girls valued most and 2 h leisure time remaining preferred to 3 h. Conclusions This pilot study indicates that providing full cost data for a future trial of the BGDP programme is feasible and practical. There is no evidence from preference data to support adjustment to intervention design. A future economic evaluation is likely to be successful utilising the resource use checklist developed. The importance of categorising separately resources used to develop, prepare, deliver and maintain the programme to estimate mainstream costs accurately is demonstrated. PMID:24362013

A pragmatic multi-centre randomised controlled trial of fluid loading and level of dependency in high-risk surgical patients undergoing major elective surgery: trial protocol

PubMed Central

2010-01-01

Background Patients undergoing major elective or urgent surgery are at high risk of death or significant morbidity. Measures to reduce this morbidity and mortality include pre-operative optimisation and use of higher levels of dependency care after surgery. We propose a pragmatic multi-centre randomised controlled trial of level of dependency and pre-operative fluid therapy in high-risk surgical patients undergoing major elective surgery. Methods/Design A multi-centre randomised controlled trial with a 2 * 2 factorial design. The first randomisation is to pre-operative fluid therapy or standard regimen and the second randomisation is to routine intensive care versus high dependency care during the early post-operative period. We intend to recruit 204 patients undergoing major elective and urgent abdominal and thoraco-abdominal surgery who fulfil high-risk surgical criteria. The primary outcome for the comparison of level of care is cost-effectiveness at six months and for the comparison of fluid optimisation is the number of hospital days after surgery. Discussion We believe that the results of this study will be invaluable in determining the future care and clinical resource utilisation for this group of patients and thus will have a major impact on clinical practice. Trial Registration Trial registration number - ISRCTN32188676 PMID:20398378

Therapeutic advances in multiple system atrophy and progressive supranuclear palsy.

PubMed

Poewe, Werner; Mahlknecht, Philipp; Krismer, Florian

2015-09-15

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included α-synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease-modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.

Implementation and results of an integrated data quality assurance protocol in a randomized controlled trial in Uttar Pradesh, India.

PubMed

Gass, Jonathon D; Misra, Anamika; Yadav, Mahendra Nath Singh; Sana, Fatima; Singh, Chetna; Mankar, Anup; Neal, Brandon J; Fisher-Bowman, Jennifer; Maisonneuve, Jenny; Delaney, Megan Marx; Kumar, Krishan; Singh, Vinay Pratap; Sharma, Narender; Gawande, Atul; Semrau, Katherine; Hirschhorn, Lisa R

2017-09-07

There are few published standards or methodological guidelines for integrating Data Quality Assurance (DQA) protocols into large-scale health systems research trials, especially in resource-limited settings. The BetterBirth Trial is a matched-pair, cluster-randomized controlled trial (RCT) of the BetterBirth Program, which seeks to improve quality of facility-based deliveries and reduce 7-day maternal and neonatal mortality and maternal morbidity in Uttar Pradesh, India. In the trial, over 6300 deliveries were observed and over 153,000 mother-baby pairs across 120 study sites were followed to assess health outcomes. We designed and implemented a robust and integrated DQA system to sustain high-quality data throughout the trial. We designed the Data Quality Monitoring and Improvement System (DQMIS) to reinforce six dimensions of data quality: accuracy, reliability, timeliness, completeness, precision, and integrity. The DQMIS was comprised of five functional components: 1) a monitoring and evaluation team to support the system; 2) a DQA protocol, including data collection audits and targets, rapid data feedback, and supportive supervision; 3) training; 4) standard operating procedures for data collection; and 5) an electronic data collection and reporting system. Routine audits by supervisors included double data entry, simultaneous delivery observations, and review of recorded calls to patients. Data feedback reports identified errors automatically, facilitating supportive supervision through a continuous quality improvement model. The five functional components of the DQMIS successfully reinforced data reliability, timeliness, completeness, precision, and integrity. The DQMIS also resulted in 98.33% accuracy across all data collection activities in the trial. All data collection activities demonstrated improvement in accuracy throughout implementation. Data collectors demonstrated a statistically significant (p = 0.0004) increase in accuracy throughout consecutive audits. The DQMIS was successful, despite an increase from 20 to 130 data collectors. In the absence of widely disseminated data quality methods and standards for large RCT interventions in limited-resource settings, we developed an integrated DQA system, combining auditing, rapid data feedback, and supportive supervision, which ensured high-quality data and could serve as a model for future health systems research trials. Future efforts should focus on standardization of DQA processes for health systems research. ClinicalTrials.gov identifier, NCT02148952 . Registered on 13 February 2014.

The feasibility and acceptability of trial procedures for a pragmatic randomised controlled trial of a structured physical activity intervention for people diagnosed with colorectal cancer: findings from a pilot trial of cardiac rehabilitation versus usual care (no rehabilitation) with an embedded qualitative study.

PubMed

Hubbard, Gill; O'Carroll, Ronan; Munro, Julie; Mutrie, Nanette; Haw, Sally; Mason, Helen; Treweek, Shaun

2016-01-01

Pilot and feasibility work is conducted to evaluate the operational feasibility and acceptability of the intervention itself and the feasibility and acceptability of a trials' protocol design. The Cardiac Rehabilitation In Bowel cancer (CRIB) study was a pilot randomised controlled trial (RCT) of cardiac rehabilitation versus usual care (no rehabilitation) for post-surgical colorectal cancer patients. A key aim of the pilot trial was to test the feasibility and acceptability of the protocol design. A pilot RCT with embedded qualitative work was conducted in three sites. Participants were randomly allocated to cardiac rehabilitation or usual care groups. Outcomes used to assess the feasibility and acceptability of key trial parameters were screening, eligibility, consent, randomisation, adverse events, retention, completion, missing data, and intervention adherence rates. Colorectal patients' and clinicians' perceptions and experiences of the main trial procedures were explored by interview. Quantitative study. Three sites were involved. Screening, eligibility, consent, and retention rates were 79 % (156/198), 67 % (133/198), 31 % (41/133), and 93 % (38/41), respectively. Questionnaire completion rates were 97.5 % (40/41), 75 % (31/41), and 61 % (25/41) at baseline, follow-up 1, and follow-up 2, respectively. Sixty-nine percent (40) of accelerometer datasets were collected from participants; 31 % (20) were removed for not meeting wear-time validation. Qualitative study: Thirty-eight patients and eight clinicians participated. Key themes were benefits for people with colorectal cancer attending cardiac rehabilitation, barriers for people with colorectal cancer attending cardiac rehabilitation, generic versus disease-specific rehabilitation, key concerns about including people with cancer in cardiac rehabilitation, and barriers to involvement in a study about cardiac rehabilitation. The study highlights where threats to internal and external validity are likely to arise in any future studies of similar structured physical activity interventions for colorectal cancer patients using similar methods being conducted in similar contexts. This study shows that there is likely to be potential recruitment bias and potential imprecision due to sub-optimal completion of outcome measures, missing data, and sub-optimal intervention adherence. Hence, strategies to manage these risks should be developed to stack the odds in favour of conducting successful future trials. ISRCTN63510637.

Effects of sources of variability on sample sizes required for RCTs, applied to trials of lipid-altering therapies on carotid artery intima-media thickness.

PubMed

Gould, A Lawrence; Koglin, Joerg; Bain, Raymond P; Pinto, Cathy-Anne; Mitchel, Yale B; Pasternak, Richard C; Sapre, Aditi

2009-08-01

Studies measuring progression of carotid artery intima-media thickness (cIMT) have been used to estimate the effect of lipid-modifying therapies cardiovascular event risk. The likelihood that future cIMT clinical trials will detect a true treatment effect is estimated by leveraging results from prior studies. The present analyses assess the impact of between- and within-study variability based on currently published data from prior clinical studies on the likelihood that ongoing or future cIMT trials will detect the true treatment effect of lipid-modifying therapies. Published data from six contemporary cIMT studies (ASAP, ARBITER 2, RADIANCE 1, RADIANCE 2, ENHANCE, and METEOR) including data from a total of 3563 patients were examined. Bayesian and frequentist methods were used to assess the impact of between study variability on the likelihood of detecting true treatment effects on 1-year cIMT progression/regression and to provide a sample size estimate that would specifically compensate for the effect of between-study variability. In addition to the well-described within-study variability, there is considerable between-study variability associated with the measurement of annualized change in cIMT. Accounting for the additional between-study variability decreases the power for existing study designs. In order to account for the added between-study variability, it is likely that future cIMT studies would require a large increase in sample size in order to provide substantial probability (> or =90%) to have 90% power of detecting a true treatment effect.Limitation Analyses are based on study level data. Future meta-analyses incorporating patient-level data would be useful for confirmation. Due to substantial within- and between-study variability in the measure of 1-year change of cIMT, as well as uncertainty about progression rates in contemporary populations, future study designs evaluating the effect of new lipid-modifying therapies on atherosclerotic disease progression are likely to be challenged by large sample sizes in order to demonstrate a true treatment effect.

A pilot randomised double blind controlled trial of the efficacy of purified fatty acids for the treatment of women with endometriosis-associated pain (PurFECT): study protocol.

PubMed

Abokhrais, Ibtisam M; Saunders, Philippa T K; Denison, Fiona C; Doust, Ann; Williams, Linda; Horne, Andrew W

2018-01-01

Endometriosis affects 6-10% of women and is associated with debilitating pelvic pain. It costs the UK > £2.8 billion per year in loss of productivity. Endometriosis can be managed by surgical excision or medically by ovarian suppression. However, ~ 75% symptoms recur after surgery and available medical treatments have undesirable side effects and are contraceptive. Omega-3 purified fatty acids (PUFA) have been shown in animal models to reduce factors that are thought to lead to endometriosis-associated pain, have minimal side effects, and no effects on fertility. This paper presents a protocol for a two-arm, pilot parallel randomised controlled trial (RCT) which aims to inform the planning of a future multicentre trial to evaluate the efficacy of Omega-3 PUFA in the management of endometriosis-associated pain in women. The study will recruit women with endometriosis over a 12-month period in the National Health Service (NHS) Lothian, UK, and randomise them to 8 weeks of treatment with Omega-3 PUFA or comparator (olive oil). The primary objective is to assess recruitment and retention rates. The secondary objectives are to determine the effectiveness/acceptability to participants of the proposed methods of recruitment/randomisation/treatments/questionnaires, to inform the sample size calculation and to refine the research methodology for a future large randomised controlled trial. Response to treatment will be monitored by pain scores and questionnaires assessing physical and emotional function compared at baseline and 8 weeks. We recognise that there may be potential difficulties in mounting a large randomised controlled trial for endometriosis to assess Omega-3 PUFA because they are a dietary supplement readily available over the counter and already used by women with endometriosis. We have therefore designed this pilot study to assess practical feasibility and following the 'Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials' recommendations for the design of chronic pain trials. ISRCTN44202346.

Selenium and glutamine supplements: where are we heading? A critical care perspective.

PubMed

Andrews, Peter J D

2010-03-01

There is considerable interest in glutamine and selenium in critical care as both offer the potential to enhance host defences, through different but complimentary mechanisms and may reduce subsequent infections and mortality. The SIGNET trial (randomized controlled factorial trial) is the largest, critical care study of both supplements. The data have been presented publicly, but the data are not published or available for review and will therefore not be discussed fully in this update. In the present review I will explore the recently available (past 1-2 years) published literature. The current literature demonstrates that there are currently insufficient data to enable confident recommendations on the optimal route, timing, duration and dosage of each of these nutritional supplements. The pending results of SIGNET, the largest critical care trial of parenteral nutrition supplemented by glutamine and or selenium promises to clarify some of the current ambiguities and inform future practice. To be able to confidently establish or refute the hypothesis that either glutamine or selenium alone or in combination improves outcome in critical care requires a well designed prospective randomized controlled trial. To design such a trial we require the optimal dose and duration of the nutritional supplement (balancing efficacy and toxicity, ease of administration and cost) and then conduct an adequately powered trial. Such a trial is still lacking for these two agents. There are some supportive data for selenium but the case is less strong for parenteral glutamine and weakest for enteral glutamine.

Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development

PubMed Central

Mulugeta, Yeruk; Barrett, Jeffrey S.; Nelson, Robert; Eshete, Abel Tilahun; Mushtaq, Alvina; Yao, Lynne; Glasgow, Nicole; Mulberg, Andrew E.; Gonzalez, Daniel; Green, Dionna; Florian, Jeffry; Krudys, Kevin; Seo, Shirley; Kim, Insook; Chilukuri, Dakshina; Burckart, Gilbert J.

2017-01-01

During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the U.S. Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the two patient populations. The main measures were the pediatric PK studies trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63-4.19 and 0.36-3.60 respectively. Seven of the 86 trials (8.1%) had a pre-defined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials. PMID:27040726

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

Development of custom measurement system for biomechanical evaluation of independent wheelchair transfers

PubMed Central

Koontz, Alicia M.; Lin, Yen-Sheng; Kankipati, Padmaja; Boninger, Michael L.; Cooper, Rory A.

2017-01-01

This study describes a new custom measurement system designed to investigate the biomechanics of sitting-pivot wheelchair transfers and assesses the reliability of selected biomechanical variables. Variables assessed include horizontal and vertical reaction forces underneath both hands and three-dimensional trunk, shoulder, and elbow range of motion. We examined the reliability of these measures between 5 consecutive transfer trials for 5 subjects with spinal cord injury and 12 non-disabled subjects while they performed a self-selected sitting pivot transfer from a wheelchair to a level bench. A majority of the biomechanical variables demonstrated moderate to excellent reliability (r > 0.6). The transfer measurement system recorded reliable and valid biomechanical data for future studies of sitting-pivot wheelchair transfers. We recommend a minimum of five transfer trials to obtain a reliable measure of transfer technique for future studies. PMID:22068376

Personalized ovarian stimulation for assisted reproductive technology: study design considerations to move from hype to added value for patients.

PubMed

Mol, Ben W; Bossuyt, Patrick M; Sunkara, Sesh K; Garcia Velasco, Juan A; Venetis, Christos; Sakkas, Denny; Lundin, Kersti; Simón, Carlos; Taylor, Hugh S; Wan, Robert; Longobardi, Salvatore; Cottell, Evelyn; D'Hooghe, Thomas

2018-06-01

Although most medical treatments are designed for the average patient with a one-size-fits-all-approach, they may not benefit all. Better understanding of the function of genes, proteins, and metabolite, and of personal and environmental factors has led to a call for personalized medicine. Personalized reproductive medicine is still in its infancy, without clear guidance on treatment aspects that could be personalized and on trial design to evaluate personalized treatment effect and benefit-harm balance. While the rationale for a personalized approach often relies on retrospective analyses of large observational studies or real-world data, solid evidence of superiority of a personalized approach will come from randomized trials comparing outcomes and safety between a personalized and one-size-fits-all strategy. A more efficient, targeted randomized trial design may recruit only patients or couples for which the personalized approach would differ from the previous, standard approach. Multiple monocenter studies using the same study protocol (allowing future meta-analysis) might reduce the major center effect associated with multicenter studies. In certain cases, single-arm observational studies can generate the necessary evidence for a personalized approach. This review describes each of the main segments of patient care in assisted reproductive technologies treatment, addressing which aspects could be personalized, emphasizing current evidence and relevant study design. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Health economics in drug development: efficient research to inform healthcare funding decisions.

PubMed

Hall, Peter S; McCabe, Christopher; Brown, Julia M; Cameron, David A

2010-10-01

In order to decide whether a new treatment should be used in patients, a robust estimate of efficacy and toxicity is no longer sufficient. As a result of increasing healthcare costs across the globe healthcare payers and providers now seek estimates of cost-effectiveness as well. Most trials currently being designed still only consider the need for prospective efficacy and toxicity data during the development life-cycle of a new intervention. Hence the cost-effectiveness estimates are inevitably less precise than the clinical data on which they are based. Methods based on decision theory are being developed by health economists that can contribute to the design of clinical trials in such a way that they can more effectively lead to better informed drug funding decisions on the basis of cost-effectiveness in addition to clinical outcomes. There is an opportunity to apply these techniques prospectively in the design of future clinical trials. This article describes the problems encountered by those responsible for drug reimbursement decisions as a consequence of the current drug development pathway. The potential for decision theoretic methods to help overcome these problems is introduced and potential obstacles in implementation are highlighted. Copyright © 2010 Elsevier Ltd. All rights reserved.

Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy

PubMed Central

Selvarajah, Dinesh; Gandhi, Rajiv; Emery, Celia J.; Tesfaye, Solomon

2010-01-01

OBJECTIVE To assess the efficacy of Sativex, a cannabis-based medicinal extract, as adjuvant treatment in painful diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS In this randomized controlled trial, 30 subjects with painful DPN received daily Sativex or placebo. The primary outcome measure was change in mean daily pain scores, and secondary outcome measures included quality-of-life assessments. RESULTS There was significant improvement in pain scores in both groups, but mean change between groups was not significant. There were no significant differences in secondary outcome measures. Patients with depression had significantly greater baseline pain scores that improved regardless of intervention. CONCLUSIONS This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN. Depression was a major confounder and may have important implications for future trials on painful DPN. PMID:19808912

Clinical development of mTOR inhibitors in breast cancer

PubMed Central

2014-01-01

The mammalian target of rapamycin (mTOR) pathway is a central pathway that regulates mRNA translation, protein synthesis, glucose metabolism, lipid synthesis and autophagy, and is involved in malignant transformation. Several randomized trials have shown that the use of mTOR inhibitors could improve patient outcome with hormone receptor-positive or human epidermal growth factor receptor-2-positive breast cancer. This review analyzes new perspectives from these trials. Preclinical studies have suggested that the mTOR pathway may play a role in the resistance to hormone therapy, trastuzumab and chemotherapy for breast cancer. This concept has been tested in clinical trials for neoadjuvant treatment and for metastatic breast cancer patients. Also, much effort has gone into the identification of biomarkers that will allow for more precise stratification of patients. Findings from these studies will provide indispensable tools for the design of future clinical trials and identify new perspectives and challenges for researchers and clinicians. PMID:25189767

The E Sibling Project – exploratory randomised controlled trial of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis

PubMed Central

2013-01-01

Background Siblings of individuals with first episode psychosis are natural partners to promote service users’ recovery and are themselves vulnerable to mental ill health due to the negative impact of psychosis within the family. This study aims to develop and undertake a preliminary evaluation of the efficacy of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis. The impetus for the intervention arose from siblings' expressed needs for peer support and information on psychosis, coping and management strategies for common symptoms and ways to promote recovery. Methods/Design The project design draws on the Medical Research Council framework for the design and evaluation of complex interventions. Mixed methods comprising collection of qualitative focus group data, systematic review and expert advisory group consultation are used to develop the theoretical basis for and design of the intervention. This protocol focuses on the modelling and piloting phase which uses a randomised controlled trial with factorial design to test the efficacy of the intervention. Outcome data on participants’ mental wellbeing, knowledge, perceived self-efficacy and experiences of caregiving will be assessed at baseline, at end of the intervention (10 weeks later) and at 10 week follow-up. In addition, a post-intervention semi-structured interview with 20% of the participants will explore their experiences and acceptability of the intervention. Discussion This multi-component online psychoeducational intervention aims to enhance siblings' knowledge about psychosis and their coping capacity, thus potentially improving their own mental wellbeing and promoting their contribution to service users’ recovery. The factorial design randomised controlled trial with a supplementary process evaluation using semi-structured interviews and usage-monitoring will collect preliminary evidence of efficacy, feasibility and acceptability, as well as feedback about the barriers and strategies to using such an innovative resource. The RCT will provide data for estimating the likely effect size of the intervention on outcomes for siblings and inform the development of a definitive future trial. Trial registration Trial registration: ISRCTN01416694 PMID:23622123

How Imaging Can Impact Clinical Trial Design: Molecular Imaging as a Biomarker for Targeted Cancer Therapy.

PubMed

Mankoff, David A; Farwell, Michael D; Clark, Amy S; Pryma, Daniel A

2015-01-01

The ability to measure biochemical and molecular processes to guide cancer treatment represents a potentially powerful tool for trials of targeted cancer therapy. These assays have traditionally been performed by analysis of tissue samples. However, more recently, functional and molecular imaging has been developed that is capable of in vivo assays of cancer biochemistry and molecular biology and is highly complementary to tissue-based assays. Cancer imaging biomarkers can play a key role in increasing the efficacy and efficiency of therapeutic clinical trials and also provide insight into the biologic mechanisms that bring about a therapeutic response. Future progress will depend on close collaboration between imaging scientists and cancer physicians and on public and commercial sponsors, to take full advantage of what imaging has to offer for clinical trials of targeted cancer therapy. This review will provide examples of how molecular imaging can inform targeted cancer clinical trials and clinical decision making by (1) measuring regional expression of the therapeutic target, (2) assessing early (pharmacodynamic) response to treatment, and (3) predicting therapeutic outcome. The review includes a discussion of basic principles of molecular imaging biomarkers in cancer, with an emphasis on those methods that have been tested in patients. We then review clinical trials designed to evaluate imaging tests as integrated markers embedded in a therapeutic clinical trial with the goal of validating the imaging tests as integral markers that can aid patient selection and direct response-adapted treatment strategies. Examples of recently completed multicenter trials using imaging biomarkers are highlighted.

A cluster randomised feasibility trial evaluating six-month nutritional interventions in the treatment of malnutrition in care home-dwelling adults: recruitment, data collection and protocol.

PubMed

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

2015-01-01

Protein energy malnutrition predisposes individuals to disease, delays recovery from illness and reduces quality of life. Care home residents are especially vulnerable, with an estimated 30%-42% at risk. There is no internationally agreed protocol for the nutritional treatment of malnutrition in the care home setting. Widely used techniques include food-based intervention and/or the use of prescribed oral nutritional supplements, but a trial comparing the efficacy of interventions is necessary. In order to define outcomes and optimise the design for an adequately powered, low risk of bias cluster randomised controlled trial, a feasibility trial with 6-month intervention is being run, to assess protocol procedures, recruitment and retention rates, consent processes and resident and staff acceptability. Trial recruitment began in September 2013 and concluded in December 2013. Six privately run care homes in Solihull, England, were selected to establish feasibility within different care home types. Residents with or at risk of malnutrition with no existing dietetic intervention in place were considered for receipt of the allocated intervention. Randomisation took place at the care home level, using a computer-generated random number list to allocate each home to either a dietetic intervention arm (food-based or prescribed supplements) or the standard care arm, continued for 6 months. Dietetic intervention aimed to increase daily calorie intake by 600 kcal and protein by 20-25 g. The primary outcomes will be trial feasibility and acceptability of trial design and allocated interventions. A range of outcome assessments and data collection tools will be evaluated for feasibility, including change in nutrient intake, anthropometric parameters and patient-centric measures, such as quality of life and self-perceived appetite. The complexities inherent in care home research has resulted in the under representation of this population in research trials. The results of this feasibility trial will be used to inform the development and design of a future cluster randomised controlled trial to compare food-based intervention with prescribed oral nutritional supplements (ONS) in the treatment of malnutrition within the care home population. Current Controlled Trials ISRCTN38047922.

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.

PubMed

Disma, Nicola; Mondardini, Maria C; Terrando, Niccolò; Absalom, Anthony R; Bilotta, Federico

2016-01-01

Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. © 2015 John Wiley & Sons Ltd.

Site disturbance and soil impacts resulting from mechanized thinning of upland hardwood stands in Southeastern Kentucky

Treesearch

Jason Thompson; Emily Carter

2015-01-01

A large scale silvicultural trial was designed to examine the effectiveness of five treatments in reducing the potential future impacts of gypsy moth infestation and oak decline on upland hardwood forests in the Daniel Boone National Forest in southeastern Kentucky. Three of the five prescriptions were implemented with a mechanical harvesting system. The system...

Current Trends in Exercise Intervention Research, Technology, and Behavioral Change Strategies for People With Disabilities: A Scoping Review.

PubMed

Lai, Byron; Young, Hui-Ju; Bickel, C Scott; Motl, Robert W; Rimmer, James H

2017-10-01

This review synthesized physical activity and exercise intervention literature for the past 10 yrs for people with physical and cognitive disabilities including intervention characteristics, behavior change strategies, and types of technologies used to improve targeted outcomes. Systematic searches yielded 132 eligible studies. The major disability groups were multiple sclerosis (41%), stroke (15%), and spinal cord injury (12%). Research designs primarily involved randomized controlled trials (61%) versus quasi-experimental designs (39%). Approximately 20% of the interventions used some form of the following technology: information and communication technology (48%), interactive technology (37%), or electronic gauges (30%). Eighteen percent of studies used intervention strategies based on behavioral theory, which was typically combined with technology to promote activity and increase adherence in generally larger study samples. The three prevailing theories included social cognitive theory (58%), supportive accountability theory (21%), and transtheoretical model (21%). Upon completing the intervention, studies reported primarily significant outcomes (80%). Exercise research for PWD has grown in both quantity and quality, but several gaps remain. Study findings provide a roadmap for future exercise trials on understudied populations and highlight technology and behavior change theory as drivers of future intervention research.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III).

PubMed

Fernández, Óscar; Arnal-García, Carmen; Arroyo-González, Rafael; Brieva, Lluís; Calles-Hernández, M Carmen; Casanova-Estruch, Bonaventura; Comabella, Manuel; de las Heras, Virginia; García-Merino, Juan A; Hernández-Pérez, Miguel A; Izquierdo, Guillermo; Matas, Elisabet; Meca-Lallana, José E; Mendibe-Bilbao, María del Mar; Muñoz-García, Delicias; Olascoaga, Javier; Oreja-Guevara, Celia; Prieto, José M; Ramió-Torrentà, Lluís; Rodríguez-Antigüedad, Alfredo; Saiz, Albert; Téllez, Nieves; Villar, Luisa M; Tintoré, Mar

2013-10-01

The most significant data presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in France in October 2012, have been summarised in the fifth edition of the Post-ECTRIMS Experts Meeting, held in Madrid in October 2012. This led to the drafting of this review, which has been published in three parts. This third part of the Post-ECTRIMS review presents the findings from the latest studies conducted with disease-modifying treatments, more specifically with glatiramer acetate, laquinimod, ponesimod, BG-12, teriflunomide, daclizumab, natalizumab and secukinumab (AIN457). Likewise, we also address the reasons that justify the search for innovative treatments for multiple sclerosis, with antigen-specific therapy, cell therapy and therapy aimed at promoting remyelination being highlighted among other future therapeutic strategies. Access to new pharmacological agents and the complexity of the therapy of multiple sclerosis in the future will require new design strategies and directions in clinical trials, including the use of surrogate markers, new statistical applications, superiority, inferiority or equivalence clinical trials and adaptable designs.

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.

Factors influencing the participation of older people in clinical trials - data analysis from the MAVIS trial.

PubMed

Fearn, P; Avenell, A; McCann, S; Milne, A C; Maclennan, G

2010-01-01

Older people are less likely to be included in clinical trials. Little is known about factors influencing older people's decisions about participating in clinical trials. To examine the views of older people about participating in clinical trials. Postal questionnaire to 801 participants who had completed the MAVIS nutrition trial, aged 65 yrs and older. Closed and open questions sought participants' views about factors important to them when deciding to take part in a trial, features of the MAVIS trial they liked and disliked and changes they would suggest. 540 (59% of MAVIS trial participants) returned the questionnaire. The most important reasons reported for taking part in the trial were helping the research team and medical knowledge, and helping other older people. Participants valued good communication with the trial staff and good organisation. Participants reported concerns about swallowing pills and taking a placebo. Participants reported that future participation in trials could be influenced by poor health status. This questionnaire surveyed older participants who had taken part in a randomised controlled trial. It did not elicit the views of people who had withdrawn or never decided to take part in the trial. Older people report altruistic reasons for taking part in trials. Simple trial designs, which minimise demands on participants and maintain good communications should be preferred. Explaining the need for older people, despite poor health, to participate in trials may help the generalisability of clinical trials.

Do Contemporary Randomized Controlled Trials Meet ESMO Thresholds for Meaningful Clinical Benefit?

PubMed

Del Paggio, J C; Azariah, B; Sullivan, R; Hopman, W M; James, F V; Roshni, S; Tannock, I F; Booth, C M

2017-01-01

The European Society for Medical Oncology (ESMO) recently released a magnitude of clinical benefit scale (ESMO-MCBS) for systemic therapies for solid cancers. Here, we evaluate contemporary randomized controlled trials (RCTs) against the proposed ESMO thresholds for meaningful clinical benefit. RCTs evaluating systemic therapy for breast cancer, nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer published 2011-2015 were reviewed. Data were abstracted regarding trial characteristics and outcomes, and these were applied to the ESMO-MCBS. We also determined whether RCTs were designed to detect an effect that would meet clinical benefit as defined by the ESMO-MCBS. About 277 eligible RCTs were included (40% breast, 31% NSCLC, 22% CRC, 6% pancreas). Median sample size was 532 and 83% were funded by industry. Among all 277 RCTs, the experimental therapy was statistically superior to the control arm in 138 (50%) trials: results of only 31% (43/138) of these trials met the ESMO-MCBS clinical benefit threshold. RCTs with curative intent were more likely to meet clinically meaningful thresholds than those with palliative intent [61% (19/31) versus 22% (24/107), P < 0.001]. Among the 226 RCTs for which the ESMO-MCBS could be applied, 31% (70/226) were designed to detect an effect size that could meet ESMO-MCBS thresholds. Less than one-third of contemporary RCTs with statistically significant results meet ESMO thresholds for meaningful clinical benefit, and this represents only 15% of all published trials. Investigators, funding agencies, regulatory agencies, and industry should adopt more stringent thresholds for meaningful benefit in the design of future RCTs. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Assessing the Generalizability of Randomized Trial Results to Target Populations

PubMed Central

Stuart, Elizabeth A.; Bradshaw, Catherine P.; Leaf, Philip J.

2014-01-01

Recent years have seen increasing interest in and attention to evidence-based practices, where the “evidence” generally comes from well-conducted randomized trials. However, while those trials yield accurate estimates of the effect of the intervention for the participants in the trial (known as “internal validity”), they do not always yield relevant information about the effects in a particular target population (known as “external validity”). This may be due to a lack of specification of a target population when designing the trial, difficulties recruiting a sample that is representative of a pre-specified target population, or to interest in considering a target population somewhat different from the population directly targeted by the trial. This paper first provides an overview of existing design and analysis methods for assessing and enhancing the ability of a randomized trial to estimate treatment effects in a target population. It then provides a case study using one particular method, which weights the subjects in a randomized trial to match the population on a set of observed characteristics. The case study uses data from a randomized trial of School-wide Positive Behavioral Interventions and Supports (PBIS); our interest is in generalizing the results to the state of Maryland. In the case of PBIS, after weighting, estimated effects in the target population were similar to those observed in the randomized trial. The paper illustrates that statistical methods can be used to assess and enhance the external validity of randomized trials, making the results more applicable to policy and clinical questions. However, there are also many open research questions; future research should focus on questions of treatment effect heterogeneity and further developing these methods for enhancing external validity. Researchers should think carefully about the external validity of randomized trials and be cautious about extrapolating results to specific populations unless they are confident of the similarity between the trial sample and that target population. PMID:25307417

Assessing the generalizability of randomized trial results to target populations.

PubMed

Stuart, Elizabeth A; Bradshaw, Catherine P; Leaf, Philip J

2015-04-01

Recent years have seen increasing interest in and attention to evidence-based practices, where the "evidence" generally comes from well-conducted randomized trials. However, while those trials yield accurate estimates of the effect of the intervention for the participants in the trial (known as "internal validity"), they do not always yield relevant information about the effects in a particular target population (known as "external validity"). This may be due to a lack of specification of a target population when designing the trial, difficulties recruiting a sample that is representative of a prespecified target population, or to interest in considering a target population somewhat different from the population directly targeted by the trial. This paper first provides an overview of existing design and analysis methods for assessing and enhancing the ability of a randomized trial to estimate treatment effects in a target population. It then provides a case study using one particular method, which weights the subjects in a randomized trial to match the population on a set of observed characteristics. The case study uses data from a randomized trial of school-wide positive behavioral interventions and supports (PBIS); our interest is in generalizing the results to the state of Maryland. In the case of PBIS, after weighting, estimated effects in the target population were similar to those observed in the randomized trial. The paper illustrates that statistical methods can be used to assess and enhance the external validity of randomized trials, making the results more applicable to policy and clinical questions. However, there are also many open research questions; future research should focus on questions of treatment effect heterogeneity and further developing these methods for enhancing external validity. Researchers should think carefully about the external validity of randomized trials and be cautious about extrapolating results to specific populations unless they are confident of the similarity between the trial sample and that target population.

A randomized controlled trial of group Stepping Stones Triple P: a mixed-disability trial.

PubMed

Roux, Gemma; Sofronoff, Kate; Sanders, Matthew

2013-09-01

Stepping Stones Triple P (SSTP) is a parenting program designed for families of a child with a disability. The current study involved a randomized controlled trial of Group Stepping Stones Triple P (GSSTP) for a mixed-disability group. Participants were 52 families of children diagnosed with an Autism Spectrum Disorder, Down syndrome, Cerebral Palsy, or an intellectual disability. The results demonstrated significant improvements in parent-reported child behavior, parenting styles, parental satisfaction, and conflict about parenting. Results among participants were similar despite children's differing impairments. The intervention effect was maintained at 6-month follow-up. The results indicate that GSSTP is a promising intervention for a mixed-disability group. Limitations of the study, along with areas for future research, are also discussed. © FPI, Inc.

Clinical trials supported by the Tinnitus Research Consortium: Lessons learned, the Southern Illinois University experience.

PubMed

Bauer, Carol A; Berry, Jennifer; Brozoski, Thomas J

2016-04-01

The Tinnitus Research Consortium funded three clinical trials investigating treatments for chronic bothersome tinnitus at Southern Illinois University School of Medicine. The trials were designed to measure the subjective changes in tinnitus distress using standardized questionnaires and objective changes in tinnitus loudness using psychophysical matching procedures. The results of the first two trials have been published and are summarized here. The first trial investigated the effect of gabapentin on the loudness and annoyance of tinnitus in adults with chronic bothersome tinnitus with and without a history of acoustic trauma. A small but significant number of subjects reported decreased tinnitus annoyance that corresponded with a decrease in objective measures of tinnitus loudness during active drug treatment with a washout effect during placebo treatment. The second trial compared the effect of tinnitus retraining therapy (TRT) on adults with normal to near-normal hearing and chronic bothersome tinnitus to treatment with general counseling without acoustic enrichment. Significant improvements in tinnitus severity, but not in objective psychometric measures of tinnitus loudness, occurred in both treatment groups, however a greater effect was observed in the TRT group compared with the control group. The third trial is nearing completion and investigates the long-term results of tinnitus retraining therapy on chronic bothersome tinnitus in adults with hearing loss. Significant lessons and observations on conducting tinnitus clinical trials were learned from these three trials. The challenges of recruiting and retaining study participants is discussed. More importantly, the reliability and stability of the Tinnitus Handicap Inventory (THI) over long intervals is presented. The implications of this variability for the design and interpretation of future tinnitus studies is discussed. This article is part of a Special Issue entitled . Copyright © 2015 Elsevier B.V. All rights reserved.

EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti‐neutrophil cytoplasm antibody‐associated vasculitis

PubMed Central

Hellmich, Bernhard; Flossmann, Oliver; Gross, Wolfgang L; Bacon, Paul; Cohen‐Tervaert, Jan Willem; Guillevin, Loic; Jayne, David; Mahr, Alfred; Merkel, Peter A; Raspe, Heiner; Scott, David G I; Witter, James; Yazici, Hasan; Luqmani, Raashid A

2007-01-01

Objectives To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. Methods An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence‐based and expert opinion‐based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. Results Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti‐neutrophil cytoplasm antibody‐associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis‐specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. Conclusions On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well‐designed research in non‐AAV systemic vasculitides. PMID:17170053

What can HIV vaccine trials teach us about future HIV vaccine dissemination?

PubMed Central

Newman, Peter A.; Duan, Naihua; Kakinami, Lisa; Roberts, Kathleen

2008-01-01

Summary This investigation explored commonalities and differences in barriers and motivators to HIV vaccine trial participation and acceptability of future U.S. Food and Drug Administration (FDA)-approved HIV vaccines in order to identify implications of clinical trials for future HIV vaccine dissemination. Fifteen focus groups were conducted with 157 predominately ethnic minority and low income participants recruited using venue-based sampling in Los Angeles. Data were analyzed using narrative thematic analysis. Barriers and motivators in common across willingness to participate (WTP) in HIV vaccine trials and future HIV vaccine acceptability (e.g., concerns about vaccine-induced infection, false-positives, side effects, efficacy, mistrust and stigma) suggest clinical trials present significant opportunities to develop and evaluate empirically based interventions to support future HIV vaccine dissemination. Barriers specific to HIV vaccine acceptability (e.g., concerns about duration of protection, cross-clade protection, cost and access) also indicate the need for formative research focused specifically on future dissemination. Protection motivation, common to WTP and acceptability, highlights the need to provide and evaluate prevention counseling and education in clinical trials, which may form the basis of evidence-informed preventive interventions to be launched in tandem with dissemination of partial efficacy HIV vaccines. PMID:18420313

Methodological Issues in Research on Web-Based Behavioral Interventions

PubMed Central

Danaher, Brian G; Seeley, John R

2013-01-01

Background Web-based behavioral intervention research is rapidly growing. Purpose We review methodological issues shared across Web-based intervention research to help inform future research in this area. Methods We examine measures and their interpretation using exemplar studies and our research. Results We report on research designs used to evaluate Web-based interventions and recommend newer, blended designs. We review and critique methodological issues associated with recruitment, engagement, and social validity. Conclusions We suggest that there is value to viewing this burgeoning realm of research from the broader context of behavior change research. We conclude that many studies use blended research designs, that innovative mantling designs such as the Multiphase Optimization Strategy and Sequential Multiple Assignment Randomized Trial methods hold considerable promise and should be used more widely, and that Web-based controls should be used instead of usual care or no-treatment controls in public health research. We recommend topics for future research that address participant recruitment, engagement, and social validity. PMID:19806416

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.

Integrating psychological theory into the design of an online intervention for sexual health: the sexunzipped website.

PubMed

Carswell, Kenneth; McCarthy, Ona; Murray, Elizabeth; Bailey, Julia V

2012-11-19

The Internet can provide a confidential and convenient medium for sexual health promotion for young people. This paper describes the development of an interactive, theory-based website (Sexunzipped) aimed at increasing safe sexual behavior of young people, as well as an outline of the evaluation protocol. The website focuses on safer sex, relationships, and sexual pleasure. An overview of the site is provided, including a description of the theoretical constructs which form the basis of the site development. An integrated behavioral model was chosen as the guiding theory for the Sexunzipped intervention. A randomized trial design will be used to evaluate the site quantitatively. The content of the site is described in detail with examples of the main content types: information pages, quizzes, and decision-making activities. We describe the protocol for quantitative evaluation of the website using a randomized trial design and discuss the principal challenges involved in developing the site, including the challenge of balancing the requirements of theory with young people's views on website content and design. Considerations for future interventions are discussed. Developing an online behavior-change intervention is costly and time consuming. Given the large public health potential, the cost involved in developing online interventions, and the need for attractive design, future interventions may benefit from collaborating with established sites that already have a user base, a brand, and a strong Internet presence. It is vital to involve users in decisions about intervention content, design, and features, paying attention to aspects that will attract and retain users' interest. A central challenge in developing effective Internet-based interventions for young people is to find effective ways to operationalize theory in ways that address the views and perspectives of young people.

Integrating Psychological Theory Into the Design of an Online Intervention for Sexual Health: The Sexunzipped Website

PubMed Central

2012-01-01

Background The Internet can provide a confidential and convenient medium for sexual health promotion for young people. Objective This paper describes the development of an interactive, theory-based website (Sexunzipped) aimed at increasing safe sexual behavior of young people, as well as an outline of the evaluation protocol. Methods The website focuses on safer sex, relationships, and sexual pleasure. An overview of the site is provided, including a description of the theoretical constructs which form the basis of the site development. An integrated behavioral model was chosen as the guiding theory for the Sexunzipped intervention. A randomized trial design will be used to evaluate the site quantitatively. Results The content of the site is described in detail with examples of the main content types: information pages, quizzes, and decision-making activities. We describe the protocol for quantitative evaluation of the website using a randomized trial design and discuss the principal challenges involved in developing the site, including the challenge of balancing the requirements of theory with young people’s views on website content and design. Conclusions Considerations for future interventions are discussed. Developing an online behavior-change intervention is costly and time consuming. Given the large public health potential, the cost involved in developing online interventions, and the need for attractive design, future interventions may benefit from collaborating with established sites that already have a user base, a brand, and a strong Internet presence. It is vital to involve users in decisions about intervention content, design, and features, paying attention to aspects that will attract and retain users’ interest. A central challenge in developing effective Internet-based interventions for young people is to find effective ways to operationalize theory in ways that address the views and perspectives of young people. PMID:23612122

Selection of nontarget arthropod taxa for field research on transgenic insecticidal crops: using empirical data and statistical power.

PubMed

Prasifka, J R; Hellmich, R L; Dively, G P; Higgins, L S; Dixon, P M; Duan, J J

2008-02-01

One of the possible adverse effects of transgenic insecticidal crops is the unintended decline in the abundance of nontarget arthropods. Field trials designed to evaluate potential nontarget effects can be more complex than expected because decisions to conduct field trials and the selection of taxa to include are not always guided by the results of laboratory tests. Also, recent studies emphasize the potential for indirect effects (adverse impacts to nontarget arthropods without feeding directly on plant tissues), which are difficult to predict because of interactions among nontarget arthropods, target pests, and transgenic crops. As a consequence, field studies may attempt to monitor expansive lists of arthropod taxa, making the design of such broad studies more difficult and reducing the likelihood of detecting any negative effects that might be present. To improve the taxonomic focus and statistical rigor of future studies, existing field data and corresponding power analysis may provide useful guidance. Analysis of control data from several nontarget field trials using repeated-measures designs suggests that while detection of small effects may require considerable increases in replication, there are taxa from different ecological roles that are sampled effectively using standard methods. The use of statistical power to guide selection of taxa for nontarget trials reflects scientists' inability to predict the complex interactions among arthropod taxa, particularly when laboratory trials fail to provide guidance on which groups are more likely to be affected. However, scientists still may exercise judgment, including taxa that are not included in or supported by power analyses.

Neighborhood Effects in a Behavioral Randomized Controlled Trial

PubMed Central

Pruitt, Sandi L.; Leonard, Tammy; Murdoch, James; Hughes, Amy; McQueen, Amy; Gupta, Samir

2015-01-01

Randomized controlled trials (RCTs) of interventions intended to modify health behaviors may be influenced by neighborhood effects which can impede unbiased estimation of intervention effects. Examining a RCT designed to increase colorectal cancer (CRC) screening (N=5,628), we found statistically significant neighborhood effects: average CRC test use among neighboring study participants was significantly and positively associated with individual patient’s CRC test use. This potentially important spatially-varying covariate has not previously been considered in a RCT. Our results suggest that future RCTs of health behavior interventions should assess potential social interactions between participants, which may cause intervention arm contamination and may bias effect size estimation. PMID:25456014

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.

Partial Gland Ablation for Prostate Cancer: Report of a Food and Drug Administration, American Urological Association, and Society of Urologic Oncology Public Workshop.

PubMed

Jarow, Jonathan P; Ahmed, Hashim U; Choyke, Peter L; Taneja, Samir S; Scardino, Peter T

2016-02-01

To summarize the discussion that took place at a public workshop, co-sponsored by the U.S. Food and Drug Administration, the American Urological Association, and Society of Urologic Oncology reviewing the current state of the art for partial gland ablation (PGA) for the management of patients with prostate cancer. The purpose of this workshop was to discuss potential indications, current available evidence, and designs for future trials to provide the evidence needed by patients and providers to decide how and when to use PGA. A workshop evaluating PGA for prostate cancer was held in New Orleans, Louisiana, in May 2015. Invited experts representing all stakeholders and attendees discussed the regulatory development of medical products, technology available, potential indications, and designs of trials to evaluate this modality of therapy. The panel presented the current information on the technologies available to perform PGA, the potential indications, and results of prior consensus conferences. Use of magnetic resonance imaging for patient selection, guide therapy, and follow-up was discussed. Designs of trials to assess PGA outcomes were discussed. The general consensus was that currently available technologies are capable of selective ablation with reasonable accuracy, but that criteria for patient selection remain debatable, and long-term cancer control remains to be established in properly designed and well-performed prospective clinical trials. Concerns include the potential for excessive, unnecessary use in patients with low-risk cancer and, conversely, that current diagnostic techniques may underestimate the extent and aggressiveness of some cancers, leading to inadequate treatment. Published by Elsevier Inc.

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

A cluster randomized control trial to assess the impact of active learning on child activity, attention control, and academic outcomes: The Texas I-CAN trial.

PubMed

Bartholomew, John B; Jowers, Esbelle M; Errisuriz, Vanessa L; Vaughn, Sharon; Roberts, Gregory

2017-10-01

Active learning is designed to pair physical activity with the teaching of academic content. This has been shown to be a successful strategy to increase physical activity and improve academic performance. The existing designs have confounded academic lessons with physical activity. As a result, it is impossible to determine if the subsequent improvement in academic performance is due to: (1) physical activity, (2) the academic content of the active learning, or (3) the combination of academic material taught through physical activity. The Texas I-CAN project is a 3-arm, cluster randomized control trial in which 28 elementary schools were assigned to either control, math intervention, or spelling intervention. As a result, each intervention condition serves as an unrelated content control for the other arm of the trial, allowing the impact of physical activity to be separated from the content. That is, schools that perform only active math lessons provide a content control for the spelling schools on spelling outcomes. This also calculated direct observations of attention and behavior control following periods of active learning. This design is unique in its ability to separate the impact of physical activity, in general, from the combination of physical activity and specific academic content. This, in combination with the ability to examine both proximal and distal outcomes along with measures of time on task will do much to guide the design of future, school-based interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Optimal Futility Interim Design: A Predictive Probability of Success Approach with Time-to-Event Endpoint.

PubMed

Tang, Zhongwen

2015-01-01

An analytical way to compute predictive probability of success (PPOS) together with credible interval at interim analysis (IA) is developed for big clinical trials with time-to-event endpoints. The method takes account of the fixed data up to IA, the amount of uncertainty in future data, and uncertainty about parameters. Predictive power is a special type of PPOS. The result is confirmed by simulation. An optimal design is proposed by finding optimal combination of analysis time and futility cutoff based on some PPOS criteria.

Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

PubMed Central

Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

2018-01-01

Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

Designing and conducting a randomized trial for pandemic critical illness: the 2009 H1N1 influenza pandemic.

PubMed

Annane, Djillali; Antona, Marion; Lehmann, Blandine; Kedzia, Cecile; Chevret, Sylvie

2012-01-01

To analyze the hurdles in implementing a randomized trial of corticosteroids for severe 2009 H1N1 influenza infections. This was an investigator-led, multicenter, randomized, placebo-controlled, double-blind trial of corticosteroids in ICU patients with 2009 H1N1 influenza pneumonia requiring mechanical ventilation. The feasibility of and hurdles in designing and initiating a phase III trial in a short-lived pandemic crisis were analyzed. The regulatory agency and ethics committee approved the study's scientific, financial, and ethical aspects within 4 weeks. Hydrocortisone and placebo were prepared centrally and shipped to participating hospitals within 6 weeks. The inclusion period started on November 9, 2009. From August 1, 2009 to March 8, 2010, only 205/224 ICU patients with H1N1 infections required mechanical ventilation. The peak of the wave was missed by 2-3 weeks and only 26 patients were randomized. The two main reasons for non-inclusion were patients' admission before the beginning of the trial and ICU personnel overwhelmed by clinical duties. Parallel rather than sequential regulatory and ethics approval, and preparation and masking of study drugs by local pharmacists would have allowed the study to start 1 month earlier and before the peak of the "flu" wave. A dedicated research team in each participating center would have increased the ratio of screened to randomized patients. This report highlights the main hurdles in implementing a randomized trial for a pandemic critical illness and proposes solutions for future trials.

A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease.

PubMed

Zhang, Richard Y; Leon, Andrew C; Chuang-Stein, Christy; Romano, Steven J

2011-02-01

The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges. To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies. Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies. The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial. A regulatory claim of disease modification for any compound will likely require additional verification of a drug's effect on a validated biomarker of Alzheimer's pathology. Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.

Study protocol: can a school gardening intervention improve children’s diets?

PubMed Central

2012-01-01

Background The current academic literature suggests there is a potential for using gardening as a tool to improve children’s fruit and vegetable intake. This study is two parallel randomised controlled trials (RCT) devised to evaluate the school gardening programme of the Royal Horticultural Society (RHS) Campaign for School Gardening, to determine if it has an effect on children’s fruit and vegetable intake. Method/Design Trial One will consist of 26 schools; these schools will be randomised into two groups, one to receive the intensive intervention as “Partner Schools” and the other to receive the less intensive intervention as “Associate Schools”. Trial Two will consist of 32 schools; these schools will be randomised into either the less intensive intervention “Associate Schools” or a comparison group with delayed intervention. Baseline data collection will be collected using a 24-hour food diary (CADET) to collect data on dietary intake and a questionnaire exploring children’s knowledge and attitudes towards fruit and vegetables. A process measures questionnaire will be used to assess each school’s gardening activities. Discussion The results from these trials will provide information on the impact of the RHS Campaign for School Gardening on children’s fruit and vegetable intake. The evaluation will provide valuable information for designing future research in primary school children’s diets and school based interventions. Trial registration ISRCTN11396528 PMID:22537179

Review of the registration of clinical trials in UMIN-CTR from 2 June 2005 to 1 June 2010 - focus on Japan domestic, academic clinical trials

PubMed Central

2013-01-01

Background Established on 1 June 2005, the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) is the largest clinical trial registry in Japan, and joined the World Health Organization (WHO) registry network in October 2008. Our aim was to understand the registration trend and overall characteristics of Japan domestic, academic (non-industry-funded) clinical trials, which constitute the main body of registrations in UMIN-CTR. In addition, we aimed to investigate the accessibility of clinical trials in UMIN-CTR to people worldwide, as well as the accessibility of clinical trials conducted in Japan but registered abroad to Japanese people in the Japanese language. Methods We obtained the data for registrations in UMIN-CTR from the UMIN Center, and extracted Japan domestic, academic clinical trials to analyze their registration trend and overall characteristics. We also investigated how many of the trials registered in UMIN-CTR could be accessed from the International Clinical Trials Registry Platform (ICTRP). Finally, we searched ClinicalTrials.gov for all clinical trials conducted in Japan and investigated how many of them were also registered in Japanese registries. All of the above analyses included clinical trials registered from 2 June 2005 to 1 June 2010. Results During the period examined, the registration trend showed an obvious peak around September 2005 and rapid growth from April 2009. Of the registered trials, 46.4% adopted a single-arm design, 34.5% used an active control, only 10.9% were disclosed before trial commencement, and 90.0% did not publish any results. Overall, 3,063 of 3,064 clinical trials registered in UMIN-CTR could be accessed from ICTRP. Only 8.7% of all clinical trials conducted in Japan and registered in ClinicalTrials.gov were also registered in Japanese registries. Conclusions The International Committee of Medical Journal Editors (ICMJE) announcements about clinical trial registration and the Ethical Guidelines for Clinical Research published by the Japanese government are considered to have promoted clinical trial registration in UMIN-CTR. However, problems associated with trial design, retrospective registration, and publication of trial results need to be addressed in future. Almost all clinical trials registered in UMIN-CTR are accessible to people worldwide through ICTRP. However, many trials conducted in Japan but registered abroad cannot be accessed from Japanese registries in Japanese. PMID:24124926

Research Review: The Role of Diet in the Treatment of Attention-Deficit/Hyperactivity Disorder--An Appraisal of the Evidence on Efficacy and Recommendations on the Design of Future Studies

ERIC Educational Resources Information Center

Stevenson, Jim; Buitelaar, Jan; Cortese, Samuele; Ferrin, Maite; Konofal, Eric; Lecendreux, Michel; Simonoff, Emily; Wong, Ian C. K.; Sonuga-Barke, Edmund

2014-01-01

Background: The efficacy of three dietary treatments for ADHD has been repeatedly tested in randomized controlled trials (RCTs). These interventions are restricted elimination diets (RED), artificial food colour elimination (AFCE) and supplementation with free fatty acids (SFFA). There have been three systematic reviews and associated…

The Appalachian Tri-State Node Experiences with the National Institute on Drug Abuse Clinical Trials Network.

PubMed

Kelly, Thomas M; Daley, Dennis C; Byrne, Mimmie; Demarzo, Larry; Smith, Doris; Madl, Stephanie

2011-07-01

The National Institute on Drug Abuse (NIDA)-sponsored Clinical Trial Network (CTN) recently celebrated 10 years of conducting "real world" research into the treatment of addiction. This article reviews the history and results of the most recent CTN studies and describes the experiences of one of the 13 participating research affiliates, the Appalachian Tri-State (ATS) Node. We discuss our "bidirectional" collaboration with multiple community treatment programs (CTPs) on research and dissemination activities and include their experiences as a member of our ATS Node.Results of CTN clinical trials have found unexpectedly that treatment as usual (TAU) is often almost as good as evidence-based interventions such as Motivational Interviewing (MI), possibly due to the difficulty in implementing evidence-based practices most effectively among divergent treatment sites and heterogeneous clinical populations. Some expected findings from the reviewed research are that severity of addiction and comorbidity moderate treatment outcomes and must be accounted for in future CTN-sponsored studies. Notwithstanding these results, much has been learned and recommendations are suggested for changes in CTN research designs that will address methodological limitations and increase treatment effectiveness in future CTN studies.

The Development of a Communication Tool to Facilitate the Cancer Trial Recruitment Process and Increase Research Literacy among Underrepresented Populations.

PubMed

Torres, Samantha; de la Riva, Erika E; Tom, Laura S; Clayman, Marla L; Taylor, Chirisse; Dong, Xinqi; Simon, Melissa A

2015-12-01

Despite increasing need to boost the recruitment of underrepresented populations into cancer trials and biobanking research, few tools exist for facilitating dialogue between researchers and potential research participants during the recruitment process. In this paper, we describe the initial processes of a user-centered design cycle to develop a standardized research communication tool prototype for enhancing research literacy among individuals from underrepresented populations considering enrollment in cancer research and biobanking studies. We present qualitative feedback and recommendations on the prototype's design and content from potential end users: five clinical trial recruiters and ten potential research participants recruited from an academic medical center. Participants were given the prototype (a set of laminated cards) and were asked to provide feedback about the tool's content, design elements, and word choices during semi-structured, in-person interviews. Results suggest that the prototype was well received by recruiters and patients alike. They favored the simplicity, lay language, and layout of the cards. They also noted areas for improvement, leading to card refinements that included the following: addressing additional topic areas, clarifying research processes, increasing the number of diverse images, and using alternative word choices. Our process for refining user interfaces and iterating content in early phases of design may inform future efforts to develop tools for use in clinical research or biobanking studies to increase research literacy.

High flow nasal cannula oxygen versus noninvasive ventilation in adult acute respiratory failure: a systematic review of randomized-controlled trials.

PubMed

Beng Leong, Lim; Wei Ming, Ng; Wei Feng, Lee

2018-06-19

We reviewed the use of noninvasive ventilation (NIV) versus high flow nasal cannula (HFNC) oxygen in adult acute respiratory failure (ARF). We searched major databases and included randomized trials comparing at least NIV with HFNC or NIV+HFNC with NIV in ARF. Primary outcomes included intubation/re-intubation rates. Secondary outcomes were ICU mortality and morbidities. Five trials were included; three compared HFNC with NIV, one compared HFNC, NIV and oxygen whereas one compared HFNC+NIV with NIV. Patients had hypoxaemic ARF (PaO2/FiO2≤300 mmHg). Heterogeneity prevented result pooling. Three and two studies had superiority and noninferiority design, respectively. Patients were postcardiothoracic surgery, mixed medical/surgical patients and those with pneumonia. Two trials were conducted after extubation, two before intubation and one during intubation. Three trials reported intubation/re-intubation rates as the primary outcomes. The other two trials reported the lowest peripheral capillary oxygen saturation readings during bronchoscopy or intubation. In the former three trials, the odds ratio for intubation/re-intubation rates between HFNC versus the NIV group ranged from 0.80 (95% confidence interval: 0.54-1.19) to 1.65 (95% confidence interval: 0.96-2.84). In the latter two trials, only one reported a difference in the lowest peripheral capillary oxygen saturation between NIV+HFNC versus the NIV group during intubation [100% (interquartile range: 95-100) vs. 96% (interquartile range: 92-99); P=0.029]. The secondary outcomes included differences in ICU mortality and patient tolerability, favouring HFNC, were conflicting, but highlighted future research directions. These include patients with hypercapneic ARF, more severe hypoxaemia (PaO2/FiO2≤200 mmHg), a superiority design, an oxygen arm and patient-centred outcomes.

Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: a cross-sectional study

PubMed Central

Lee, Andy H; Zhou, Xu; Kang, Deying; Luo, Yanan; Liu, Jiali; Sun, Xin

2018-01-01

Objective To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). Methods PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. Results A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to-treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. Conclusion The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA. PMID:29511016

Lessons from HIV-1 vaccine efficacy trials.

PubMed

Excler, Jean-Louis; Michael, Nelson L

2016-11-01

Only four HIV-1 vaccine concepts have been tested in six efficacy trials with no product licensed to date. Several scientific and programmatic lessons can be learned from these studies generating new hypotheses and guiding future steps. RV144 [ALVAC-HIV (canarypox vector) and AIDSVAX B/E (bivalent gp120 HIV-1 subtype B and CRF01_AE)] remains the only efficacy trial that demonstrated a modest vaccine efficacy, which led to the identification of immune correlates of risk. Progress on subtype-specific, ALVAC (canarypox vector) and gp120 vaccine prime-boost approaches has been slow, but we are finally close to the launch of an efficacy study in Africa in 2016. The quest of a globally effective HIV-1 vaccine has led to the development of new approaches. Efficacy studies of combinations of Adenovirus type 26 (Ad26)/Modified Vaccinia Ankara (MVA)/gp140 vaccines with mosaic designs will enter efficacy studies mid-2017 and cytomegalovirus (CMV)-vectored vaccines begin Phase I studies at the same time. Future HIV-1 vaccine efficacy trials face practical challenges as effective nonvaccine prevention programs are projected to decrease HIV-1 incidence. An HIV-1 vaccine is urgently needed. Increased industry involvement, mobilization of resources, expansion of a robust pipeline of new concepts, and robust preclinical challenge studies will be essential to accelerate efficacy testing of next generation HIV-1 vaccine candidates.

Cervical pessaries for prevention of spontaneous preterm birth: past, present and future

PubMed Central

Arabin, B; Alfirevic, Z

2013-01-01

This Review describes the rationale for the use of cervical pessaries to prevent spontaneous preterm birth and their gradual introduction into clinical practice, discusses technical aspects of the more commonly used designs and provides guidance for their use and future evaluation. Possible advantages of cervical pessaries include the easy, ‘one-off’ application, good side-effect profile, good patient tolerance and relatively low cost compared with current alternatives. Use of transvaginal sonography to assess cervical length in the second trimester allows much better selection of patients who may benefit from the use of a cervical pessary, but future clinical trials are needed to establish clearly the role of pessaries as a preterm birth prevention strategy worldwide. PMID:23775862

Establishing Correlates of Protection for Vaccine Development: Considerations for the Respiratory Syncytial Virus Vaccine Field.

PubMed

Kulkarni, Prasad S; Hurwitz, Julia L; Simões, Eric A F; Piedra, Pedro A

2018-03-01

Correlates of protection (CoPs) can play a significant role in vaccine development by assisting the selection of vaccine candidates for clinical trials, supporting clinical trial design and implementation, and simplifying tests of vaccine modifications. Because of this important role in vaccine development, it is essential that CoPs be defined by well-designed immunogenicity and efficacy studies, with attention paid to benefits and limitations. The respiratory syncytial virus (RSV) field is unique in that a great deal of information about the humoral response is available from basic research and clinical studies. Polyclonal and monoclonal antibodies have been used routinely in the clinic to protect vulnerable infants from infection, providing a wealth of information about correlations between neutralizing antibodies and disease prevention. Considerations for the establishment of future CoPs to support RSV vaccine development in different populations are therefore discussed.

New treatments for mitochondrial disease—no time to drop our standards

PubMed Central

Pfeffer, Gerald; Horvath, Rita; Klopstock, Thomas; Mootha, Vamsi K.; Suomalainen, Anu; Koene, Saskia; Hirano, Michio; Zeviani, Massimo; Bindoff, Laurence A.; Yu-Wai-Man, Patrick; Hanna, Michael; Carelli, Valerio; McFarland, Robert; Majamaa, Kari; Turnbull, Douglas M.; Smeitink, Jan; Chinnery, Patrick F.

2016-01-01

Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new biomarkers of mitochondrial disease. In this Perspectives article, we make recommendations for the design of future treatment trials in mitochondrial diseases. Patients and physicians should no longer rely on potentially biased data, with the associated costs and risks. PMID:23817350

A randomized clinical trial aimed at preventing poor psychosocial and glycemic outcomes in teens with type 1 diabetes (T1D)

PubMed Central

Weissberg-Benchell, Jill; Rausch, Joseph; Iturralde, Esti; Jedraszko, Aneta; Hood, Korey

2016-01-01

Adolescents with type 1 diabetes have an increased risk for a variety of emotional and behavioral challenges as well as negative diabetes outcomes. This study was designed to compare the effectiveness of a depression-prevention, resilience promotion program with an advanced diabetes education program. Each program consisted of 9 group-based sessions. There were 264 adolescents enrolled in this multi-site randomized clinical trial. The primary outcomes were depressive symptoms and glycemic control; secondary outcomes included resilience skills, diabetes management and adherence, and diabetes-specific distress. The goal of the present paper is to describe the study design, the intervention, and the baseline characteristics of the sample. Preliminary data suggests that enrollment, randomization and retention were successful. Longitudinal follow-up and examination of mechanisms of action as they relate to psychosocial and glycemic outcomes will be explored in the future. PMID:27267154

Rhodiola rosea therapy for major depressive disorder: a study protocol for a randomized, double-blind, placebo- controlled trial

PubMed Central

Mao, Jun J; Li, Qing S.; Soeller, Irene; Xie, Sharon X; Amsterdam, Jay D.

2014-01-01

Background Rhodiola rosea (R. rosea), a botanical of both western and traditional Chinese medicine, has been used as a folk remedy for improving stamina and reducing stress. However, few controlled clinical trials have examined the safety and efficacy of R. rosea for the treatment of major depressive disorder (MDD). This study seeks to evaluate the safety and efficacy of R. rosea in a 12-week, randomized, double-blind, placebo-controlled, parallel group study design. Methods / Design Subjects with MDD not receiving antidepressant therapy will be randomized to either R. rosea extract 340–1,360 mg daily; sertraline 50–200 mg daily, or placebo for 12 weeks. The primary outcome measure will be change over time in the mean 17-item Hamilton Depression Rating score. Secondary outcome measures will include safety and quality of life ratings. Statistical procedures will include mixed-effects models to assess efficacy for primary and secondary outcomes. Discussion This study will provide valuable preliminary information on the safety and efficacy data of R. rosea versus conventional antidepressant therapy of MDD. It will also inform additional hypotheses and study design of future, fully powered, phase III clinical trials with R. rosea to determine its safety and efficacy in MDD. PMID:25610752

Are Anti-Stigma Films a Useful Strategy for Reducing Weight Bias Among Trainee Healthcare Professionals? Results of a Pilot Randomized Control Trial

PubMed Central

Swift, Judy Anne; Tischler, Victoria; Markham, Sophie; Gunning, Ingrid; Glazebrook, Cris; Beer, Charlotte; Puhl, Rebecca

2013-01-01

Background Weight bias is an important clinical issue that the educators of tomorrow's healthcare professionals cannot afford to ignore. This study, therefore, aimed to pilot a randomized controlled trial of the effects of educational films designed to reduce weight stigmatization toward obese patients on trainee dietitians’ and doctors’ attitudes. Methods A pre-post experimental design with a 6-week follow-up, which consisted of an intervention group (n = 22) and a control group (n = 21), was conducted to assess the efficacy of brief anti-stigma films in reducing weight bias, and to test whether future, larger-scale studies among trainee healthcare professionals are feasible. Results Participants at baseline demonstrated weight bias, on both implicit and explicit attitude measures, as well as strong beliefs that obesity is under a person's control. The intervention films significantly improved explicit attitudes and beliefs toward obese people, and participant evaluation was very positive. The intervention did not significantly improve implicit anti-fat bias. Conclusion The current study suggests both that it is possible to conduct a substantive trial of the effects of educational films designed to reduce weight stigma on a larger cohort of trainee healthcare professionals, and that brief educational interventions may be effective in reducing stigmatizing attitudes in this population. PMID:23466551

Are anti-stigma films a useful strategy for reducing weight bias among trainee healthcare professionals? Results of a pilot randomized control trial.

PubMed

Swift, Judy Anne; Tischler, Victoria; Markham, Sophie; Gunning, Ingrid; Glazebrook, Cris; Beer, Charlotte; Puhl, Rebecca

2013-01-01

Weight bias is an important clinical issue that the educators of tomorrow's healthcare professionals cannot afford to ignore. This study, therefore, aimed to pilot a randomized controlled trial of the effects of educational films designed to reduce weight stigmatization toward obese patients on trainee dietitians' and doctors' attitudes. A pre-post experimental design with a 6-week follow-up, which consisted of an intervention group (n = 22) and a control group (n = 21), was conducted to assess the efficacy of brief anti-stigma films in reducing weight bias, and to test whether future, larger-scale studies among trainee healthcare professionals are feasible. Participants at baseline demonstrated weight bias, on both implicit and explicit attitude measures, as well as strong beliefs that obesity is under a person's control. The intervention films significantly improved explicit attitudes and beliefs toward obese people, and participant evaluation was very positive. The intervention did not significantly improve implicit anti-fat bias. The current study suggests both that it is possible to conduct a substantive trial of the effects of educational films designed to reduce weight stigma on a larger cohort of trainee healthcare professionals, and that brief educational interventions may be effective in reducing stigmatizing attitudes in this population.

Treatment of substance use disorders in schizophrenia.

PubMed

Bennett, Melanie E; Bradshaw, Kristen R; Catalano, Lauren T

2017-07-01

Substance use disorders (SUDs) represent a great barrier to functional recovery for individuals with schizophrenia. It is important to use research on treatment of SUDs in schizophrenia to guide treatment recommendations and program planning. We review studies of pharmacological and psychosocial interventions to treat SUDs in individuals with schizophrenia. The criteria used to select studies for inclusion are (1) the percentage of the sample with a schizophrenia spectrum diagnosis is at least 25%; (2) participants have a comorbid SUD or problem use of substances; (3) an intervention for SUD is provided; (4) a substance use-related outcome is measured; and (5) the study design enabled examination of pre-post outcome measures including open label trials, nonrandomized evaluations (quasi-experimental designs, nonrandom assignment to groups), or randomized controlled trials. There are few psychopharmacology outcomes studies. Most have examined use of antipsychotic medications to treat SUDs in schizophrenia. Several trials have yielded positive findings for naltrexone in reducing drinking compared to placebo in this population. Motivational and cognitive-behavioral interventions are associated with decreased substance use in several trials. Treatment for SUDs is feasible within a range of settings and acceptable to many individuals with schizophrenia. All individuals with schizophrenia should be offered brief or more extended psychosocial interventions that incorporate discussion of personal reasons to change and training in cognitive-behavioral strategies to reduce use, cope with cravings and stress, and avoid relapse. Future research must include larger samples, longitudinal designs, and similar outcome measures across studies.

Patient-centered clinical trials.

PubMed

Chaudhuri, Shomesh E; Ho, Martin P; Irony, Telba; Sheldon, Murray; Lo, Andrew W

2018-02-01

We apply Bayesian decision analysis (BDA) to incorporate patient preferences in the regulatory approval process for new therapies. By assigning weights to type I and type II errors based on patient preferences, the significance level (α) and power (1-β) of a randomized clinical trial (RCT) for a new therapy can be optimized to maximize the value to current and future patients and, consequently, to public health. We find that for weight-loss devices, potentially effective low-risk treatments have optimal αs larger than the traditional one-sided significance level of 5%, whereas potentially less effective and riskier treatments have optimal αs below 5%. Moreover, the optimal RCT design, including trial size, varies with the risk aversion and time-to-access preferences and the medical need of the target population. Copyright © 2017 Elsevier Ltd. All rights reserved.

Complimentary and Alternative Medicine for Sleep Disturbances in Older Adults

PubMed Central

Gooneratne, Nalaka S.

2008-01-01

Synopsis Complimentary and alternative medicines (CAM) are frequently used for the treatment of sleep disorders, but in many cases, patients do not discuss these therapies directly with their health care provider. There is a growing body of well-designed clinical trials using CAM that have shown the following: 1) Melatonin is an effective agent for the treatment of circadian phase disorders that affect sleep, however, the role of melatonin in the treatment of primary or secondary insomnia is less well established. 2) Valerian has shown a benefit in some, but not all clinical trials. 3) Several other modalities, such as Tai Chi, acupuncture, acupressure, yoga and meditation have improved sleep parameters in a limited number of early trials. Future work examining CAM has the potential to significantly add to our treatment options for sleep disorders in older adults. PMID:18035236

The role of private industry in pragmatic comparative effectiveness trials.

PubMed

Buesching, Don P; Luce, Bryan R; Berger, Marc L

2012-03-01

Comparative effectiveness research (CER) includes pragmatic clinical trials (PCTs) to address 'real-world' effectiveness. CER interest would be expected to stimulate biopharmaceutical manufacturer PCT investment; however, this does not seem to be the case. In this article we identify all industry-sponsored PCT studies from 1996 to 2010; analyze them across a variety of characteristics, including sponsor, research question, design, comparators and results; and suggest methodological and policy changes to spur future manufacturer PCT investment. Nine 'naturalistic', head-to-head versus standard of care or similar agent PCTs were identified. Two included a 'usual care' arm. Chronic care trials' length averaged 12 months (range: 6-24 months), six of which reported equivocal or no difference in effectiveness; results of two chronic and the single acute care PCTs favored the sponsor drug. None reported the sponsor drug inferior. Of seven that evaluated utilization or costs, six reported no differences and four of five studies comparing brand-generic drugs reported no difference. Whereas private investment in PCTs is in the public interest, manufacturers apparently have not yet seen the business case. To induce investment, we propose several methodological and regulatory policy innovations designed to reduce business risk by decreasing outcome variability and increasing trial efficiency, flexibility and market applicability.

Post-trial follow-up methodology in large randomized controlled trials: a systematic review protocol.

PubMed

Llewellyn-Bennett, Rebecca; Bowman, Louise; Bulbulia, Richard

2016-12-15

Clinical trials typically have a relatively short follow-up period, and may both underestimate potential benefits of treatments investigated, and fail to detect hazards, which can take much longer to emerge. Prolonged follow-up of trial participants after the end of the scheduled trial period can provide important information on both efficacy and safety outcomes. This protocol describes a systematic review to qualitatively compare methods of post-trial follow-up used in large randomized controlled trials. A systematic search of electronic databases and clinical trial registries will use a predefined search strategy. All large (more than 1000 adult participants) randomized controlled trials will be evaluated. Two reviewers will screen and extract data according to this protocol with the aim of 95% concordance of papers checked and discrepancies will be resolved by a third reviewer. Trial methods, participant retention rates and prevalence of missing data will be recorded and compared. The potential for bias will be evaluated using the Cochrane Risk of Bias tool (applied to the methods used during the in-trial period) with the aim of investigating whether the quality of the post-trial follow-up methodology might be predicted by the quality of the methods used for the original trial. Post-trial follow-up can provide valuable information about the long-term benefits and hazards of medical interventions. However, it can be logistically challenging and costly. The aim of this systematic review is to describe how trial participants have been followed-up post-trial in order to inform future post-trial follow-up designs. Not applicable for PROSPERO registration.

Determining the impact of a new physiotherapist-led primary care model for back pain: protocol for a pilot cluster randomized controlled trial.

PubMed

Miller, Jordan; Barber, David; Donnelly, Catherine; French, Simon; Green, Michael; Hill, Jonathan; MacDermid, Joy; Marsh, Jacquelyn; Norman, Kathleen; Richardson, Julie; Taljaard, Monica; Wideman, Timothy; Cooper, Lynn; McPhee, Colleen

2017-11-09

Back pain is a leading contributor to disability, healthcare costs, and lost work. Family physicians are the most common first point of contact in the healthcare system for people with back pain, but physiotherapists (PTs) may be able to support the primary care team through evidence-based primary care. A cluster randomized trial is needed to determine the clinical, health system, and societal impact of a primary care model that integrates physiotherapists at the first visit for people with back pain. Prior to conducting a future fully powered cluster randomized trial, we need to demonstrate feasibility of the methods. Therefore, the purpose of this pilot study will be to: 1) Determine feasibility of patient recruitment, assessment procedures, and retention. 2) Determine the feasibility of training and implementation of a new PT-led primary care model for low back pain (LBP) 3) Explore the perspectives of patients and healthcare providers (HCPs) related to their experiences and attitudes towards the new service delivery model, barriers/facilitators to implementation, perceived satisfaction, perceived value, and impact on clinic processes and patient outcomes. This pilot cluster randomized controlled trial will enroll four sites and randomize them to implement a new PT-led primary care model for back pain or a usual physician-led primary care model. All adults booking a primary care visit for back pain will be invited to participate. Feasibility outcomes will include: recruitment and retention rates, completeness of assessment data, PT training participation and confidence after training, and PT treatment fidelity. Secondary outcomes will include the clinical, health system, cost, and process outcomes planned for the future fully powered cluster trial. Results will be analyzed and reported descriptively and qualitatively. To explore perspectives of both HCPs and patients, we will conduct semi-structured qualitative interviews with patients and focus groups with HCPs from participants in the PT-led primary care sites. If this pilot demonstrates feasibility, a fully powered trial will provide evidence that has the potential to transform primary care for back pain. The full trial will inform future service design, whether these models should be more widely implemented, and training agendas. ClinicalTrials.gov, NCT03320148 . Submitted for registration on 17 September 2017.

Perceptions of Massage Therapists Participating in a Randomized Controlled Trial

PubMed Central

Perlman, Adam; Dreusicke, Mark; Keever, Teresa; Ali, Ather

2015-01-01

Background Clinical practice and randomized trials often have disparate aims, despite involving similar interventions. Attitudes and expectancies of practitioners influence patient outcomes, and there is growing emphasis on optimizing provider–patient relationships. In this study, we evaluated the experiences of licensed massage therapists involved in a randomized controlled clinical trial using qualitative methodology. Methods Seven massage therapists who were interventionists in a randomized controlled trial participated in structured interviews approximately 30 minutes in length. Interviews focused on their experiences and perceptions regarding aspects of the clinical trial, as well as recommendations for future trials. Transcribed interviews were analyzed for emergent topics and themes using standard qualitative methods. Results Six themes emerged. Therapists discussed 1) promoting the profession of massage therapy through research, 2) mixed views on using standardized protocols, 3) challenges of sham interventions, 4) participant response to the sham intervention, 5) views on scheduling and compensation, and 6) unanticipated benefits of participating in research. Conclusions Therapists largely appreciated the opportunity to promote massage through research. They demonstrated insight and understanding of the rationale for a clinical trial adhering to a standardized protocol. Evaluating the experiences and ideas of complementary and alternative medicine practitioners provides valuable insight that is relevant for the implementation and design of randomized trials. PMID:26388961

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.

Neurosecurity: security and privacy for neural devices.

PubMed

Denning, Tamara; Matsuoka, Yoky; Kohno, Tadayoshi

2009-07-01

An increasing number of neural implantable devices will become available in the near future due to advances in neural engineering. This discipline holds the potential to improve many patients' lives dramatically by offering improved-and in some cases entirely new-forms of rehabilitation for conditions ranging from missing limbs to degenerative cognitive diseases. The use of standard engineering practices, medical trials, and neuroethical evaluations during the design process can create systems that are safe and that follow ethical guidelines; unfortunately, none of these disciplines currently ensure that neural devices are robust against adversarial entities trying to exploit these devices to alter, block, or eavesdrop on neural signals. The authors define "neurosecurity"-a version of computer science security principles and methods applied to neural engineering-and discuss why neurosecurity should be a critical consideration in the design of future neural devices.

Heterogeneity in recent-onset type 1 diabetes - a clinical trial perspective.

PubMed

Bollyky, Jennifer B; Xu, Ping; Butte, Atul J; Wilson, Darrell M; Beam, Craig A; Greenbaum, Carla J

2015-09-01

Type 1 diabetes (T1D) TrialNet is a National Institutes of Health-sponsored clinical trial network aimed at altering the disease course of T1D. The purpose of this study is to evaluate age-dependent heterogeneity in clinical, metabolic and immunologic characteristics of individuals with recent-onset T1D, to identify cohorts of interest and to aid in planning of future studies. Eight hundred eighty-three individuals with recent-onset T1D involved in five TrialNet studies were categorized by age as follows: ≥18 years, 12-17 years, 8-12 years and <8 years. Data were compared with healthy age-matched subjects in the National Health and Nutrition Examination Survey. Only 2.0% of the individuals overall were excluded from trial participation because of insufficient C-peptide values (<0.2 pmol/mL). A disproportionate number of these subjects were <8 years old. Leukopenia was present in 21.2% of individuals and lymphopenia in 11.6%; these frequencies were markedly higher than age-matched healthy National Health and Nutrition Examination Survey population. Of the cohort, 24.5% were overweight or obese. Neither high-risk human leukocyte antigen type DR3 nor DR4 was present in 31% of adults and 21% of children. The ability of recent-onset T1D patients to meet key entry criteria for TrialNet studies, including C-peptide >0.2 pmol/mL, varies by age. Lower C-peptide level requirements for younger participants and other aspects of heterogeneity of recent-onset T1D patients, such as white blood cell count abnormalities and body mass index should be considered in the design of future clinical studies. Copyright © 2015 John Wiley & Sons, Ltd.

Heterogeneity in Recent Onset Type 1 Diabetes – A Clinical Trial Perspective

PubMed Central

Bollyky, Jennifer B.; Xu, Ping; Butte, Atul J.; Wilson, Darrell M.; Beam, Craig A.; Greenbaum, Carla J.

2015-01-01

Background Type 1 Diabetes TrialNet is an NIH-sponsored clinical trial network aimed at altering the disease course of type 1 diabetes. The purpose of this study is to evaluate age-dependent heterogeneity in clinical, metabolic, and immunologic characteristics of individuals with recent-onset type 1 diabetes (T1D), to identify cohorts of interest and to aid in planning of future studies. Methods 883 individuals with recent onset T1D involved in five TrialNet studies were categorized by age as: ≥ 18, age 12-17, ages 8-12, and age <8. Data was compared with healthy age-matched subjects in the National Health and Nutrition Examination Survey. Results While only 2.0 % of individuals overall were excluded due to insufficient C-peptide values (<0.2 pmol/ml), 9.0% of those < age 8 did not meet this entry criteria. Leukopenia was present in 21.2% of individuals and lymphopenia in 11.6%; these frequencies were markedly different than age-matched healthy population. 24.5% of the cohort was overweight or obese. 31.1% of adults and 21.1% of children had neither HLA DR3 nor DR4. Conclusions The ability of recent onset T1D patients to meet key entry criteria for TrialNet studies, including C-peptide >0.2 pmol/ml, varies by age. Lower C-peptide level requirements for younger participants should be considered in the design of future trials. These data also highlight subgroups of type 1 diabetes patients, such as those with abnormal WBC or who are overweight, which allow for targeted studies of etiopathology and interventions. PMID:25689602

Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

PubMed Central

Jonker, Simone J.; Menting, Theo P.; Warlé, Michiel C.; Ritskes-Hoitinga, Merel; Wever, Kimberley E.

2016-01-01

Background Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. Method We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. Results We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. Conclusion High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID:26963819

A Systematic Review of Randomized Controlled Trials Examining Psychological Interventions for Needle-related Procedural Pain and Distress in Children and Adolescents: An Abbreviated Cochrane Review*

PubMed Central

Chambers, Christine T.; McGrath, Patrick J.; Kisely, Stephen

2008-01-01

Objective To report the results of a systematic review of randomized controlled trials (RCTs) of psychological interventions for children and adolescents undergoing needle-related procedures. Methods A variety of cognitive-behavioral psychological interventions for managing procedural pain and distress in children and adolescents between 2 and 19 years of age were examined. Outcome measures included pain and distress as assessed by self-report, observer report, behavioral/observational measures, and physiological correlates. Results Twenty-eight trials met the criteria for inclusion in the review and provided the data necessary for pooling the results. Together, the trials included 1,039 participants in treatment conditions and 951 in control conditions. The largest effect sizes for treatment improvement over control conditions were found for distraction, combined cognitive-behavioral interventions, and hypnosis, with promising but limited evidence for several other psychological interventions. Conclusions Recommendations for conducting future RCTs are provided, and particular attention to the quality of trial design and reporting is highlighted. PMID:18387963

Liquid biopsy-based clinical research in early breast cancer: The EORTC 90091-10093 Treat CTC trial.

PubMed

Ignatiadis, Michail; Rack, Brigitte; Rothé, Francoise; Riethdorf, Sabine; Decraene, Charles; Bonnefoi, Hervé; Dittrich, Christian; Messina, Carlo; Beauvois, Melanie; Trapp, Elisabeth; Goulioti, Theodora; Tryfonidis, Konstantinos; Pantel, Klaus; Repollet, Madeline; Janni, Wolfgang; Piccart, Martine; Sotiriou, Christos; Litiere, Saskia; Pierga, Jean-Yves

2016-08-01

There is increasing evidence that breast cancer evolves over time under the selection pressure of systemic treatment. Today, treatment decisions in early breast cancer are based on primary tumour characteristics without considering the disease evolution. Chemoresistant micrometastatic disease is poorly characterised and thus it is not used in current clinical practice as a tool to personalise treatment approaches. The detection of chemoresistant circulating tumour cells (CTCs) has been shown to be associated with worse prognosis in early breast cancer. The ongoing Treat CTC trial is the first international, liquid biopsy-based trial evaluating the concept of targeting chemoresistant minimal residual disease: detection of CTCs following adjuvant chemotherapy (adjuvant cohort) or neoadjuvant chemotherapy in patients who did not achieve pathological complete response (neoadjuvant cohort). This article presents the rational and design of this trial and the results of the pilot phase after 350 patients have been screened and provides insights that might provide information for future trials using the liquid biopsy approach as a tool towards precision medicine (NCT01548677). Copyright © 2016 Elsevier Ltd. All rights reserved.

Presence of music while eating: Effects on energy intake, eating rate and appetite sensations.

PubMed

Mamalaki, Eirini; Zachari, Konstantina; Karfopoulou, Eleni; Zervas, Efthimios; Yannakoulia, Mary

2017-01-01

The role of music in energy and dietary intake of humans is poorly understood. The purpose of the present laboratory study was to examine the effect of background music, its presence and its intensity, on energy intake, eating rate and appetite feelings. The study had a randomized crossover design. Twenty-six normal weight and overweight/obese men participated in random order in three trials: the control trial (no music was playing), the 60dB and the 90dB music trials, while an ad libitum lunch was consumed. Visual analogue scales for hunger, fullness/satiety, as well as desire to eat were administered to the participants. Energy intake at the ad libitum lunch did not differ between trials, even when covariates were taken into account. There were no statistically significant differences between trials on meal characteristics, such as meal duration, number of servings, number of bites eaten and on appetite indices. Future studies are needed to replicate these results and investigate the effect of different types of music and/or sound. Copyright © 2016 Elsevier Inc. All rights reserved.

Summary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer

PubMed Central

Lerner, Seth P.; Bajorin, Dean F.; Dinney, Colin P.; Efstathiou, Jason A.; Groshen, Susan; Hahn, Noah M.; Hansel, Donna; Kwiatkowski, David; O’Donnell, Michael; Rosenberg, Jonathan; Svatek, Robert; Abrams, Jeffrey S.; Al-Ahmadie, Hikmat; Apolo, Andrea B.; Bellmunt, Joaquim; Callahan, Margaret; Cha, Eugene K.; Drake, Charles; Jarow, Jonathan; Kamat, Ashish; Kim, William; Knowles, Margaret; Mann, Bhupinder; Marchionni, Luigi; McConkey, David; McShane, Lisa; Ramirez, Nilsa; Sharabi, Andrew; Sharpe, Arlene H.; Solit, David; Tangen, Catherine M.; Amiri, Abdul Tawab; Van Allen, Eliezer; West, Pamela J.; Witjes, J. A.; Quale, Diane Zipursky

2016-01-01

The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure). PMID:27376138

Professional ethics and professional etiquette in dentistry: are they compatible?

PubMed

Newbrun, Ernest

2007-01-01

In keeping with the theme of this colloquium, two aspects of ethics in dentistry are addressed: its evolution and its future. With respect to its evolution, two examples of changes in the design of clinical trials in dentistry are discussed. These concern the current requirement of informed consent from the subjects in the trial, now taken for granted, but not necessarily observed before 1964. The Vipeholm dental caries study is one example of pre-Helsinki Declaration experimentation. The second example, also drawn from caries research design, concerns the stricture on the use of placebo-controlled trials in the face of a proven drug. For example, the design of clinical trials of fluoride dentifrices has evolved since the mid 1970s. The use of a placebo-inactive control group is no longer acceptable as it would deprive its subjects of a proven caries-preventive agent and would expose its subjects to increased caries risk. While definitions of professional ethics in dentistry may vary, the ADA Code of Ethics includes five principles: patient autonomy ("self-governance"), non-maleficence ("do no harm"), beneficence ("do good"), justice ("fairness") and veracity ("truthfulness"). Professional etiquette refers to the way dentists relate to one another and is governed by the ADA Code of Professional Conduct which expresses specific types of conduct that are either required or prohibited. Sometimes, ethics and etiquette may conflict. The problem of financial issues that conflict with ethical ones is discussed along with the problem of commercialism in the practice of dentistry. Debts from dental school may adversely affect the professional behavior of young dentists, while general dentists might succumb to "goodies" provided by specialists. These often include continuing education courses, gifts, trips, and kickbacks. Specialists may fail to inform patients of improper or poor quality treatment by the referring general practitioner, fearing loss of referrals. Of course these issues are not unique to dentistry; they apply to all health care providers. Nor is this a new problem, but it requires fixing for the future of ethical dental practice.

The macular degeneration and aging study: Design and research protocol of a randomized trial for a psychosocial intervention with macular degeneration patients.

PubMed

Sörensen, Silvia; White, Katherine; Mak, Wingyun; Zanibbi, Katherine; Tang, Wan; O'Hearn, Amanda; Hegel, Mark T

2015-05-01

Age-related Macular Degeneration (AMD) is the leading cause of irreversible and predictable blindness among older adults with serious physical and mental health consequences. Visual impairment is associated with negative future outlook and depression and has serious consequences for older adults' quality of life and, by way of depression, on long-term survival. Psychosocial interventions have the potential to alleviate and prevent depression symptoms among older AMD patients. We describe the protocol of the Macular Degeneration and Aging Study, a randomized clinical trial of a psychosocial Preventive Problem-Solving Intervention. The intervention is aimed at enhancing well-being and future planning among older adults with macular degeneration by increasing preparation for future care. Adequate randomization and therapeutic fidelity were achieved. Current retention rates were acceptable, given the vulnerability of the population. Acceptability (adherence and satisfaction) was high. Given the high public health significance and impact on quality of life among older adults with vision loss, this protocol contributes a valid test of a promising intervention for maintaining mental and physical health in this population. Copyright © 2015 Elsevier Inc. All rights reserved.

Aromatherapy for treatment of hypertension: a systematic review.

PubMed

Hur, Myung-Haeng; Lee, Myeong Soo; Kim, Chan; Ernst, Edzard

2012-02-01

The objective of this review is to systematically review the evidence for the effectiveness of aromatherapy in the treatment of high blood pressure. Twelve databases were searched from their inception through December 2009. Controlled trials testing aromatherapy in patients with hypertension of any origin that assessed blood pressure were considered. The selection of studies, data extraction and validations were performed independently by two reviewers. One randomized clinical trial (RCT) and four non-randomized controlled clinical trials (CCTs) met our inclusion criteria. The one RCT included tested the effects of aromatherapy as compared with placebo and showed significant reduction of systolic blood pressure and diastolic blood pressure. All of the four CCTs showed favourable effects of aromatherapy. However, all of the CCTs also had a high risk of bias. The existing trial evidence does not show convincingly that aromatherapy is effective for hypertension. Future studies should be of high quality with a particular emphasis on designing an adequate control intervention. © 2010 Blackwell Publishing Ltd.

Pre-market version of a commercially available hearing instrument with a tinnitus sound generator: feasibility of evaluation in a clinical trial.

PubMed

Sereda, Magdalena; Davies, Jeff; Hall, Deborah A

2017-04-01

This report considers feasibility of conducting a UK trial of combination devices for tinnitus, using data from the study which evaluated different listener programmes available within the pre-market version of Oticon Alta with Tinnitus Sound Generator. Open and closed questions addressed the following feasibility issues: (1) Participant recruitment; (2) Device acceptability; (3) Programme preferences in different self-nominated listening situations; (4) Usability; (5) Compliance; (6) Adverse events. Eight current combination hearing aid users (all males) aged between 62-72 years (mean age 67.25 years, SD = 3.8). All eight participants reported the physical aspects and noise options on the experimental device to be acceptable. Programmes with amplification and masking features were equally preferred over the basic amplification-only programme. Individual preferences for the different programme options varied widely, both across participants and across listening situations. A set of recommendations for future trials were formulated which calls for more "real world" trial design rather than tightly controlling the fitting procedure.

Renal denervation in the management of resistant hypertension: current evidence and perspectives.

PubMed

Jin, Yu; Persu, Alexandre; Staessen, Jan A

2013-09-01

Catheter-based renal denervation has emerged as a novel treatment modality for resistant hypertension. This review summarizes the current evidence on this procedure in treatment of resistant hypertension, limitations of available evidence and questions to be answered. The SYMPLICITY studies showed that renal denervation is feasible in treating resistant hypertension, but failed to provide conclusive evidence on the size and durability of the antihypertensive, renal and sympatholytic effects, as well as the long-term safety. The definition of resistant hypertension was loose in the SYMPLICITY studies and the management of resistant hypertension was suboptimal. Future studies should have a randomized design and enroll truly resistant hypertension patients by excluding secondary hypertension, white-coat hypertension and nonadherent patients. Questions to be addressed by the ongoing and future trials include the long-term efficacy and safety of this procedure, identification of responders and uncovering of the underlying mechanisms. Only well-designed, randomized clinical trials addressing the limitations of the SYMPLICITY studies will be able to demonstrate whether renal denervation is an efficacious treatment modality in resistant hypertension and in which patients. For now, renal denervation remains an experimental procedure and should only be offered to truly resistant hypertensive patients in a research context after careful selection.

Intervention studies to foster resilience - A systematic review and proposal for a resilience framework in future intervention studies.

PubMed

Chmitorz, A; Kunzler, A; Helmreich, I; Tüscher, O; Kalisch, R; Kubiak, T; Wessa, M; Lieb, K

2018-02-01

Psychological resilience refers to the phenomenon that many people are able to adapt to the challenges of life and maintain mental health despite exposure to adversity. This has stimulated research on training programs to foster psychological resilience. We evaluated concepts, methods and designs of 43 randomized controlled trials published between 1979 and 2014 which assessed the efficacy of such training programs and propose standards for future intervention research based on recent developments in the field. We found that concepts, methods and designs in current resilience intervention studies are of limited use to properly assess efficacy of interventions to foster resilience. Major problems are the use of definitions of resilience as trait or a composite of resilience factors, the use of unsuited assessment instruments, and inappropriate study designs. To overcome these challenges, we propose 1) an outcome-oriented definition of resilience, 2) an outcome-oriented assessment of resilience as change in mental health in relation to stressor load, and 3) methodological standards for suitable study designs of future intervention studies. Our proposals may contribute to an improved quality of resilience intervention studies and may stimulate further progress in this growing research field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

'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.

Critical review, with an optimistic outlook, on Boron Neutron Capture Therapy (BNCT).

PubMed

Moss, Raymond L

2014-06-01

The first BNCT trials took place in the USA in the early 1960's, yet BNCT is still far from mainstream medicine. Nonetheless, in recent years, reported results in the treatment of head and neck cancer and recurrent glioma, coupled with the progress in developing linear accelerators specifically for BNCT applications, have given some optimism to the future of BNCT. This article provides a brief reminder on the ups and downs of the history of BNCT and supports the view that controlled and prospective clinical trials with a modern design will make BNCT an evidence-based treatment modality within the coming decade. © 2013 Elsevier Ltd. All rights reserved.

Neighborhood effects in a behavioral randomized controlled trial.

PubMed

Pruitt, Sandi L; Leonard, Tammy; Murdoch, James; Hughes, Amy; McQueen, Amy; Gupta, Samir

2014-11-01

Randomized controlled trials (RCTs) of interventions intended to modify health behaviors may be influenced by neighborhood effects which can impede unbiased estimation of intervention effects. Examining a RCT designed to increase colorectal cancer (CRC) screening (N=5628), we found statistically significant neighborhood effects: average CRC test use among neighboring study participants was significantly and positively associated with individual patient's CRC test use. This potentially important spatially-varying covariate has not previously been considered in a RCT. Our results suggest that future RCTs of health behavior interventions should assess potential social interactions between participants, which may cause intervention arm contamination and may bias effect size estimation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cardiac stem cell therapy and arrhythmogenicity: prometheus and the arrows of Apollo and Artemis.

PubMed

Lyon, Alexander R; Harding, Sian E; Peters, Nicholas S

2008-09-01

Cardiac cell therapy is an expanding scientific field which is yielding new insights into the pathogenesis of cardiac disease and offers new therapeutic strategies. Inherent to both these areas of research are the electrical properties of individual cells, the electrical interplay between cardiomyocytes, and their roles in arrhythmogenesis. This review discusses the potential mechanisms by which various candidate cells for cardiac therapy may modulate the ventricular arrhythmic substrate and highlights the data and lessons learnt from the clinical cardiac cell therapy trials published to date. Pro- and antiarrhythmic mechanistic factors are discussed, and the importance of their consideration in the design of any future clinical cell therapy trials.

Adjuvant treatment of stage IB NSCLC: the problem of stage subset heterogeneity.

PubMed

Calhoun, Royce; Jablons, David; Lau, Derick; Gandara, David R

2008-04-30

While 5-year survival rates in patients with stage IB non-small-cell lung cancer (NSCLC) are historically modest (40% to 67%), adjuvant chemotherapy trials including this subgroup have shown little evidence of chemotherapeutic benefit. This article reviews the available data regarding adjuvant chemotherapy following surgically resected stage IB NSCLC, framed within the context of present and future proposed definitions of this diagnosis. The discussion addresses limitations of the current staging system and how this contributes to the mixed results seen with adjuvant treatment. In addition, the authors consider current treatment options for stage IB NSCLC and review planned clinical trials for stage I disease designed to exploit new pharmacogenomic findings.

The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials.

PubMed

Schmitt, Jochen; Spuls, Phyllis I; Thomas, Kim S; Simpson, Eric; Furue, Masutaka; Deckert, Stefanie; Dohil, Magdalene; Apfelbacher, Christian; Singh, Jasvinder A; Chalmers, Joanne; Williams, Hywel C

2014-10-01

The lack of core outcome sets for atopic eczema (AE) is a major obstacle for advancing evidence-based treatment. The global Harmonising Outcome Measures for Eczema (HOME) initiative has already defined clinical signs, symptoms, quality of life, and long-term control of flares as core outcome domains for AE trials. This article deals with the standardization of measurement instruments to assess clinical signs of AE. To resolve the current lack of standardization of the assessment of clinical signs of AE, we followed a structured process of systematic reviews and international consensus sessions to identify 1 core outcome measurement instrument for assessment of clinical signs in all future AE trials. Systematic reviews indicated that from 16 different instruments identified to assess clinical signs of AE, only the Eczema Area and Severity Index (EASI) and the objective Scoring Atopic Dermatitis (SCORAD) index were identified as extensively validated. The EASI has adequate validity, responsiveness, internal consistency, and intraobserver reliability. The objective SCORAD index has adequate validity, responsiveness, and interobserver reliability but unclear intraobserver reliability to measure clinical signs of AE. In an international consensus study, patients, physicians, nurses, methodologists, and pharmaceutical industry representatives agreed that the EASI is the preferred core instrument to measure clinical signs in all future AE trials. All stakeholders involved in designing, reporting, and using clinical trials on AE are asked to comply with this consensus to enable better evidence-based decision making, clearer scientific communication, and improved patient care. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Firefighter willingness to participate in a stem cell clinical trial for burns: A mixed methods study.

PubMed

Horch, Jenny D; Carr, Eloise C J; Harasym, Patricia; Burnett, Lindsay; Biernaskie, Jeff; Gabriel, Vincent

2016-12-01

Adult stem cells represent a potentially renewable and autologous source of cells to regenerate skin and improve wound healing. Firefighters are at risk of sustaining a burn and potentially benefiting from a split thickness skin graft (STSG). This mixed methods study examined firefighter willingness to participate in a future stem cell clinical trial, outcome priorities and factors associated with this decision. A sequential explanatory mixed methods design was used. The quantitative phase (online questionnaire) was followed by the qualitative phase (semi-structured interviews). A sample of 149 firefighters completed the online survey, and a purposeful sample of 15 firefighters was interviewed. A majority (74%) reported they would participate in a future stem cell clinical trial if they experienced burn benefiting from STSG. Hypothetical concerns related to receiving a STSG were pain, itch, scarring/redness and skin durability. Participants indicated willingness to undergo stem cell therapy if the risk of no improvement was 43% or less. Risk tolerance was predicted by perceived social support and having children. Interviews revealed four main themes: a desire to help others, improving clinical outcomes, trusting relationships, and a belief in scientific investigation. Many participants admitted lacking sufficient knowledge to make an informed decision regarding stem cell therapies. Firefighters indicated they were largely willing to participate in a stem cell clinical trial but also indicated a lack of knowledge upon which to make a decision. Public education of the role of stem cells in STSG will be increasingly important as clinical trials are developed. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

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.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

PubMed

Burbach, J P M; Kurk, S A; Coebergh van den Braak, R R J; Dik, V K; May, A M; Meijer, G A; Punt, C J A; Vink, G R; Los, M; Hoogerbrugge, N; Huijgens, P C; Ijzermans, J N M; Kuipers, E J; de Noo, M E; Pennings, J P; van der Velden, A M T; Verhoef, C; Siersema, P D; van Oijen, M G H; Verkooijen, H M; Koopman, M

2016-11-01

Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

The effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trials

PubMed Central

Whitten, D L; Myers, S P; Hawrelak, J A; Wohlmuth, H

2006-01-01

Aim The aim of this systematic review was to assess the quality and outcomes of clinical trials investigating the effect of St John’s wort extracts on the metabolism of drugs by CYP3A. Methods Prospective clinical trials assessing the effect of St John’s wort (SJW) extracts on metabolism by CYP3A were identified through computer-based searches (from their inception to May 2005) of Medline, Cinahl, PsycINFO, AMED, Current Contents and Embase, hand-searches of bibliographies of relevant papers and consultation with manufacturers and researchers in the field. Two reviewers selected trials for inclusion, independently extracted data and recorded details on study design. Results Thirty-one studies met the eligibility criteria. More than two-thirds of the studies employed a before-and-after design, less than one-third of the studies used a crossover design, and only three studies were double-blind and placebo controlled. In 12 studies the SJW extract had been assayed, and 14 studies stated the specific SJW extract used. Results from 26 studies, including all of the 19 studies that used high-dose hyperforin extracts (>10 mg day−1), had outcomes consistent with CYP3A induction. The three studies using low-dose hyperforin extracts (<4 mg day−1) demonstrated no significant effect on CYP3A. Conclusion There is reasonable evidence to suggest that high-dose hyperforin SJW extracts induce CYP3A. More studies are required to determine whether decreased CYP3A induction occurs after low-dose hyperforin extracts. Future studies should adopt study designs with a control phase or control group, identify the specific SJW extract employed and provide quantitative analyses of key constituents. PMID:17010103

A perspective on B-cell-targeting therapy for SLE.

PubMed

Looney, R John; Anolik, Jennifer; Sanz, Inaki

2010-02-01

In recent years, large controlled trials have tested several new agents for systemic lupus erythematosus (SLE). Unfortunately, none of these trials has met its primary outcome. This does not mean progress has not been made. In fact, a great deal has been learned about doing clinical trials in lupus and about the biological and clinical effects of the drugs being tested. Many of these drugs were designed to target B cells directly, e.g., rituximab, belimumab, epratuzumab, and transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig). The enthusiasm for targeting B cells derives from substantial evidence showing the critical role of B cells in murine models of SLE, as well promising results from multiple open trials with rituximab, a chimeric anti-CD20 monoclonal antibody that specifically depletes B cells (Martin and Chan in Immunity 20(5):517-527, 2004; Sobel et al. in J Exp Med 173:1441-1449, 1991; Silverman and Weisman in Arthritis Rheum 48:1484-1492, 2003; Silverman in Arthritis Rheum 52(4):1342, 2005; Shlomchik et al. in Nat Rev Immunol 1:147-153, 2001; Looney et al. in Arthritis Rheum 50:2580-2589, 2004; Lu et al. in Arthritis Rheum 61(4):482-487, 2009; Saito et al. in Lupus 12(10):798-800, 2003; van Vollenhoven et al. in Scand J Rheumatol 33(6):423-427, 2004; Sfikakis et al. Arthritis Rheum 52(2):501-513, 2005). Why have the controlled trials of B-cell-targeting therapies failed to demonstrate efficacy? Were there flaws in design or execution of these trials? Or, were promising animal studies and open trials misleading, as so often happens? This perspective discusses the current state of B-cell-targeting therapies for human lupus and the future development of these therapies.

Using an internet intervention to support self-management of low back pain in primary care: findings from a randomised controlled feasibility trial (SupportBack)

PubMed Central

Geraghty, Adam W A; Stanford, Rosie; Stuart, Beth; Little, Paul; Roberts, Lisa C; Foster, Nadine E; Hill, Jonathan C; Hay, Elaine M; Turner, David; Malakan, Wansida; Leigh, Linda; Yardley, Lucy

2018-01-01

Objective To determine the feasibility of a randomised controlled trial of an internet intervention for low back pain (LBP) using three arms: (1) usual care, (2) usual care plus an internet intervention or (3) usual care plus an internet intervention with additional physiotherapist telephone support. Design and setting A three-armed randomised controlled feasibility trial conducted in 12 general practices in England. Participants Primary care patients aged over 18 years, with current LBP, access to the internet and without indicators of serious spinal pathology or systemic illness. Interventions The ‘SupportBack’ internet intervention delivers a 6-week, tailored programme, focused on graded goal setting, self-monitoring and provision of tailored feedback to encourage physical activity. Additional physiotherapist telephone support consisted of three brief telephone calls over a 4-week period, to address any concerns and provide reassurance. Outcomes The primary outcomes were the feasibility of the trial design including recruitment, adherence and retention at follow-up. Secondary descriptive and exploratory analyses were conducted on clinical outcomes including LBP-related disability at 3 months follow-up. Results Primary outcomes: 87 patients with LBP were recruited (target 60–90) over 6 months, and there were 3 withdrawals. Adherence to the intervention was higher in the physiotherapist-supported arm, compared with the stand-alone internet intervention. Trial physiotherapists adhered to the support protocol. Overall follow-up rate on key clinical outcomes at 3 months follow-up was 84%. Conclusions This study demonstrated the feasibility of a future definitive randomised controlled trial to determine the clinical and cost-effectiveness of the SupportBack intervention in primary care patients with LBP. Trial registration number ISRCTN31034004; Results. PMID:29525768

Bayesian Dose-Response Modeling in Sparse Data

NASA Astrophysics Data System (ADS)

Kim, Steven B.

This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a wrong parametric assumption. In this regard, we consider a robust experimental design which does not require any parametric assumption.

Interventions to increase immunisation coverage among children 12–23 months of age in India through participatory learning and community engagement: pilot study for a cluster randomised trial

PubMed Central

Johri, Mira; Chandra, Dinesh; Koné, Georges K; Dudeja, Sakshi; Sylvestre, Marie-Pierre; Sharma, Jitendar K; Pahwa, Smriti

2015-01-01

Objective With the aim of conducting a future cluster randomised trial to assess intervention impact on child vaccination coverage, we designed a pilot study to assess feasibility and aid in refining methods for the larger study. Trial design Cluster-randomised design with a 1:1 allocation ratio. Methods Clusters were 12 villages in rural Uttar Pradesh. All women residing in a selected village who were mothers of a child 0–23 months of age were eligible; participants were chosen at random. Over 4 months, intervention group (IG) villages received: (1) home visits by volunteers; (2) community mobilisation events to promote immunisation. Control group (CG) villages received community mobilisation to promote nutrition. A toll-free number for immunisation was offered to all IG and CG village residents. Primary outcomes were ex-ante criteria for feasibility of the main study related to processes for recruitment and randomisation (50% of villages would agree to participate and accept randomisation; 30 women could be recruited in 70% of villages), and retention of participants (50% of women retained from baseline to endline). Clusters were assigned to IG or CG using a computer-generated randomisation schedule. Neither participants nor those delivering interventions were blinded, but those assessing outcomes were blinded to group assignment. Results All villages contacted agreed to participate and accepted randomisation. 36 women were recruited per village; 432 participants were randomised (IG n=216; CG n=216). No clusters were lost to follow-up. The main analysis included 86% (373/432) of participants, 90% (195/216) from the IG and 82% (178/216) from the CG. Conclusions Criteria related to feasibility were satisfied, giving us confidence that we can successfully conduct a larger cluster randomised trial. Methodological lessons will inform design of the main study. Trial registration number ISRCTN16703097 PMID:26384721

Feasibility randomised multicentre, double-blind, double-dummy controlled trial of anakinra, an interleukin-1 receptor antagonist versus intramuscular methylprednisolone for acute gout attacks in patients with chronic kidney disease (ASGARD): protocol study.

PubMed

Balasubramaniam, Gowrie; Parker, Trisha; Turner, David; Parker, Mike; Scales, Jonathan; Harnett, Patrick; Harrison, Michael; Ahmed, Khalid; Bhagat, Sweta; Marianayagam, Thiraupathy; Pitzalis, Costantino; Mallen, Christian; Roddy, Edward; Almond, Mike; Dasgupta, Bhaskar

2017-09-05

Acute gout occurs in people with chronic kidney disease, who are commonly older people with comorbidities such as hypertension, heart disease and diabetes. Potentially harmful treatments are administered to these vulnerable patients due to a lack of clear evidence. Newly available treatment that targets a key inflammatory pathway in acute gout attacks provides an opportunity to undertake the first-ever trial specifically looking treating people with kidney disease. This paper describes the protocol for a feasibility randomised controlled trial (RCT) comparing anakinra, a novel interleukin-1 antagonist versus steroids in people with chronic kidney disease (ASGARD). ASGARD is a two-parallel group double-blind, double-dummy multicentre RCT comparing anakinra 100 mg, an interleukin-1 antagonist, subcutaneous for 5 days against intramuscular methylprednisolone 120 mg. The primary objective is to assess the feasibility of the trial design and procedures for a definitive RCT. The specific aims are: (1) test recruitment and retention rates and willingness to be randomised; (2) test eligibility criteria; (3) collect and analyse outcome data to inform sample and power calculations for a trial of efficacy; (4) collect economic data to inform a future economic evaluation estimating costs of treatment and (5) assess capacity of the project to scale up to a national multicentre trial. We will also gather qualitative insights from participants. It aims to recruit 32 patients with a 1:1 randomisation. Information from this feasibility study will help design a definitive trial and provide general information in designing acute gout studies. The London-Central Ethics Committee approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences. EudraCT No. 2015-001787-19, NCT/Clinicalstrials.gov No. NCT02578394, pre-results, WHO Universal Trials Reference No. U1111-1175-1977. NIHR Grant PB-PG-0614-34090. © 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.

MMP Inhibitors: Past, present and future.

PubMed

Cathcart, Jillian M; Cao, Jian

2015-06-01

  Development of inhibitors of matrix metalloproteinases (MMPs) has been fraught with challenges. Early compounds largely failed due to poor selectivity and bioavailability. Dose-limiting side effects, off-target interactions, and improperly designed clinical trials significantly impeded clinical success. As information becomes available and technology evolves, tools to combat these obstacles have been developed. Improved methods for high throughput screening and drug design have led to identification of compounds exhibiting high potency, binding affinity, and favorable pharmacokinetic profiles. Current research into MMP inhibitors employs innovative approaches for drug delivery methods and allosteric inhibitors. Such innovation is key for development of clinically successful compounds.

Patient Navigation As a Model to Increase Participation of African Americans in Cancer Clinical Trials.

PubMed

Fouad, Mona N; Acemgil, Aras; Bae, Sejong; Forero, Andres; Lisovicz, Nedra; Martin, Michelle Y; Oates, Gabriela R; Partridge, Edward E; Vickers, Selwyn M

2016-06-01

Less than 10% of patients enrolled in clinical trials are minorities. The patient navigation model has been used to improve access to medical care but has not been evaluated as a tool to increase the participation of minorities in clinical trials. The Increasing Minority Participation in Clinical Trials project used patient navigators (PNs) to enhance the recruitment of African Americans for and their retention in therapeutic cancer clinical trials in a National Cancer Institute-designated comprehensive cancer center. Lay individuals were hired and trained to serve as PNs for clinical trials. African American patients potentially eligible for clinical trials were identified through chart review or referrals by clinic nurses, physicians, and social workers. PNs provided two levels of services: education about clinical trials and tailored support for patients who enrolled in clinical trials. Between 2007 and 2014, 424 African American patients with cancer were referred to the Increasing Minority Participation in Clinical Trials project. Of those eligible for a clinical trial (N = 378), 304 (80.4%) enrolled in a trial and 272 (72%) consented to receive patient navigation support. Of those receiving patient navigation support, 74.5% completed the trial, compared with 37.5% of those not receiving patient navigation support. The difference in retention rates between the two groups was statistically significant (P < .001). Participation of African Americans in therapeutic cancer clinical trials increased from 9% to 16%. Patient navigation for clinical trials successfully retained African Americans in therapeutic trials compared with non-patient navigation trial participation. The model holds promise as a strategy to reduce disparities in cancer clinical trial participation. Future studies should evaluate it with racial/ethnic minorities across cancer centers. Copyright © 2016 by American Society of Clinical Oncology.

Resisting distraction and response inhibition trigger similar enhancements of future performance.

PubMed

Bissett, Patrick G; Grant, Lauren D; Weissman, Daniel H

2017-10-01

Resisting distraction and response inhibition are crucial aspects of cognitive control. Interestingly, each of these abilities transiently improves just after it is utilized. Competing views differ, however, as to whether utilizing either of these abilities (e.g., resisting distraction) enhances future performance involving the other ability (e.g., response inhibition). To distinguish between these views, we combined a Stroop-like task that requires resisting distraction with a restraint variant of the stop-signal task that requires response inhibition. We observed similar sequential-trial effects (i.e., performance enhancements) following trials in which participants (a) resisted distraction (i.e., incongruent go trials) and (b) inhibited a response (i.e., congruent stop trials). First, the congruency effect in go trials, which indexes overall distractibility, was smaller after both incongruent go trials and congruent stop trials than it was after congruent go trials. Second, stop failures were less frequent after both incongruent go trials and congruent stop trials than after congruent go trials. A control experiment ruled out the possibility that perceptual conflict or surprise engendered by occasional stop signals triggers sequential-trial effects independent of stopping. Thus, our findings support a novel, integrated view in which resisting distraction and response inhibition trigger similar sequential enhancements of future performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Herbal medicines for treating acute otitis media: A systematic review of randomised controlled trials.

PubMed

Son, Mi Ju; Kim, Young-Eun; Song, Young Il; Kim, Yun Hee

2017-12-01

This systematic review aimed to assess the clinical evidence for the widespread use of herbal medicines in treating acute otitis media. Eleven electronic databases, including MEDLINE, EMBASE, and the CENTRAL were searched, without language limitations. All randomised controlled trials involving the use of herbal medicines, alone or in combination with conventional therapies, for acute otitis media were included. We identified 4956 studies, of which seven randomised clinical trials met the inclusion criteria. The overall risk of bias of the included trials was relatively high or unclear. Treatment with Longdan-xiegan decoction or Shenling-baizhu powder, combined with antibiotics, appeared to be more effective than treatment with antibiotics alone in terms of the proportion of patients with total symptom recovery. Moreover, combination treatment of Sinupret ® and antibiotics facilitated the recovery of middle ear conditions and hearing acuity. Despite some indications of potential symptom improvement, the evidence regarding the effectiveness and efficacy of herbal medicine for acute otitis media is inconclusive due to the poor quality of trials included. Moreover, we only analysed seven trials in this review. Therefore, to properly evaluate the effectiveness of herbal medicine for acute otitis media, systematic reviews based on more rigorously designed randomized trials are warranted in the future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Allergen immunotherapy: exploring areas for further inquiry.

PubMed

Ramsey, Tam; Lai, Wanda; Svider, Peter F; Hojjat, Houmehr; Eloy, Jean Anderson; Folbe, Adam J

2017-12-01

Allergy-related illness impacts millions of individuals worldwide. Our objectives were to characterize current trends of clinical trials research relating to allergen immunotherapy and to describe the landscape of allergen immunotherapy in National Institutes of Health (NIH)-supported research inquiry. On ClinicalTrials.gov, the following terms were searched: allergen immunotherapy OR allergy immunotherapy. Variables, including completion status, dates, design, study population, funder, location, and allergen were recorded. The NIH Research Portfolio Online Reporting Tools (RePORTER) system was also used to gather relevant variables. A total of 372 clinical trials met inclusion criteria. The proportion of industry-funded clinical trials has declined over 15 years. There has been a slow decline in pollen allergy immunotherapy research, with an increase in both food and animal allergy immunotherapy research. Otolaryngologists comprised only 6.4% of clinical trials principal investigators (PIs). There was a total adjusted NIH funding of $74,986,125 for the 118 total funding years. Despite an immense interest in allergen immunotherapy, this analysis demonstrates that otolaryngologists represented a small proportion of PIs leading associated clinical trials and basic science inquiry. The proportion of trials with industry sponsorship has declined considerably in recent decades. These trends could help direct future resource allocation for allergen immunotherapy. © 2017 ARS-AAOA, LLC.

Combination therapy with PD-1/PD-L1 blockade: An overview of ongoing clinical trials.

PubMed

Johnson, C Bryce; Win, Shwe Y

2018-01-01

Monoclonal antibodies (mAbs) that block the programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) receptors are the most clinically advanced tumor immunotherapies. Given the broad antitumor efficacy and novel mechanism of action, numerous combinatorial approaches incorporating PD-1/PD-L1 blockade have been suggested; herein we present a comprehensive analysis of these clinical trials. We queried clinicaltrials.gov for all PD-1/PD-L1 mAbs administered for cancer therapy with an end date of 4/30/2017. A total of 1,218 clinical trials met our search criteria. These trials have a planned enrollment of 227,190 patients, and approximately half (493) were initiated in 2016 alone. Of these over 1,200 trials, 916 combine PD-1/PD-L1 blockade with at least one additional therapy, ranging from traditional treatment modalities like surgery and chemoradiation to newer therapies like small molecule inhibitors and other immunotherapies. The staggering proliferation of clinical trials combining PD-1/PD-L1 blockade with disparate treatments necessitates careful accounting to maximize efficiency and highlight areas of unmet needs. We believe our analysis provides this data and expect it will facilitate the design of future clinical trials in this burgeoning area of oncology research.

The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

PubMed Central

Bowers, Laura W.; Rossi, Emily L.; O’Flanagan, Ciara H.; deGraffenried, Linda A.; Hursting, Stephen D.

2015-01-01

Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted. PMID:26029167

A systematic review of randomized trials of mind-body interventions for PTSD.

PubMed

Niles, Barbara L; Mori, DeAnna L; Polizzi, Craig; Pless Kaiser, Anica; Weinstein, Elizabeth S; Gershkovich, Marina; Wang, Chenchen

2018-05-10

To systematically review outcomes from randomized controlled trials (RCTs) of mind-body treatments for PTSD. Inclusion criteria based on guidelines for assessing risk of bias were used to evaluate articles identified through electronic literature searches. Twenty-two RCTs met inclusion standards. In most of the nine mindfulness and six yoga studies, significant between-group effects were found indicating moderate to large effect size advantages for these treatments. In all seven relaxation RCT's, relaxation was used as a control condition and five studies reported significant between-group differences on relevant PTSD outcomes in favor of the target treatments. However, there were large within-group symptom improvements in the relaxation condition for the majority of studies. Although many studies are limited by methodologic weaknesses, recent studies have increased rigor and, in aggregate, the results for mindfulness, yoga, and relaxation are promising. Recommendations for design of future mind-body trials are offered. © 2018 Wiley Periodicals, Inc.

An examination of effect estimation in factorial and standardly-tailored designs

PubMed Central

Allore, Heather G; Murphy, Terrence E

2012-01-01

Background Many clinical trials are designed to test an intervention arm against a control arm wherein all subjects are equally eligible for all interventional components. Factorial designs have extended this to test multiple intervention components and their interactions. A newer design referred to as a ‘standardly-tailored’ design, is a multicomponent interventional trial that applies individual interventional components to modify risk factors identified a priori and tests whether health outcomes differ between treatment arms. Standardly-tailored designs do not require that all subjects be eligible for every interventional component. Although standardly-tailored designs yield an estimate for the net effect of the multicomponent intervention, it has not yet been shown if they permit separate, unbiased estimation of individual component effects. The ability to estimate the most potent interventional components has direct bearing on conducting second stage translational research. Purpose We present statistical issues related to the estimation of individual component effects in trials of geriatric conditions using factorial and standardly-tailored designs. The medical community is interested in second stage translational research involving the transfer of results from a randomized clinical trial to a community setting. Before such research is undertaken, main effects and synergistic and or antagonistic interactions between them should be identified. Knowledge of the relative strength and direction of the effects of the individual components and their interactions facilitates the successful transfer of clinically significant findings and may potentially reduce the number of interventional components needed. Therefore the current inability of the standardly-tailored design to provide unbiased estimates of individual interventional components is a serious limitation in their applicability to second stage translational research. Methods We discuss estimation of individual component effects from the family of factorial designs and this limitation for standardly-tailored designs. We use the phrase ‘factorial designs’ to describe full-factorial designs and their derivatives including the fractional factorial, partial factorial, incomplete factorial and modified reciprocal designs. We suggest two potential directions for designing multicomponent interventions to facilitate unbiased estimates of individual interventional components. Results Full factorial designs and their variants are the most common multicomponent trial design described in the literature and differ meaningfully from standardly-tailored designs. Factorial and standardly-tailored designs result in similar estimates of net effect with different levels of precision. Unbiased estimation of individual component effects from a standardly-tailored design will require new methodology. Limitations Although clinically relevant in geriatrics, previous applications of standardly-tailored designs have not provided unbiased estimates of the effects of individual interventional components. Discussion Future directions to estimate individual component effects from standardly-tailored designs include applying D-optimal designs and creating independent linear combinations of risk factors analogous to factor analysis. Conclusion Methods are needed to extract unbiased estimates of the effects of individual interventional components from standardly-tailored designs. PMID:18375650

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for primary prevention of osteoarthritis by joint injury prevention in sport and recreation.

PubMed

Emery, C A; Roos, E M; Verhagen, E; Finch, C F; Bennell, K L; Story, B; Spindler, K; Kemp, J; Lohmander, L S

2015-05-01

The risk of post-traumatic osteoarthritis (PTOA) substantially increases following joint injury. Research efforts should focus on investigating the efficacy of preventative strategies in high quality randomized controlled trials (RCT). The objective of these OARSI RCT recommendations is to inform the design, conduct and analytical approaches to RCTs evaluating the preventative effect of joint injury prevention strategies. Recommendations regarding the design, conduct, and reporting of RCTs evaluating injury prevention interventions were established based on the consensus of nine researchers internationally with expertise in epidemiology, injury prevention and/or osteoarthritis (OA). Input and resultant consensus was established through teleconference, face to face and email correspondence over a 1 year period. Recommendations for injury prevention RCTs include context specific considerations regarding the research question, research design, study participants, randomization, baseline characteristics, intervention, outcome measurement, analysis, implementation, cost evaluation, reporting and future considerations including the impact on development of PTOA. Methodological recommendations for injury prevention RCTs are critical to informing evidence-based practice and policy decisions in health care, public health and the community. Recommendations regarding the interpretation and conduct of injury prevention RCTs will inform the highest level of evidence in the field. These recommendations will facilitate between study comparisons to inform best practice in injury prevention that will have the greatest public health impact. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

PubMed

Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.

An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

PubMed

Pasipanodya, Jotam; Gumbo, Tawanda

2011-01-01

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

Stabilized helical peptides: overview of the technologies and its impact on drug discovery.

PubMed

Klein, Mark

2017-11-01

Protein-protein interactions are predominant in the workings of all cells. Until now, there have been a few successes in targeting protein-protein interactions with small molecules. Peptides may overcome some of the challenges of small molecules in disrupting protein-protein interactions. However, peptides present a new set of challenges in drug discovery. Thus, the study of the stabilization of helical peptides has been extensive. Areas covered: Several technological approaches to helical peptide stabilization have been studied. In this review, stapled peptides, foldamers, and hydrogen bond surrogates are discussed. Issues regarding design principles are also discussed. Furthermore, this review introduces select computational techniques used to aid peptide design and discusses clinical trials of peptides in a more advanced stage of development. Expert opinion: Stabilized helical peptides hold great promise in a wide array of diseases. However, the field is still relatively new and new design principles are emerging. The possibilities of peptide modification are quite extensive and expanding, so the design of stabilized peptides requires great attention to detail in order to avoid a large number of failed lead peptides. The start of clinical trials with stapled peptides is a promising sign for the future.

Addressing challenges of clinical trials in acute pain: The Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study.

PubMed

Nottage, Kerri A; Hankins, Jane S; Faughnan, Lane G; James, Dustin M; Richardson, Julie; Christensen, Robbin; Kang, Guolian; Smeltzer, Matthew; Cancio, Maria I; Wang, Winfred C; Anghelescu, Doralina L

2016-08-01

Neuropathic pain is a known component of vaso-occlusive pain in sickle cell disease; however, drugs targeting neuropathic pain have not been studied in this population. Trials of acute pain are complicated by the need to obtain consent, to randomize participants expeditiously while optimally treating pain. We describe the challenges in designing and implementing the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study (NCT01954927), a phase II, randomized, double-blind, placebo-controlled trial to determine the effect of gabapentin for vaso-occlusive crisis. In the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study, we aim to assess the analgesic effect of gabapentin during vaso-occlusive crisis. Difficulties we identified included avoiding delay of notification of study staff of potential participants which we resolved by automated notification. Concern for rapid randomization and drug dispensation was addressed through careful planning with an investigational pharmacy and a single liquid formulation. We considered obtaining consent during well-visits to avoid the time constraints with acute presentations, but the large number of patients and limited duration that consent is valid made this impractical. In all, 79% of caregivers/children approached have agreed to participate. The trial is currently active, and enrollment is at 45.8% of that targeted (76 of 166) and expected to continue for two more years. Maintaining staff availability after-hours remains problematic, with 8% of screened patients missed for lack of available staff. Lessons learned in designing a trial to expedite procedures in the acute pain setting include (1) building study evaluations upon a standard-of-care backbone; (2) implementing a simple study design to facilitate consent and data capture; (3) assuring ample, well-trained study staff; and (4) utilizing technology to automate procedures whenever possible. This study design has circumvented many of the logistical barriers usually associated with acute pain trials and may serve as a prototype for future studies. © The Author(s) 2016.

Clinical decision making and the expected value of information.

PubMed

Willan, Andrew R

2007-01-01

The results of the HOPE study, a randomized clinical trial, provide strong evidence that 1) ramipril prevents the composite outcome of cardiovascular death, myocardial infarction or stroke in patients who are at high risk of a cardiovascular event and 2) ramipril is cost-effective at a threshold willingness-to-pay of $10,000 to prevent an event of the composite outcome. In this report the concept of the expected value of information is used to determine if the information provided by the HOPE study is sufficient for decision making in the US and Canada. and results Using the cost-effectiveness data from a clinical trial, or from a meta-analysis of several trials, one can determine, based on the number of future patients that would benefit from the health technology under investigation, the expected value of sample information (EVSI) of a future trial as a function of proposed sample size. If the EVSI exceeds the cost for any particular sample size then the current information is insufficient for decision making and a future trial is indicated. If, on the other hand, there is no sample size for which the EVSI exceeds the cost, then there is sufficient information for decision making and no future trial is required. Using the data from the HOPE study these concepts are applied for various assumptions regarding the fixed and variable cost of a future trial and the number of patients who would benefit from ramipril. Expected value of information methods provide a decision-analytic alternative to the standard likelihood methods for assessing the evidence provided by cost-effectiveness data from randomized clinical trials.

A core outcome set for localised prostate cancer effectiveness trials: protocol for a systematic review of the literature and stakeholder involvement through interviews and a Delphi survey.

PubMed

MacLennan, Steven; Bekema, Hendrika J; Williamson, Paula R; Campbell, Marion K; Stewart, Fiona; MacLennan, Sara J; N'Dow, James M O; Lam, Thomas B L

2015-03-04

Prostate cancer is a growing health problem worldwide. The management of localised prostate cancer is controversial. It is unclear which of several surgical, radiotherapeutic, ablative, and surveillance treatments is the most effective. All have cost, process and recovery, and morbidity implications which add to treatment decision-making complexity for patients and healthcare professionals. Evidence from randomised controlled trials (RCTs) is not optimal because of uncertainty as to what constitutes important outcomes. Another issue hampering evidence synthesis is heterogeneity of outcome definition, measurement, and reporting. This project aims to determine which outcomes are the most important to patients and healthcare professionals, and use these findings to recommend a standardised core outcome set for comparative effectiveness trials of treatments for localised prostate cancer, to optimise decision-making. The range of potentially important outcomes and measures will be identified through systematic reviews of the literature and semi-structured interviews with patients. A consultation exercise involving representatives from two key stakeholder groups (patients and healthcare professionals) will ratify the list of outcomes to be entered into a three round Delphi study. The Delphi process will refine and prioritise the list of identified outcomes. A methodological substudy (nested RCT design) will also be undertaken. Participants will be randomised after round one of the Delphi study to one of three feedback groups, based on different feedback strategies, in order to explore the potential impact of feedback strategies on participant responses. This may assist the design of a future core outcome set and Delphi studies. Following the Delphi study, a final consensus meeting attended by representatives from both stakeholder groups will determine the final recommended core outcome set. This study will inform clinical practice and future trials of interventions of localised prostate cancer by standardising a core outcome set which should be considered in comparative effectiveness studies for localised prostate cancer.

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.

Human Systems Integration and Automation Issues in Small Unmanned Aerial Vehicles

NASA Technical Reports Server (NTRS)

McCauley, Michael E.; Matsangas, Panagiotis

2004-01-01

The goal of this report is to identify Human System Integration (HSI) and automation issues that contribute to improved effectiveness and efficiency in the operation of U.S. military Small Unmanned Aerial Vehicles (SUAVs). HSI issues relevant to SUAV operations are reviewed and observations from field trials are summarized. Short-term improvements are suggested research issues are identified and an overview is provided of automation technologies applicable to future SUAV design.

Randomized trial of an uncertainty self-management telephone intervention for patients awaiting liver transplant.

PubMed

Bailey, Donald E; Hendrix, Cristina C; Steinhauser, Karen E; Stechuchak, Karen M; Porter, Laura S; Hudson, Julie; Olsen, Maren K; Muir, Andrew; Lowman, Sarah; DiMartini, Andrea; Salonen, Laurel Williams; Tulsky, James A

2017-03-01

We tested an uncertainty self-management telephone intervention (SMI) with patients awaiting liver transplant and their caregivers. Participants were recruited from four transplant centers and completed questionnaires at baseline, 10, and 12 weeks from baseline (generally two and four weeks after intervention delivery, respectively). Dyads were randomized to either SMI (n=56) or liver disease education (LDE; n=59), both of which involved six weekly telephone sessions. SMI participants were taught coping skills and uncertainty management strategies while LDE participants learned about liver function and how to stay healthy. Outcomes included illness uncertainty, uncertainty management, depression, anxiety, self-efficacy, and quality of life. General linear models were used to test for group differences. No differences were found between the SMI and LDE groups for study outcomes. This trial offers insight regarding design for future interventions that may allow greater flexibility in length of delivery beyond our study's 12-week timeframe. Our study was designed for the time constraints of today's clinical practice setting. This trial is a beginning point to address the unmet needs of these patients and their caregivers as they wait for transplants that could save their lives. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

‘Help for Hay Fever’, a goal-focused intervention for people with intermittent allergic rhinitis, delivered in Scottish community pharmacies: study protocol for a pilot cluster randomized controlled trial

PubMed Central

2013-01-01

Background Despite the availability of evidence-based guidelines for managing allergic rhinitis in primary care, management of the condition in the United Kingdom (UK) remains sub-optimal. Its high prevalence and negative effects on quality of life, school performance, productivity and co-morbid respiratory conditions (in particular, asthma), and high health and societal costs, make this a priority for developing novel models of care. Recent Australian research demonstrated the potential of a community pharmacy-based ‘goal-focused’ intervention to help people with intermittent allergic rhinitis to self-manage their condition better, reduce symptom severity and improve quality of life. In this pilot study we will assess the transferability of the goal-focused intervention to a UK context, the suitability of the intervention materials, procedures and outcome measures and collect data to inform a future definitive UK randomized controlled trial (RCT). Methods/Design A pilot cluster RCT with associated preliminary economic analysis and embedded qualitative evaluation. The pilot trial will take place in two Scottish Health Board areas: Grampian and Greater Glasgow & Clyde. Twelve community pharmacies will be randomly assigned to intervention or usual care group. Each will recruit 12 customers seeking advice or treatment for intermittent allergic rhinitis. Pharmacy staff in intervention pharmacies will support recruited customers in developing strategies for setting and achieving goals that aim to avoid/minimize triggers for, and eliminate/minimize symptoms of allergic rhinitis. Customers recruited in non-intervention pharmacies will receive usual care. The co-primary outcome measures, selected to inform a sample size calculation for a future RCT, are: community pharmacy and customer recruitment and completion rates; and effect size of change in the validated mini-Rhinoconjunctivitis Quality of Life Questionnaire between baseline, one-week and six-weeks post-intervention. Secondary outcome measures relate to changes in symptom severity, productivity, medication adherence and self-efficacy. Quantitative data about accrual, retention and economic measures, and qualitative data about participants’ experiences during the trial will be collected to inform the future RCT. Discussion This work will lay the foundations for a definitive RCT of a community pharmacy-based ‘goal-focused’ self-management intervention for people with intermittent allergic rhinitis. Results of the pilot trial are expected to be available in April 2013. Trial registration Current Controlled Trials ISRCTN43606442 PMID:23856015

The role of incretin-based therapies in prediabetes: a review.

PubMed

Ahmadieh, Hala; Azar, Sami T

2014-12-01

Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance. Copyright © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Physical Activity Outcomes of Nurse-Delivered Lifestyle Interventions.

PubMed

Richards, Elizabeth A; Cai, Yun

2016-02-01

Promotion of physical activity has been a public health priority for decades. Over two million home healthcare nurses are at the front line to deliver effective health education and health promotion interventions in the United States. The purpose of this systematic review is to examine the effectiveness of nurse-delivered lifestyle physical interventions on physical activity outcomes conducted in home settings. Computerized database and ancestry search strategies located distinct intervention trials between 1990 and 2015. A total of eight quantitative studies were reviewed. Four of the eight studies were randomized control trials and four studies used an uncontrolled pretest-posttest design. The eight studies represented a total of 1,221 participants with mean ages from 43 to 81. Study sample sizes ranged from 16 to 504. Seven of the eight studies demonstrated modest effect of nurse-delivered home-based interventions on physical activity behaviors. Home-based physical activity promotion was most often incorporated into secondary prevention of postacute diseases, chronic disease management, or disease prevention/health promotion. Findings indicate that nurse-delivered home-based physical activity promotion show overall effectiveness in general adult populations. Possible effective intervention domains were also discussed in this review to guide future home-based health promotion. More large randomized controlled trials with longer study/follow-up periods and studies with cost-effectiveness data are warranted in future research.

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.

Reliability of digital ulcer definitions as proposed by the UK Scleroderma Study Group: A challenge for clinical trial design.

PubMed

Hughes, Michael; Tracey, Andrew; Bhushan, Monica; Chakravarty, Kuntal; Denton, Christopher P; Dubey, Shirish; Guiducci, Serena; Muir, Lindsay; Ong, Voon; Parker, Louise; Pauling, John D; Prabu, Athiveeraramapandian; Rogers, Christine; Roberts, Christopher; Herrick, Ariane L

2018-06-01

The reliability of clinician grading of systemic sclerosis-related digital ulcers has been reported to be poor to moderate at best, which has important implications for clinical trial design. The aim of this study was to examine the reliability of new proposed UK Scleroderma Study Group digital ulcer definitions among UK clinicians with an interest in systemic sclerosis. Raters graded (through a custom-built interface) 90 images (80 unique and 10 repeat) of a range of digital lesions collected from patients with systemic sclerosis. Lesions were graded on an ordinal scale of severity: 'no ulcer', 'healed ulcer' or 'digital ulcer'. A total of 23 clinicians - 18 rheumatologists, 3 dermatologists, 1 hand surgeon and 1 specialist rheumatology nurse - completed the study. A total of 2070 (1840 unique + 230 repeat) image gradings were obtained. For intra-rater reliability, across all images, the overall weighted kappa coefficient was high (0.71) and was moderate (0.55) when averaged across individual raters. Overall inter-rater reliability was poor (0.15). Although our proposed digital ulcer definitions had high intra-rater reliability, the overall inter-rater reliability was poor. Our study highlights the challenges of digital ulcer assessment by clinicians with an interest in systemic sclerosis and provides a number of useful insights for future clinical trial design. Further research is warranted to improve the reliability of digital ulcer definition/rating as an outcome measure in clinical trials, including examining the role for objective measurement techniques, and the development of digital ulcer patient-reported outcome measures.

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.

Civil society perspectives on negative biomedical HIV prevention trial results and implications for future trials.

PubMed

Essack, Zaynab; Koen, Jennifer; Slack, Catherine; Lindegger, Graham; Newman, Peter A

2012-01-01

Community engagement is crucial to ongoing development and testing of sorely needed new biomedical HIV prevention technologies. Yet, negative trial results raise significant challenges for community engagement in HIV prevention trials, including the early termination of the Cellulose Sulfate microbicide trial and two Phase IIb HIV vaccine trials (STEP and Phambili). The present study aimed to explore the perspectives and experiences of civil society organization (CSO) representatives regarding negative HIV prevention trial results and perceived implications for future trials. We conducted in-depth interviews with 14 respondents from a broad range of South African and international CSOs, and analyzed data using thematic analysis. CSO representatives reported disappointment in response to negative trial results, but acknowledged such outcomes as inherent to clinical research. Respondents indicated that in theory negative trial results seem likely to impact on willingness to participate in future trials, but that in practice people in South Africa have continued to volunteer. Negative trial results were described as having contributed to improving ethical standards, and to a re-evaluation of the scientific agenda. Such negative results were identified as potentially impacting on funding for trials and engagement activities. Our findings indicate that trial closures may be used constructively to support opportunities for reflection and renewed vigilance in strategies for stakeholder engagement, communicating trial outcomes, and building research literacy among communities; however, these strategies require sustained resources for community engagement and capacity-building.

The E Sibling Project - exploratory randomised controlled trial of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis.

PubMed

Sin, Jacqueline; Henderson, Claire; Pinfold, Vanessa; Norman, Ian

2013-04-26

Siblings of individuals with first episode psychosis are natural partners to promote service users' recovery and are themselves vulnerable to mental ill health due to the negative impact of psychosis within the family. This study aims to develop and undertake a preliminary evaluation of the efficacy of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis. The impetus for the intervention arose from siblings' expressed needs for peer support and information on psychosis, coping and management strategies for common symptoms and ways to promote recovery. The project design draws on the Medical Research Council framework for the design and evaluation of complex interventions. Mixed methods comprising collection of qualitative focus group data, systematic review and expert advisory group consultation are used to develop the theoretical basis for and design of the intervention. This protocol focuses on the modelling and piloting phase which uses a randomised controlled trial with factorial design to test the efficacy of the intervention. Outcome data on participants' mental wellbeing, knowledge, perceived self-efficacy and experiences of caregiving will be assessed at baseline, at end of the intervention (10 weeks later) and at 10 week follow-up. In addition, a post-intervention semi-structured interview with 20% of the participants will explore their experiences and acceptability of the intervention. This multi-component online psychoeducational intervention aims to enhance siblings' knowledge about psychosis and their coping capacity, thus potentially improving their own mental wellbeing and promoting their contribution to service users' recovery. The factorial design randomised controlled trial with a supplementary process evaluation using semi-structured interviews and usage-monitoring will collect preliminary evidence of efficacy, feasibility and acceptability, as well as feedback about the barriers and strategies to using such an innovative resource. The RCT will provide data for estimating the likely effect size of the intervention on outcomes for siblings and inform the development of a definitive future trial. Trial registration: ISRCTN01416694.

Physiotherapy for patients with soft tissue shoulder disorders: a systematic review of randomised clinical trials.

PubMed Central

van der Heijden, G. J.; van der Windt, D. A.; de Winter, A. F.

1997-01-01

OBJECTIVE: To assess the effectiveness of physiotherapy for patients with soft tissue shoulder disorders. DESIGN: A systematic computerised literature search of Medline and Embase, supplemented with citation tracking, for relevant trials with random allocation published before 1996. SUBJECTS: Patients treated with physiotherapy for disorders of soft tissue of the shoulder. MAIN OUTCOME MEASURES: Success rates, mobility, pain, functional status. RESULTS: Six of the 20 assessed trials satisfied at least five of eight validity criteria. Assessment of methods was often hampered by insufficient information on various validity criteria, and trials were often flawed by lack of blinding, high proportions of withdrawals from treatment, and high proportions of missing values. Trial sizes were small: only six trials included intervention groups of more than 25 patients. Ultrasound therapy, evaluated in six trials, was not shown to be effective. Four other trials favoured physiotherapy (laser therapy or manipulation), but the validity of their methods was unsatisfactory. CONCLUSIONS: There is evidence that ultrasound therapy is ineffective in the treatment of soft tissue shoulder disorders. Due to small trial sizes and unsatisfactory methods, evidence for the effectiveness of other methods of physiotherapy is inconclusive. For all methods of treatment, trials were too heterogeneous with respect to included patients, index and reference treatments, and follow up to merit valid statistical pooling. Future studies should show whether physiotherapy is superior to treatment with drugs, steroid injections, or a wait and see policy. PMID:9233322

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.

Experiences of recruiting to a pilot trial of Cardiac Rehabilitation In patients with Bowel cancer (CRIB) with an embedded process evaluation: lessons learned to improve recruitment.

PubMed

Hubbard, Gill; Campbell, Anna; Davies, Zoe; Munro, Julie; Ireland, Aileen V; Leslie, Stephen; Watson, Angus Jm; Treweek, Shaun

2015-01-01

Recruitment to randomised controlled trials (RCTs) is a perennial problem. Calls have been made for trialists to make recruitment performance publicly available. This article presents our experience of recruiting to a pilot RCT of cardiac rehabilitation for patients with bowel cancer with an embedded process evaluation. Recruitment took place at three UK hospitals. Recruitment figures were based on the following: i) estimated number of patient admissions, ii) number of patients likely to meet inclusion criteria from clinician input and iii) recruitment rates in previous studies. The following recruitment procedure was used:Nurse assessed patients for eligibility.Patients signed a screening form indicating interest in and agreement to be approached by a researcher about the study.An appointment was made at which the patient signed a consent form and was randomised to the intervention or control group. Information about all patients considered for the study and subsequently included or excluded at each stage of the recruitment process and reasons given were recorded. There were variations in the time taken to award Research Management approval to run the study at the three sites (45-359 days). Sixty-two percent of the original recruitment estimate was reached. The main reason for under-recruitment was due to over-estimation of the number of patient admissions; other reasons were i) not assessing all patients for eligibility, ii) not completing a screening form for eligible patients and iii) patients who signed a screening form being lost to the study before consenting and randomisation. Pilot trials should not simply aim to improve recruitment estimates but should also identify factors likely to influence recruitment performance in a future trial and inform the development of that trial's recruitment strategies. Pilot trials are a crucial part of RCT design. Nevertheless, pilot trials are likely to be small scale, involving only a small number of sites, and contextual differences between sites are likely to impact recruitment performance in any future trial. This means that ongoing monitoring and evaluation in trials are likely to be required. ISRCTN63510637; UKCRN id 14092.

The Primary Prevention of PTSD in Firefighters: Preliminary Results of an RCT with 12-Month Follow-Up

PubMed Central

Rees, Clare S.; Mazzucchelli, Trevor G.; Kane, Robert T.

2016-01-01

Aim To develop and evaluate an evidence-based and theory driven program for the primary prevention of Post-traumatic Stress Disorder (PTSD). Design A pre-intervention / post-intervention / follow up control group design with clustered random allocation of participants to groups was used. The “control” group received “Training as Usual” (TAU). Method Participants were 45 career recruits within the recruit school at the Department of Fire and Emergency Services (DFES) in Western Australia. The intervention group received a four-hour resilience training intervention (Mental Agility and Psychological Strength training) as part of their recruit training school curriculum. Data was collected at baseline and at 6- and 12-months post intervention. Results We found no evidence that the intervention was effective in the primary prevention of mental health issues, nor did we find any significant impact of MAPS training on social support or coping strategies. A significant difference across conditions in trauma knowledge is indicative of some impact of the MAPS program. Conclusion While the key hypotheses were not supported, this study is the first randomised control trial investigating the primary prevention of PTSD. Practical barriers around the implementation of this program, including constraints within the recruit school, may inform the design and implementation of similar programs in the future. Trial Registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12615001362583 PMID:27382968

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.

Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans.

PubMed

Evans, Erica K; Tester, Richland; Aslanian, Sharon; Karp, Russell; Sheets, Michael; Labenski, Matthew T; Witowski, Steven R; Lounsbury, Heather; Chaturvedi, Prasoon; Mazdiyasni, Hormoz; Zhu, Zhendong; Nacht, Mariana; Freed, Martin I; Petter, Russell C; Dubrovskiy, Alex; Singh, Juswinder; Westlin, William F

2013-08-01

Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

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

PubMed

Yusoff, K

2005-06-01

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

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.

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.

Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: a cross-sectional study.

PubMed

Jia, Pengli; Tang, Li; Yu, Jiajie; Lee, Andy H; Zhou, Xu; Kang, Deying; Luo, Yanan; Liu, Jiali; Sun, Xin

2018-03-06

To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to-treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A Systematic Review of the Safety and Efficacy of Mesenchymal Stem Cells for Disc Degeneration: Insights and Future Directions for Regenerative Therapeutics

PubMed Central

Yim, Rita Lok-Hay; Lee, Juliana Tsz-Yan; Bow, Cora H.; Meij, Björn; Leung, Victor; Cheung, Kenneth M.C.; Vavken, Patrick

2014-01-01

Intervertebral disc degeneration is associated with low-back pain. Mesenchymal stem cells (MSCs) have been used to “regenerate” the disc. The aim of this study was to perform a systematic review of comparative controlled studies that have assessed the safety and efficacy of using MSCs for disc regeneration. Literature databases were extensively searched. Trial design, subject-type, MSC sources, injection method, disc assessment, outcome intervals, and complication events were assessed. Validity of each study was performed. Twenty-four animal studies were included with 20.8% of the studies reporting randomization of groups. Trials in humans fulfilling inclusion criteria were not noted. The studies represented 862 discs that were injected with MSCs and 1,603 discs as controls. All three types of MSCs (ie, bone marrow, synovial, and adipose tissues) showed successful inhibition of disc degeneration. Bone-marrow-derived MSCs demonstrated superior quality of repair compared with other non-MSC treatments. A 2.7% overall complication rate was noted, whereby complications were noted only in rabbits. Overall, evidence suggested that MSCs increased disc space height in the majority of animal models. This is the first systematic review to assess the safety and efficacy of MSCs for the treatment of disc degeneration. Short-term MSC transplantation is safe and effective; however, additional, larger, and higher-quality studies are needed to assess the long-term safety and efficacy. Inconsistencies in methodological design and outcome parameters prevent any robust conclusions. Human-based clinical trials are needed. Recommendations are further made to improve efficacy, reduce potential complications, and standardize techniques for future studies. PMID:25050446

Radiobiology of systemic radiation therapy.

PubMed

Murray, David; McEwan, Alexander J

2007-02-01

Although systemic radionuclide therapy (SRT) is effective as a palliative therapy in patients with metastatic cancer, there has been limited success in expanding patterns of utilization and in bringing novel systemic radiotherapeutic agents to routine clinical use. Although there are many factors that contribute to this situation, we hypothesize that a better understanding of the radiobiology and mechanism of action of SRT will facilitate the development of future compounds and the future designs of prospective clinical trials. If these trials can be rationalized to the biological basis of the therapy, it is likely that the long-term outcome would be enhanced therapeutic efficacy. In this review, we provide perspectives of the current state of low-dose-rate (LDR) radiation research and offer linkages where appropriate with current clinical knowledge. These include the recently described phenomena of low-dose hyper-radiosensitivity-increased radioresistance (LDH-IRR), adaptive responses, and biological bystander effects. Each of these areas require a major reconsideration of existing models for radiation action and an understanding of how this knowledge will integrate into the evolution of clinical SRT practice. Validation of a role in vivo for both LDH-IRR and biological bystander effects in SRT would greatly impact the way we would assess therapeutic response to SRT, the design of clinical trials of novel SRT radiopharmaceuticals, and risk estimates for both therapeutic and diagnostic radiopharmaceuticals. We believe that the current state of research in LDR effects offers a major opportunity to the nuclear medicine community to address the basic science of clinical SRT practice, to use this new knowledge to expand the use and roles of SRT, and to facilitate the introduction of new therapeutic radiopharmaceuticals.

Uveal Melanoma: From Diagnosis to Treatment and the Science in Between

PubMed Central

Chattopahdyay, Chandrani; Kim, Dae Won; Gombos, Dan; Oba, Junna; Qin, Yong; Williams, Michelle; Esmaeli, Bita; Grimm, Elizabeth; Wargo, Jennifer; Woodman, Scott; Patel, Sapna

2017-01-01

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the U.S., an age-adjusted risk of 5 per million. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomical spread, molecular changes, and responses to systemic therapy. Once metastatic, therapy options are limited, and often extrapolated from cutaneous melanoma therapies despite routine exclusion of uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress and data from these well-designed investigations will help guide future directions in this orphan disease. PMID:26991400

Prognostic factors, predictive markers and cancer biology: the triad for successful oral cancer chemoprevention.

PubMed

Monteiro de Oliveira Novaes, Jose Augusto; William, William N

2016-10-01

Oral squamous cell carcinomas represent a significant cancer burden worldwide. Unfortunately, chemoprevention strategies investigated to date have failed to produce an agent considered standard of care to prevent oral cancers. Nonetheless, recent advances in clinical trial design may streamline drug development in this setting. In this manuscript, we review some of these improvements, including risk prediction tools based on molecular markers that help select patients most suitable for chemoprevention. We also discuss the opportunities that novel preclinical models and modern molecular profiling techniques will bring to the prevention field in the near future, and propose a clinical trials framework that incorporates molecular prognostic factors, predictive markers and cancer biology as a roadmap to improve chemoprevention strategies for oral cancers.

Towards antiviral therapies for treating dengue virus infections.

PubMed

Kaptein, Suzanne Jf; Neyts, Johan

2016-10-01

Dengue virus is an emerging human pathogen that poses a huge public health burden by infecting annually about 390 million individuals of which a quarter report with clinical manifestations. Although progress has been made in understanding dengue pathogenesis, a licensed vaccine or antiviral therapy against this virus is still lacking. Treatment of patients is confined to symptomatic alleviation and supportive care. The development of dengue therapeutics thus remains of utmost importance. This review focuses on the few molecules that were evaluated in dengue virus-infected patients: balapiravir, chloroquine, lovastatin, prednisolone and celgosivir. The lessons learned from these clinical trials can be very helpful for the design of future trials for the next generation of dengue virus inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

The patient perspective on remote monitoring of patients with an implantable cardioverter defibrillator: Narrative review and future directions.

PubMed

Timmermans, Ivy; Meine, Matias; Zitron, Edgar; Widdershoven, Jos; Kimman, Geert; Prevot, Sébastien; Rauwolf, Thomas; Anselme, Frédéric; Szendey, Istvan; Romero Roldán, Javier; Mabo, Philippe; Schaer, Beat; Denollet, Johan; Versteeg, Henneke

2017-07-01

Studies have shown that remote patient monitoring (RPM) of implantable cardioverter defibrillators (ICDs) is at least comparable to in-clinic follow-up with regard to clinical outcomes and might be cost-effective, yet RPM is not standard clinical practice within Europe. Better insight into the patient perspective on RPM may aid in its acceptance, implementation, and reimbursement. This narrative review (1) summarizes existing evidence on the impact of RPM on patient-reported outcomes and (2) discusses future directions in examining the patient perspective. Literature review indicated that only five randomized trials on RPM in ICD patients included patient-reported outcomes, with inconclusive results. Observational studies show a trend toward good patient satisfaction and acceptation of RPM. Yet, results should be interpreted with caution due to a number of limitations including a potential selection bias, use of generic/nonvalidated questionnaires, relatively short follow-up durations, and a lack of subgroup identification. Although RPM seems to be safe, effective, timely, and efficient, the patient perspective has received little attention so far. The scarce evidence on patient-reported outcomes in RPM studies seems to be positive, but future trials with a follow-up of ≥12 months and validated patient-reported outcome measures are needed. The REMOTE-CIED study from our group is the first prospective randomized controlled trial primarily designed to examine the patient perspective on RPM, and is powered to identify characteristics associated with RPM satisfaction and benefit. Results are expected in 2018 and will add valuable information to the current evidence. © 2017 Wiley Periodicals, Inc.

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

Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes

PubMed Central

2013-01-01

Background The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas β-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. Methods/design This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. Discussion This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. Trial registration ChiCTR-TRC-12002546 PMID:23442225

Physiotherapy for sleep disturbance in chronic low back pain: a feasibility randomised controlled trial

PubMed Central

2010-01-01

Background Sleep disturbance is becoming increasingly recognised as a clinically important symptom in people with chronic low back pain (CLBP, low back pain >12 weeks), associated with physical inactivity and depression. Current research and international clinical guidelines recommend people with CLBP assume a physically active role in their recovery to prevent chronicity, but the high prevalence of sleep disturbance in this population may be unknowingly limiting their ability to participate in exercise-based rehabilitation programmes and contributing to poor outcomes. There is currently no knowledge concerning the effectiveness of physiotherapy on sleep disturbance in people with chronic low back pain and no evidence of the feasibility of conducting randomized controlled trials that comprehensively evaluate sleep as an outcome measure in this population. Methods/Design This study will evaluate the feasibility of a randomised controlled trial (RCT), exploring the effects of three forms of physiotherapy (supervised general exercise programme, individualized walking programme and usual physiotherapy, which will serve as the control group) on sleep quality in people with chronic low back pain. A presenting sample of 60 consenting patients will be recruited in the physiotherapy department of Beaumont Hospital, Dublin, Ireland, and randomly allocated to one of the three groups in a concealed manner. The main outcomes will be sleep quality (self-report and objective measurement), and self-reported functional disability, pain, quality of life, fear avoidance, anxiety and depression, physical activity, and patient satisfaction. Outcome will be evaluated at baseline, 3 months and 6 months. Qualitative telephone interviews will be embedded in the research design to obtain feedback from a sample of participants' about their experiences of sleep monitoring, trial participation and interventions, and to inform the design of a fully powered future RCT. Planned analysis will explore trends in the data, effect sizes and clinically important effects (quantitative data), and thematic analysis (qualitative data). Discussion This study will evaluate the feasibility of a randomised controlled trial exploring the effects of three forms of physiotherapy (supervised general exercise programme, individualized walking programme and usual physiotherapy, which will serve as the control group) on sleep quality in people with chronic low back pain. Trial Registration Current controlled trial ISRCTN54009836 PMID:20398349

An integrated vegetated ditch system reduces chlorpyrifos loading in agricultural runoff.

PubMed

Phillips, Bryn M; Anderson, Brian S; Cahn, Michael; Rego, Jessa L; Voorhees, Jennifer P; Siegler, Katie; Zhang, Xuyang; Budd, Robert; Goh, Kean; Tjeerdema, Ron S

2017-03-01

Agricultural runoff containing toxic concentrations of the organophosphate pesticide chlorpyrifos has led to impaired water body listings and total maximum daily load restrictions in California's central coast watersheds. Chlorpyrifos use is now tightly regulated by the Central Coast Regional Water Quality Control Board. This study evaluated treatments designed to reduce chlorpyrifos in agricultural runoff. Initial trials evaluated the efficacy of 3 different drainage ditch installations individually: compost filters, granulated activated carbon (GAC) filters, and native grasses in a vegetated ditch. Treatments were compared to bare ditch controls, and experiments were conducted with simulated runoff spiked with chlorpyrifos at a 1.9 L/s flow rate. Chlorpyrifos concentrations and toxicity to Ceriodaphnia dubia were measured at the input and output of the system. Input concentrations of chlorpyrifos ranged from 858 ng/L to 2840 ng/L. Carbon filters and vegetation provided the greatest load reduction of chlorpyrifos (99% and 90%, respectively). Toxicity was completely removed in only one of the carbon filter trials. A second set of trials evaluated an integrated approach combining all 3 treatments. Three trials were conducted each at 3.2 L/s and 6.3 L/s flow rates at input concentrations ranging from 282 ng/L to 973 ng/L. Chlorpyrifos loadings were reduced by an average of 98% at the low flow rate and 94% at the high flow rate. Final chlorpyrifos concentrations ranged from nondetect (<50 ng/L) to 82 ng/L. Toxicity to C. dubia was eliminated in 3 of 6 integrated trials. Modeling of the ditch and its components informed design alterations that are intended to eventually remove up to 100% of pesticides and sediment. Future work includes investigating the adsorption capacity of GAC, costs associated with GAC disposal, and real-world field trials to further reduce model uncertainties and confirm design optimization. Trials with more water-soluble pesticides such as neonicotinoids are also recommended. Integr Environ Assess Manag 2017;13:423-430. © 2016 SETAC. © 2016 SETAC.

Detailed systematic analysis of recruitment strategies in randomised controlled trials in patients with an unscheduled admission to hospital.

PubMed

Rowlands, Ceri; Rooshenas, Leila; Fairhurst, Katherine; Rees, Jonathan; Gamble, Carrol; Blazeby, Jane M

2018-02-02

To examine the design and findings of recruitment studies in randomised controlled trials (RCTs) involving patients with an unscheduled hospital admission (UHA), to consider how to optimise recruitment in future RCTs of this nature. Studies within the ORRCA database (Online Resource for Recruitment Research in Clinical TriAls; www.orrca.org.uk) that reported on recruitment to RCTs involving UHAs in patients >18 years were included. Extracted data included trial clinical details, and the rationale and main findings of the recruitment study. Of 3114 articles populating ORRCA, 39 recruitment studies were eligible, focusing on 68 real and 13 hypothetical host RCTs. Four studies were prospectively planned investigations of recruitment interventions, one of which was a nested RCT. Most recruitment papers were reports of recruitment experiences from one or more 'real' RCTs (n=24) or studies using hypothetical RCTs (n=11). Rationales for conducting recruitment studies included limited time for informed consent (IC) and patients being too unwell to provide IC. Methods to optimise recruitment included providing patients with trial information in the prehospital setting, technology to allow recruiters to cover multiple sites, screening logs to uncover recruitment barriers, and verbal rather than written information and consent. There is a paucity of high-quality research into recruitment in RCTs involving UHAs with only one nested randomised study evaluating a recruitment intervention. Among the remaining studies, methods to optimise recruitment focused on how to improve information provision in the prehospital setting and use of screening logs. Future research in this setting should focus on the prospective evaluation of the well-developed interventions to optimise recruitment. © 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.

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...

Explaining high and low performers in complex intervention trials: a new model based on diffusion of innovations theory.

PubMed

McMullen, Heather; Griffiths, Chris; Leber, Werner; Greenhalgh, Trisha

2015-05-31

Complex intervention trials may require health care organisations to implement new service models. In a recent cluster randomised controlled trial, some participating organisations achieved high recruitment, whereas others found it difficult to assimilate the intervention and were low recruiters. We sought to explain this variation and develop a model to inform organisational participation in future complex intervention trials. The trial included 40 general practices in a London borough with high HIV prevalence. The intervention was offering a rapid HIV test as part of the New Patient Health Check. The primary outcome was mean CD4 cell count at diagnosis. The process evaluation consisted of several hundred hours of ethnographic observation, 21 semi-structured interviews and analysis of routine documents (e.g., patient leaflets, clinical protocols) and trial documents (e.g., inclusion criteria, recruitment statistics). Qualitative data were analysed thematically using--and, where necessary, extending--Greenhalgh et al.'s model of diffusion of innovations. Narrative synthesis was used to prepare case studies of four practices representing maximum variety in clinicians' interest in HIV (assessed by level of serological testing prior to the trial) and performance in the trial (high vs. low recruiters). High-recruiting practices were, in general though not invariably, also innovative practices. They were characterised by strong leadership, good managerial relations, readiness for change, a culture of staff training and available staff time ('slack resources'). Their front-line staff believed that patients might benefit from the rapid HIV test ('relative advantage'), were emotionally comfortable administering it ('compatibility'), skilled in performing it ('task issues') and made creative adaptations to embed the test in local working practices ('reinvention'). Early experience of a positive HIV test ('observability') appeared to reinforce staff commitment to recruiting more participants. Low-performing practices typically had less good managerial relations, significant resource constraints, staff discomfort with the test and no positive results early in the trial. An adaptation of the diffusion of innovations model was an effective analytical tool for retrospectively explaining high and low-performing practices in a complex intervention research trial. Whether the model will work prospectively to predict performance (and hence shape the design of future trials) is unknown. ISRCTN Registry number: ISRCTN63473710. Date assigned: 22 April 2010.

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations.

PubMed Central

Webster, Lucy; Groskreutz, Derek; Grinbergs-Saull, Anna; Howard, Rob; O'Brien, John T; Mountain, Gail; Banerjee, Sube; Woods, Bob; Perneczky, Robert; Lafortune, Louise; Roberts, Charlotte; McCleery, Jenny; Pickett, James; Bunn, Frances; Challis, David; Charlesworth, Georgina; Featherstone, Katie; Fox, Chris; Goodman, Claire; Jones, Roy; Lamb, Sallie; Moniz-Cook, Esme; Schneider, Justine; Shepperd, Sasha; Surr, Claire; Thompson-Coon, Jo; Ballard, Clive; Brayne, Carol; Burke, Orlaith; Burns, Alistair; Clare, Linda; Garrard, Peter; Kehoe, Patrick; Passmore, Peter; Holmes, Clive; Maidment, Ian; Murtagh, Fliss; Robinson, Louise; Livingston, Gill

2017-01-01

BACKGROUND There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. OBJECTIVES To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). DATA SOURCES We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. REVIEW METHODS The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. RESULTS We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. LIMITATIONS Most of the trials included participants with Alzheimer's disease, so recommendations may not apply to other types of dementia. We did not conduct economic analyses. The PPI consultation was limited to members of the Alzheimer's Society Research Network. CONCLUSIONS Cognitive outcomes and biological markers form the core outcome set for future disease modification trials, measured by the MMSE or ADAS-Cog, and structural MRI in a subset of participants. FUTURE WORK We envisage that the core set may be superseded in the future, particularly for other types of dementia. There is a need to develop an algorithm to compare scores on the MMSE and ADAS-Cog. STUDY REGISTRATION The project was registered with Core Outcome Measures in Effectiveness Trials [ www.comet-initiative.org/studies/details/819?result=true (accessed 7 April 2016)]. The systematic review protocol is registered as PROSPERO CRD42015027346. FUNDING The National Institute for Health Research Health Technology Assessment programme. PMID:28625273

Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer.

PubMed

Rada, Gabriel; Schünemann, Holger J; Labedi, Nawman; El-Hachem, Pierre; Kairouz, Victor F; Akl, Elie A

2013-02-14

Randomized controlled trials (RCTs) that are inappropriately designed or executed may provide biased findings and mislead clinical practice. In view of recent interest in the treatment and prevention of thrombotic complications in cancer patients we evaluated the characteristics, risk of bias and their time trends in RCTs of anticoagulation in patients with cancer. We conducted a comprehensive search, including a search of four electronic databases (MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL) up to February 2010. We included RCTs in which the intervention and/or comparison consisted of: vitamin K antagonists, unfractionated heparin (UFH), low molecular weight heparin (LMWH), direct thrombin inhibitors or fondaparinux. We performed descriptive analyses and assessed the association between the variables of interest and the year of publication. We included 67 RCTs with 24,071 participants. In twenty one trials (31%) DVT diagnosis was triggered by clinical suspicion; the remaining trials either screened for DVT or were unclear about their approach. 41 (61%), 22 (33%), and 11 (16%) trials respectively reported on major bleeding, minor bleeding, and thrombocytopenia. The percentages of trials satisfying risk of bias criteria were: adequate sequence generation (85%), adequate allocation concealment (61%), participants' blinding (39%), data collectors' blinding (44%), providers' blinding (41%), outcome assessors' blinding (75%), data analysts' blinding (15%), intention to treat analysis (57%), no selective outcome reporting (12%), no stopping early for benefit (97%). The mean follow-up rate was 96%. Adequate allocation concealment and the reporting of intention to treat analysis were the only two quality criteria that improved over time. Many RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. It is not clear whether this reflects a problem in the design, conduct or the reporting of these trials, or both. Future trials should avoid the shortcomings described in this article.

Children’s Oxygen Administration Strategies Trial (COAST):  A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia

PubMed Central

Maitland, Kathryn; Kiguli, Sarah; Opoka, Robert O.; Olupot-Olupot, Peter; Engoru, Charles; Njuguna, Patricia; Bandika, Victor; Mpoya, Ayub; Bush, Andrew; Williams, Thomas N.; Grieve, Richard; Sadique, Zia; Fraser, John; Harrison, David; Rowan, Kathy

2018-01-01

Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia. Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO 2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO 2 TM compared with low flow delivery (routine care). Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%. Clinical trial registration: ISRCTN15622505 Trial status: Recruiting PMID:29383331

Reducing breast cancer recurrence with weight loss, a vanguard trial: the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial.

PubMed

Rock, Cheryl L; Byers, Tim E; Colditz, Graham A; Demark-Wahnefried, Wendy; Ganz, Patricia A; Wolin, Kathleen Y; Elias, Anthony; Krontiras, Helen; Liu, Jingxia; Naughton, Michael; Pakiz, Bilgé; Parker, Barbara A; Sedjo, Rebecca L; Wyatt, Holly

2013-03-01

Breast cancer is the most common invasive cancer among women in developed countries. Obesity is a major risk factor for breast cancer recurrence and mortality in both pre- and postmenopausal women. Co-morbid medical conditions are common among breast cancer survivors. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is a 4-year randomized clinical trial of 693 overweight/obese women aged ≥21years diagnosed with any early stage breast cancer (stages I[≥1cm]-III) within the previous five years, designed to demonstrate the feasibility of achieving sustained weight loss and to examine the impact of weight loss on quality of life and co-morbidities, and to enable future exploration of biochemical mechanisms linking obesity to lower likelihood of disease-free survival. This trial is strategically designed as a vanguard for a fully-powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival. Participants were recruited between 2010 and 2012 at four sites, had completed initial therapies, and had a body mass index between 25 and 45kg/m(2). The intervention featured a group-based cognitive-behavioral weight loss program with telephone counseling and tailored newsletters to support initial weight loss and subsequent maintenance, with the goal of 7% weight loss at two years. This study has high potential to have a major impact on clinical management and outcomes after a breast cancer diagnosis. This trial initiates the effort to establish weight loss support for overweight or obese breast cancer survivors as a new standard of clinical care. Copyright © 2012 Elsevier Inc. All rights reserved.

A systematic review assessing non-pharmacological conservative treatment studies for people with non-inflammatory multi-joint pain: clinical outcomes and research design considerations.

PubMed

Comer, C; Smith, T O; Drew, B; Raja, R; Kingsbury, S R; Conaghan, Philip G

2018-03-01

To systematically review the evidence to determine the clinical outcomes and the important methodological quality features of interventional studies on adults with non-inflammatory multi-joint pain (MJP). Systematic search of published and unpublished literature using the databases: AMED, CINAHL, MEDLINE, EMBASE, psycINFO, SPORTDiscus, PEDro, OpenGrey, the EU Clinical Trials Register, World Health Organization International Clinical Trial Registry Platform, ClinicalTrials.gov and the ISRCTN registry (search: inception to 19th October 2017). All papers reporting the clinical outcomes of non-pharmacological interventions for people with non-inflammatory MJP were included. Studies were critically appraised using the Downs and Black Critical Appraisal and the TIDieR reporting checklists. Data were analysed using a Best Evidence Synthesis approach. From 3824 citations, four papers satisfied the eligibility criteria. Three studies reported outcomes from multidisciplinary rehabilitation programmes and one study reported the findings of a spa therapy intervention. All interventions significantly improved pain, function and quality of life in the short-term. There was limited reporting of measures for absenteeism, presenteeism and psychosocial outcomes. The evidence was 'weak', and due to a lack of controlled trials, there is limited evidence to ascertain treatment effectiveness. Design consideration for future trials surround improved reporting of participant characteristics, interventions and the standardisation of core outcome measures. There is insufficient high-quality trial data to determine the effectiveness of treatments for non-inflammatory MJP. Given the significant health burden which this condition presents on both individuals and wider society, developing and testing interventions and accurately reporting these, should be a research priority. Registration PROSPERO (CRD42013005888).

Coach development programmes to improve interpersonal coach behaviours: a systematic review using the re-aim framework.

PubMed

Evans, M Blair; McGuckin, Matthew; Gainforth, Heather L; Bruner, Mark W; Côté, Jean

2015-07-01

Although evidence supports the effectiveness of interpersonal Coach Development Programmes (CDPs), which are designed to foster coach-athlete relationships, an intervention's impact is shaped by numerous factors over and above effectiveness. The purpose of this systematic review was to examine the extent that published articles describing interpersonal CDP trials reported on indicators of internal and external validity, as conceptualised in the RE-AIM framework (ie, Reach, Effectiveness, Adoption, Implementation and Maintenance). The search strategy was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, involving a database search and supplemental manual search of key articles and journals. After initial screening, the full-text search strategy involved identifying articles describing CDP trials and then selecting a specific subgroup of articles involving interpersonal CDP trials and excluding ineligible articles. Resulting trials were coded using a 47-item sport coaching adaptation of the RE-AIM coding sheet. 17 published articles met eligibility criteria, representing 10 distinct CDP trials. After attaining coder agreement, global ratings of RE-AIM indicators within interpersonal CDP trials ranged from the low to moderate quality. Whereas indicators of effectiveness and implementation were reported to some extent across all studies, maintenance within sport organisations and a number of specific indicators from across dimensions were rarely reported. These findings inform the future design and evaluation of CDPs that have the potential to be adopted in numerous settings and reach athletes and coaches who can most benefit. 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.

Recent advances in anti-neutrophil cytoplasmic antibody-associated vasculitis

PubMed Central

Lazarus, B.; John, G. T.; O’Callaghan, C.; Ranganathan, D.

2016-01-01

Anti-neutrophil cytoplasmic antibody-associated vasculitis is an uncommon inflammatory disease of small to medium-sized vessels that frequently presents with rapidly progressive glomerulonephritis and renal failure though it can affect any organ system. If untreated, the vast majority of patients will die within a year. Current treatments improve prognosis but affected patients remain at a substantially higher risk of death and adverse outcomes. We review the classification of the disease, our understanding of the pathogenesis and epidemiology, and propose future directions for research. We also evaluate the evidence supporting established treatment regimens and the progress of clinical trials for newer treatments to inform the design of future studies. PMID:27051131

Test-retest reliability of pulse amplitude tonometry measures of vascular endothelial function: implications for clinical trial design.

PubMed

McCrea, Cindy E; Skulas-Ray, Ann C; Chow, Mosuk; West, Sheila G

2012-02-01

Endothelial dysfunction is an important outcome for assessing vascular health in intervention studies. However, reliability of the standard non-invasive method (flow-mediated dilation) is a significant challenge for clinical applications and multicenter trials. We evaluated the repeatability of pulse amplitude tonometry (PAT) to measure change in pulse wave amplitude during reactive hyperemia (Itamar Medical Ltd, Caesarea, Israel). Twenty healthy adults completed two PAT tests (mean interval = 19.5 days) under standardized conditions. PAT-derived measures of endothelial function (reactive hyperemia index, RHI) and arterial stiffness (augmentation index, AI) showed strong repeatability (intra-class correlations = 0.74 and 0.83, respectively). To guide future research, we also analyzed sample size requirements for a range of effect sizes. A crossover design powered at 0.90 requires 28 participants to detect a 15% change in RHI. Our study is the first to show that PAT measurements are repeatable in adults over an interval greater than 1 week.

Design principles for noninvasive, longitudinal and quantitative cell tracking with nanoparticle-based CT imaging.

PubMed

Meir, Rinat; Betzer, Oshra; Motiei, Menachem; Kronfeld, Noam; Brodie, Chaya; Popovtzer, Rachela

2017-02-01

Contradictory results in clinical trials are preventing the advancement and implementation of cell-based therapy. To explain such results, there is a need to uncover the mystery regarding the fate of the transplanted cells. To answer this need, we developed a technique for noninvasive in vivo cell tracking, which uses gold nanoparticles as contrast agents for CT imaging. Herein, we investigate the design principles of this technique for intramuscular transplantation of therapeutic cells. Longitudinal studies were performed, displaying the ability to track cells over long periods of time. As few as 500 cells could be detected and a way to quantify the number of cells visualized by CT was demonstrated. Moreover, monitoring of cell functionality was demonstrated on a mouse model of Duchenne muscular dystrophy. This cell-tracking technology has the potential to become an essential tool in pre-clinical as well as clinical trials and to advance the future of cell therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Use of personalized Dynamic Treatment Regimes (DTRs) and Sequential Multiple Assignment Randomized Trials (SMARTs) in mental health studies

PubMed Central

Liu, Ying; ZENG, Donglin; WANG, Yuanjia

2014-01-01

Summary Dynamic treatment regimens (DTRs) are sequential decision rules tailored at each point where a clinical decision is made based on each patient’s time-varying characteristics and intermediate outcomes observed at earlier points in time. The complexity, patient heterogeneity, and chronicity of mental disorders call for learning optimal DTRs to dynamically adapt treatment to an individual’s response over time. The Sequential Multiple Assignment Randomized Trial (SMARTs) design allows for estimating causal effects of DTRs. Modern statistical tools have been developed to optimize DTRs based on personalized variables and intermediate outcomes using rich data collected from SMARTs; these statistical methods can also be used to recommend tailoring variables for designing future SMART studies. This paper introduces DTRs and SMARTs using two examples in mental health studies, discusses two machine learning methods for estimating optimal DTR from SMARTs data, and demonstrates the performance of the statistical methods using simulated data. PMID:25642116

Traffic Aware Planner for Cockpit-Based Trajectory Optimization

NASA Technical Reports Server (NTRS)

Woods, Sharon E.; Vivona, Robert A.; Henderson, Jeffrey; Wing, David J.; Burke, Kelly A.

2016-01-01

The Traffic Aware Planner (TAP) software application is a cockpit-based advisory tool designed to be hosted on an Electronic Flight Bag and to enable and test the NASA concept of Traffic Aware Strategic Aircrew Requests (TASAR). The TASAR concept provides pilots with optimized route changes (including altitude) that reduce fuel burn and/or flight time, avoid interactions with known traffic, weather and restricted airspace, and may be used by the pilots to request a route and/or altitude change from Air Traffic Control. Developed using an iterative process, TAP's latest improvements include human-machine interface design upgrades and added functionality based on the results of human-in-the-loop simulation experiments and flight trials. Architectural improvements have been implemented to prepare the system for operational-use trials with partner commercial airlines. Future iterations will enhance coordination with airline dispatch and add functionality to improve the acceptability of TAP-generated route-change requests to pilots, dispatchers, and air traffic controllers.

Mindfulness-based Intervention in Elementary School Students With Anxiety and Depression: A Series of n-of-1 Trials on Effects and Feasibility

PubMed Central

Malboeuf-Hurtubise, Catherine; Lacourse, Eric; Herba, Catherine; Taylor, Geneviève; Amor, Leila Ben

2017-01-01

Mindfulness-based interventions constitute a promising option to address anxiety and depression in elementary school students. This study evaluated the effect of a mindfulness-based intervention on anxiety and depression in elementary school students with a diagnosis of anxiety or depression disorder. A single-subject experimental A-B-A design was used. Participants were three elementary school students from grades three and four, along with their teacher. Anxiety and depression were measured on 10 occasions at baseline, during the intervention, and at follow-up. Primary hypotheses were tested using a univariate single case multilevel modeling strategy and visual analysis. Following intervention, 2 participants reported improvements on anxiety and depression, while their teachers reported deteriorating scores on these variables. Results from this n-of-1 trial design is consistent with other work suggesting caution with regard to the overall impact and efficacy of mindfulness-based interventions as a universal treatment option for youth. Future research is warranted. PMID:28853297

The Risk of Bias in Randomized Trials in General Dentistry Journals.

PubMed

Hinton, Stephanie; Beyari, Mohammed M; Madden, Kim; Lamfon, Hanadi A

2015-01-01

The use of a randomized controlled trial (RCT) research design is considered the gold standard for conducting evidence-based clinical research. In this present study, we aimed to assess the quality of RCTs in dentistry and create a general foundation for evidence-based dentistry on which to perform subsequent RCTs. We conducted a systematic assessment of bias of RCTs in seven general dentistry journals published between January 2011 and March 2012. We extracted study characteristics in duplicate and assessed each trial's quality using the Cochrane Risk of Bias tool. We compared risk of bias across studies graphically. Among 1,755 studies across seven journals, we identified 67 RCTs. Many included studies were conducted in Europe (39%), with an average sample size of 358 participants. These studies included 52% female participants and the maximum follow-up period was 13 years. Overall, we found a high percentage of unclear risk of bias among included RCTs, indicating poor quality of reporting within the included studies. An overall high proportion of trials with an "unclear risk of bias" suggests the need for better quality of reporting in dentistry. As such, key concepts in dental research and future trials should focus on high-quality reporting.

Design of the value of imaging in enhancing the wellness of your heart (VIEW) trial and the impact of uncertainty on power.

PubMed

Ambrosius, Walter T; Polonsky, Tamar S; Greenland, Philip; Goff, David C; Perdue, Letitia H; Fortmann, Stephen P; Margolis, Karen L; Pajewski, Nicholas M

2012-04-01

Although observational evidence has suggested that the measurement of coronary artery calcium (CAC) may improve risk stratification for cardiovascular events and thus help guide the use of lipid-lowering therapy, this contention has not been evaluated within the context of a randomized trial. The Value of Imaging in Enhancing the Wellness of Your Heart (VIEW) trial is proposed as a randomized study in participants at low intermediate risk of future coronary heart disease (CHD) events to evaluate whether CAC testing leads to improved patient outcomes. To describe the challenges encountered in designing a prototypical screening trial and to examine the impact of uncertainty on power. The VIEW trial was designed as an effectiveness clinical trial to examine the benefit of CAC testing to guide therapy on a primary outcome consisting of a composite of nonfatal myocardial infarction, probable or definite angina with revascularization, resuscitated cardiac arrest, nonfatal stroke (not transient ischemic attack (TIA)), CHD death, stroke death, other atherosclerotic death, or other cardiovascular disease (CVD) death. Many critical choices were faced in designing the trial, including (1) the choice of primary outcome, (2) the choice of therapy, (3) the target population with corresponding ethical issues, (4) specifications of assumptions for sample size calculations, and (5) impact of uncertainty in these assumptions on power/sample size determination. We have proposed a sample size of 30,000 (800 events), which provides 92.7% power. Alternatively, sample sizes of 20,228 (539 events), 23,138 (617 events), and 27,078 (722 events) provide 80%, 85%, and 90% power. We have also allowed for uncertainty in our assumptions by computing average power integrated over specified prior distributions. This relaxation of specificity indicates a reduction in power, dropping to 89.9% (95% confidence interval (CI): 89.8-89.9) for a sample size of 30,000. Samples sizes of 20,228, 23,138, and 27,078 provide power of 78.0% (77.9-78.0), 82.5% (82.5-82.6), and 87.2% (87.2-87.3), respectively. These power estimates are dependent on form and parameters of the prior distributions. Despite the pressing need for a randomized trial to evaluate the utility of CAC testing, conduct of such a trial requires recruiting a large patient population, making efficiency of critical importance. The large sample size is primarily due to targeting a study population at relatively low risk of a CVD event. Our calculations also illustrate the importance of formally considering uncertainty in power calculations of large trials as standard power calculations may tend to overestimate power.

Design of the Value of Imaging in Enhancing the Wellness of Your Heart (VIEW) Trial and the Impact of Uncertainty on Power

PubMed Central

Ambrosius, Walter T.; Polonsky, Tamar S.; Greenland, Philip; Goff, David C.; Perdue, Letitia H.; Fortmann, Stephen P.; Margolis, Karen L.; Pajewski, Nicholas M.

2014-01-01

Background Although observational evidence has suggested that the measurement of CAC may improve risk stratification for cardiovascular events and thus help guide the use of lipid-lowering therapy, this contention has not been evaluated within the context of a randomized trial. The Value of Imaging in Enhancing the Wellness of Your Heart (VIEW) trial is proposed as a randomized study in participants at low intermediate risk of future coronary heart disease (CHD) events to evaluate whether coronary artery calcium (CAC) testing leads to improved patient outcomes. Purpose To describe the challenges encountered in designing a prototypical screening trial and to examine the impact of uncertainty on power. Methods The VIEW trial was designed as an effectiveness clinical trial to examine the benefit of CAC testing to guide therapy on a primary outcome consisting of a composite of non-fatal myocardial infarction, probable or definite angina with revascularization, resuscitated cardiac arrest, non-fatal stroke (not transient ischemic attack (TIA)), CHD death, stroke death, other atherosclerotic death, or other cardiovascular disease (CVD) death. Many critical choices were faced in designing the trial, including: (1) the choice of primary outcome, (2) the choice of therapy, (3) the target population with corresponding ethical issues, (4) specifications of assumptions for sample size calculations, and (5) impact of uncertainty in these assumptions on power/sample size determination. Results We have proposed a sample size of 30,000 (800 events) which provides 92.7% power. Alternatively, sample sizes of 20,228 (539 events), 23,138 (617 events) and 27,078 (722 events) provide 80, 85, and 90% power. We have also allowed for uncertainty in our assumptions by computing average power integrated over specified prior distributions. This relaxation of specificity indicates a reduction in power, dropping to 89.9% (95% confidence interval (CI): 89.8 to 89.9) for a sample size of 30,000. Samples sizes of 20,228, 23,138, and 27,078 provide power of 78.0% (77.9 to 78.0), 82.5% (82.5 to 82.6), and 87.2% (87.2 to 87.3), respectively. Limitations These power estimates are dependent on form and parameters of the prior distributions. Conclusions Despite the pressing need for a randomized trial to evaluate the utility of CAC testing, conduct of such a trial requires recruiting a large patient population, making efficiency of critical importance. The large sample size is primarily due to targeting a study population at relatively low risk of a CVD event. Our calculations also illustrate the importance of formally considering uncertainty in power calculations of large trials as standard power calculations may tend to overestimate power. PMID:22333998

Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

PubMed

London, Wendy B; Bagatell, Rochelle; Weigel, Brenda J; Fox, Elizabeth; Guo, Dongjing; Van Ryn, Collin; Naranjo, Arlene; Park, Julie R

2017-12-15

Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment. This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. © 2017 American Cancer Society. © 2017 American Cancer Society.

Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting.

PubMed

Sam, Davis; Gresham, Gillian; Abdel-Rahman, Omar; Cheung, Winson Y

2018-06-18

Results from novel therapeutics trials are not always generalizable to real-world patients. We aimed to determine the pattern in which trial findings are applied in a population-based setting of melanoma patients and consequent treatment outcomes. Patients with unresectable disease during 2011-2014 and referred to cancer centers in a large Canadian province were retrospectively reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified patients into trial-eligible and ineligible and those treated and untreated with these agents. We identified 290 patients with known BRAF status for the Vem analysis and 212 patients previously treated with first-line agents for the Ipi analysis. For the Vem cohort, a total of 49 patients were considered trial-eligible, of whom 36 (73%) received treatment. For the Ipi cohort, there were 119 trial-eligible cases of whom 43 (36%) received therapy. Factors other than eligibility criteria most frequently associated with non-treatment in these cohorts included concerns regarding treatment harm and patient preferences. In multivariable analysis, overall survival was improved in Vem cohort patients considered trial-eligible and treated compared to those who were ineligible. Within the Ipi cohort, survival was improved in trial-eligible patients regardless of whether they received Ipi compared to ineligible patients. Real-world uptake of new melanoma treatments was suboptimal, and non-use in trial-eligible patients was frequent. Future clinical trials that are more pragmatically designed to include participants who better reflect the real-world population may facilitate increased uptake of novel therapeutics into routine clinical practice.

"I understood…but some parts were confusing and hard to grasp": Patients' perception of informed consent forms and clinical trials in Eldoret, Kenya.

PubMed

Naanyu, Violet; Some, Fatma F; Siika, Abraham M

2014-01-01

A signed informed consent (IC) form proves voluntary participation in a study. Yet the development of accessible and understandable IC forms comes with its own set of challenges, particularly when conducting international research. This study explores understanding by participants in an Eldoret-based clinical trial of IC and its implications as well as whether they will volunteer for future trials. In mid-2010, in-depth interviews with trial participants were recorded in audio format. Content analysis provides a description of trial participants' experiences and thoughts. All participants were informed about the trial and its voluntariness and they consented. However, some were too ill to scrutinize trial details. Thus, they relied on their health care provider's advice, or on their guardians. In general, participants understood their role and were happy to volunteer or invite others to participate in future trials. They also emphasised the importance of an open on-going dialogue in order for participants to be able to ask questions. Clinical trial participants in Eldoret seem to understand their role, but rely on providers and guardians when consenting. They are very willing to participate in future trials. Evaluation of research participants' opinions may improve trial protocols, increase comprehension and guard against manipulation of study participants. In addition, this research focus should guide development of consent forms and process that facilitates a truly IC.

Phase II drugs that are currently in development for the treatment of cachexia.

PubMed

Dingemans, Anne-Marie C; de Vos-Geelen, Judith; Langen, Ramon; Schols, Annemie M W

2014-12-01

Cachexia is a syndrome presenting with progressive unintentional weight loss and wasting and weakness of skeletal muscle. Cachexia is prevalent in cancer and in chronic diseases including chronic obstructive pulmonary disease (COPD). The authors searched trial registers for current Phase II clinical trials on cachexia. Twelve studies were found with 11 compounds, including the anti-inflammatory drugs thalidomide, OHR/AVR118, celecoxib, VT-122, omega-3 supplements, and anabolic agents such as ghrelin analogues, MT-102, BYM338 and ruxolotinib. The authors note that one of the studies related to COPD while the others were related to different cancers. Herein, the authors describe the mechanisms of action and their Phase II study design. The compounds under study affect several pathways involved in cachexia by modulating inflammatory activity, anabolic potential, digestion and direct interaction with the muscle. Due to the multifactorial aspects of cachexia syndrome, combinations of these new drugs with nutritional intervention is probably the most promising approach. Furthermore, future studies should include interventions in pre-cachetic patients, as this stage might be more responsive to treatment. Future studies will benefit from well-defined end points and improved measures of cachexia, providing new insight into the disease. This insight, in combination with the elucidation of cachexia's underlying mechanism, will yield new treatment strategies in the near future.

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

Potential subjects' responses to an ethics questionnaire in a phase I study of deep brain stimulation in early Parkinson's disease.

PubMed

Finder, Stuart G; Bliton, Mark J; Gill, Chandler E; Davis, Thomas L; Konrad, Peter E; Charles, P David

2012-01-01

Central to ethically justified clinical trial design is the need for an informed consent process responsive to how potential subjects actually comprehend study participation, especially study goals, risks, and potential benefits. This will be particularly challenging when studying deep brain stimulation and whether it impedes symptom progression in Parkinson's disease, since potential subjects will be Parkinson's patients for whom deep brain stimulation will likely have therapeutic value in the future as their disease progresses. As part of an expanded informed consent process for a pilot Phase I study of deep brain stimulation in early stage Parkinson's disease, an ethics questionnaire composed of 13 open-ended questions was distributed to potential subjects. The questionnaire was designed to guide potential subjects in thinking about their potential participation. While the purpose of the study (safety and tolerability) was extensively presented during the informed consent process, in returned responses 70 percent focused on effectiveness and 91 percent included personal benefit as poten- tial benefit from enrolling. However, 91 percent also indicated helping other Parkinson's patients as motivation when considering whether or not to enroll. This combination of responses highlights two issues to which investigators need to pay close attention in future trial designs: (1) how, and in what ways, informed consent processes reinforce potential subjects' preconceived understandings of benefit, and (2) that potential subjects see themselves as part of a community of Parkinson's sufferers with responsibilities extending beyond self-interest. More importantly, it invites speculation that a different paradigm for informed consent may be needed.

Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies.

PubMed

Lin, Ja-An; He, Pei

2015-06-01

Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

Beyond refractory obsessions and anxiety states: toward remission.

PubMed

Hollander, Eric; Zohar, Joseph

2004-01-01

At the Sixth International Obsessive-Compulsive Disorder Conference (IOCDC), held November 13-15, 2003, in Lanzarote, Spain, 2 issues were discussed that are of great importance to future research on obsessive-compulsive disorder (OCD). The first of these is the possible inclusion of obsessive-compulsive spectrum disorders (OCSD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. OCSD resemble OCD in their clinical symptoms, associated features, comorbidity, family/genetics, etiology, and neurocircuitry, as well as their selective response to treatment with serotonin reuptake inhibitors. The second issue is considering remission as the ultimate goal of treatment for OCD instead of just symptom reduction, as has been suggested in other disorders. These and other issues should be discussed at future meetings of the IOCDC and influence how we conceptualize the disorder and design future treatment trials.

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.

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.

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

PubMed Central

Abraham, Clara; Dulai, Parambir S.; Vermeire, Séverine; Sandborn, William J.

2016-01-01

Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics. PMID:27780712

Intertwining Implicit and Explicit Awareness of Wellbeing to Support Peace of Mind and Connectedness

NASA Astrophysics Data System (ADS)

Dadlani, Pavan; Markopoulos, Panos; Aarts, Emile

An awareness system was designed to provide peace of mind and a sense of connectedness to adults who care for an elderly parent living alone. Our empirical research, including a field trial of six months, confirms the potential of awareness systems to support both generations suggesting that future research should examine, firstly, how to convey long-term trends regarding the wellbeing of the elderly and, secondly, how to intertwine the communication of awareness information with expressive forms of communication. We discuss implications of our studies for the design of ambient intelligent systems supporting awareness between elderly and their adult children.

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).

HFIR Fuel Casting Support

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

Imhoff, Seth D.; Gibbs, Paul Jacob; Solis, Eunice Martinez

Process exploration for fuel production for the High Flux Isotope Reactor (HFIR) using cast LEU-10wt.%Mo as an initial processing step has just begun. This project represents the first trials concerned with casting design and quality. The studies carried out over the course of this year and information contained in this report address the initial mold development to be used as a starting point for future operations. In broad terms, the final billet design is that of a solid rolling blank with an irregular octagonal cross section. The work covered here is a comprehensive view of the initial attempts to producemore » a sound casting. This report covers the efforts to simulate, predict, cast, inspect, and revise the initial mold design.« less

Enhancing clinical evidence by proactively building quality into clinical trials.

PubMed

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

2016-08-01

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

Quality assurance in MR image guided adaptive brachytherapy for cervical cancer: Final results of the EMBRACE study dummy run.

PubMed

Kirisits, Christian; Federico, Mario; Nkiwane, Karen; Fidarova, Elena; Jürgenliemk-Schulz, Ina; de Leeuw, Astrid; Lindegaard, Jacob; Pötter, Richard; Tanderup, Kari

2015-12-01

Upfront quality assurance (QA) is considered essential when starting a multicenter clinical trial in radiotherapy. Despite the long experience gained for external beam radiotherapy (EBRT) trials, there are only limited audit QA methods for brachytherapy (BT) and none include the specific aspects of image guided adaptive brachytherapy (IGABT). EMBRACE is a prospective multicenter trial aiming to assess the impact of (MRI)-based IGABT in locally advanced cervical cancer. An EMBRACE dummy run was designed to identify sources and magnitude of uncertainties and errors considered important for the evaluation of clinical, and dosimetric parameters and their relation to outcome. Contouring, treatment planning and dose reporting was evaluated and scored with a categorical scale of 1-10. Active feedback to centers was provided to improve protocol compliance and reporting. A second dummy run was required in case of major deviations (score <7) for any item. Overall 27/30 centers passed the dummy run. 16 centers had to repeat the dummy run in order to clarify major inconsistencies to the protocol. The most pronounced variations were related to contouring for both EBRT and BT. Centers with experience in IGABT (>30 cases) had better performance as compared to centers with limited experience. The comprehensive dummy run designed for the EMBRACE trial has been a feasible tool for QA in IGABT of cervix cancer. It should be considered for future IGABT trials and could serve as the basis for continuous quality checks for brachytherapy centers. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Long-term follow-up of HIV seroconverters in microbicide trials - rationale, study design, and challenges in MTN-015.

PubMed

Riddler, Sharon A; Husnik, Marla; Gorbach, Pamina M; Levy, Lisa; Parikh, Urvi; Livant, Edward; Pather, Arendevi; Makanani, Bonus; Muhlanga, Felix; Kasaro, Margaret; Martinson, Francis; Elharrar, Vanessa; Balkus, Jennifer E

2016-09-01

As the effect of biomedical prevention interventions on the natural history of HIV-1 infection in participants who seroconvert is unknown, the Microbicide Trials Network (MTN) established a longitudinal study (MTN-015) to monitor virologic, immunological, and clinical outcomes, as well as behavioral changes among women who become HIV-infected during MTN trials. We describe the rationale, study design, implementation, and enrollment of the initial group of participants in the MTN seroconverter cohort. Initiated in 2008, MTN-015 is an ongoing observational cohort study enrolling participants who acquire HIV-1 infection during effectiveness studies of candidate microbicides. Eligible participants from recently completed and ongoing MTN trials are enrolled after seroconversion and return for regular follow-up visits with clinical and behavioral data collection. Biologic samples including blood and genital fluids are stored for future testing. MTN-015 was implemented initially at six African sites and enrolled 100/139 (72%) of eligible women who seroconverted in HIV Prevention Trials Network protocol 035 (HPTN 035, conducted by the MTN). The median time from seroconversion in HPTN 035 to enrollment in MTN-015 was 18 months. Retention was good with >70% of visits completed. Implementation challenges included regulatory reviews, translation, and testing of questionnaires, and site readiness. Enrollment of HIV-seroconverters into a longitudinal observational follow-up study is feasible and acceptable to participants. Data and samples collected in this protocol will be used to assess safety of investigational HIV microbicides and answer other important public health questions for HIV infected women.

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/.

Predicting Low Accrual in the National Cancer Institute’s Cooperative Group Clinical Trials

PubMed Central

Bennette, Caroline S.; Ramsey, Scott D.; McDermott, Cara L.; Carlson, Josh J.; Basu, Anirban; Veenstra, David L.

2016-01-01

Background: The extent to which trial-level factors differentially influence accrual to trials has not been comprehensively studied. Our objective was to evaluate the empirical relationship and predictive properties of putative risk factors for low accrual in the National Cancer Institute’s (NCI’s) Cooperative Group Program, now the National Clinical Trials Network (NCTN). Methods: Data from 787 phase II/III adult NCTN-sponsored trials launched between 2000 and 2011 were used to develop a logistic regression model to predict low accrual, defined as trials that closed with or were accruing at less than 50% of target; 46 trials opened between 2012 and 2013 were used for prospective validation. Candidate predictors were identified from a literature review and expert interviews; final predictors were selected using stepwise regression. Model performance was evaluated by calibration and discrimination via the area under the curve (AUC). All statistical tests were two-sided. Results: Eighteen percent (n = 145) of NCTN-sponsored trials closed with low accrual or were accruing at less than 50% of target three years or more after initiation. A multivariable model of twelve trial-level risk factors had good calibration and discrimination for predicting trials with low accrual (AUC in trials launched 2000–2011 = 0.739, 95% confidence interval [CI] = 0.696 to 0.783]; 2012–2013: AUC = 0.732, 95% CI = 0.547 to 0.917). Results were robust to different definitions of low accrual and predictor selection strategies. Conclusions: We identified multiple characteristics of NCTN-sponsored trials associated with low accrual, several of which have not been previously empirically described, and developed a prediction model that can provide a useful estimate of accrual risk based on these factors. Future work should assess the role of such prediction tools in trial design and prioritization decisions. PMID:26714555

Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial.

PubMed

Karim, Quarraisha Abdool; Kharsany, Ayesha B M; Naidoo, Kasavan; Yende, Nonhlanhla; Gengiah, Tanuja; Omar, Zaheen; Arulappan, Natasha; Mlisana, Koleka P; Luthuli, Londiwe R; Karim, Salim S Abdool

2011-05-01

In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of alignment perturbations in a trans-tibial prosthesis user: A pilot study.

PubMed

Courtney, Anna; Orendurff, Michael S; Buis, Arjan

2016-04-01

A recurring complication in trans-tibial prosthetic limb users is "poor socket fit" with painful residuum-socket interfaces, a consequence of excess pressure. This is due to both poor socket fit and poor socket alignment; however, the interaction of these factors has not been quantified. Through evaluation of kinetic data this study aimed to articulate an interaction uniting socket design, alignment and interface pressures. The results will help to refine future studies and will hopefully help determine whether sockets can be designed, fitted and aligned to maximize mobility whilst minimizing injurious forces. Interface pressures were recorded throughout ambulation in one user with "optimal (reference) alignment" followed by 5 malalignments in a patellar tendon-bearing and a hydrocast socket. Marked differences in pressure distribution were discovered when equating the patellar tendon-bearing against the hydrocast socket and when comparing interface pressures from reference with offset alignment. Patellar tendon-bearing sockets were found to be more sensitive to alignment perturbations than hydrocast sockets. A complex interaction was found, with the most prominent finding demonstrating the requisite for attainment of optimal alignment: a translational alignment error of 10 mm can increase maximum peak pressures by 227% (mean 17.5%). Refinements for future trials are described and the necessity for future research into socket design, alignment and interface pressures has been estabilished.

Gas fired boilers: Perspective for near future fuel composition and impact on burner design process

NASA Astrophysics Data System (ADS)

Schiro, Fabio; Stoppato, Anna; Benato, Alberto

2017-11-01

The advancements on gas boiler technology run in parallel with the growth of renewable energy production. The renewable production will impact on the fuel gas quality, since the gas grid will face an increasing injection of alternative fuels (biogas, biomethane, hydrogen). Biogas allows producing energy with a lower CO2 impact; hydrogen production by electrolysis can mitigate the issues related to the mismatch between energy production by renewable and energy request. These technologies will contribute to achieve the renewable production targets, but the impact on whole fuel gas production-to-consumption chain must be evaluated. In the first part of this study, the Authors present the future scenario of the grid gas composition and the implications on gas fed appliances. Given that the widely used premixed burners are currently designed mainly by trial and error, a broader fuel gas quality range means an additional hitch on this design process. A better understanding and structuring of this process is helpful for future appliance-oriented developments. The Authors present an experimental activity on a premixed condensing boiler setup. A test protocol highlighting the burners' flexibility in terms of mixture composition is adopted and the system fuel flexibility is characterized around multiple reference conditions.

A stepped wedge, cluster-randomized trial of a household UV-disinfection and safe storage drinking water intervention in rural Baja California Sur, Mexico.

PubMed

Gruber, Joshua S; Reygadas, Fermin; Arnold, Benjamin F; Ray, Isha; Nelson, Kara; Colford, John M

2013-08-01

In collaboration with a local non-profit organization, this study evaluated the expansion of a program that promoted and installed Mesita Azul, an ultraviolet-disinfection system designed to treat household drinking water in rural Mexico. We conducted a 15-month, cluster-randomized stepped wedge trial by randomizing the order in which 24 communities (444 households) received the intervention. We measured primary outcomes (water contamination and diarrhea) during seven household visits. The intervention increased the percentage of households with access to treated and safely stored drinking water (23-62%), and reduced the percentage of households with Escherichia coli contaminated drinking water (risk difference (RD): -19% [95% CI: -27%, -14%]). No significant reduction in diarrhea was observed (RD: -0.1% [95% CI: -1.1%, 0.9%]). We conclude that household water quality improvements measured in this study justify future promotion of the Mesita Azul, and that future studies to measure its health impact would be valuable if conducted in populations with higher diarrhea prevalence.

A Stepped Wedge, Cluster-Randomized Trial of a Household UV-Disinfection and Safe Storage Drinking Water Intervention in Rural Baja California Sur, Mexico

PubMed Central

Gruber, Joshua S.; Reygadas, Fermin; Arnold, Benjamin F.; Ray, Isha; Nelson, Kara; Colford, John M.

2013-01-01

In collaboration with a local non-profit organization, this study evaluated the expansion of a program that promoted and installed Mesita Azul, an ultraviolet-disinfection system designed to treat household drinking water in rural Mexico. We conducted a 15-month, cluster-randomized stepped wedge trial by randomizing the order in which 24 communities (444 households) received the intervention. We measured primary outcomes (water contamination and diarrhea) during seven household visits. The intervention increased the percentage of households with access to treated and safely stored drinking water (23–62%), and reduced the percentage of households with Escherichia coli contaminated drinking water (risk difference (RD): −19% [95% CI: −27%, −14%]). No significant reduction in diarrhea was observed (RD: −0.1% [95% CI: −1.1%, 0.9%]). We conclude that household water quality improvements measured in this study justify future promotion of the Mesita Azul, and that future studies to measure its health impact would be valuable if conducted in populations with higher diarrhea prevalence. PMID:23732255

Muslim communities learning about second-hand smoke (MCLASS): study protocol for a pilot cluster randomised controlled trial

PubMed Central

2013-01-01

Background In the UK, 40% of Bangladeshi and 29% of Pakistani men smoke cigarettes regularly compared to the national average of 24%. As a consequence, second-hand smoking is also widespread in their households which is a serious health hazard to non-smokers, especially children. Smoking restrictions in households can help reduce exposure to second-hand smoking. This is a pilot trial of ‘Smoke Free Homes’, an educational programme which has been adapted for use by Muslim faith leaders, in an attempt to find an innovative solution to encourage Pakistani- and Bangladeshi-origin communities to implement smoking restrictions in their homes. The primary objectives for this pilot trial are to establish the feasibility of conducting such an evaluation and provide information to inform the design of a future definitive study. Methods/Design This is a pilot cluster randomised controlled trial of ‘Smoke Free Homes’, with an embedded preliminary health economic evaluation and a qualitative analysis. The trial will be carried out in around 14 Islamic religious settings. Equal randomisation will be employed to allocate each cluster to a trial arm. The intervention group will be offered the Smoke Free Homes package (Smoke Free Homes: a resource for Muslim religious teachers), trained in its use, and will subsequently implement the package in their religious settings. The remaining clusters will not be offered the package until the completion of the study and will form the control group. At each cluster, we aim to recruit around 50 households with at least one adult resident who smokes tobacco and at least one child or a non-smoking adult. Households will complete a household survey and a non-smoking individual will provide a saliva sample which will be tested for cotinine. All participant outcomes will be measured before and after the intervention period in both arms of the trial. In addition, a purposive sample of participants and religious leaders/teachers will take part in interviews and focus groups. Discussion The results of this pilot study will inform the protocol for a definitive trial. Trial registration Current Controlled Trials ISRCTN03035510 PMID:24034853

The national drug abuse treatment clinical trials network data share project: website design, usage, challenges, and future directions.

PubMed

Shmueli-Blumberg, Dikla; Hu, Lian; Allen, Colleen; Frasketi, Michael; Wu, Li-Tzy; Vanveldhuisen, Paul

2013-01-01

There are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the 'gold standard' for establishing treatment effectiveness, but clinical trial research is very costly, and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. We describe the goals, developments, and usage of the Data Share website (http://www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the United States, including lessons learned, limitations, and major revisions, and considerations for future directions to improve data sharing. Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. The Data Share website offers researchers easy access to de-identified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, ongoing collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses.

The National Drug Abuse Treatment Clinical Trials Network Data Share Project: Website Design, Usage, Challenges and Future Directions

PubMed Central

Shmueli-Blumberg, Dikla; Hu, Lian; Allen, Colleen; Frasketi, Michael; Wu, Li-Tzy; VanVeldhuisen, Paul

2014-01-01

Background The are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the “gold standard” for establishing treatment effectiveness, but clinical trial research is very costly and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. Purpose We describe the goals, developments, and usage of the Data Share website (www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the US, including lessons learned, limitations and major revisions and considerations for future directions to improve data sharing. Methods Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Results Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Limitations Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. Conclusions The Data Share website offers researchers easy access to deidentified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, on-going collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses. PMID:24085772

Clinical Trials - Information for Participants

MedlinePlus

... Study Near You Learn More Share Clinical Trials – Information for Participants Overview Clinical research trials are at ... improved health in the future. Learn More Contact Information For more information about clinical trials conducted at ...

2-D or 3-D Mammography? The Future of Breast Cancer Detection

MedlinePlus

... D or 3-D Mammography?: The Future of Breast Cancer Detection NIH-supported clinical trial tests diagnostic imaging ... new trial may be the answer for finding breast cancer in women who don’t have symptoms. The ...

Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

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

Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca; Hoskin, Peter; Mitera, Gunita

2012-04-01

Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time. Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadianmore » Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey. Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments. Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.« less

Generalizing boundaries for triangular designs, and efficacy estimation at extended follow-ups.

PubMed

Allison, Annabel; Edwards, Tansy; Omollo, Raymond; Alves, Fabiana; Magirr, Dominic; E Alexander, Neal D

2015-11-16

Visceral leishmaniasis (VL) is a parasitic disease transmitted by sandflies and is fatal if left untreated. Phase II trials of new treatment regimens for VL are primarily carried out to evaluate safety and efficacy, while pharmacokinetic data are also important to inform future combination treatment regimens. The efficacy of VL treatments is evaluated at two time points, initial cure, when treatment is completed and definitive cure, commonly 6 months post end of treatment, to allow for slow response to treatment and detection of relapses. This paper investigates a generalization of the triangular design to impose a minimum sample size for pharmacokinetic or other analyses, and methods to estimate efficacy at extended follow-up accounting for the sequential design and changes in cure status during extended follow-up. We provided R functions that generalize the triangular design to impose a minimum sample size before allowing stopping for efficacy. For estimation of efficacy at a second, extended, follow-up time, the performance of a shrinkage estimator (SHE), a probability tree estimator (PTE) and the maximum likelihood estimator (MLE) for estimation was assessed by simulation. The SHE and PTE are viable approaches to estimate an extended follow-up although the SHE performed better than the PTE: the bias and root mean square error were lower and coverage probabilities higher. Generalization of the triangular design is simple to implement for adaptations to meet requirements for pharmacokinetic analyses. Using the simple MLE approach to estimate efficacy at extended follow-up will lead to biased results, generally over-estimating treatment success. The SHE is recommended in trials of two or more treatments. The PTE is an acceptable alternative for one-arm trials or where use of the SHE is not possible due to computational complexity. NCT01067443 , February 2010.

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.

Whose data set is it anyway? Sharing raw data from randomized trials.

PubMed

Vickers, Andrew J

2006-05-16

Sharing of raw research data is common in many areas of medical research, genomics being perhaps the most well-known example. In the clinical trial community investigators routinely refuse to share raw data from a randomized trial without giving a reason. Data sharing benefits numerous research-related activities: reproducing analyses; testing secondary hypotheses; developing and evaluating novel statistical methods; teaching; aiding design of future trials; meta-analysis; and, possibly, preventing error, fraud and selective reporting. Clinical trialists, however, sometimes appear overly concerned with being scooped and with misrepresentation of their work. Both possibilities can be avoided with simple measures such as inclusion of the original trialists as co-authors on any publication resulting from data sharing. Moreover, if we treat any data set as belonging to the patients who comprise it, rather than the investigators, such concerns fall away. Technological developments, particularly the Internet, have made data sharing generally a trivial logistical problem. Data sharing should come to be seen as an inherent part of conducting a randomized trial, similar to the way in which we consider ethical review and publication of study results. Journals and funding bodies should insist that trialists make raw data available, for example, by publishing data on the Web. If the clinical trial community continues to fail with respect to data sharing, we will only strengthen the public perception that we do clinical trials to benefit ourselves, not our patients.

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.

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.

Reasons for participation and non-participation in a diabetes prevention trial among women with prior gestational diabetes mellitus (GDM)

PubMed Central

2014-01-01

Background Gestational diabetes mellitus (GDM) is a risk factor for the development of type 2 diabetes. Lifestyle intervention can prevent progression to type 2 diabetes in high risk populations. We designed a randomised controlled trial (RCT) to evaluate the effectiveness of an established lifestyle intervention compared to standard care for delaying diabetes onset in European women with recent GDM. Recruitment into the RCT was more challenging than anticipated with only 89 of 410 (22%) women agreeing to participate. This paper identifies factors that could enhance participation of the target population in future interventions. Methods We hypothesised that women who agreed to participate would have higher diabetes risk profiles than those who declined, and secondly that it would be possible to predict participation on the bases of those risk factors. To test our hypothesis, we identified the subset of women for whom we had comprehensive data on diabetes risks factors 3-5 years following GDM, reducing the sample to 43 participants and 73 decliners. We considered established diabetes risk factors: smoking, daily fruit and vegetable intake, participation in exercise, family history of diabetes, glucose values and BMI scores on post-partum re-screens, use of insulin during pregnancy, and age at delivery. We also analysed narrative data from 156 decliners to further understand barriers to and facilitators of participation. Results Two factors differentiated participants and decliners: age at delivery (with women older than 34 years being more likely to participate) and insulin use during pregnancy (with women requiring the use of insulin in pregnancy less likely to participate). Binary logistic regression confirmed that insulin use negatively affected the odds of participation. The most significant barriers to participation included the accessibility, affordability and practicality of the intervention. Conclusions Women with recent GDM face multiple barriers to lifestyle change. Intervention designers should consider: (i) the practicalities of participation for this population, (ii) research designs that capitalise on motivational differences between participants, (iii) alleviating concerns about long-term diabetes management. We hope this work will support future researchers in developing interventions that are more relevant, effective and successful in recruiting the desired population. Trial registration Current Controlled Trials ISRCTN41202110 PMID:24461045

How parents and practitioners experience research without prior consent (deferred consent) for emergency research involving children with life threatening conditions: a mixed method study

PubMed Central

Woolfall, Kerry; Frith, Lucy; Gamble, Carrol; Gilbert, Ruth; Mok, Quen; Young, Bridget

2015-01-01

Objective Alternatives to prospective informed consent to enable children with life-threatening conditions to be entered into trials of emergency treatments are needed. Across Europe, a process called deferred consent has been developed as an alternative. Little is known about the views and experiences of those with first-hand experience of this controversial consent process. To inform how consent is sought for future paediatric critical care trials, we explored the views and experiences of parents and practitioners involved in the CATheter infections in CHildren (CATCH) trial, which allowed for deferred consent in certain circumstances. Design Mixed method survey, interview and focus group study. Participants 275 parents completed a questionnaire; 20 families participated in an interview (18 mothers, 5 fathers). 17 CATCH practitioners participated in one of four focus groups (10 nurses, 3 doctors and 4 clinical trial unit staff). Setting 12 UK children's hospitals. Results Some parents were momentarily shocked or angered to discover that their child had or could have been entered into CATCH without their prior consent. Although these feelings resolved after the reasons why consent needed to be deferred were explained and that the CATCH interventions were already used in clinical care. Prior to seeking deferred consent for the first few times, CATCH practitioners were apprehensive, although their feelings abated with experience of talking to parents about CATCH. Parents reported that their decisions about their child's participation in the trial had been voluntary. However, mistiming the deferred consent discussion had caused distress for some. Practitioners and parents supported the use of deferred consent in CATCH and in future trials of interventions already used in clinical care. Conclusions Our study provides evidence to support the use of deferred consent in paediatric emergency medicine; it also indicates the crucial importance of practitioner communication and appropriate timing of deferred consent discussions. PMID:26384724

Simulating clinical trial visits yields patient insights into study design and recruitment.

PubMed

Lim, S Sam; Kivitz, Alan J; McKinnell, Doug; Pierson, M Edward; O'Brien, Faye S

2017-01-01

We elicited patient experiences from clinical trial simulations to aid in future trial development and to improve patient recruitment and retention. Two simulations of draft Phase II and Phase III anifrolumab studies for systemic lupus erythematosus (SLE)/lupus nephritis (LN) were performed involving African-American patients from Grady Hospital, an indigent care hospital in Atlanta, GA, USA, and white patients from Altoona Arthritis and Osteoporosis Center in Altoona, PA, USA. The clinical trial simulation included an informed consent procedure, a mock screening visit, a mock dosing visit, and a debriefing period for patients and staff. Patients and staff were interviewed to obtain sentiments and perceptions related to the simulated visits. The Atlanta study involved 6 African-American patients (5 female) aged 27-60 years with moderate to severe SLE/LN. The Altoona study involved 12 white females aged 32-75 years with mild to moderate SLE/LN. Patient experiences had an impact on four patient-centric care domains: 1) information, communication, and education; 2) responsiveness to needs; 3) access to care; and 4) coordination of care; and continuity and transition. Patients in both studies desired background material, knowledgeable staff, family and friend support, personal results, comfortable settings, shorter wait times, and greater scheduling flexibility. Compared with the Altoona study patients, Atlanta study patients reported greater preferences for information from the Internet, need for strong community and online support, difficulties in discussing SLE, emphasis on transportation and child care help during the visits, and concerns related to financial matters; and they placed greater importance on time commitment, understanding of potential personal benefit, trust, and confidentiality of patient data as factors for participation. Using these results, we present recommendations to improve study procedures to increase retention, recruitment, and compliance for clinical trials. Insights from these two studies can be applied to the development and implementation of future clinical trials to improve patient recruitment, retention, compliance, and advocacy.

The feasibility of a pragmatic randomised controlled trial to compare usual care with usual care plus individualised homeopathy, in children requiring secondary care for asthma.

PubMed

Thompson, E A; Shaw, A; Nichol, J; Hollinghurst, S; Henderson, A J; Thompson, T; Sharp, D

2011-07-01

To test the feasibility of a pragmatic trial design with economic evaluation and nested qualitative study, comparing usual care (UC) with UC plus individualised homeopathy, in children requiring secondary care for asthma. This included recruitment and retention, acceptability of outcome measures patients' and health professionals' views and experiences and a power calculation for a definitive trial. In a pragmatic parallel group randomised controlled trial (RCT) design, children on step 2 or above of the British Thoracic Society Asthma Guidelines (BTG) were randomly allocated to UC or UC plus a five visit package of homeopathic care (HC). Outcome measures included the Juniper Asthma Control Questionnaire, Quality of Life Questionnaire and a resource use questionnaire. Qualitative interviews were used to gain families' and health professionals' views and experiences. 226 children were identified from hospital clinics and related patient databases. 67 showed an interest in participating, 39 children were randomised, 18 to HC and 21 to UC. Evidence in favour of adjunctive homeopathic treatment was lacking. Economic evaluation suggests that the cost of additional consultations was not offset by the reduced cost of homeopathic remedies and the lower use of primary care by children in the homeopathic group. Qualitative data gave insights into the differing perspectives of families and health care professionals within the research process. A future study using this design is not feasible, further investigation of a potential role for homeopathy in asthma management might be better conducted in primary care with children with less severe asthma. Copyright © 2011 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

Nature, nurture, and capital punishment: How evidence of a genetic-environment interaction, future dangerousness, and deliberation affect sentencing decisions.

PubMed

Gordon, Natalie; Greene, Edie

2018-01-01

Research has shown that the low-activity MAOA genotype in conjunction with a history of childhood maltreatment increases the likelihood of violent behaviors. This genetic-environment (G × E) interaction has been introduced as mitigation during the sentencing phase of capital trials, yet there is scant data on its effectiveness. This study addressed that issue. In a factorial design that varied mitigating evidence offered by the defense [environmental (i.e., childhood maltreatment), genetic, G × E, or none] and the likelihood of the defendant's future dangerousness (low or high), 600 mock jurors read sentencing phase evidence in a capital murder trial, rendered individual verdicts, and half deliberated as members of a jury to decide a sentence of death or life imprisonment. The G × E evidence had little mitigating effect on sentencing preferences: participants who received the G × E evidence were no less likely to sentence the defendant to death than those who received evidence of childhood maltreatment or a control group that received neither genetic nor maltreatment evidence. Participants with evidence of a G × E interaction were more likely to sentence the defendant to death when there was a high risk of future dangerousness than when there was a low risk. Sentencing preferences were more lenient after deliberation than before. We discuss limitations and future directions. Copyright © 2017 John Wiley & Sons, Ltd.

Setting up a cohort study in speech and language therapy: lessons from The UK Cleft Collective Speech and Language (CC-SL) study.

PubMed

Wren, Yvonne; Humphries, Kerry; Stock, Nicola Marie; Rumsey, Nichola; Lewis, Sarah; Davies, Amy; Bennett, Rhiannon; Sandy, Jonathan

2018-05-01

Efforts to increase the evidence base in speech and language therapy are often limited by methodological factors that have restricted the strength of the evidence to the lower levels of the evidence hierarchy. Where higher graded studies, such as randomized controlled trials, have been carried out, it has sometimes been difficult to obtain sufficient power to detect a potential effect of intervention owing to small sample sizes or heterogeneity in the participants. With certain clinical groups such as cleft lip and palate, systematic reviews of intervention studies have shown that there is no robust evidence to support the efficacy of any one intervention protocol over another. To describe the setting up of an observational clinical cohort study and to present this as an alternative design for answering research questions relating to prevalence, risk factors and outcomes from intervention. The Cleft Collective Speech and Language (CC-SL) study is a national cohort study of children born with cleft palate. Working in partnership with regional clinical cleft centres, a sample size of over 600 children and 600 parents is being recruited and followed up from birth to age 5 years. Variables being collected include demographic, psychological, surgical, hearing, and speech and language data. The process of setting up the study has led to the creation of a unique, large-scale data set which is available for researchers to access now and in future. As well as exploring predictive factors, the data can be used to explore the impact of interventions in relation to individual differences. Findings from these investigations can be used to provide information on sample criteria and definitions of intervention and dosage which can be used in future trials. The observational cohort study is a useful alternative design to explore questions around prevalence, risk factors and intervention for clinical groups where robust research data are not yet available. Findings from such a study can be used to guide service-delivery decisions and to determine power for future clinical trials. © 2017 Royal College of Speech and Language Therapists.

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

PubMed

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

2014-03-01

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

Collaborative, individualised lifestyle interventions are acceptable to people with first episode psychosis; a qualitative study.

PubMed

Pedley, Rebecca; Lovell, Karina; Bee, Penny; Bradshaw, Tim; Gellatly, Judith; Ward, Kate; Woodham, Adrine; Wearden, Alison

2018-04-25

The adverse impact of unhealthy lifestyle choices and the prescription of antipsychotic medications contribute to weight gain, poor cardiovascular health and reduced life expectancy for people with psychosis. The present study aimed to explore the acceptability and perceived outcomes of a lifestyle intervention designed to prevent or reduce weight gain in people with first-episode psychosis. This was a qualitative study using a data-driven approach. People recovering from first-episode psychosis recruited from UK early intervention services and taking part in the active arm of a randomised controlled trial of a lifestyle intervention (the InterACT trial), were interviewed using a semi-structured interview schedule. Interviews were transcribed verbatim and analysed using Framework Analysis. Participants valued the collaborative and individualised approach taken by the intervention deliverers, and formed high quality relationships with them. Aspects of the intervention that were positively appraised included goal setting, social opportunities, and progress monitoring. Benefits of the intervention, including increased levels of exercise; improved diet and physical health; increased psychological wellbeing (e.g. confidence, self-esteem); and improved social relationships, were identified by participants, independent of actual weight loss. Future interventions should ensure that workers have the skills to form high quality relationships with users, and to individualise the intervention according to users' needs and preferences. Future trials that test healthy living interventions should consider supplementing physical outcome measures with wider psychosocial outcome assessments, in particular social relationship quality, psychological wellbeing, self-esteem and self-efficacy. Current Controlled Trials: ISRCTN22581937 . Date of registration: 27 October 2010 (retrospectively registered).

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.

Understanding the outcomes measures used in Huntington disease pharmacologicaltrials: A systematic review

PubMed Central

Carlozzi, Noelle E; Miciura, Angela; Migliore, Nicholas; Dayalu, Praveen

2014-01-01

Background The identification of the gene mutation causing Huntington disease has raised hopes for new treatments to ease symptoms and slow functional decline. As such, there has been a push towards designing efficient pharmacological trials (i.e., drug trials), especially with regard to selecting outcomes measures that are both brief and sensitive to changes across the course of the disease, from subtle prodromal changes, to more severe end-stage changes. Objectives Recently, to aid in efficient development of new HD research studies, the National Institute of Neurological Disorders and Stroke (NINDS) published recommendations for measurement selection in HD. While these recommendations are helpful, many of the recommended measures have little published data in HD. As such, we conducted a systematic review of the literature to identify the most common outcomes measures used in HD clinical trials. Methods Major medical databases, including PubMed, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were used to identify peer-reviewed journal articles in English from 2001 through April 2013; 151 pharmacological trials were identified. Results The majority of HD clinical trials employed clinician-reported outcomes measures (93%); patient reported outcome measures (11%) and observer reported outcome measures (3%) were used with much less frequency. Conclusions We provide a review of the most commonly used measures across these trials, compare these measures to the clinical recommendations made by the NINDS working groups, and provide recommendations for selecting measures for future clinical trials that meet the Food and Drug Administration standards. PMID:25300328

Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial. A registry-based randomized clinical trial.

PubMed

Fröbert, Ole; Götberg, Matthias; Angerås, Oskar; Jonasson, Lena; Erlinge, David; Engstrøm, Thomas; Persson, Jonas; Jensen, Svend E; Omerovic, Elmir; James, Stefan K; Lagerqvist, Bo; Nilsson, Johan; Kåregren, Amra; Moer, Rasmus; Yang, Cao; Agus, David B; Erglis, Andrejs; Jensen, Lisette O; Jakobsen, Lars; Christiansen, Evald H; Pernow, John

2017-07-01

Registry studies and case-control studies have demonstrated that the risk of acute myocardial infarction (AMI) is increased following influenza infection. Small randomized trials, underpowered for clinical end points, indicate that future cardiovascular events can be reduced following influenza vaccination in patients with established cardiovascular disease. Influenza vaccination is recommended by international guidelines for patients with cardiovascular disease, but uptake is varying and vaccination is rarely prioritized during hospitalization for AMI. The Influenza vaccination After Myocardial Infarction (IAMI) trial is a double-blind, multicenter, prospective, registry-based, randomized, placebo-controlled, clinical trial. A total of 4,400 patients with ST-segment elevation myocardial infarction (STEMI) or non-STEMI undergoing coronary angiography will randomly be assigned either to in-hospital influenza vaccination or to placebo. Baseline information is collected from national heart disease registries, and follow-up will be performed using both registries and a structured telephone interview. The primary end point is a composite of time to all-cause death, a new AMI, or stent thrombosis at 1 year. The IAMI trial is the largest randomized trial to date to evaluate the effect of in-hospital influenza vaccination on death and cardiovascular outcomes in patients with STEMI or non-STEMI. The trial is expected to provide highly relevant clinical data on the efficacy of influenza vaccine as secondary prevention after AMI. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Acellular pertussis vaccines--a question of efficacy.

PubMed

Olin, P

1995-06-01

Whole cell pertussis vaccine is considered to offer at least 80% protection against typical whooping cough. The quest for an equally effective but less reactogenic vaccine is now drawing to a close. During the forthcoming year a number of efficacy trials of acellular pertussis vaccines will be terminated. A variety of vaccines containing one, two, three or five purified pertussis antigens are being tested in Germany, Italy, Senegal and Sweden. About 30,000 infants have been enrolled in placebo-controlled studies and more than 100,000 in whole cell vaccine-controlled trials. The final plans for analysis of a Swedish placebo-controlled trial of whole cell and acellular vaccines is presented. Due to the unexpected high incidence of pertussis in Sweden during 1993-1994, relative risk comparisons between vaccines will be attempted in that trial, in addition to estimating absolute efficacy. A crucial issue is to what extent data may be compared between trials, given differences in design, vaccination schedules, and chosen endpoints. A primary case definition of laboratory-confirmed pertussis with at least 21 days of paroxysmal cough have been adopted in most trials. Pre-planned meta-analysis using this single endpoint will facilitate comparisons between vaccines. Serological correlates to protection in individuals will be sought in the ongoing placebo-controlled trials. The concept of a serological correlate valid for a vaccinated population but not necessarily for the vaccinated individual, as is the case with Hib vaccines, may turn out to be the only alternative to performing large efficacy trials in the future.

Ask: a health advocacy program for adolescents with an intellectual disability: a cluster randomised controlled trial

PubMed Central

2012-01-01

Background Adolescents with intellectual disability often have poor health and healthcare. This is partly as a consequence of poor communication and recall difficulties, and the possible loss of specialised paediatric services. Methods/Design A cluster randomised trial was conducted with adolescents with intellectual disability to investigate a health intervention package to enhance interactions among adolescents with intellectual disability, their parents/carers, and general practitioners (GPs). The trial took place in Queensland, Australia, between February 2007 and September 2010. The intervention package was designed to improve communication with health professionals and families’ organisation of health information, and to increase clinical activities beneficial to improved health outcomes. It consisted of the Comprehensive Health Assessment Program (CHAP), a one-off health check, and the Ask Health Diary, designed for on-going use. Participants were drawn from Special Education Schools and Special Education Units. The education component of the intervention was delivered as part of the school curriculum. Educators were surveyed at baseline and followed-up four months later. Carers were surveyed at baseline and after 26 months. Evidence of health promotion, disease prevention and case-finding activities were extracted from GPs clinical records. Qualitative interviews of educators occurred after completion of the educational component of the intervention and with adolescents and carers after the CHAP. Discussion Adolescents with intellectual disability have difficulty obtaining many health services and often find it difficult to become empowered to improve and protect their health. The health intervention package proposed may aid them by augmenting communication, improving documentation of health encounters, and improving access to, and quality of, GP care. Recruitment strategies to consider for future studies in this population include ensuring potential participants can identify themselves with the individuals used in promotional study material, making direct contact with their families at the start of the study, and closely monitoring the implementation of the educational intervention. Trial Registration Number ClinicalTrials.gov Identifier: NCT00519311 PMID:22958354

Association Splitting: A randomized controlled trial of a new method to reduce craving among inpatients with alcohol dependence.

PubMed

Schneider, Brooke C; Moritz, Steffen; Hottenrott, Birgit; Reimer, Jens; Andreou, Christina; Jelinek, Lena

2016-04-30

Association Splitting, a novel cognitive intervention, was tested in patients with alcohol dependence as an add-on intervention in an initial randomized controlled trial. Preliminary support for Association Splitting has been found in patients with obsessive-compulsive disorder, as well as in an online pilot study of patients with alcohol use disorders. The present variant sought to reduce craving by strengthening neutral associations with alcohol-related stimuli, thus, altering cognitive networks. Eighty-four inpatients with verified diagnoses of alcohol dependence, who were currently undergoing inpatient treatment, were randomly assigned to Association Splitting or Exercise Therapy. Craving was measured at baseline, 4-week follow-up, and six months later with the Obsessive-Compulsive Drinking Scale (primary outcome) and the Alcohol Craving Questionnaire. There was no advantage for Association Splitting after three treatment sessions relative to Exercise Therapy. Among Association Splitting participants, 51.9% endorsed a subjective decline in craving and 88.9% indicated that they would use Association Splitting in the future. Despite high acceptance, an additional benefit of Association Splitting beyond standard inpatient treatment was not found. Given that participants were concurrently undergoing inpatient treatment and Association Splitting has previously shown moderate effects, modification of the study design may improve the potential to detect significant effects in future trials. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Designing clinical trials to assess antiepileptic drugs as monotherapy : difficulties and solutions.

PubMed

Perucca, Emilio

2008-01-01

Designing monotherapy trials in epilepsy is fraught with many hurdles, including diagnostic and classification difficulties, sparse information regarding the natural history of the disorder, and ethical objections to the use of placebo or a suboptimal comparator in a condition where the consequences of therapeutic failure can be serious. These issues are further complicated by regulatory differences between the US and the EU.In the US, the FDA considers that evidence of efficacy requires demonstration of superiority to a comparator. Because available antiepileptic drugs possess relatively high efficacy, in most settings it is unrealistic to expect that a new treatment will be superior to a standard treatment used at optimized dosages. To circumvent this problem, trial designs have been developed whereby patients in the control group are assigned to receive a suboptimal comparator and are required to exit from the trial if seizure deterioration occurs. This allows demonstration of a between-group difference in efficacy endpoints, such as time to exit or time to first seizure. Although these trials have come under increasing criticism because of ethical concerns, extensive information is now available on the outcome of patients with chronic epilepsy randomized to suboptimal treatment in similarly designed conversion to monotherapy trials. This has allowed the construction of a dataset of historical controls against which response to a fully active treatment can be compared. A number of studies using this novel approach are now in progress.In the EU, in addition to requiring data on conversion to monotherapy in refractory patients, the European Medicines Agency stipulates that a monotherapy indication in newly diagnosed epilepsy can only be granted if a candidate drug has shown at least a similar benefit/risk balance compared with an acknowledged standard at its optimal use during an assessment period of no less than 1 year. This has led to the implementation of noninferiority trials, one of which has been completed and which led to approval of the monotherapy indication for levetiracetam in the EU. Noninferiority trials provide valuable data in a setting that most closely resembles routine clinical practice, but their interpretation can be complicated by uncertainties on assay sensitivity.Major evidence gaps in the treatment of epilepsy still remain and it is hoped that these will be addressed in the near future. High quality monotherapy trials are particularly needed to assess the comparative efficacy of older and newer drugs in less common epilepsy syndromes, including most generalized epilepsies, and to investigate the different treatment options in populations homogeneous not only in terms of syndromic classification, but also in terms of underlying aetiology and associated phenotypes.

Death, bereavement and randomised controlled trials (BRACELET): a methodological study of policy and practice in neonatal and paediatric intensive care trials.

PubMed

Snowdon, Claire; Brocklehurst, Peter; Tasker, Robert; Ward Platt, Martin; Harvey, Sheila; Elbourne, Diana

2014-07-01

Researchers have seldom included bereaved parents in studies of participants' views of randomised controlled trials (RCTs); hence our understanding of the impact of trials is based on skewed and incomplete samples. Little is known about parental experiences of the death of a child subsequent to their enrolment in a trial or of provision made for this experience by clinicians and trial teams. The Bereavement and RAndomised ControlLEd Trials (BRACELET) study was funded to consider bereavement in the context of paediatric intensive care (PIC) and neonatal intensive care (NIC) trials. The study comprised three interlinked components: a quantitative survey of RCT activity in UK paediatric intensive care units (PICUs) and neonatal intensive care units (NICUs), UK RCT recruitment and mortality rates, and provision for bereavement during 2002-6; a qualitative interview study involving 51 bereaved parents and 59 clinicians and trial team members associated with five neonatal trials; and a methodological study to inform future research. Fifty RCTs were identified as having enrolled babies or children from 2002 to 2006. Approximately 50% of UK NICUs and PICUs (54 NICUs, six PICUs) participated in at least one of these trials. Collectively they enrolled over 3000 children. Most enrolled small numbers, the majority of participants being enrolled by a small group of academic medical units. The proportion of deaths following trial enrolment was 17% in NIC trials and 6% in PIC trials. The qualitative study showed that trial-related decisions were made in a range of circumstances, some after extremely preterm births, others after complicated term deliveries, often under time pressures and in escalating crises. Parents' interest in trials appeared to recede initially but could re-emerge over time. They often valued opportunities to engage with a trial and were interested in more contact and information than they actually received. Clinicians often saw NICU bereavement policies as meeting parental needs, and trial participation as being of relatively minor significance in bereavement. This view may result from the positioning of clinicians' encounters with parents only in the initial stages of grief when trials were not a priority. Trial teams used a range of bereavement strategies, from no further contact to a pioneering multipart follow-up package. Communication with bereaved parents was complicated by limited contact opportunities. Trial teams were obliged to work without knowing whether their communications were appreciated, were problematic, or even whether they were received by parents. The methodological component highlighted strategies for recruitment and data collection in this sensitive setting. Recruitment by unsupported postal contact generally failed and a more personal approach via clinicians was more effective, supplemented by publicity material distributed via trusted organisations. A co-ordinated response to bereavement is as much a part of the running of trials as recruitment, and needs to be considered at trial inception. BRACELET has demonstrated the value and feasibility of research with bereaved parents involved in NIC trials. In order to respond to bereavement in a fair and sensitive way, as well as to better inform the design of RCTs, it is crucial that we listen to bereaved parents and evaluate new methods for so doing. More research is therefore needed into the experiences of bereavement subsequent to trial enrolment, with study of bereavement strategies in NIC trials as they are introduced. In addition, future studies should determine whether parents and triallists in PIC trials (and trials in adults) face the same issues as in NIC trials. Careful studies are necessary to explore how feedback of trial results are received and understood by bereaved and non-bereaved parents, and how individual trial teams manage this situation. An additional research area for exploring experiences of parenting twins and higher-order births in trials arose from BRACELET. Developmental research should continue to explore means of involving a wider range of parents in future research, including via publicity and specialist websites. Finally, methodological research is needed to ensure that we have the tools to explore, with parents and other relatives, as partners in research, a range of trial-related topics, which might be challenging, as the information is complex or the focus is sensitive. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.

PubMed

Wiggers, Jimme K; Coelen, Robert J S; Rauws, Erik A J; van Delden, Otto M; van Eijck, Casper H J; de Jonge, Jeroen; Porte, Robert J; Buis, Carlijn I; Dejong, Cornelis H C; Molenaar, I Quintus; Besselink, Marc G H; Busch, Olivier R C; Dijkgraaf, Marcel G W; van Gulik, Thomas M

2015-02-14

Liver surgery in perihilar cholangiocarcinoma (PHC) is associated with high postoperative morbidity because the tumor typically causes biliary obstruction. Preoperative biliary drainage is used to create a safer environment prior to liver surgery, but biliary drainage may be harmful when severe drainage-related complications deteriorate the patients' condition or increase the risk of postoperative morbidity. Biliary drainage can cause cholangitis/cholecystitis, pancreatitis, hemorrhage, portal vein thrombosis, bowel wall perforation, or dehydration. Two methods of preoperative biliary drainage are mostly applied: endoscopic biliary drainage, which is currently used in most regional centers before referring patients for surgical treatment, and percutaneous transhepatic biliary drainage. Both methods are associated with severe drainage-related complications, but two small retrospective series found a lower incidence in the number of preoperative complications after percutaneous drainage compared to endoscopic drainage (18-25% versus 38-60%, respectively). The present study randomizes patients with potentially resectable PHC and biliary obstruction between preoperative endoscopic or percutaneous transhepatic biliary drainage. The study is a multi-center trial with an "all-comers" design, randomizing patients between endoscopic or percutaneous transhepatic biliary drainage. All patients selected to potentially undergo a major liver resection for presumed PHC are eligible for inclusion in the study provided that the biliary system in the future liver remnant is obstructed (even if they underwent previous inadequate endoscopic drainage). Primary outcome measure is the total number of severe preoperative complications between randomization and exploratory laparotomy. The study is designed to detect superiority of percutaneous drainage: a provisional sample size of 106 patients is required to detect a relative decrease of 50% in the number of severe preoperative complications (alpha = 0.95; beta = 0.8). Interim analysis after inclusion of 53 patients (50%) will provide the definitive sample size. Secondary outcome measures encompass the success of biliary drainage, quality of life, and postoperative morbidity and mortality. The DRAINAGE trial is designed to identify a difference in the number of severe drainage-related complications after endoscopic and percutaneous transhepatic biliary drainage in patients selected to undergo a major liver resection for perihilar cholangiocarcinoma. Netherlands Trial Register [ NTR4243 , 11 October 2013].

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

Design and methodology of a randomized clinical trial of home-based telemental health treatment for U.S. military personnel and veterans with depression.

PubMed

Luxton, David D; Pruitt, Larry D; O'Brien, Karen; Stanfill, Katherine; Jenkins-Guarnieri, Michael A; Johnson, Kristine; Wagner, Amy; Thomas, Elissa; Gahm, Gregory A

2014-05-01

Home-based telemental health (TMH) treatments have the potential to address current and future health needs of military service members, veterans, and their families, especially for those who live in rural or underserved areas. The use of home-based TMH treatments to address the behavioral health care needs of U.S. military healthcare beneficiaries is not presently considered standard of care in the Military Health System. The feasibility, safety, and clinical efficacy of home-based TMH treatments must be established before broad dissemination of home-based treatment programs can be implemented. This paper describes the design, methodology, and protocol of a clinical trial that compares in-office to home-based Behavioral Activation for Depression (BATD) treatment delivered via web-based video technology for service members and veterans with depression. This grant funded three-year randomized clinical trial is being conducted at the National Center for Telehealth and Technology at Joint-base Lewis-McChord and at the Portland VA Medical Center. Best practice recommendations regarding the implementation of in-home telehealth in the military setting as well as the cultural and contextual factors of providing in-home care to active duty and veteran military populations are also discussed. Published by Elsevier Inc.

Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection.

PubMed

Holland, David P; Sanders, Gillian D; Hamilton, Carol D; Stout, Jason E

2011-01-01

Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability. To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI). We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and isoniazid daily for nine months; a strategy of "no treatment" used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms. Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen. Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries.

Regression to the Mean in SYMPLICITY HTN-3: Implications for Design and Reporting of Future Trials.

PubMed

Pocock, Stuart J; Bakris, George; Bhatt, Deepak L; Brar, Sandeep; Fahy, Martin; Gersh, Bernard J

2016-11-01

Regression to the mean (RTM) describes the tendency for an extreme measurement on 1 occasion to become less extreme when measured again. RTM may affect clinical trial data interpretation when the outcome measure has high variability. We investigated RTM in the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial of renal denervation versus a sham procedure. Analysis of covariance was performed on the 6-month change in systolic blood pressure, estimating a mean treatment difference of -4.11 mm Hg (95% confidence interval: -8.44 to 0.22 mm Hg; p = 0.064), which was similar to the unadjusted difference but with a smaller confidence interval. RTM occurred in both arms, but it had a negligible effect on the observed treatment difference. A second example concerns changes in hemoglobin A1c in a nonrandomized study. These findings emphasize the importance of incorporating RTM and analysis of covariance into the design and reporting of clinical studies of how treatments affect time changes in quantitative outcomes. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial): study protocol

PubMed Central

2014-01-01

Background Insertion of a ventriculoperitoneal shunt (VPS) for the treatment of hydrocephalus is one of the most common neurosurgical procedures in the UK, but failures caused by infection occur in approximately 8% of primary cases. VPS infection is associated with considerable morbidity and mortality and its management results in substantial cost to the health service. Antibiotic-impregnated (rifampicin and clindamycin) and silver-impregnated VPS have been developed to reduce infection rates. Whilst there is some evidence showing that such devices may lead to a reduction in VPS infection, there are no randomised controlled trials (RCTs) to support their routine use. Methods/design Overall, 1,200 patients will be recruited from 17 regional neurosurgical units in the UK and Ireland. Patients of any age undergoing insertion of their first VPS are eligible. Patients with previous indwelling VPS, active and on-going cerebrospinal fluid (CSF) or peritoneal infection, multiloculated hydrocephalus requiring multiple VPS or neuroendoscopy, and ventriculoatrial or ventriculopleural shunt planned will be excluded. Patients will be randomised 1:1:1 to either standard silicone (comparator), antibiotic-impregnated, or silver-impregnated VPS. The primary outcome measure is time to VPS infection. Secondary outcome measures include time to VPS failure of any cause, reason for VPS failure (infection, mechanical failure, or patient failure), types of bacterial VPS infection (organism type and antibiotic resistance), and incremental cost per VPS failure averted. Discussion The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial) is the first multi-centre RCT designed to determine whether antibiotic or silver-impregnated VPS reduce early shunt infection compared to standard silicone VPS. The results of this study will be used to inform current neurosurgical practice and may potentially benefit patients undergoing shunt surgery in the future. Trial registration International Standard Randomised Controlled Trial Number: ISRCTN49474281. PMID:24383496

Fixation using alternative implants for the treatment of hip fractures (FAITH): design and rationale for a multi-centre randomized trial comparing sliding hip screws and cancellous screws on revision surgery rates and quality of life in the treatment of femoral neck fractures

PubMed Central

2014-01-01

Background Hip fractures are a common type of fragility fracture that afflict 293,000 Americans (over 5,000 per week) and 35,000 Canadians (over 670 per week) annually. Despite the large population impact the optimal fixation technique for low energy femoral neck fractures remains controversial. The primary objective of the FAITH study is to assess the impact of cancellous screw fixation versus sliding hip screws on rates of revision surgery at 24 months in individuals with femoral neck fractures. The secondary objective is to determine the impact on health-related quality of life, functional outcomes, health state utilities, fracture healing, mortality and fracture-related adverse events. Methods/Design FAITH is a multi-centre, multi-national randomized controlled trial utilizing minimization to determine patient allocation. Surgeons in North America, Europe, Australia, and Asia will recruit a total of at least 1,000 patients with low-energy femoral neck fractures. Using central randomization, patients will be allocated to receive surgical treatment with cancellous screws or a sliding hip screw. Patient outcomes will be assessed at one week (baseline), 10 weeks, 6, 12, 18, and 24 months post initial fixation. We will independently adjudicate revision surgery and complications within 24 months of the initial fixation. Outcome analysis will be performed using a Cox proportional hazards model and likelihood ratio test. Discussion This study represents major international efforts to definitively resolve the treatment of low-energy femoral neck fractures. This trial will not only change current Orthopaedic practice, but will also set a benchmark for the conduct of future Orthopaedic trials. Trial registration The FAITH trial is registered at ClinicalTrials.gov (Identifier NCT00761813). PMID:24965132

Launching Effectiveness Research to Guide Practice in Neurosurgery: A National Institute Neurological Disorders and Stroke Workshop Report

PubMed Central

Walicke, Patricia; Abosch, Aviva; Asher, Anthony; Barker, Fred G.; Ghogawala, Zoher; Harbaugh, Robert; Jehi, Lara; Kestle, John; Koroshetz, Walter; Little, Roderick; Rubin, Donald; Valadka, Alex; Wisniewski, Stephen

2017-01-01

Abstract This workshop addressed challenges of clinical research in neurosurgery. Randomized controlled clinical trials (RCTs) have high internal validity, but often insufficiently generalize to real-world practice. Observational studies are inclusive but often lack sufficient rigor. The workshop considered possible solutions, such as (1) statistical methods for demonstrating causality using observational data; (2) characteristics required of a registry supporting effectiveness research; (3) trial designs combining advantages of observational studies and RCTs; and (4) equipoise, an identified challenge for RCTs. In the future, advances in information technology potentially could lead to creation of a massive database where clinical data from all neurosurgeons are integrated and analyzed, ending the separation of clinical research and practice and leading to a new “science of practice.” PMID:28362926

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

Enhanced Recovery After Surgery (ERAS®) in Individuals with Diabetes: A Systematic Review.

PubMed

Albalawi, Zaina; Laffin, Michael; Gramlich, Leah; Senior, Peter; McAlister, Finlay A

2017-08-01

Prevalence of diabetes in surgical patients is 10-40%. It is well recognized that they have higher rates of complications, and longer stays in hospital compared to patients without diabetes. Enhanced recovery after surgery (ERAS) is an evidence-based multimodal surgical care pathway that improves postoperative complications and length of stay in patients without diabetes. This review evaluates the evidence on whether individuals with diabetes would benefit from ERAS implementation. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE searched with no language restrictions applied. Conference proceedings and bibliographies were reviewed. Experts in the field were contacted, and www.clinicaltrials.gov searched for ongoing trials. Randomized controlled trials (RCT) looking at individuals with diabetes undergoing surgery randomized to ERAS ® or conventional care. Non-randomized controlled trials, controlled before-after studies, interrupted time series, and cohort studies with concurrent controls were also considered. Two authors independently screened studies. The electronic search yielded 437 references. After removing duplicates, 376 were screened for eligibility. Conference proceedings and bibliographies identified additional references. Searching www.clinicaltrials.gov yielded 59 references. Contacting experts in the field identified no further studies. Fourteen full articles were assessed and subsequently excluded for the following reasons: used an intervention other than ERAS ® , did not include patients with diabetes, or used an uncontrolled observational design. To date, the effects of ERAS ® on patients with diabetes have not been rigorously evaluated. This review highlights the lack of evidence in this area and provides guidance on design for future studies.

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

A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania.

PubMed

Magalhães, Pedro Vieira da Silva; Dean, Olivia M; Bush, Ashley I; Copolov, David L; Malhi, Gin S; Kohlmann, Kristy; Jeavons, Susan; Schapkaitz, Ian; Anderson-Hunt, Murray; Berk, Michael

2013-06-01

Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC). This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period. Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint. Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.

PubMed

Giovannoni, Gavin; Cutter, Gary; Sormani, Maria Pia; Belachew, Shibeshih; Hyde, Robert; Koendgen, Harold; Knappertz, Volker; Tomic, Davorka; Leppert, David; Herndon, Robert; Wheeler-Kingshott, Claudia A M; Ciccarelli, Olga; Selwood, David; di Cantogno, Elisabetta Verdun; Ben-Amor, Ali-Frederic; Matthews, Paul; Carassiti, Daniele; Baker, David; Schmierer, Klaus

2017-02-01

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials. Copyright © 2016 Elsevier B.V. All rights reserved.

Taxonomy for colorectal cancer screening promotion: Lessons from recent randomized controlled trials.

PubMed

Ritvo, Paul; Myers, Ronald E; Serenity, Mardie; Gupta, Samir; Inadomi, John M; Green, Beverly B; Jerant, Anthony; Tinmouth, Jill; Paszat, Lawrence; Pirbaglou, Meysam; Rabeneck, Linda

2017-08-01

To derive a taxonomy for colorectal cancer screening that advances Randomized Controlled Trials (RCTs) and screening uptake. Detailed publication review, multiple interviews with principal investigators (PIs) and collaboration with PIs as co-authors produced a CRCS intervention taxonomy. Semi-structured interview questions with PIs (Drs. Inadomi, Myers, Green, Gupta, Jerant and Ritvo) yielded details about trial conduct. Interview comparisons led to an iterative process informing serial interviews until a consensus was obtained on final taxonomy structure. These taxonomy headings (Engagement Sponsor, Population Targeted, Alternative Screening Tests, Delivery Methods, and Support for Test Performance (EPADS)) were used to compare studies. Exemplary insights emphasized: 1) direct test delivery to patients; 2) linguistic-ethnic matching of staff to minority subjects; and 3) authorization of navigators to schedule or refer for colonoscopies and/or distribute stool blood tests during screening promotion. PIs of key RCTs (2012-2015) derived a CRCS taxonomy useful in detailed examination of CRCS promotion and design of future RCTs. Copyright © 2017 Elsevier Inc. All rights reserved.

Design and implementation of a physical activity intervention to enhance children's use of the built environment (the CUBE study).

PubMed

Oreskovic, Nicolas M; Goodman, Elizabeth; Park, Elyse R; Robinson, Alyssa I; Winickoff, Jonathan P

2015-01-01

Adequate physical activity promotes physical and mental health and decreases obesity risk. However, most adolescents do not attain recommended physical activity levels and effective interventions are lacking. Physical activity trials rarely incorporate built environment use patterns. This paper describes the design and rationale of the Children's Use of the Built Environment (CUBE) Study, an office-based intervention designed to teach youth how to use their surrounding built environment to increase physical activity. CUBE is a 6-month intervention trial among 60 overweight and obese 10-16 year old adolescents from a community health center in Massachusetts. The study began in the winter of 2013. Patients are sequentially assigned to either the intervention or control group. Baseline physical activity by accelerometry and location by GPS, along with measured height, weight, and blood pressure are collected. Control subjects receive standard of care lifestyle counseling. Intervention subjects receive tailored recommendations on how to increase their physical activity based on their accelerometer and GPS data. Data collections are repeated at end-of-treatment, and again 3 months later. The findings from this study should help guide future efforts to design interventions aimed at increasing adolescent physical activity as well as to inform design professionals and government officials charged with creating outdoor spaces where adolescents spend time. Copyright © 2014 Elsevier Inc. All rights reserved.

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.

Stakeholder Engagement in Trial Design: Survey of Visitors to Critically Ill Patients Regarding Preferences for Outcomes and Treatment Options during Weaning from Mechanical Ventilation.

PubMed

Burns, Karen E A; Jacob, Sonu Karottaiyamvelil; Aguirre, Valeria; Gomes, Janice; Mehta, Sangeeta; Rizvi, Leena

2016-11-01

Stakeholder engagement in research is expected to provide unique insights, make research investments more accountable and transparent, and ensure that future research is applicable to patients and family members. To inform the design of a trial of strategies for weaning from mechanical ventilation, we sought to identify preferences of patient visitors regarding outcome and treatment measures. We conducted an interviewer-administered questionnaire of visitors of critically ill patients in two family waiting rooms serving three intensive care units (ICUs) in Toronto, Canada. Respondents rated the importance of general and ventilation-related outcomes in two hypothetical scenarios (before a first spontaneous breathing trial, and after a failed spontaneous breathing trial) and selected a preferred technique for the breathing trials. With regard to the patient they were visiting, respondents identified the most important outcome to them at ICU admission, during the ICU stay, and at ICU discharge. We analyzed 322 questionnaires (95.5% response rate). All outcomes were highly rated (average range: 7.82-9.74). Across scenarios, outcomes rated as most important were ICU and hospital survival (9.72, 9.70), avoiding complications (9.45), quality of life (9.394), patient comfort (9.393), and returning to previous living arrangements (9.31). Overall, the most important ventilation-related outcomes were being ventilator-free (8.95), avoiding reintubation (8.905), and passing a spontaneous breathing trial (8.903). Passing a spontaneous breathing trial assumed greater importance after an initial failed attempt. "Time to event" outcomes were less important to visitors. We did not identify a preferred spontaneous breathing trial technique. Although ICU survival was the most important outcome at ICU admission and during the ICU stay, visitors rated quality of life higher than hospital survival at ICU discharge. Visitors to critically ill patients prioritized two general outcomes (ICU and hospital survival) and three ventilation-related outcomes (being ventilator free, avoiding reintubation, passing a spontaneous breathing trial), and valued avoiding complications, maintaining quality of life, comfort, and returning to previous living arrangements. The outcomes preferences of the survey respondents evolved temporally during the ICU stay.

Points to consider: efficacy and safety evaluations in the clinical development of ultra-orphan drugs.

PubMed

Maeda, Kojiro; Kaneko, Masayuki; Narukawa, Mamoru; Arato, Teruyo

2017-08-23

The unmet medical needs of individuals with very rare diseases are high. The clinical trial designs and evaluation methods used for 'regular' drugs are not applicable in the clinical development of ultra-orphan drugs (<1000 patients) in many cases. In order to improve the clinical development of ultra-orphan drugs, we examined several points regarding the efficient evaluations of drug efficacy and safety that could be conducted even with very small sample sizes, based on the review reports of orphan drugs approved in Japan. The clinical data packages of 43 ultra-orphan drugs approved in Japan from January 2001 to December 2014 were investigated. Japanese clinical trial data were not included in the clinical data package for eight ultra-orphan drugs, and non-Japanese clinical trial data were included for six of these eight drug. Japanese supportive data that included retrospective studies, published literature, clinical research and Japanese survey results were clinical data package attachments in 22 of the 43 ultra-orphan drugs. Multinational trials were conducted for three ultra-orphan drugs. More than two randomized controlled trials (RCTs) were conducted for only 11 of the 43 ultra-orphan drugs. The smaller the number of patients, the greater the proportion of forced titration and optional titration trials were conducted. Extension trials were carried out for enzyme preparations and monoclonal antibodies with high ratio. Post-marketing surveillance of all patients was required in 36 of the 43 ultra-orphan drugs. For ultra-orphan drugs, clinical endpoints were used as the primary efficacy endpoint of the pivotal trial only for two drugs. The control groups in RCTs were classified as follows: placebo groups different dosage groups, and active controls groups. Sample sizes have been determined on the basis of feasibility for some ultra-orphan drugs. We provide "Draft Guidance on the Clinical Development of Ultra-Orphan Drugs" based on this research. The development of ultra-orphan drugs requires various arrangements regarding evidence collection, data sources and the clinical trial design. We expect that this draft guidance is useful for ultra-orphan drugs developments in future.

Estimation of the optimum dose of vitamin D for disease prevention in older people: rationale, design and baseline characteristics of the BEST-D trial.

PubMed

Clarke, Robert; Newman, Connie; Tomson, Joseph; Hin, Harold; Kurien, Rijo; Cox, Jolyon; Lay, Michael; Sayer, Jenny; Hill, Michael; Emberson, Jonathan; Armitage, Jane

2015-04-01

Previous large trials of vitamin D for prevention of fractures and other disease outcomes have reported conflicting results, possibly because the doses tested were insufficient to maintain optimum blood levels of vitamin D (25[OH]D) predicted by the observational studies. This report describes the design and baseline characteristics of the BEST-D (Biochemical Efficacy and Safety Trial of vitamin D) trial which aims to establish the best dose of vitamin D to assess in a future large outcome trial. The BEST-D trial will compare the biochemical and other effects of daily dietary supplementation with 100 μg or 50 μg vitamin D3 or placebo, when administered for 12 months, in 305 ambulant community-dwelling older people living in Oxfordshire, England. The primary analyses will compare 12-month mean plasma concentrations of 25(OH)D as well as the proportion of participants with a 12-month concentration >90 nmol/L between participants allocated 100 μg and participants allocated 50 μg daily. Secondary analyses will compare the two active doses (both separately and when combined) with placebo. Additional end-points include biochemical assessments of safety, blood pressure, arterial stiffness, falls, fractures, heel and wrist bone density, grip strength and physical performance and echocardiographic assessments of cardiac function in a random sample of participants. About one-third of eligible participants agreed to participate in the trial. The mean age was 72 (SD 6) years with equal numbers of men and women. About one third reported a prior history of fracture or hypertension, one-fifth reported a prior cardiovascular event, and one tenth reported diabetes or a fall in the previous 6 months. The results of this trial will help determine the optimum dose of vitamin D to test in a larger trial investigating whether vitamin D supplementation can reduce the risk of fractures, cardiovascular disease or cancer. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

21st century trucking: A trajectory for ergonomics and road freight.

PubMed

Bedinger, M; Walker, G H; Piecyk, M; Greening, P

2016-03-01

Over the past decade there has been significant pressure to minimise emissions and safety risks related to commercial driving. This pressure to meet the triple bottom line of cost, environment, and society has often resulted in the rapid application of vehicle technologies designed to mitigate undesired effects. Often the cognitive and behavioural effects of technologies on the commercial driver have not received in-depth analysis to determine comprehensive viability. As such, this paper aims to identify a timescale for implementation for future technologies for UK road freight, and likely associated human factors issues, improving upon the currently employed 'trial-and-error' approach to implementation which may carry high economic, environmental, safety-related risk. Thought experiments are carried out to broadly explore these future systems. Furthermore, this work aims to examine whether technology alone will be enough to meet future CO2 reduction targets, and assess the role of behavioural and systems interventions for future research. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

From selection hits to clinical leads: progress in aptamer discovery

PubMed Central

Maier, Keith E; Levy, Matthew

2016-01-01

Aptamers were discovered more than 25 years ago, yet only one has been approved by the US Food and Drug Administration to date. With some noteworthy advances in their chemical design and the enzymes we use to make them, aptamers and aptamer-based therapeutics have seen a resurgence in interest. New aptamer drugs are being approved for clinical evaluation, and it is certain that we will see increasingly more aptamers and aptamer-like drugs in the future. In this review, we will discuss the production of aptamers with an emphasis on the advances and modifications that enabled early aptamers to succeed in clinical trials as well as those that are likely to be important for future generations of these drugs. PMID:27088106

Substance abuse prevention intervention research with Hispanic populations.

PubMed

Castro, Felipe González; Barrera, Manuel; Pantin, Hilda; Martinez, Charles; Felix-Ortiz, Maria; Rios, Rebeca; Lopez, Vera A; Lopez, Cristy

2006-09-01

Selected studies with specific relevance to substance abuse prevention interventions with Hispanic youth and families were examined to identify prior findings and emerging issues that may guide the design of future substance abuse prevention intervention research and its implementation with Hispanic populations. The origins of prevention research and role of risk and protective factors are examined, including culturally-specific risk and protective factors for Hispanic populations. Correlational studies, non-experimental interventions, and randomized controlled trials were examined for the period of 1974-2003. The literature search yielded 15 articles selected for this review that exhibited adequate methodological rigor. An added search for more recent studies identified three additional articles, for a total of 18 prevention intervention articles that were reviewed. Theoretical and methodological issues and recommendations are presented for future research aimed at improving the efficacy and effectiveness of future prevention intervention studies and their cultural relevance for Hispanic populations.

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.

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.

Social Stories™ to alleviate challenging behaviour and social difficulties exhibited by children with autism spectrum disorder in mainstream schools: design of a manualised training toolkit and feasibility study for a cluster randomised controlled trial with nested qualitative and cost-effectiveness components.

PubMed

Wright, Barry; Marshall, David; Adamson, Joy; Ainsworth, Hannah; Ali, Shehzad; Allgar, Victoria; Collingridge Moore, Danielle; Cook, Elizabeth; Dempster, Paul; Hackney, Lisa; McMillan, Dean; Trepél, Dominic; Williams, Chris

2016-01-01

A Social Story™ (Carol Gray) is a child-friendly intervention that is used to give children with autism spectrum disorders (ASDs) social information in situations where they have social difficulties. Limited evidence mainly using single-case designs suggests that they can reduce anxiety and challenging behaviour. The objectives were to conduct a systematic review, use this to develop a manualised intervention and run a feasibility trial to inform a fully powered randomised controlled trial (RCT) on their clinical effectiveness and cost-effectiveness in schools. This is a three-stage study following the Medical Research Council framework for complex interventions. Specifically, it involved a theoretical phase, a qualitative stage and a feasibility trial stage. Qualitative interviews and focus groups took place in Child and Adolescent Mental Health Service and primary care settings. The feasibility study took place in 37 local mainstream schools. Fifty children (aged 5-15 years) in mainstream school settings with a diagnosis of ASD were entered into the trial. For each child, an associated teacher and parent was also recruited. The intervention was a goal-setting session followed by a manualised toolkit (including a training session) for creating Social Stories™ for use with school-aged children. The comparator treatment was a goal-setting session followed by an attention control. Both arms received treatment as usual. Outcomes tested as part of the feasibility study included child- and proxy-completed questionnaires for mental health, quality of life and goal-based outcome measures. Adults additionally completed behaviour diaries and the parental stress index. The review found that the research into social stories is predominantly based in the USA, carried out in under-12-year-olds and using single-case designs. Most studies either did not follow established Social Story criteria or did not report if they did. The assessment of effectiveness presents a largely positive picture but is limited by methodological issues. There were no adequate RCTs and insufficient information to assess a number of important sources of potential bias in most studies. A manualised intervention was produced using an iterative process between user focus groups and a writing team, and assessed in the feasibility study. All 50 participant groups were recruited within the study time frame. Two outcome measures, the Social Responsiveness Scale-2 and the custom-made goal-based measure, showed high levels of completion rates and appeared to be capturing social and behaviour skills targeted by the use of Social Stories. Detailed recommendations for a full trial are provided. Blinding of participants was not feasible. Treatment fidelity was not assessed because of low levels of story return rates. The study showed that a fully powered RCT is feasible with an extended geographical footprint. A large amount of data and information has helped to inform the design of this RCT, which will be the subject of a future research grant application. Future work could focus on developing an appropriate blinded outcome measure for this population. This study is registered as PROSPERO CRD42011001440. Current Controlled Trials ISRCTN96286707. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 6. See the NIHR Journals Library website for further project information.

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

The effect of pelvic physiotherapy on reduction of functional constipation in children: design of a multicentre randomised controlled trial

PubMed Central

2013-01-01

Background Functional constipation is a common disorder worldwide and is found in all paediatric age groups. Functional constipation can be caused by delayed colonic transit or dysfunction of the pelvic floor muscles. Standard medical care in paediatric practice is often based on clinical experience and mainly consists of a behavioural approach and toilet training, along with the prescription of laxatives. Evidence to evaluate the effectiveness of pelvic physiotherapy for this complaint is lacking. Methods/design A two-armed multicentre randomised controlled trial has been designed. We hypothesise that the combination of pelvic physiotherapy and standard medical care will be more effective than standard medical care alone for constipated children, aged 5 to 17 years. Children with functional constipation according to the Rome III will be included. Web-based baseline and follow-up measurements, scheduled at 3 and 6 months after inclusion, consist of the numeric rating scale in relation to the perceived severity of the problem, the Strength and Difficulties Questionnaire and subjective improvement post-intervention (global perceived effect). Examination of the pelvic floor muscle functions, including digital testing and biofeedback, will take place during baseline and follow-up measurements at the physiotherapist. The control group will only receive standard medical care, involving at least three contacts during five months, whereas the experimental group will receive standard medical care plus pelvic physiotherapy, with a maximum of six contacts. The physiotherapy intervention will include standard medical care, pelvic floor muscle training, attention to breathing, relaxation and awareness of body and posture. The study duration will be six months from randomisation, with a three-year recruitment period. The primary outcome is the absence of functional constipation according to the Rome III criteria. Discussion This section discusses the relevance of publishing the study design and the development of the presented physiotherapy protocol. It also addresses difficulties when interpreting the literature with regard to the effectiveness of biofeedback, potential confounding, and future research indications. To our knowledge, this article is the first to describe the design of a randomised controlled trial among children with constipation to assess the effect of pelvic physiotherapy as an add-on to standard medical care. Trial registration Current Controlled Trials NL30551.068.09 PMID:23914827

Children, parents, and pets exercising together (CPET) randomised controlled trial: study rationale, design, and methods.

PubMed

Yam, Philippa S; Morrison, Ryan; Penpraze, Viki; Westgarth, Carri; Ward, Dianne S; Mutrie, Nanette; Hutchison, Pippa; Young, David; Reilly, John J

2012-03-19

Objectively measured physical activity is low in British children, and declines as childhood progresses. Observational studies suggest that dog-walking might be a useful approach to physical activity promotion in children and adults, but there are no published public health interventions based on dog-walking with children. The Children, Parents, and Pets Exercising Together Study aims to develop and evaluate a theory driven, generalisable, family-based, dog walking intervention for 9-11 year olds. The Children, Parents, and Pets Exercising Together Study is an exploratory, assessor-blinded, randomised controlled trial as defined in the UK MRC Framework on the development and evaluation of complex interventions in public health. The trial will follow CONSORT guidance. Approximately 40 dog-owning families will be allocated randomly in a ratio of 1.5:1 to receive a simple behavioural intervention lasting for 10 weeks or to a 'waiting list' control group. The primary outcome is change in objectively measured child physical activity using Actigraph accelerometry. Secondary outcomes in the child, included in part to shape a future more definitive randomised controlled trial, are: total time spent sedentary and patterning of sedentary behaviour (Actigraph accelerometry); body composition and bone health from dual energy x-ray absorptiometry; body weight, height and BMI; and finally, health-related quality of life using the PedsQL. Secondary outcomes in parents and dogs are: changes in body weight; changes in Actigraph accelerometry measured physical activity and sedentary behaviour. Process evaluation will consist of assessment of simultaneous child, parent, and dog accelerometry data and brief interviews with participating families. The Children, Parents, and Pets Exercising Together trial should be the first randomised controlled study to establish and evaluate an intervention aimed at dog-based physical activity promotion in families. It should advance our understanding of whether and how to use pet dogs to promote physical activity and/or to reduce sedentary behaviour in children and adults. The trial is intended to lead to a subsequent more definitive randomised controlled trial, and the work should inform future dog-based public health interventions such as secondary prevention interventions in children or adults. ISRCTN85939423.

A Randomized trial of an Asthma Internet Self-management Intervention (RAISIN): study protocol for a randomized controlled trial.

PubMed

Morrison, Deborah; Wyke, Sally; Thomson, Neil C; McConnachie, Alex; Agur, Karolina; Saunderson, Kathryn; Chaudhuri, Rekha; Mair, Frances S

2014-05-24

The financial costs associated with asthma care continue to increase while care remains suboptimal. Promoting optimal self-management, including the use of asthma action plans, along with regular health professional review has been shown to be an effective strategy and is recommended in asthma guidelines internationally. Despite evidence of benefit, guided self-management remains underused, however the potential for online resources to promote self-management behaviors is gaining increasing recognition. The aim of this paper is to describe the protocol for a pilot evaluation of a website 'Living well with asthma' which has been developed with the aim of promoting self-management behaviors shown to improve outcomes. The study is a parallel randomized controlled trial, where adults with asthma are randomly assigned to either access to the website for 12 weeks, or usual asthma care for 12 weeks (followed by access to the website if desired). Individuals are included if they are over 16-years-old, have a diagnosis of asthma with an Asthma Control Questionnaire (ACQ) score of greater than, or equal to 1, and have access to the internet. Primary outcomes for this evaluation include recruitment and retention rates, changes at 12 weeks from baseline for both ACQ and Asthma Quality of Life Questionnaire (AQLQ) scores, and quantitative data describing website usage (number of times logged on, length of time logged on, number of times individual pages looked at, and for how long). Secondary outcomes include clinical outcomes (medication use, health services use, lung function) and patient reported outcomes (including adherence, patient activation measures, and health status). Piloting of complex interventions is considered best practice and will maximise the potential of any future large-scale randomized controlled trial to successfully recruit and be able to report on necessary outcomes. Here we will provide results across a range of outcomes which will provide estimates of efficacy to inform the design of a future full-scale randomized controlled trial of the 'Living well with asthma' website. This trial is registered with Current Controlled Trials ISRCTN78556552 on 18/06/13.

Estimating dead-space fraction for secondary analyses of ARDS clinical trials

PubMed Central

Beitler, Jeremy R.; Thompson, B. Taylor; Matthay, Michael A.; Talmor, Daniel; Liu, Kathleen D.; Zhuo, Hanjing; Hayden, Douglas; Spragg, Roger G.; Malhotra, Atul

2015-01-01

Objective Pulmonary dead-space fraction is one of few lung-specific independent predictors of mortality from acute respiratory distress syndrome (ARDS). However, it is not measured routinely in clinical trials and thus altogether ignored in secondary analyses that shape future research directions and clinical practice. This study sought to validate an estimate of dead-space fraction for use in secondary analyses of clinical trials. Design Analysis of patient-level data pooled from ARDS clinical trials. Four approaches to estimate dead-space fraction were evaluated: three required estimating metabolic rate; one estimated dead-space fraction directly. Setting U.S. academic teaching hospitals. Patients Data from 210 patients across three clinical trials were used to compare performance of estimating equations with measured dead-space fraction. A second cohort of 3,135 patients from six clinical trials without measured dead-space fraction was used to confirm whether estimates independently predicted mortality. Interventions None. Measurements and Main Results Dead-space fraction estimated using the unadjusted Harris-Benedict equation for energy expenditure was unbiased (mean ± SD Harris-Benedict 0.59 ± 0.13; measured 0.60 ± 0.12). This estimate predicted measured dead-space fraction to within ± 0.10 in 70% of patients and ± 0.20 in 95% of patients. Measured dead-space fraction independently predicted mortality (OR 1.36 per 0.05 increase in dead-space fraction, 95% CI 1.10–1.68; p < .01). The Harris-Benedict estimate closely approximated this association with mortality in the same cohort (OR 1.55, 95% CI 1.21–1.98; p < .01) and remained independently predictive of death in the larger ARDSNet cohort. Other estimates predicted measured dead-space fraction or its association with mortality less well. Conclusions Dead-space fraction should be measured in future ARDS clinical trials to facilitate incorporation into secondary analyses. For analyses where dead-space fraction was not measured, the Harris-Benedict estimate can be used to estimate dead-space fraction and adjust for its association with mortality. PMID:25738857

2014 Section on Pediatrics Knowledge translation Lecture: Clinicians and researchers on the same path toward facilitating family goals for mobility & participation

PubMed Central

Damiano, Diane L.; Leonard, Rebecca

2015-01-01

BACKGROUND The Knowledge Translation (KT) Lecture at CSM 2014 was a personal perspective from a researcher who had been a therapist and a longtime clinician, now a Ph.D. candidate. OBJECTIVE To better integrate research and clinical care, so KT is a seamless rather than separate process. KEY POINTS KT can be enhanced by improved receptivity to evidence, and increasing use of research designs that encourage and even require clinician involvement, from single-subject designs to large-scale pragmatic trials. Clinical practice databases and hiring therapists to provide intervention in research efforts also serve to integrate research and clinical care. Limitations of applying mean group research results to an individual patient were also discussed and suggest an important unanswered topic for future research. CONCLUSION We all need to assume responsibility for the researcher-clinician partnership, making our jobs more joyful and fulfilling, and hopefully the biggest beneficiaries will be our current and future patients. PMID:25822350

2014 section on pediatrics knowledge translation lecture: clinicians and researchers on the same path toward facilitating family goals for mobility and participation.

PubMed

Damiano, Diane L; Leonard, Rebecca

2015-01-01

The knowledge translation (KT) lecture at the Combined Sections Meeting 2014 was a personal perspective from a researcher who had been a therapist and a longtime clinician, now a PhD candidate. To better integrate research and clinical care, KT is a seamless rather than separate process. Knowledge translation can be enhanced by improved receptivity to evidence, and increasing use of research designs that encourage and even require clinician involvement, from single-subject designs to large-scale pragmatic trials. Clinical practice databases and hiring therapists to provide intervention in research efforts also serve to integrate research and clinical care. Limitations of applying mean group research results to an individual patient were also discussed and suggest an important unanswered topic for future research. We all need to assume responsibility for the researcher-clinician partnership, making our jobs more joyful and fulfilling, and hopefully the biggest beneficiaries will be our current and future patients.

Service of Remembrance: a comprehensive cancer center's response to bereaved family members.

PubMed

Knight, Louise; Cooper, Rhonda S; Hypki, Cinder

2012-01-01

Comprehensive cancer centers that offer an array of clinical trials and treatment options often experience significant patient mortality rates. Bereavement resources may not be routinely incorporated into the service delivery model in these specialty hospitals. In response, an interdisciplinary team at one cancer center proposed, planned, and implemented an annual Service of Remembrance. The incorporation of music, poetry, and visual arts was important in designing a program that would provide a meaningful, spiritual experience. A community artist who designed an interactive memorial art piece played a pivotal role. This article outlines the process of institutional culture change and describes future challenges in the implementation of this type of bereavement service.

Tissue engineering, stem cells, and cloning for the regeneration of urologic organs.

PubMed

Atala, Anthony

2003-10-01

Tissue engineering efforts are currently being undertaken for every type of tissue and organ within the urinary system. Most of the effort expended to engineer genitourinary tissues has occurred within the last decade. Tissue engineering techniques require a cell culture facility designed for human application. Personnel who have mastered the techniques of cell harvest, culture, and expansion as well as polymer design are essential for the successful application of this technology. Various engineered genitourinary tissues are at different stages of development, with some already being used clinically, a few in preclinical trials, and some in the discovery stage. Recent progress suggests that engineered urologic tissues may have an expanded clinical applicability in the future.

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.

Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance.

PubMed

Lu, Ellen; Wang, Bing Wei; Guimond, Colleen; Synnes, Anne; Sadovnick, A Dessa; Dahlgren, Leanne; Traboulsee, Anthony; Tremlett, Helen

2013-03-01

When contemplating a pregnancy, women treated for multiple sclerosis (MS) with a disease-modifying drug must decide to discontinue their medication before conception or risk exposing their unborn child to potential drug toxicity. Few studies exist as reference for patients and physicians, and of those available, the majority are less than ideal due to real-world constraints, ethical issues and methodological shortcomings. The authors provide a brief summary of existing animal and human data with current recommendations regarding the safety of IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod and teriflunomide during pregnancy and lactation in women with MS. We also assess the quality, strengths and limitations of the existing studies including challenges with study design. The investigation of outcomes such as spontaneous abortion and congenital anomalies are highlighted with potential methodological improvements for future studies on drug safety in pregnancy suggested. The authors explore the pharmacokinetics and pharmacodynamics of the MS disease-modifying drugs for their possible mechanistic role in fetal harm and discuss the potential role of clinical trials. Future pharmacovigilance studies should continue to pursue multicenter collaboration with an emphasis on appropriate study design.

Targeted chemotherapy, the medical ecosystem, and the future of American health care.

PubMed

Gillick, Muriel R

2014-01-01

In light of the difficulties experienced by the pharmaceutical industry in developing important new drugs, the rapid design and introduction of the targeted chemotherapeutic agent, crizotinib, is a significant achievement. Understanding the roles of the patient, the physician, the regulator (FDA), health insurance companies, and the manufacturer (Pfizer) in the development of this drug can shed light on the prospects for future drugs and on the workings of the complicated health-care ecosystem. Patients were eager for an effective drug against lung cancer with minimal toxicity but were reluctant to enroll in clinical trials. Oncologists were enthusiastic about the new drug but have a financial incentive favoring intravenous medicines over oral agents. The FDA was under pressure to approve new drugs quickly. The drug manufacturer modified its corporate structure and developed collaborations with academics and international partners, but was pressured by stockholders to maximize short-term profitability. Insurance companies balked at the price of the drug and used tiered pricing to limit their costs. The successful design, development, and diffusion of crizotinib may signal a new departure for the pharmaceutical industry, but whether such successes are replicated in the future will depend on the delicately balanced ecosystem that constitutes American health care.

A randomized controlled trial of the effectiveness of a pre-recruitment primer letter to increase participation in a study of colorectal screening and surveillance.

PubMed

Paul, Christine; Courtney, Ryan; Sanson-Fisher, Rob; Carey, Mariko; Hill, David; Simmons, Jody; Rose, Shiho

2014-04-01

Recruiting cancer patients is a barrier often encountered in research trials. However, very few randomized trials explore strategies to improve participation rates. The purpose of this study was to evaluate the effectiveness of a pre-recruitment primer letter to recruit persons diagnosed with colorectal cancer for a research trial. Potentially eligible participants were identified by the Victorian Cancer Registry. A total of 1,062 participants were randomized to receive either a mailed explanatory primer letter designed to encourage research participation, or no primer letter. Two weeks after the intervention, the Victorian Cancer Registry sought permission from patients to release their contact details to researchers. Those who agreed were contacted and invited to the study. Pre-recruitment encouragement was not effective at increasing recruitment, with no significant differences demonstrated between experimental groups. Overall, 40% (n = 425) consented to participate, 25% (n = 243) refused and 35% (n = 394) did not respond. While this study demonstrated disappointing outcomes, pre-recruitment letters should not be ruled out as an approach altogether. Rather, future research should explore whether other factors to increase motivation, such as intensity and timing, are feasible and acceptable for contacting cancer patients. Australian and New Zealand Clinical Trials Registry, ACTRN12609000628246.

A standard-driven approach for electronic submission to pharmaceutical regulatory authorities.

PubMed

Lin, Ching-Heng; Chou, Hsin-I; Yang, Ueng-Cheng

2018-03-01

Using standards is not only useful for data interchange during the process of a clinical trial, but also useful for analyzing data in a review process. Any step, which speeds up approval of new drugs, may benefit patients. As a result, adopting standards for regulatory submission becomes mandatory in some countries. However, preparing standard-compliant documents, such as annotated case report form (aCRF), needs a great deal of knowledge and experience. The process is complex and labor-intensive. Therefore, there is a need to use information technology to facilitate this process. Instead of standardizing data after the completion of a clinical trial, this study proposed a standard-driven approach. This approach was achieved by implementing a computer-assisted "standard-driven pipeline (SDP)" in an existing clinical data management system. SDP used CDISC standards to drive all processes of a clinical trial, such as the design, data acquisition, tabulation, etc. RESULTS: A completed phase I/II trial was used to prove the concept and to evaluate the effects of this approach. By using the CDISC-compliant question library, aCRFs were generated automatically when the eCRFs were completed. For comparison purpose, the data collection process was simulated and the collected data was transformed by the SDP. This new approach reduced the missing data fields from sixty-two to eight and the controlled term mismatch field reduced from eight to zero during data tabulation. This standard-driven approach accelerated CRF annotation and assured data tabulation integrity. The benefits of this approach include an improvement in the use of standards during the clinical trial and a reduction in missing and unexpected data during tabulation. The standard-driven approach is an advanced design idea that can be used for future clinical information system development. Copyright © 2018 Elsevier Inc. All rights reserved.

A Bayesian elicitation of veterinary beliefs regarding systemic dry cow therapy: variation and importance for clinical trial design.

PubMed

Higgins, H M; Dryden, I L; Green, M J

2012-09-15

The two key aims of this research were: (i) to conduct a probabilistic elicitation to quantify the variation in veterinarians' beliefs regarding the efficacy of systemic antibiotics when used as an adjunct to intra-mammary dry cow therapy and (ii) to investigate (in a Bayesian statistical framework) the strength of future research evidence required (in theory) to change the beliefs of practising veterinary surgeons regarding the efficacy of systemic antibiotics, given their current clinical beliefs. The beliefs of 24 veterinarians in 5 practices in England were quantified as probability density functions. Classic multidimensional scaling revealed major variations in beliefs both within and between veterinary practices which included: confident optimism, confident pessimism and considerable uncertainty. Of the 9 veterinarians interviewed holding further cattle qualifications, 6 shared a confidently pessimistic belief in the efficacy of systemic therapy and whilst 2 were more optimistic, they were also more uncertain. A Bayesian model based on a synthetic dataset from a randomised clinical trial (showing no benefit with systemic therapy) predicted how each of the 24 veterinarians' prior beliefs would alter as the size of the clinical trial increased, assuming that practitioners would update their beliefs rationally in accordance with Bayes' theorem. The study demonstrated the usefulness of probabilistic elicitation for evaluating the diversity and strength of practitioners' beliefs. The major variation in beliefs observed raises interest in the veterinary profession's approach to prescribing essential medicines. Results illustrate the importance of eliciting prior beliefs when designing clinical trials in order to increase the chance that trial data are of sufficient strength to alter the clinical beliefs of practitioners and do not merely serve to satisfy researchers. Copyright © 2012 Elsevier B.V. All rights reserved.

Systematic review of randomised controlled trials of interventions that aim to reduce the risk, either directly or indirectly, of overweight and obesity in infancy and early childhood

PubMed Central

Edmonds, Barrie; Swift, Judy Anne; Siriwardena, Aloysius Niroshan; Weng, Stephen; Nathan, Dilip; Glazebrook, Cris

2016-01-01

Abstract The risk factors for childhood overweight and obesity are known and can be identified antenatally or during infancy, however, the majority of effective interventions are designed for older children. This review identified interventions designed to reduce the risk of overweight/obesity that were delivered antenatally or during the first 2 years of life, with outcomes reported from birth to 7 years of age. Six electronic databases were searched for papers reporting randomised controlled trials of interventions published from January 1990 to September 2013. A total of 35 eligible studies were identified, describing 27 unique trials of which 24 were behavioural and three were non‐behavioural. The 24 behavioural trials were categorised by type of intervention: (1) nutritional and/or responsive feeding interventions targeted at parents of infants, which improved feeding practices and had some impact on child weight (n = 12); (2) breastfeeding promotion and lactation support for mothers, which had a positive effect on breastfeeding but not child weight (n = 5); (3) parenting and family lifestyle (n = 4); and (4) maternal health (n = 3) interventions that had some impact on feeding practices but not child weight. The non‐behavioural trials comprised interventions manipulating formula milk composition (n = 3). Of these, lower/hydrolysed protein formula milk had a positive effect on weight outcomes. Interventions that aim to improve diet and parental responsiveness to infant cues showed most promise in terms of self‐reported behavioural change. Despite the known risk factors, there were very few intervention studies for pregnant women that continue during infancy which should be a priority for future research. PMID:25894857

Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects?

PubMed Central

Fouts, Alexandra; Pyle, Laura; Yu, Liping; Miao, Dongmei; Michels, Aaron; Krischer, Jeffrey; Sosenko, Jay; Gottlieb, Peter

2016-01-01

OBJECTIVE To explore whether electrochemiluminescence (ECL) assays can help improve prediction of time to type 1 diabetes in the TrialNet autoantibody-positive population. RESEARCH DESIGN AND METHODS TrialNet subjects who were positive for one or more autoantibodies (microinsulin autoantibody, GAD65 autoantibody [GADA], IA-2A, and ZnT8A) with available ECL-insulin autoantibody (IAA) and ECL-GADA data at their initial visit were analyzed; after a median follow-up of 24 months, 177 of these 1,287 subjects developed diabetes. RESULTS Univariate analyses showed that autoantibodies by radioimmunoassays (RIAs), ECL-IAA, ECL-GADA, age, sex, number of positive autoantibodies, presence of HLA DR3/4-DQ8 genotype, HbA1c, and oral glucose tolerance test (OGTT) measurements were all significantly associated with progression to diabetes. Subjects who were ECL positive had a risk of progression to diabetes within 6 years of 58% compared with 5% for the ECL-negative subjects (P < 0.0001). Multivariate Cox proportional hazards models were compared, with the base model including age, sex, OGTT measurements, and number of positive autoantibodies by RIAs. The model with positivity for ECL-GADA and/or ECL-IAA was the best, and factors that remained significantly associated with time to diabetes were area under the curve (AUC) C-peptide, fasting C-peptide, AUC glucose, number of positive autoantibodies by RIAs, and ECL positivity. Adding ECL to the Diabetes Prevention Trial risk score (DPTRS) improved the receiver operating characteristic curves with AUC of 0.83 (P < 0.0001). CONCLUSIONS ECL assays improved the ability to predict time to diabetes in these autoantibody-positive relatives at risk for developing diabetes. These findings might be helpful in the design and eligibility criteria for prevention trials in the future. PMID:27456836

Video-game based exercises for older people with chronic low back pain: a protocol for a feasibility randomised controlled trial (the GAMEBACK trial).

PubMed

Zadro, Joshua Robert; Shirley, Debra; Simic, Milena; Mousavi, Seyed Javad; Ceprnja, Dragana; Maka, Katherine; Ferreira, Paulo

2017-06-01

To investigate the feasibility of implementing a video-game exercise programme for older people with chronic low back pain (LBP). Single-centred single-blinded randomised controlled trial (RCT). Physiotherapy outpatient department in a public hospital in Western Sydney, Australia. We will recruit 60 participants over 55 years old with chronic LBP from the waiting list. Participants will be randomised to receive video-game exercise (n=30) or to remain on the waiting list (n=30) for 8 weeks, with follow up at 3 and 6 months. Participants engaging in video-game exercises will be unsupervised and will complete video-game exercise for 60minutes, 3 times per week. Participants allocated to remain on the waiting list will be encouraged to maintain their usual levels of physical activity. The primary outcomes for this feasibility study will be study processes (recruitment and response rates, adherence to and experience with the intervention, and incidence of adverse events) relevant to the future design of a large RCT. Estimates of treatment efficacy (point estimates and 95% confidence intervals) on pain self-efficacy, care seeking, physical activity, fear of movement/re-injury, pain, physical function, disability, falls-efficacy, strength, and walking speed, will be our secondary outcome measures. Recruitment for this trial began in November 2015. This study describes the rationale and processes of a feasibility study investigating a video-game exercise programme for older people with chronic LBP. Results from the feasibility study will inform on the design and sample required for a large multicentre RCT. Australian New Zealand Clinical Trials Registry: ACTRN12615000703505. Copyright © 2016 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness: executive summary of a Cochrane Collaboration systematic review.

PubMed

Connolly, Bronwen; Salisbury, Lisa; O'Neill, Brenda; Geneen, Louise; Douiri, Abdel; Grocott, Michael P W; Hart, Nicholas; Walsh, Timothy S; Blackwood, Bronagh

2016-12-01

Skeletal muscle wasting and weakness are major complications of critical illness and underlie the profound physical and functional impairments experienced by survivors after discharge from the intensive care unit (ICU). Exercise-based rehabilitation has been shown to be beneficial when delivered during ICU admission. This review aimed to determine the effectiveness of exercise rehabilitation initiated after ICU discharge on primary outcomes of functional exercise capacity and health-related quality of life. We sought randomized controlled trials, quasi-randomized controlled trials, and controlled clinical trials comparing an exercise intervention commenced after ICU discharge vs. any other intervention or a control or 'usual care' programme in adult survivors of critical illness. Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database, and Cumulative Index to Nursing and Allied Health Literature databases were searched up to February 2015. Dual, independent screening of results, data extraction, and quality appraisal were performed. We included six trials involving 483 patients. Overall quality of evidence for both outcomes was very low. All studies evaluated functional exercise capacity, with three reporting positive effects in favour of the intervention. Only two studies evaluated health-related quality of life and neither reported differences between intervention and control groups. Meta-analyses of data were precluded due to variation in study design, types of interventions, and selection and reporting of outcome measurements. We were unable to determine an overall effect on functional exercise capacity or health-related quality of life of interventions initiated after ICU discharge for survivors of critical illness. Findings from ongoing studies are awaited. Future studies need to address methodological aspects of study design and conduct to enhance rigour, quality, and synthesis.

Systematic review of randomised controlled trials of interventions that aim to reduce the risk, either directly or indirectly, of overweight and obesity in infancy and early childhood.

PubMed

Redsell, Sarah A; Edmonds, Barrie; Swift, Judy Anne; Siriwardena, Aloysius Niroshan; Weng, Stephen; Nathan, Dilip; Glazebrook, Cris

2016-01-01

The risk factors for childhood overweight and obesity are known and can be identified antenatally or during infancy, however, the majority of effective interventions are designed for older children. This review identified interventions designed to reduce the risk of overweight/obesity that were delivered antenatally or during the first 2 years of life, with outcomes reported from birth to 7 years of age. Six electronic databases were searched for papers reporting randomised controlled trials of interventions published from January 1990 to September 2013. A total of 35 eligible studies were identified, describing 27 unique trials of which 24 were behavioural and three were non-behavioural. The 24 behavioural trials were categorised by type of intervention: (1) nutritional and/or responsive feeding interventions targeted at parents of infants, which improved feeding practices and had some impact on child weight (n = 12); (2) breastfeeding promotion and lactation support for mothers, which had a positive effect on breastfeeding but not child weight (n = 5); (3) parenting and family lifestyle (n = 4); and (4) maternal health (n = 3) interventions that had some impact on feeding practices but not child weight. The non-behavioural trials comprised interventions manipulating formula milk composition (n = 3). Of these, lower/hydrolysed protein formula milk had a positive effect on weight outcomes. Interventions that aim to improve diet and parental responsiveness to infant cues showed most promise in terms of self-reported behavioural change. Despite the known risk factors, there were very few intervention studies for pregnant women that continue during infancy which should be a priority for future research. © 2015 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.

Subgroup identification of early preterm birth (ePTB): informing a future prospective enrichment clinical trial design.

PubMed

Zhang, Chuanwu; Garrard, Lili; Keighley, John; Carlson, Susan; Gajewski, Byron

2017-01-10

Despite the widely recognized association between the severity of early preterm birth (ePTB) and its related severe diseases, little is known about the potential risk factors of ePTB and the sub-population with high risk of ePTB. Moreover, motivated by a future confirmatory clinical trial to identify whether supplementing pregnant women with docosahexaenoic acid (DHA) has a different effect on the risk subgroup population or not in terms of ePTB prevalence, this study aims to identify potential risk subgroups and risk factors for ePTB, defined as babies born less than 34 weeks of gestation. The analysis data (N = 3,994,872) were obtained from CDC and NCHS' 2014 Natality public data file. The sample was split into independent training and validation cohorts for model generation and model assessment, respectively. Logistic regression and CART models were used to examine potential ePTB risk predictors and their interactions, including mothers' age, nativity, race, Hispanic origin, marital status, education, pre-pregnancy smoking status, pre-pregnancy BMI, pre-pregnancy diabetes status, pre-pregnancy hypertension status, previous preterm birth status, infertility treatment usage status, fertility enhancing drug usage status, and delivery payment source. Both logistic regression models with either 14 or 10 ePTB risk factors produced the same C-index (0.646) based on the training cohort. The C-index of the logistic regression model based on 10 predictors was 0.645 for the validation cohort. Both C-indexes indicated a good discrimination and acceptable model fit. The CART model identified preterm birth history and race as the most important risk factors, and revealed that the subgroup with a preterm birth history and a race designation as Black had the highest risk for ePTB. The c-index and misclassification rate were 0.579 and 0.034 for the training cohort, and 0.578 and 0.034 for the validation cohort, respectively. This study revealed 14 maternal characteristic variables that reliably identified risk for ePTB through either logistic regression model and/or a CART model. Moreover, both models efficiently identify risk subgroups for further enrichment clinical trial design.

Central pathology review for phase III clinical trials: the enabling effect of virtual microscopy.

PubMed

Mroz, Pawel; Parwani, Anil V; Kulesza, Piotr

2013-04-01

Central pathology review (CPR) was initially designed as a quality control measure. The potential of CPR in clinical trials was recognized as early as in the 1960s and quickly became embedded as an integral part of many clinical trials since. To review the current experience with CPR in clinical trials, to summarize current developments in virtual microscopy, and to discuss the potential advantages and disadvantages of this technology in the context of CPR. A PubMed (US National Library of Medicine) search for published studies was conducted, and the relevant articles were reviewed, accompanied by the authors' experience at their practicing institution. The review of the available literature strongly suggests the growing importance of CPR both in the clinical trial setting as well as in second opinion cases. However, the currently applied approach significantly impedes efficient transfer of slides and patient data. Recent advances in imaging, digital microscopy, and Internet technologies suggest that the CPR process may be dramatically streamlined in the foreseeable future to allow for better diagnosis and quality assurance than ever before. In particular, whole slide imaging may play an important role in this process and result in a substantial reduction of the overall turnaround time required for slide review at the central location. Above all, this new approach may benefit the large clinical trials organized by oncology cooperative groups, since most of those trials involve complicated logistics owing to enrollment of large number of patients at several remotely located participating institutions.

The Brustkrebs-Studien.de website for breast cancer patients: User acceptance of a German internet portal offering information on the disease and treatment options, and a clinical trials matching service

PubMed Central

2010-01-01

Background The internet portal http://www.brustkrebs-studien.de (BKS) was launched in 2000 by the German Society of Senology (DGS) and the Baden-Württemberg Institute for Women's Health (IFG) to provide expert-written information on breast cancer online and to encourage and facilitate the participation of breast cancer patients in clinical trials. We describe the development of BKS and its applications, and report on website statistics and user acceptance. Methods Existing registries, including ClinicalTrials.gov, were analysed before we designed BKS, which combines a trial registry, a knowledge portal, and an online second opinion service. An advisory board guided the process. Log files and patient enquiries for trial participation and second opinions were analysed. A two-week user satisfaction survey was conducted online. Results During 10/2005-06/2010, the portal attracted 702,655 visitors, generating 15,507,454 page views. By 06/2010, the website's active scientific community consisted of 189 investigators and physicians, and the registry covered 163 clinical trial protocols. In 2009, 143 patients requested trial enrolment and 119 sought second opinions or individual treatment advice from the expert panel. During the two-week survey in 2008, 5,702 BKS visitors submitted 507 evaluable questionnaires. Portal acceptance was high. Respondents trusted information correctness (80%), welcomed self-matching to clinical trials (79%) and planned to use the portal in the future (76%) and recommend it to others (81%). Conclusions BKS is an established and trusted breast cancer information platform offering up-to-date resources and protocols to the growing physician and patient community to encourage participation in clinical trials. Further studies are needed to assess potential increases in trial enrolment by eligibility matching services. PMID:21126358

The OPERA trial: a protocol for the process evaluation of a randomised trial of an exercise intervention for older people in residential and nursing accommodation

PubMed Central

2011-01-01

Background The OPERA trial is large cluster randomised trial testing a physical activity intervention to address depression amongst people living in nursing and residential homes for older people. A process evaluation was commissioned alongside the trial and we report the protocol for this process evaluation. Challenges included the cognitive and physical ability of the participants, the need to respect the privacy of all home residents, including study non-participants, and the physical structure of the homes. Evaluation activity had to be organised around the structured timetable of homes, leaving limited opportunities for data collection. The aims of this process evaluation are to provide findings that will assist in the interpretation of the clinical trial results, and to inform potential implementation of the physical activity intervention on a wider scale. Methods/design Quantitative data on recruitment of homes and individuals is being collected. For homes in the intervention arm, data on dose and fidelity of the intervention delivered; including individual rates of participation in exercise classes are collected. In the control homes, uptake and delivery of depression awareness training is monitored. These data will be combined with qualitative data from an in-depth study of a purposive sample of eight homes (six intervention and two control). Discussion Although process evaluations are increasingly funded alongside trials, it is still rare to see the findings published, and even rarer to see the protocol for such an evaluation published. Process evaluations have the potential to assist in interpreting and understanding trial results as well as informing future roll-outs of interventions. If such evaluations are funded they should also be reported and reviewed in a similar way to the trial outcome evaluation. Trial Registration ISRCTN No: ISRCTN43769277 PMID:21288341

Executive summary and recommendations from the WHO/UNAIDS/IAVI expert group consultation on 'Phase IIB-TOC trials as a novel strategy for evaluation of preventive HIV vaccines', 31 January-2 February 2006, IAVI, New York, USA.

PubMed

2007-02-19

This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January-2 February 2006) organized by the joint World Health Organization-United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), also referred to as 'proof of concept' trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process.

Benefits and challenges of using the cohort multiple randomised controlled trial design for testing an intervention for depression.

PubMed

Viksveen, Petter; Relton, Clare; Nicholl, Jon

2017-07-06

Trials which test the effectiveness of interventions compared with the status quo frequently encounter challenges. The cohort multiple randomised controlled trial (cmRCT) design is an innovative approach to the design and conduct of pragmatic trials which seeks to address some of these challenges. In this article, we report our experiences with the first completed randomised controlled trial (RCT) using the cmRCT design. This trial-the Depression in South Yorkshire (DEPSY) trial-involved comparison of treatment as usual (TAU) with TAU plus the offer of an intervention for people with self-reported long-term moderate to severe depression. In the trial, we used an existing large population-based cohort: the Yorkshire Health Study. We discuss our experiences with recruitment, attrition, crossover, data analysis, generalisability of results, and cost. The main challenges in using the cmRCT design were the high crossover to the control group and the lower questionnaire response rate among patients who refused the offer of treatment. However, the design did help facilitate efficient and complete recruitment of the trial population as well as analysable data that were generalisable to the population of interest. Attrition rates were also smaller than those reported in other depression trials. This first completed full trial using the cmRCT design testing an intervention for self-reported depression was associated with a number of important benefits. Further research is required to compare the acceptability and cost effectiveness of standard pragmatic RCT design with the cmRCT design. ISRCTN registry: ISRCTN02484593 . Registered on 7 Jan 2013.

Design, randomization and methodology of the TriAtiva Program to reduce obesity in school children in Southern Brazil.

PubMed

Friedrich, Roberta R; Caetano, Lisandrea C; Schiffner, Mariana D; Wagner, Mário B; Schuch, Ilaine

2015-04-11

The prevalence of child obesity in Brazil has increased rapidly in recent decades. There is, therefore, an urgent need to develop effective strategies to prevent and control child obesity. In light of these considerations, an intervention program with a focus on nutrition education and physical activity was developed for to prevent and control obesity in schools. The intervention was called the TriAtiva Program: Education, Nutrition and Physical Activity. This article describes the design, randomization and method used to evaluate the TriAtiva program. This randomized controlled cluster trial was performed in 12 municipal schools in the city of Porto Alegre/RS (six schools in the intervention group and six control schools) which offered first- through fourth grade, during one school year. The TriAtiva Program was implemented through educational activities related to healthy eating and physical activity, creating an environment which promoted student health while involving the school community and student families. The primary outcome of the present study was body mass, while its secondary outcomes were waist circumference, percent body fat, blood pressure and behavioural variables such as eating habits and physical activity levels, as well as the prevalence, incidence and remission rates of obesity. The intervention was developed based on a comprehensive review of controlled trials of similar design. The TriAtiva Program: Education, Nutrition and Physical Activity was the first study in Southern Brazil to use a randomized controlled design to evaluate an intervention involving both nutrition education and physical activity in schools. Our results will contribute to the development of future interventions aimed at preventing and controlling child obesity in schools, especially in Brazil. Brazilian Clinical Trials Registry (REBEC) number RBR2xx2z4.

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.

PRagmatic trial Of Video Education in Nursing homes: The design and rationale for a pragmatic cluster randomized trial in the nursing home setting.

PubMed

Mor, Vincent; Volandes, Angelo E; Gutman, Roee; Gatsonis, Constantine; Mitchell, Susan L

2017-04-01

Background/Aims Nursing homes are complex healthcare systems serving an increasingly sick population. Nursing homes must engage patients in advance care planning, but do so inconsistently. Video decision support tools improved advance care planning in small randomized controlled trials. Pragmatic trials are increasingly employed in health services research, although not commonly in the nursing home setting to which they are well-suited. This report presents the design and rationale for a pragmatic cluster randomized controlled trial that evaluated the "real world" application of an Advance Care Planning Video Program in two large US nursing home healthcare systems. Methods PRagmatic trial Of Video Education in Nursing homes was conducted in 360 nursing homes (N = 119 intervention/N = 241 control) owned by two healthcare systems. Over an 18-month implementation period, intervention facilities were instructed to offer the Advance Care Planning Video Program to all patients. Control facilities employed usual advance care planning practices. Patient characteristics and outcomes were ascertained from Medicare Claims, Minimum Data Set assessments, and facility electronic medical record data. Intervention adherence was measured using a Video Status Report embedded into electronic medical record systems. The primary outcome was the number of hospitalizations/person-day alive among long-stay patients with advanced dementia or cardiopulmonary disease. The rationale for the approaches to facility randomization and recruitment, intervention implementation, population selection, data acquisition, regulatory issues, and statistical analyses are discussed. Results The large number of well-characterized candidate facilities enabled several unique design features including stratification on historical hospitalization rates, randomization prior to recruitment, and 2:1 control to intervention facilities ratio. Strong endorsement from corporate leadership made randomization prior to recruitment feasible with 100% participation of facilities randomized to the intervention arm. Critical regulatory issues included minimal risk determination, waiver of informed consent, and determination that nursing home providers were not engaged in human subjects research. Intervention training and implementation were initiated on 5 January 2016 using corporate infrastructures for new program roll-out guided by standardized training elements designed by the research team. Video Status Reports in facilities' electronic medical records permitted "real-time" adherence monitoring and corrective actions. The Centers for Medicare and Medicaid Services Virtual Research Data Center allowed for rapid outcomes ascertainment. Conclusion We must rigorously evaluate interventions to deliver more patient-focused care to an increasingly frail nursing home population. Video decision support is a practical approach to improve advance care planning. PRagmatic trial Of Video Education in Nursing homes has the potential to promote goal-directed care among millions of older Americans in nursing homes and establish a methodology for future pragmatic randomized controlled trials in this complex healthcare setting.

WE-G-BRB-04: Leveraging Innovation to Design Future Clinical Trials

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

Michalski, J.

Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview willmore » be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.« less

Impact of PCA Strategies on Pain Intensity and Functional Assessment Measures in Adults with Sickle Cell Disease during Hospitalized Vaso-Occlusive Episodes

PubMed Central

Dampier, Carlton D.; Wager, Carrie G.; Harrison, Ryan; Hsu, Lewis L.; Minniti, Caterina P.; Smith, Wally R.

2012-01-01

Clinical trials of sickle cell disease (SCD) pain treatment usually observe only small decrements in pain intensity during the course of hospitalization. Sub-optimal analgesic management and inadequate pain assessment methods are possible explanations for these findings. In a search for better methods for assessing inpatient SCD pain in adults, we examined several pain intensity and interference measures in both arms of a randomized controlled trial comparing two different opioid PCA therapies. Based upon longitudinal analysis of pain episodes, we found that scores from daily average Visual Analogue Scales (VAS) and several other measures, especially the Brief Pain Inventory (BPI), were sensitive to change in daily improvements in pain intensity associated with resolution of vaso-occlusive pain. In this preliminary trial, the low demand, high basal infusion (LDHI) strategy demonstrated faster, larger improvements in various measures of pain than the high demand, low basal infusion (HDLI) strategy for opioid PCA dosing, however, verification in larger studies is required. The measures and statistical approaches used in this analysis may facilitate design, reduce sample size, and improve analyses of treatment response in future SCD clinical trials of vaso-occlusive episodes. PMID:22886853

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

PubMed

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

2018-02-28

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

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

PubMed Central

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

2016-01-01

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

Methodology Series Module 4: Clinical Trials.

PubMed

Setia, Maninder Singh

2016-01-01

In a clinical trial, study participants are (usually) divided into two groups. One group is then given the intervention and the other group is not given the intervention (or may be given some existing standard of care). We compare the outcomes in these groups and assess the role of intervention. Some of the trial designs are (1) parallel study design, (2) cross-over design, (3) factorial design, and (4) withdrawal group design. The trials can also be classified according to the stage of the trial (Phase I, II, III, and IV) or the nature of the trial (efficacy vs. effectiveness trials, superiority vs. equivalence trials). Randomization is one of the procedures by which we allocate different interventions to the groups. It ensures that all the included participants have a specified probability of being allocated to either of the groups in the intervention study. If participants and the investigator know about the allocation of the intervention, then it is called an "open trial." However, many of the trials are not open - they are blinded. Blinding is useful to minimize bias in clinical trials. The researcher should familiarize themselves with the CONSORT statement and the appropriate Clinical Trials Registry of India.

Methodology Series Module 4: Clinical Trials

PubMed Central

Setia, Maninder Singh

2016-01-01

In a clinical trial, study participants are (usually) divided into two groups. One group is then given the intervention and the other group is not given the intervention (or may be given some existing standard of care). We compare the outcomes in these groups and assess the role of intervention. Some of the trial designs are (1) parallel study design, (2) cross-over design, (3) factorial design, and (4) withdrawal group design. The trials can also be classified according to the stage of the trial (Phase I, II, III, and IV) or the nature of the trial (efficacy vs. effectiveness trials, superiority vs. equivalence trials). Randomization is one of the procedures by which we allocate different interventions to the groups. It ensures that all the included participants have a specified probability of being allocated to either of the groups in the intervention study. If participants and the investigator know about the allocation of the intervention, then it is called an “open trial.” However, many of the trials are not open – they are blinded. Blinding is useful to minimize bias in clinical trials. The researcher should familiarize themselves with the CONSORT statement and the appropriate Clinical Trials Registry of India. PMID:27512184

Oil industry first field trial of inter-well reservoir nanoagent tracers

NASA Astrophysics Data System (ADS)

Kanj, Mazen Y.; Kosynkin, Dmitry V.

2015-05-01

This short manuscript highlights the industry's first proven reservoir nanoagents' design and demonstrates a successful multi-well field trial using these agents. Our fundamental nanoparticles tracer template, A-Dots or Arab-D Dots, is intentionally geared towards the harsh but prolific Arab-D carbonate reservoir environment of 100+°C temperature, 150,000+ppm salinity, and an abundant presence of divalent ions in the connate water. Preliminary analyses confirmed nanoparticles' breakthrough at a producer nearly 500m from the injector at the reservoir level; thus, proving the tracer nanoparticles' mobility and transport capability. This is considered industry-first and a breakthrough achievement complementing earlier accomplishments in regard to the nanoagents' reservoir stability with the first successful single well test and ease of scale up with the synthesis of one metric ton of this material. The importance of this accomplishment is not in how sophisticated is the sensing functionalities of this design but rather in its stability, mobility, scalability, and field application potentials. This renders the concept of having active, reactive, and even communicative, in-situ reservoir nanoagents for underground sensing and intervention a well anticipated near-future reality.

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

Work, Weight, and Wellness: the 3W Program: a worksite obesity prevention and intervention trial.

PubMed

Williams, Andrew E; Vogt, Thomas M; Stevens, Victor J; Albright, Cheryl A; Nigg, Claudio R; Meenan, Richard T; Finucane, Melissa L

2007-11-01

In this paper, we describe the aims, intervention, and design of the Work, Weight, and Wellness program, a group-randomized worksite obesity prevention and intervention trial being conducted at 31 hotels with 11,559 employees on the island of Oahu in Hawaii. We report baseline prevalence of overweight and obesity, and the distribution of BMI (kilograms per meter squared) across sex, race, and job categories. We also describe factors that have influenced intervention adoption and employee participation. The study's primary outcome is change in BMI among hotel employees over a 2-year intervention period. The intervention includes environmental and group components that target diet, physical activity, and weight management. Men, Pacific Islanders, and individuals employed in managerial or facility maintenance roles had higher prevalence of obesity and higher mean BMI than women and individuals from other races or in other occupational categories. These results may be helpful in guiding choices about the adoption or design of future worksite and community interventions addressing at-risk ethnically diverse populations and are especially relevant to the hotel industry and similar industries.

Development of dapivirine vaginal ring for HIV prevention.

PubMed

Devlin, Bríd; Nuttall, Jeremy; Wilder, Susan; Woodsong, Cynthia; Rosenberg, Zeda

2013-12-01

In the continuing effort to develop effective HIV prevention methods for women, a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine is currently being tested in two safety and efficacy trials. This paper reviews dapivirine ring's pipeline development process, including efforts to determine safe and effective dosing levels as well as identify delivery platforms with the greatest likelihood of success for correct and consistent use. Dapivirine gel and other formulations were developed and tested in preclinical and clinical studies. Multiple vaginal ring prototypes were also tested, resulting in the current ring design as well as additional designs under consideration for future testing. Efficacy results from clinical trials are expected in 2015. Through ongoing consultations with national regulatory authorities, licensure requirements for dapivirine vaginal ring approval have been defined. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research. Copyright © 2013 Elsevier B.V. All rights reserved.

Quantifying and visualizing site performance in clinical trials.

PubMed

Yang, Eric; O'Donovan, Christopher; Phillips, JodiLyn; Atkinson, Leone; Ghosh, Krishnendu; Agrafiotis, Dimitris K

2018-03-01

One of the keys to running a successful clinical trial is the selection of high quality clinical sites, i.e., sites that are able to enroll patients quickly, engage them on an ongoing basis to prevent drop-out, and execute the trial in strict accordance to the clinical protocol. Intuitively, the historical track record of a site is one of the strongest predictors of its future performance; however, issues such as data availability and wide differences in protocol complexity can complicate interpretation. Here, we demonstrate how operational data derived from central laboratory services can provide key insights into the performance of clinical sites and help guide operational planning and site selection for new clinical trials. Our methodology uses the metadata associated with laboratory kit shipments to clinical sites (such as trial and anonymized patient identifiers, investigator names and addresses, sample collection and shipment dates, etc.) to reconstruct the complete schedule of patient visits and derive insights about the operational performance of those sites, including screening, enrollment, and drop-out rates and other quality indicators. This information can be displayed in its raw form or normalized to enable direct comparison of site performance across studies of varied design and complexity. Leveraging Covance's market leadership in central laboratory services, we have assembled a database of operational metrics that spans more than 14,000 protocols, 1400 indications, 230,000 unique investigators, and 23 million patient visits and represents a significant fraction of all clinical trials run globally in the last few years. By analyzing this historical data, we are able to assess and compare the performance of clinical investigators across a wide range of therapeutic areas and study designs. This information can be aggregated across trials and geographies to gain further insights into country and regional trends, sometimes with surprising results. The use of operational data from Covance Central Laboratories provides a unique perspective into the performance of clinical sites with respect to many important metrics such as patient enrollment and retention. These metrics can, in turn, be used to guide operational planning and site selection for new clinical trials, thereby accelerating recruitment, improving quality, and reducing cost.

Women's reasons for participation in a clinical trial for menstrual pain: a qualitative study

PubMed Central

Blödt, Susanne; Witt, Claudia M; Holmberg, Christine

2016-01-01

Objectives The aim of the study was to explore women's motivations for participating in a clinical trial and to evaluate how financial compensation impacts women's explanations for participation. Design, setting and participants Semistructured interviews were conducted face to face or by telephone with 25 of 220 women who participated in a pragmatic randomised trial for app-administered self-care acupressure for dysmenorrhoea (AKUD). Of these 25 women, 10 had entered AKUD knowing they would receive a financial compensation of €30. A purposive sampling strategy was used. Results Women had a long history of seeking help and were unsatisfied with the options available, namely painkillers and oral contraceptives. While interviewees were open to painkillers, they were uneasy about taking them on a monthly basis. The AKUD trial offered the possibility to find an alternative solution. A second reason for participation was the desire to add a new treatment to routine medical care, for which the interviewees considered randomised trials a prerequisite. The financial incentive was a subsidiary motivation in the interviewees' narratives. Conclusions Our results contribute to the ongoing discussion of the impact of financial compensation on research participants' assessment of risk. The interviewed women considered all research participants able to make their own choices regarding trial participation, even in the face of financial compensation or payment of study participants. Furthermore, the importance of clinical trials providing new treatments that could change medical practice might be an overlooked reason for trial participation and could be used in future recruitment strategies. PMID:27965251

Age and rate of cognitive decline in Alzheimer disease: implications for clinical trials.

PubMed

Bernick, Charles; Cummings, Jeffrey; Raman, Rema; Sun, Xiaoying; Aisen, Paul

2012-07-01

Factors that affect the rate of progression of Alzheimer disease (AD) need to be considered in the clinical trial designs of potential disease-modifying therapies. To determine the influence of age on AD course in a clinical trial setting. Pooled cohort study from 3 AD clinical trials of 18-month duration conducted by the Alzheimer Disease Cooperative Study group. Alzheimer disease research centers from across the United States. Four hundred seventy-one subjects with mild to moderate AD assigned to the placebo arm of 3 clinical trials. The relationships between baseline age and rate of change in the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) 11, Mini-Mental State Examination, Clinical Dementia Rating scale Sum of Boxes score, Alzheimer Disease Cooperative Study–activities of daily living scale, and Neuropsychiatric Inventory were analyzed using a mixed-effect regression model. Sample size calculation for possible future AD clinical trials lasting 18 months using the results of the change in ADAS-cog 11 by tertiles of age groups. Older age at baseline was associated with a slower rate of decline in the ADAS-cog 11 and the Mini-Mental State Examination scores. Almost twice as many subjects aged 80 years and older compared with those aged younger than 70 years would be required to demonstrate a 30% treatment effect on the ADAS-cog 11 in an 18-month AD trial. Subject age is an important factor to consider when defining the study population in and analyzing data from AD trials of potential disease-modifying therapies.

What Value Can Qualitative Research Add to Quantitative Research Design? An Example From an Adolescent Idiopathic Scoliosis Trial Feasibility Study.

PubMed

Toye, Francine; Williamson, Esther; Williams, Mark A; Fairbank, Jeremy; Lamb, Sarah E

2016-08-09

Using an example of qualitative research embedded in a non-surgical feasibility trial, we explore the benefits of including qualitative research in trial design and reflect on epistemological challenges. We interviewed 18 trial participants and used methods of Interpretive Phenomenological Analysis. Our findings demonstrate that qualitative research can make a valuable contribution by allowing trial stakeholders to see things from alternative perspectives. Specifically, it can help to make specific recommendations for improved trial design, generate questions which contextualize findings, and also explore disease experience beyond the trial. To make the most out of qualitative research embedded in quantitative design it would be useful to (a) agree specific qualitative study aims that underpin research design, (b) understand the impact of differences in epistemological truth claims, (c) provide clear thematic interpretations for trial researchers to utilize, and (d) include qualitative findings that explore experience beyond the trial setting within the impact plan. © The Author(s) 2016.