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Abstract: An alternative to clinical trial paper-based data collection (PDC) is internet based electronic data collection (EDC), where the investigators over the internet enter data directly in the electronic database by themselves. In our study we considered clinical trial as a business process. Our objective was to model PDC and EDC process and to estimate the difference of the costs of PDC and EDC process for a sample clinical trial based on these models. We used Extended Event-driven Process Chains (eEPC) modeling technique to model PDC and EDC process. In order to evaluate the costs of the processes we assigned costs functions to each process function which appears in the model. The parameters which appear in these functions include efforts, staff prices and data quality parameters. We estimated the values of all these parameters and performed costs calculations for a sample clinical trial. Through an analysis and modeling efforts we identified sub-processes which contain main differences affecting duration and costs of the PDC and EDC process: data gathering at the research center; monitoring; and data management. The most significant model difference between PDC and EDC process appeared in data management sub-process. For the sample clinical trial considered in our simulation study and our parameters estimations the EDC process decreased data collection costs for 55%. For different scenarios of parameters variations we show that the EDC process may bring from 49% to 62% of savings when compared to PDC process. [Copyright &y& Elsevier]

Stratification in randomization and analysis are widely employed to balance treatment groups in clinical trials. However, the potential power loss due to under-stratification or over-stratification has not been thoroughly evaluated in the typical setting of confirmatory clinical trials. In cases where there are too many strata and some have small sample sizes or a small number of events, it is common practice to combine these small strata during analysis. However, there is a lack of guidance on how those small strata should be combined. This paper presents extensive simulation studies to evaluate the impact of under-stratification or over-stratification on the power of survival analysis and the estimate of hazard ratio using stratified log-rank test and Cox PH model, respectively. The difference in power between stratified and unstratified log-rank tests is also investigated under different scenarios. Our results suggest that failing to consider prognostic stratification factors with strong effects, and/or accounting for non-prognostic factors such as noise and predictive factors, may reduce the power of the stratified log-rank test. Additionally, methods of combining small strata are explored and compared. [ABSTRACT FROM AUTHOR]

There are high rates of posttraumatic stress disorder (PTSD) among treatment-seeking veterans with substance use disorders (SUD). While addiction programs traditionally do not address PTSD, there is evidence that trauma treatments for individuals with this comorbidity have improved PTSD and SUD outcomes. Written exposure therapy (WET), a five-session evidence-based psychotherapy (EBP) for PTSD, has high patient satisfaction, and lower dropout compared to other EBPs for PTSD. WET may be ideally suited for clinical settings that may not have the trauma expertise found in PTSD specialty clinics, given it requires less training time, treatment sessions, preparation time, and therapist involvement than existing EBPs, and no homework assignments. This paper describes the design, methodology, and protocol of a randomized clinical trial to evaluate whether treatment as usual (TAU) plus WET (n = 51) is superior to TAU plus a neutral topic writing condition (n = 51) on both PTSD and addiction outcomes for veterans in SUD treatment. The primary hypothesis is that participants assigned to TAU+WET, compared to those in TAU+ neutral topic writing, will report reduced symptoms of PTSD. The secondary hypothesis is that veterans receiving WET will have greater decreases in number of days of substance use compared to TAU+ neutral topic controls at follow-up. Assessments will take place at baseline, post-treatment, 8-week, and 12-week follow-up. Exploratory aims will examine the association between heart rate variability and treatment outcomes. If results prove promising, they will support WET as an effective brief, easy to disseminate, adjunct to current SUD treatment for veterans with comorbid PTSD. Trial registration: ClinicalTrials.gov ID NCT05327504 • Posttraumatic stress disorder (PTSD) is common among veterans seeking SUD treatment. • Written exposure therapy may be ideally suited to treat PTSD in addiction clinics. • Participation in PTSD-focused treatment might improve substance and PTSD outcomes. • WET, a brief effective PTSD intervention, may help those with comorbid SUD-PTSD. [ABSTRACT FROM AUTHOR]

Clinical trials often include interim analyses of the proportion of participants experiencing an event by a fixed time-point. A pre-specified proportion excluded from a corresponding confidence interval (CI) may lead an independent monitoring committee to recommend stopping the trial. Frequently this cumulative proportion is estimated by the Kaplan-Meier estimator with a Wald approximate CI, which may have coverage issues with small samples. We reviewed four alternative CI methods for cumulative proportions (Beta Product Confidence Procedure (BPCP), BPCP Mid P, Rothman-Wilson, Thomas-Grunkemeier) and two CI methods for simple proportions (Clopper-Pearson, Wilson). We conducted a simulation study comparing CI methods across true event proportions for 12 scenarios differentiated by sample sizes and censoring patterns. We re-analyzed interim data from A5340, a HIV cure trial considering the proportion of participants experiencing virologic failure. Our simulation study highlights the lower and upper tail error probabilities for each CI method. Across scenarios, we found differences in the performance of lower versus upper bounds. No single method is always preferred. The upper bound of a Wald approximate CI performed reasonably with some error inflation, whereas the lower bound of the BPCP Mid P method performed well. For a trial design similar to A5340, we recommend BPCP Mid P. The design of future single-arm interim analyses of event proportions should consider the most appropriate CI method based on the relevant bound, anticipated sample size and event proportion. Our paper summarizes available methods, demonstrates performance in a simulation study, and includes code for implementation. [ABSTRACT FROM AUTHOR]

Clinical trials (CTs) test new medical products for safety and effectiveness. Despite federal policy aimed at generating greater inclusivity of people of color (POC) in CTs, disparity in (CT) enrollment persists. Non-Hispanic White patients comprise the majority of CT participants while Black and Hispanic patient participation has declined over the past decade. The scope of Clinical Research Nurses (CRNs) includes recruitment of participants for CTs. The aim of this phenomenological study was to describe adult oncology CRNs' lived experiences of recruiting POC cancer patients to participate in CTs. The first paper for this study identified three major themes regarding how CRNs view their role in caring for POC considering or enrolling onto cancer clinical trials (CCTs): CRNs act as advocates, care coordinators and educators. This paper focuses on two additional major themes regarding how CRNs view the unique needs of POC in clinical research: establishing and maintaining trusting relationships and recruitment infrastructure. Nineteen nurses participated in semi-structured one-to-one interviews and data analysis was based on Colaizzi's method. CRNs described a history of past research injustices, disparate access to care, inadequate cultural training, a physician-driven recruitment structure and provider-based implicit biases that hinder POC enrollment in CTs. Diversity in CCT enrollment requires CRNs to establish trust with POC, advocate for POC when implicit biases are observed and become competent practitioners of culturally sensitive care. Further, meaningful policy change at both federal and organizational levels must occur to ensure equitable access to novel cancer therapies. [ABSTRACT FROM AUTHOR]

About half of people living with dementia have not received a diagnosis, delaying access to treatment, education, and support. We previously developed a tool, eRADAR, which uses information in the electronic health record (EHR) to identify patients who may have undiagnosed dementia. This paper provides the protocol for an embedded, pragmatic clinical trial (ePCT) implementing eRADAR in two healthcare systems to determine whether an intervention using eRADAR increases dementia diagnosis rates and to examine the benefits and harms experienced by patients and other stakeholders. We will conduct an ePCT within an integrated healthcare system and replicate it in an urban academic medical center. At primary care clinics serving about 27,000 patients age 65 and above, we will randomize primary care providers (PCPs) to have their patients with high eRADAR scores receive targeted outreach (intervention) or usual care. Intervention patients will be offered a "brain health" assessment visit with a clinical research interventionist mirroring existing roles within the healthcare systems. The interventionist will make follow-up recommendations to PCPs and offer support to newly-diagnosed patients. Patients with high eRADAR scores in both study arms will be followed to identify new diagnoses of dementia in the EHR (primary outcome). Secondary outcomes include healthcare utilization from the EHR and patient, family member and clinician satisfaction assessed through surveys and interviews. If this pragmatic trial is successful, the eRADAR tool and intervention could be adopted by other healthcare systems, potentially improving dementia detection, patient care and quality of life. [ABSTRACT FROM AUTHOR]

Introduction In November 2016, the Integrated Addendum to ICH-GCP E6 (R2) will advise trial sponsors to develop a risk-based approach to clinical trial monitoring. This new process is commonly known as risk based monitoring (RBM). To date, a variety of tools have been developed to guide RBM. However, a gold standard approach does not exist. This review aims to identify and examine RBM tools. Methods Review of published and grey literature using a detailed search-strategy and cross-checking of reference lists. This review included academic and commercial instruments that met the Organisation for Economic Co-operation and Development (OECD) classification of RBM tools. Results Ninety-one potential RBM tools were identified and 24 were eligible for inclusion. These tools were published between 2000 and 2015. Eight tools were paper based or electronic questionnaires and 16 operated as Service as a System (SaaS). Risk associated with the investigational medicinal product (IMP), phase of the clinical trial and study population were examined by all tools and suitable mitigation guidance through on-site and centralised monitoring was provided. Conclusion RBM tools for clinical trials are relatively new, their features and use varies widely and they continue to evolve. This makes it difficult to identify the “best” RBM technique or tool. For example, equivalence testing is required to determine if RBM strategies directed by paper based and SaaS based RBM tools are comparable. Such research could be embedded within multi-centre clinical trials and conducted as a SWAT (Study within a Trial). [ABSTRACT FROM AUTHOR]

Sample size plays a crucial role in clinical trials. Flexible sample-size designs, as part of the more general category of adaptive designs that utilize interim data, have been a popular topic in recent years. In this paper, we give a comparative review of four related methods for such a design. The likelihood method uses the likelihood ratio test with an adjusted critical value. The weighted method adjusts the test statistic with given weights rather than the critical value. The dual test method requires both the likelihood ratio statistic and the weighted statistic to be greater than the unadjusted critical value. The promising zone approach uses the likelihood ratio statistic with the unadjusted value and other constraints. All four methods preserve the type-I error rate. In this paper we explore their properties and compare their relationships and merits. We show that the sample size rules for the dual test are in conflict with the rules of the promising zone approach. We delineate what is necessary to specify in the study protocol to ensure the validity of the statistical procedure and what can be kept implicit in the protocol so that more flexibility can be attained for confirmatory phase III trials in meeting regulatory requirements. We also prove that under mild conditions, the likelihood ratio test still preserves the type-I error rate when the actual sample size is larger than the re-calculated one. [ABSTRACT FROM AUTHOR]

Zinc in pancreatic insulin is essential for processing and action of the peptide, while in commercial preparations zinc promotes hexameric structure and prevents aggregate formation. In 2002, for the first time, insulin was delivered to humans intranasally with resulting cerebrospinal fluid insulin increases, but steady peripheral insulin levels. The novel method of increasing brain insulin levels without changes in the periphery resulted in an expansion of brain insulin research in clinical trials. As pre-clinical research has shown that brain insulin modulates a number functions, including food cravings and eating behavior, learning and memory functions, stress and mood regulation; realization of beneficial effects of insulin in modulating these functions in clinical populations became a possibility with the new direct-to-brain insulin delivery methodology. However, zinc, being integral to insulin structure and function, is neurotoxic, and has resulted in adverse effects to human health. In the last century, intranasal zinc was given preventively during the time of polio outbreak, and in the 21st century intranasal zinc was widely used over the counter to prevent common cold. In both cases, patients experienced partial or complete loss of smell. This paper is the first one to analyze zinc salts and concentrations of those two epidemiological adversities and directly compare formulations distributed to the public with animal toxicity data. The information gained from animal and epidemiological data provides a foundation for the formation of opinion given in this paper regarding safety of intranasal zinc in emerging clinical trials with intranasal insulin. [ABSTRACT FROM AUTHOR]

Most adolescents with T1D do not meet glycemic recommendations or consistently perform the required self-management behaviors to prevent acute- and long-term deleterious health outcomes. In addition, most youth with T1D do not have access to behavioral health services to address T1D management barriers. Thus, delivering behavioral interventions during routine medical appointments may hold promise for improving T1D outcomes in adolescents. The overall objective of this study was to examine the effect of behavioral interventions, either a Personalized T1D Self-Management Behaviors Feedback Report or Problem-Solving Skills, delivered by a T1D behavioral health provider and a T1D medical provider during a joint, fully integrated appointment to improve health outcomes in youth with T1D. This paper describes the study rationale, design, and baseline characteristics for the 109 adolescent-caregiver dyads who participated. Primary and secondary outcomes include hemoglobin A1c (A1C), T1D self-management behaviors, and biological indicators of complications. [ABSTRACT FROM AUTHOR]

Public health orders were introduced in many countries, including Australia, during the COVID-19 pandemic to reduce the spread of the virus. However, for many people this led to an exacerbation of mental health symptoms, particularly those living with severe or persistent mental illness (SPMI). Additionally, the conduct of clinical research was severely impacted during the pandemic, with many difficulties encountered in the conduct of clinical trials. This paper describes the COVID-related impacts experienced during the implementation of a randomised controlled trial (RCT) testing the effectiveness of a community pharmacist-led support service for people living with SPMI in Australia (the PharMIbridge RCT), and the strategies used to successfully implement the RCT. Australian public health orders led to interstate border closures, stay-at-home orders and work-from-home requirements, resulting in necessary changes to allow for the continuation of the RCT including; changes to trial regions, transferring some training materials online while delaying face-to-face (F2F) training components, delays in pharmacy and consumer recruitment, encouraging telehealth service delivery and extensions to timelines with existing funding. Having a solution-focussed and flexible approach, while still ensuring critical trial protocol elements were adhered to, such as providing opportunities for F2F skills-based training for pharmacists, as well as F2F site visits from researchers and mentors to support trial implementation, resulted in high pharmacy and consumer participant retention through to trial conclusion. Future planning for RCTs should consider possible pandemic-related risks and rapid responses from approval bodies to ensure researchers can be agile and adapt to ensure successful trial completion. [ABSTRACT FROM AUTHOR]

Aim We studied the use of patient/disease registries to recruit potential subjects for prospective clinical trials — describing the number, types and major benefits of using this approach. Methods In December 2013, we conducted a focused database search in PubMed, EMBASE, and Web of Science for studies (English language only) that used registries to recruit subjects for clinical trials published in 2004–2013. Of the 233 unique citations identified, 21 used registries to recruit subjects — 10 papers and 11 abstracts. Pearling and search for subsequent full papers of the abstracts identified 4 more papers. Results Our analysis, based on these 25 citations, showed that 14 are related to cancer, 3 to diabetes mellitus, 1 each to stroke, asthma, and celiac disease and 5 are disease neutral. Many types of registries (population-based cancer, quality improvement, disease-specific, web-based disease-neutral registries, local general practice registers, and national health database) are used to recruit subjects for clinical trials and uncover new knowledge. Overall, 16 registries are in the US, 4 in UK, 1 each in Canada, Spain, and Australia and 1 involved in many countries. Registries can identify very large number of subjects for screening for eligibility for clinical trials, especially in very large trials, rare disease trials, and trials involving minority patients. Conclusions Registries can retrospectively identify very large numbers of potential subjects for screening for eligibility and enrollment in prospective clinical trials. This matching can lead to more timely recruitment and help solve a major problem in conducting clinical trials. [ABSTRACT FROM AUTHOR]

Missing data exist in all clinical trials and missing data issue is a very serious issue in terms of the interpretability of the trial results. There is no universally applicable solution for all missing data problems. Methods used for handling missing data issue depend on the circumstances particularly the assumptions on missing data mechanisms. In recent years, if the missing at random mechanism cannot be assumed, conservative approaches such as the control-based and returning to baseline multiple imputation approaches are applied for dealing with the missing data issues. In this paper, we focus on the variability in data analysis of these approaches. As demonstrated by examples, the choice of the variability can impact the conclusion of the analysis. Besides the methods for continuous endpoints, we also discuss methods for binary and time to event endpoints as well as consideration for non-inferiority assessment. [ABSTRACT FROM AUTHOR]

Parents of infants hospitalized in a neonatal intensive care unit (NICU) experience increased anxiety and stress, which may persist after discharge. The rationale and design of a randomized clinical trial assessing the impact of a 1-year, post-discharge, peer support intervention (parent navigation) on parental mental health and infant health care utilization is described. Qualitative methods guided the adaptation of an existing parent support program to target emotional and resource-related needs of NICU families. Approximately 300 parent-infant dyads were enrolled at discharge and randomized to either receive a care notebook (control group) or a parent navigator and a care notebook (intervention group). We aim to determine if the parent navigator intervention: 1) increases self-efficacy and decreases stress in parents, 2) decreases overall levels of anxiety and depression in parents, 3) decreases infant hospitalizations and emergency department visits, and 4) increases adherence to infant vaccination recommendations during 1 year of follow-up. Standardized, self-reported psychological scales to assess parent depression, anxiety, self-efficacy and social support were administered at baseline (NICU discharge) and at 1-week, 1-, 3-, 6- and 12-month intervals. Infant immunization status and health care utilization during the study period were also assessed. This paper reviews challenges and successes during implementation. If this intervention improves outcomes, NICUs may choose to provide similar parent navigation services for infants and families transitioning from the NICU to home. This study was registered with ClinicalTrials.gov ( NCT02643472 ) on December 31, 2015. [ABSTRACT FROM AUTHOR]

Construction workers have the highest smoking rate among all occupations (39%). Hispanic/Latino workers constitute a large and increasing group in the US construction industry (over 2.6 million; 23% of all workers). These minority workers have lower cessation rates compared to other groups due to their limited access to cessation services, and lack of smoking cessation interventions adapted to their culture and work/life circumstances. Formative research was conducted to create an intervention targeting Hispanic/Latino construction workers. This paper describes the intervention development and the design, methods, and data analysis plans for an ongoing cluster pilot two-arm randomized controlled trial comparing an Enhanced Care worksite cessation program to Standard Care. Fourteen construction sites will be randomized to either Enhanced Care or Standard Care and 126 participants (63/arm) will be recruited. In both arms, recruitment and intervention delivery occur around “food trucks” that regularly visit the construction sites. Participants at Enhanced Care sites will receive the developed intervention consisting of a single face-to-face group counseling session, 2 phone calls, and a fax referral to Florida tobacco quitline (QL). Participants at Standard Care sites will receive a fax referral to the QL. Both groups will receive eight weeks of nicotine replacement treatment and two follow-up assessments at three and six months. Feasibility outcomes are estimated recruitment yield, barriers to delivering the intervention onsite, and rates of adherence/compliance to the intervention, follow-ups, and QL enrollment. Efficacy outcomes are point-prevalence and prolonged abstinence rates at six month follow-up confirmed by saliva cotinine <15 ng/ml. [ABSTRACT FROM AUTHOR]

Benefit-risk (BR) assessment is essential to ensure the best decisions are made for a medical product in the clinical development process, regulatory marketing authorization, post-market surveillance, and coverage and reimbursement decisions. One challenge of BR assessment in practice is that the benefit and risk profile may keep evolving while new evidence is accumulating. Regulators and the International Conference on Harmonization (ICH) recommend performing periodic benefit-risk evaluation report (PBRER) through the product's lifecycle. In this paper, we propose a general statistical framework for periodic benefit-risk assessment, in which Bayesian meta-analysis and stochastic multi-criteria acceptability analysis (SMAA) will be combined to synthesize the accumulating evidence. The proposed approach allows us to compare the acceptability of different drugs dynamically and effectively and accounts for the uncertainty of clinical measurements and imprecise or incomplete preference information of decision makers. We apply our approaches to two real examples in a post-hoc way for illustration purpose. The proposed method may easily be modified for other pre and post market settings, and thus be an important complement to the current structured benefit-risk assessment (sBRA) framework to improve the transparent and consistency of the decision-making process. [ABSTRACT FROM AUTHOR]

Background Despite established guidelines for regular walking as a first line therapy for adults with peripheral arterial disease (PAD), most patients do not walk routinely. This paper presents the design specifications for a randomized clinical trial to examine the effectiveness of an internet-based walking program compared to a telephone intervention, or the combination (internet-based with telephone counseling) for promotion of regular walking in patients with PAD. Methods Sedentary adults with documented lower extremity PAD are being recruited from the University of Michigan Health System and the surrounding area. Participants are randomized to one of four arms in a 2 × 2 factorial design: 1) telephone counseling to promote walking, 2) an internet-based walking program with tailored step-count goals, 3) the combination of telephone counseling with the internet-based walking program, or 4) waitlist control. Participants receive a 4-month intervention phase, after which all participants are followed for an additional 8 months to assess long-term adherence to regular walking. Outcomes are assessed at baseline, 4 and 12 months. The primary outcome is walking distance assessed through a standardized treadmill protocol. Additional outcomes include change in step-counts measured with a commercial activity tracker, pain-free walking distance, and changes in health-related quality of life from baseline to follow-up. Conclusion Finding effective and feasible programs to promote walking among PAD patients is warranted. This study will add to current evidence regarding use of internet based programs with and without telephone counseling to promote regular walking in this population. [ABSTRACT FROM AUTHOR]

Background Adults over age 65 represent the fastest growing population in the US. Decline in cognitive abilities is a hallmark of advanced age and is associated with loss of independence and dementia risk. There is a pressing need to develop effective interventions for slowing or reversing the cognitive aging process. While certain forms of cognitive training have shown promise in this area, effects only sometimes transfer to neuropsychological tests within or outside the trained domain. This paper describes a NIA-funded Phase III adaptive multisite randomized clinical trial, examining whether transcranial direct current stimulation (tDCS) of frontal cortices enhances neurocognitive outcomes achieved from cognitive training in older adults experiencing age-related cognitive decline: the Augmenting Cognitive Training in Older Adults study (ACT). Methods ACT will enroll 360 participants aged 65 to 89 with age-related cognitive decline, but not dementia. Participants will undergo cognitive training intervention or education training-control combined with tDCS or sham tDCS control. Cognitive training employs a suite of eight adaptive training tasks focused on attention/speed of processing and working memory from Posit Science BrainHQ. Training control involves exposure to educational nature/history videos and related content questions of the same interval/duration as the cognitive training. Participants are assessed at baseline, after training (12 weeks), and 12-month follow-up on our primary outcome measure, NIH Toolbox Fluid Cognition Composite Score, as well as a comprehensive neurocognitive, functional, clinical and multimodal neuroimaging battery. Significance The findings from this study have the potential to significantly enhance efforts to ameliorate cognitive aging and slow dementia. [ABSTRACT FROM AUTHOR]

Objectives The primary objective of this systematic survey was to examine the percentage of studies in which there was agreement in the reporting of the primary outcome between the currently updated version of the clinical trial registry and the published paper. We also investigated the factors associated with agreement in reporting of the primary outcome. Methods We searched PubMed for all randomized control trials (RCT)s published in 2012–2015 in the top five general medicine journals (based on the 2014 impact factor). Two hundred abstracts (50 from each year) were randomly selected for data extraction. Agreement in reporting of 11 key study conduct items (e.g., sample size) and study characteristics (e.g., funding, number of sites) were extracted by two independent reviewers. Analysis Descriptive analyses were conducted to determine the proportion of studies on which there was agreement in reporting of key study conduct items. Generalized estimating equations were used to explore factors associated with agreement in reporting of the primary outcome. Results Of the 200 included studies, 87% had agreement in reporting of the primary outcome. After adjusting for other covariates, having greater than 50 sites was associated with an increased likelihood of agreement in reporting of the primary outcome (odds ratio = 7.1, 95% confidence interval = 1.39, 36.27, p = 0.018). Conclusions We identified substantive disagreement in reporting between publications and current clinical trial registry, which were associated with several study characteristics. Further measures are needed to improve reporting given the potential threats to the quality and integrity of scientific research. [ABSTRACT FROM AUTHOR]

Introduction Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in older adults. Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial is a multi-site clinical trial to determine if physical rehabilitation intervention in older patients with ADHF improves physical function and reduces rehospitalizations. The REHAB-HF intervention aims to improve functional performance utilizing reproducible and progressive exercises that are individually tailored to the patient's physiological and physical capabilities. Fidelity of the intervention is essential to the trial's integrity and success. Maintaining fidelity is challenged by the complex, multi-domain design of the intervention implemented across multiple sites and delivered to an older, heterogeneous participant pool with severe underlying disease and multi-morbidity. Methods/design Given the dynamic nature of the REHAB-HF intervention, rigorous fidelity strategies were formulated. In this paper we summarize the specific strategies that REHAB-HF is using to meet the National Institutes of Health (NIH) Behavior Change Consortium Treatment Fidelity Workgroup recommendations in 5 key areas: 1) ensuring the intervention dose is consistent across participants, 2) standardizing interventionist training, 3) monitoring intervention delivery, 4) evaluating participants' understanding of information provided, and 5) ensuring that participants use the skills taught in the intervention. Discussion Effective intervention fidelity strategies are essential to the reliability and validity of physical function intervention trials. The REHAB-HF trial has developed comprehensive, specific strategies to ensure intervention fidelity despite a challenging study population and a complex intervention to meet NIH recommendations. This experience provides a strong working model for future physical function intervention trials. [ABSTRACT FROM AUTHOR]

Women were historically excluded from clinical trials. Despite numerous guidance and policy, we are still seeing this exclusion throughout the research pipeline more than 40 years later. The progress that has been made to include women in clinical trials and to report data disaggregated by sex continues to be limited due to multiple factors. In this paper, we aim to review some of the current FDA funding, policies, and practice in regard to inclusion of biological sex and sociocultural gender variables. This paper provides some recommendations and actionable policies to ensure that women as well as men can benefit from the updated biomedical research and clinical trials designed to take these variables into account. Strong regulations and mandates should be in place to direct pharmaceutical companies and industry toward the inclusion of women in biomedical research instead of a series of guidelines and recommendations that have not led to sufficient progress. Additionally, regulatory agencies should be completely independent in their decision-making process. Provision of Food and Drug Administration (FDA) funding by industry user fee for instance, might compromise FDA's impartiality in the approval process. Finally, better oversight is needed by the FDA for the labeling of drugs. FDA has made a significant contribution to the progress that has been made to this date, however, some of the current action plans including the Drug Trial Snapshots need to be refined to be more responsive to the current needs. [ABSTRACT FROM AUTHOR]

In confirmatory clinical trials, it is critical to have appropriate control of multiplicity for multiple comparisons or endpoints. When multiplicity-related issues arise from different sources (e.g., multiple endpoints, multiple treatment arms, multiple interim data-cuts and other factors), it can become complicated to control the family-wise type I error rate (FWER). Therefore, it is crucial for statisticians to fully understand the multiplicity adjustment methods and the objectives of the analysis regarding study power, sample size and feasibility in order to identify the proper multiplicity adjustment strategy. In the context of multiplicity adjustment of multiple dose levels and multiple endpoints in a confirmatory trial, we proposed a modified truncated Hochberg procedure in combination with a fixed-sequence hierarchical testing procedure to strongly control the FWER. In this paper, we provided a brief review of the mathematical framework of the regular Hochberg procedure, the truncated Hochberg procedure and the proposed modified truncated Hochberg procedure. An ongoing phase 3 confirmatory trial for pediatric functional constipation was used as a real case application to illustrate how the proposed modified truncated Hochberg procedure will be implemented. A simulation study was conducted to demonstrate that the study was adequately powered and the FWER was strongly controlled. This work is expected to facilitate the understanding and selection of adjustment methods for statisticians. [ABSTRACT FROM AUTHOR]

Purpose Most phases 2 and 3 blinded randomized clinical trials package study drug, e.g., active and placebo, into drug kits for distribution to investigational sites. Kits are made so that it is not possible to determine the type of drug in the kit. This enables investigators to administer drug to patients in a manner that blinds investigators and patients. Kits are labeled with unique kit IDs that code for the drug type. Kit lists contain the assignment of kit IDs to drug. Algorithms for making kit lists, like algorithms for randomizing patients, incorporate randomness to ensure investigators and patients are blind to the process. This paper reviews three types of kit list: blocked, double randomized, and scrambled, and discusses the operational benefits of what a pharmaceutical company might obtain using scrambled lists along with an overview of the challenges of generating and extending the lists for large trials. Methods We reviewed the operational characteristics of three types of kit list: blocked, double randomized, and scrambled. Results Blocked kit lists were a popular choice until their unblinding and operational deficiencies became well known. The many difficulties associated with blocked kit lists are unnecessary and can be avoided by using a double randomized kit list or a scrambled kit list. Compared to double randomized kit lists, scrambled kit lists can be more easily extended due to their advantage of having randomly sized gaps between kit IDs. Conclusions Among the three types of kit list, scrambled kit lists offer the most flexibility. The adoption of scrambled kit lists has in practice provided the many operational benefits described in this paper. [ABSTRACT FROM AUTHOR]

Abstract: This paper is the first of five papers in this issue that describes a new research consortium funded by the National Institutes of Health. It describes the design characteristics of the Childhood Obesity Prevention and Treatment Research (COPTR) trials and common measurements across the trials. The COPTR Consortium is conducting interventions to prevent obesity in pre-schoolers and treat overweight or obese 7–13year olds. Four randomized controlled trials will enroll a total of 1700 children and adolescents (~50% female, 70% minorities), and will test innovative multi-level and multi-component interventions in multiple settings involving primary care physicians, parks and recreational centers, family advocates, and schools. For all the studies, the primary outcome measure is body mass index; secondary outcomes, moderators and mediators of intervention include diet, physical activity, home and neighborhood influences, and psychosocial factors. COPTR is being conducted collaboratively among four participating field centers, a coordinating center, and NIH project offices. Outcomes from COPTR have the potential to enhance our knowledge of interventions to prevent and treat childhood obesity. [Copyright &y& Elsevier]

Background Posttraumatic stress disorder (PTSD) from warzone exposure is associated with chronic and disabling social and occupational problems. However, functional impairment is rarely assessed or targeted directly in PTSD treatments, which instead focus on symptom reduction. Trauma-related contributors to diminished functioning, including guilt, shame, and anger resulting from morally compromising or loss-based war experiences, are also underemphasized. The goal of this clinical trial is to fill a substantial gap in the treatment of military-related PTSD by testing a modified Adaptive Disclosure (AD) therapy for war-related PTSD stemming from moral injury and traumatic loss focused on improving psychosocial functioning AD. Method and design This paper describes the rationale and design of a multi-site randomized controlled trial comparing AD to Present-Centered Therapy (PCT). We will recruit 186 veterans with PTSD, who will be assessed at baseline, post-treatment, and 3- and 6-months post-treatment. Primary outcomes are functional changes (i.e., functioning/disability and quality of life). Secondary outcomes are mental health variables (i.e., PTSD, depression, guilt, shame). We hypothesize that veterans treated with AD will experience greater improvements in all outcomes compared to those treated with PCT. Discussion This trial will advance knowledge in rehabilitation research by testing the first therapy specifically designed to address psychosocial functioning among veterans with war-related PTSD. The results may improve the quality of mental health care for veterans by offering an ecologically sound treatment for experiences that are uniquely impactful for war veterans. [ABSTRACT FROM AUTHOR]

Background Health behaviors related to diet, tobacco usage, physical activity, medication adherence, and alcohol use are highly determinative of risk for developing cardiovascular disease. This paper describes a study protocol to evaluate a problem-solving intervention that aims to help patients at risk for developing cardiovascular disease address barriers to adopting positive health behaviors in order to reduce cardiovascular risk. Methods Eligible patients are adults enrolled in Veterans Affairs (VA) health care who have not experienced a cardiovascular event but are at elevated risk based on their Framingham Risk Score (FRS). Participants in this two-site study are randomized to either the intervention or care as usual, with a target of 400 participants. The study intervention, Healthy Living Problem-Solving (HELPS), consists of six group sessions conducted approximately monthly interspersed with individualized coaching calls to help participants apply problem-solving principles. The primary outcome is FRS, analyzed at the beginning and end of the study intervention (6 months). Participants also complete measures of physical activity, caloric intake, self-efficacy, group cohesion, problem-solving capacities, and demographic characteristics. Conclusion Results of this trial will inform behavioral interventions to change health behaviors in those at risk for cardiovascular disease and other health conditions. Trial registration: ClinicalTrials.gov identifier NCT01838226 [ABSTRACT FROM AUTHOR]

Platforms trials are clinical trials that allow for concurrent evaluations of multiple treatments, thus allowing for more efficient and ethical studies compared to traditional two-arm trials. Conventional group-sequential multi-arm multi-stage (MAMS) designs use pre-specified stopping boundaries and treatment selection rules to determine if experimental treatments should be dropped. Flexible MAMS designs allow for interim modifications to the design plan without compromising error rates. Bayesian response adaptive randomization (BRAR) designs increase patient allocation to treatment arms that are performing well during the course of the trial. In this paper, we compare these two major methods and their extensions under several scenarios in the platform trials setting. Results show that BRAR and flexible MAMS designs have comparable power and type 1 error rate under varying simulated scenarios, allowing for addition of flexible treatment selection. BRAR outperforms flexible MAMS when there is a single effective treatment. Flexible MAMS designs are more efficient compared to BRAR when there are no effective treatments. BRAR performance increases as the probability of a treatment arm being dropped increases. [ABSTRACT FROM AUTHOR]

For molecularly targeted therapy and immunotherapy, the targeted dose in the early phase clinical trial has been shifted from the maximum tolerated dose for the cytotoxic drug to the optimal biological dose where both toxicity and efficacy are considered. In this paper, we consider the situation that the responses of toxicity and efficacy are mixed in binary and continuous types, respectively, where the continuous endpoint bears more magnitude information than the binary endpoint after dichotomization. We propose combining two model-based designs to sequentially identify the most efficacious and tolerably safe dose. The employed designs both take the dose level information into account to achieve high estimation efficiency. We demonstrate the superiority of the proposed method to some existing methods by simulation. [ABSTRACT FROM AUTHOR]

Chronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment. A multisite randomized controlled trial will examine the efficacy of ACT+MBRP in comparison to a parallel education control condition, focusing on opioid safety and pain education. Participants include veterans (n = 160; 21–75 years old) recruited from three Veterans Administration (VA) Healthcare Systems with chronic pain who are on a stable dose of buprenorphine. Both conditions include twelve weekly 90 min group sessions delivered via telehealth. Primary outcomes include pain interference (Patient Reported Outcome Measurement Information System - Pain Interference) and hazardous opioid use (Current Opioid Misuse Measure), which will be examined at the end of the active treatment phase and through 12 months post-intervention. Secondary analyses will evaluate outcomes including pain intensity, depression, pain-related fear, and substance use, as well as treatment mechanisms. This study will determine the efficacy of an integrated behavioral treatment program for pain interference and hazardous opioid use among veterans with chronic pain and OUD who are prescribed buprenorphine, addressing a critical need for more integrated treatments for chronic pain and OUD. ClinicalTrials.gov Identifier: NCT04648228 [ABSTRACT FROM AUTHOR]

In oncology clinical trials the guiding principle of model-based dose-finding designs for cytotoxic agents is to progress as fast as possible towards, and identify, the dose level most likely to be the MTD. Recent developments with non-cytotoxic agents have broadened the scope of early phase trials to include multiple objectives. The ultimate goal of dose-finding designs in our modern era is to collect the relevant information in the study for final RP2D determination. While some information is collected on dose levels below and in the vicinity of the MTD during the escalation (using conventional tools such as the Continual Reassessment Method for example), designs that include expansion cohorts or backfill patients effectively amplify the information collected on the lower dose levels. This is achieved by allocating patients to dose levels slightly differently during the study in order to take into account the possibility that "less (dose) might be more". The objective of this paper is to study the concept of amplification. Under the heading of controlled amplification we can include dose expansion cohorts and backfill patients among others. We make some general observations by defining these concepts more precisely and study a specific design that exploits the concept of controlled amplification. [ABSTRACT FROM AUTHOR]

Abstract: The informed consent process for research has come under scrutiny, as consent documents are increasingly long and difficult to understand. Innovations are needed to improve comprehension in order to make the consent process truly informed. We report on the development and pilot testing of video clips that could be used during the consent process to better explain research procedures to potential participants. Based on input from researchers and community partners, 15 videos of common research procedures/concepts were produced. The utility of the videos was then tested by embedding them in mock-informed consent documents that were presented via an online electronic consent system designed for delivery via iPad. Three mock consents were developed, each containing five videos. All participants (n =61) read both a paper version and the video-assisted iPad version of the same mock consent and were randomized to which format they reviewed first. Participants were given a competency quiz that posed specific questions about the information in the consent after reviewing the first consent document to which they were exposed. Most participants (78.7%) preferred the video-assisted format compared to paper (12.9%). Nearly all (96.7%) reported that the videos improved their understanding of the procedures described in the consent document; however, the comprehension of material did not significantly differ by consent format. Results suggest videos may be helpful in providing participants with information about study procedures in a way that is easy to understand. Additional testing of video consents for complex protocols and with subjects of lower literacy is warranted. [Copyright &y& Elsevier]

Abstract: This paper describes the application of a translational research model in developing The Trial Using Motivational Interviewing and Positive Affect and Self-Affirmation in African-Americans with Hypertension (TRIUMPH), a theoretically-based, randomized controlled trial. TRIUMPH targets blood pressure control among African-Americans with hypertension in a community health center and public hospital setting. TRIUMPH applies positive affect, self-affirmation, and motivational interviewing as strategies to increase medication adherence and blood pressure control. A total of 220 participants were recruited in TRIUMPH and are currently being followed. This paper provides a detailed description of the theoretical framework and study design of TRIUMPH and concludes with a critical reflection of the lessons learned in the process of implementing a health behavior intervention in a community-based setting. TRIUMPH provides a model for incorporating the translational science research paradigm to conducting pragmatic behavioral trials in a real-world setting in a vulnerable population. Lessons learned through interactions with our community partners reinforce the value of community engagement in research. [Copyright &y& Elsevier]

Abstract: Despite several advances in the care of critically ill patients, sepsis and septic shock continue to carry the largest burden of mortality and morbidity. Trials comparing vasopressors in shock have been disappointing and several key issues in methodology may need to be explored. There has been substantial progress in evolving adaptive trial methodology, however these have seldom been translated to clinical trials. This paper discusses some of the issues relevant to critical illness. To illustrate the potential contribution of adaptive trials we discuss fixed sample size design including event and time to event studies. We then explore group sequential and adaptive trial design, enrichment strategies and sample size re-estimation. An attractive feature of responsive adaptive designs is the flexibility to deal with unanticipated treatment effect size. If the observed effect size is larger than expected, early stopping is permitted. If the effect size is smaller than expected, sample size recalculation would be a reasonable choice in the face of an underpowered study. This allows for optimal efficiency in trial design. Reservations about adaptive trial design centre on issues of validity, feasibility and integrity of the study and are discussed in this paper. [Copyright &y& Elsevier]

Abstract: There is currently little reliable and quantifiable compliance data reported for preventive trials of oral disease. During a two-year, school-based caries clinical trial of sugar-free chewing gum, strategies to promote compliance with a gum-chewing protocol were implemented and outcomes measured. Methods: Over a 28-month period 2720 subjects, aged 11½–13½ at baseline, were recruited from 29 secondary colleges in Melbourne, Australia. Subjects were required to chew gum (test or control) for 10min 3× daily, including once during a supervised school chewing session. The main compliance promotion strategies were regular school visits, regular provision of information and performance feedback and reimbursement. Compliance was measured using supervised school chewing logs, self-report paper diaries and returned unused home-use gum. The primary compliance outcome was the percentage of supervised school sessions attended by the subject over a 24-month period. Results: Overall supervised session attendance was 63.9±17.6%. There was no significant difference between control and test groups in supervised session attendance. Average diary return rate was 76%, with final diary returns of 84%. Data from diaries were not considered sufficiently robust to analyse and report. The return rate for unused home-use gum was poor. Conclusions: This research highlights the importance of: (1) dedicated compliance trial personnel in an adequate ratio to trial subjects; (2) inclusion in protocols of direct methods of measuring compliance; (3) prompt analysis of compliance data; (4) piloting of compliance data collection tools and (5) self-report paper diaries having questionable feasibility as a compliance data collection tool. [Copyright &y& Elsevier]

Abstract: Many clinical studies such as those in the areas of toxicology, early phase clinical trials and bioequivalence studies use small samples due to the high cost of experimentation. These studies test hypotheses based on small samples. These small samples result in low power and therefore even if the alternative hypotheses may be true the chance of it being rejected is low. The sample size is determined in an ad-hoc way and no proper scientific approach is used. Sample size calculations for clinical studies are usually conducted to determine the total number of patients needed to satisfy a specified power requirement, and their validity is dependent on pre-trial knowledge of nuisance parameters and distributional and modelling assumptions. Another short coming is that often hypotheses are tested without checking the assumptions required by the test. This paper looks at design reviews in the context of small samples. It examines several design modifications done with asmall internal pilot study. In the past similar techniques have been applied to large scale studies but it sperformance is yet to be established in small scale clinical studies thus the contribution of this paper is in justifying the validity of these techniques for small samples too. The methodology is illustrated on an uncontrolled observational toxicology study. In this paper simulations will be presented showing that the design modifications would not influence the type-I error rate and that these would be successful in preserving the power, and the implementation of the design review procedure will be described. [ABSTRACT FROM AUTHOR]

Abstract: Background: The primary form of treatment for obesity today is behavioral therapy. Self-monitoring diet and physical activity plays an important role in interventions targeting behavior and weight change. The SMART weight loss trial examined the impact of replacing the standard paper record used for self-monitoring with a personal digital assistant (PDA). This paper describes the design, methods, intervention, and baseline sample characteristics of the SMART trial. Methods: The SMART trial used a 3-group design to determine the effects of different modes of self-monitoring on short- and long-term weight loss and on adherence to self-monitoring in a 24-month intervention. Participants were randomized to one of three conditions (1) use of a standard paper record (PR); (2) use of a PDA with dietary and physical activity software (PDA); or (3), use of a PDA with the same software plus a customized feedback program (PDA+FB). Results: We screened 704 individuals and randomized 210. There were statistically but not clinically significant differences among the three cohorts in age, education, HDL cholesterol, blood glucose and systolic blood pressure. At 24months, retention rate for the first of three cohorts was 90%. Conclusions: To the best of our knowledge, the SMART trial is the first large study to compare different methods of self-monitoring in a behavioral weight loss intervention and to compare the use of PDAs to conventional paper records. This study has the potential to reveal significant details about self-monitoring patterns and whether technology can improve adherence to this vital intervention component. [Copyright &y& Elsevier]

Abstract: Objective : Utilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett''s Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett''s esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and −2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE). Design : The study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett''s. Measurements : The response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate. Results : Controlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett''s involvement decreased for patients in the treatment group. Conclusions : That there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence. [Copyright &y& Elsevier]

Abstract: The placebo effect has been the subject of much controversy. For a scientific investigation of placebo effects to advance it is important to establish whether a placebo response in any particular illness is reliable — i.e., if there is a response to a single placebo administration there will also be a placebo response to the repeated administration of a similar placebo in similar conditions. A positive answer would allow more sophisticated clinical trial designs and more precise basic research experiments on the placebo effect. This article reviews experiments that used multiple administrations of placebo to answer the question “do reliable placebo responders exist?” This paper also examines the evidence for the existence of a consistent placebo responder, i.e. a person who responds to placebo in one situation will respond in another condition or using a different type of placebo ritual. Much of the existing evidence for these two questions was performed before 1967. This early evidence is contradictory, methodologically weak and is sufficiently old to be considered medical history. Since 1969, at least eight experiments exposed asthma patients to multiple administrations of placebo given with deceptive suggestions that the “treatment” was an active medication. While the results of this research are not unequivocal, and may not be equivalent to non-deceptive conditions, this line of inquiry suggests that if a reliable and consistent placebo response exists it could be detected within this population. Finally, this paper proposes one model to rigorously investigate the stability of placebo responses. [Copyright &y& Elsevier]

Abstract: The risk ratio (RR), defined as the ratio of probabilities of having an adverse event between an experimental treatment and a control treatment, is one of the most commonly used indices to measure the efficacy of an experimental treatment in a randomized clinical trial (RCT). When we want to obtain a summary estimator of the RR in stratified analysis, it is important that we can examine the assumption whether the underlying RR varies between strata. Although we can find a few publications on testing the homogeneity of RR, all these papers focus the ideal situation in which every patient complies with his/her assigned treatment. The research on testing the homogeneity of RR for a noncompliance RCT is limited. In this paper, we develop three simple test statistics for testing homogeneity of the RR under a noncompliance stratified RCT with large strata. To evaluate the performance of these statistics, we apply Monte Carlo simulation to calculate Type I error and power in a variety of situations. Based on the findings, we provide a general guideline of selecting a preferable test statistic under various situations. Finally, we include a large field trial studying the effect of a multifactor intervention program on the mortality of coronary heart disease (CHD) in middle-aged men to illustrate the practical use of these test statistics. [Copyright &y& Elsevier]

Abstract: This paper examines the design of phase II trials in oncology and recommends departing from the traditional uncontrolled trial design. Entrance into phase II clinical evaluation represents a key milestone in the development of any new cancer therapy. As novel molecular-targeted therapies are introduced, whose primary action is to slow the growth of tumors, it will be important to ensure that the clinical trial design will effectively capture any clinical benefit of these agents. The objective of a phase II trial should, in addition to identifying active therapies, be extended to identifying those that are likely to be successful in pivotal trials. It is therefore necessary to quantify the likelihood of either incorrectly halting the development of an active agent or continuing development of an ineffective agent. We believe only randomized studies with comparative intent and including a concurrent active control, can reliably assess these risks corresponding to significance and power. Given that the objective of phase II studies is to identify promising treatments, it is important not be constrained by conventional levels of significance. This paper will review the various approaches to phase II trial design in oncology and provide a framework for fully powered randomized trials of a moderate size. For example, a randomized trial of just 100 patients could lead to the termination of development of 90% of inactive agents whereas at least 80% of agents with a meaningful and realistic increase in progression-free survival would be identified for confirmatory study. We believe randomized studies with progression-free survival endpoints are the most powerful and economical method of determining the clinical activity of new cytostatic agents. [Copyright &y& Elsevier]

Abstract: Background: Three types of randomized consent designs are distinguished and ranked according to the extent to which participants are informed about treatment options: single-consent (those in the experimental group learn about their assigned treatment), incomplete-double-consent (all participants learn about their assigned treatment), and complete-double-consent (all participants learn about all treatments studied). All are methodologically, ethically, and judicially controversial. Even so, their use is justified if blinding is deemed necessary, but impossible to achieve by sham procedures (placebo), and experimental treatment seems attractive to potential participants. Objective: The aim of this study is to give a comprehensive overview of the use of randomized consent designs. Data sources are MEDLINE (1/1977-2/2003), EMBASE (1/1984-2/2003), PsycINFO (1/1996–2/2003), the Cochrane Library, and the Science Citation Index database. Review methods: Eligible were studies using a randomized consent design. Cluster randomized trials were excluded. One reviewer selected and data-extracted eligible papers. A second reviewer independently data-extracted 10% of the papers. Data on country of study conduct, year of commencement, area of medicine, type of design, reason(s) for use, details on approval by a research ethics committee, the index and reference intervention, nature of endpoints, and details on collection of data were extracted. Furthermore, for each trial, the rates of non-compliance and loss to follow-up were registered by treatment arm. The three types of randomized consent designs were compared as to differences between the rates of non-compliance and loss to follow-up in the separate trial arms. Results: Randomized consent designs are seldom used (n =50). When used, they have often been used in the wrong circumstances (misuse). In 65% of the studies the non-compliance in the index group is larger than in the reference group. Contrary to expectation, trials using the incomplete-double design were associated with significantly higher rates of non-compliance and loss to follow-up in the reference groups than trials employing the other two versions. Conclusion: Trialists and physicians should be aware of the proper indication for the use of randomized consent designs. [Copyright &y& Elsevier]

Abstract: Background: In 1979, Zelen described a trial method of randomising participants before acquiring consent in order to enhance recruitment to clinical trials. The method has been criticised ethically due to lack of consent and scientifically due to high crossover rates. This paper reviews recent published trials using this method and describes the reasons authors gave for using the method, examines the crossover rates, and looks at the quality of identified trials. Methods: Literature review searching for all citations to the relevant Zelen''s papers of trials published since 1990 plus inclusion of trials from personal knowledge. Results: We identified 58 relevant trials. The most common justification for the use of Zelen method was to avoid the introduction of bias (e.g., to avoid the Hawthorne effect). Few trialists had explicitly used the design to enhance participant recruitment. Most trials (n =41) experienced some crossover from one group to the other (median crossover=8.9%, mean=13.8%, IQR 2.6% to 15%) although this was usually within acceptable limits. Conclusion: The most important reason stated by authors for using Zelen''s method was to limit bias. Zelen''s method, if carefully used, can avoid ‘resentful demoralisation’ and the Hawthorne effect biasing a trial. Unlike a previous review, we found that crossover was not a problem for most trials. [Copyright &y& Elsevier]

Abstract: Pharmaceutical and device companies are more frequently considering and using electronic data collection (EDC) to collect patient-reported outcomes such as satisfaction and quality of life for clinical trials. The transition from paper-and-pencil data collection to EDC is not without risks. The unique context of clinical trials presents challenges that, if not addressed, can lead to expensive mistakes. The advantages inherent to EDC can easily be cancelled out without careful attention to the characteristics of the clinical setting. This paper provides an overview of EDC issues specific to clinical trials and health care settings. In particular, it evaluates usability issues associated with methods of EDC and suggests strategies to minimize potential problems. Lessons learned from usability testing in the unique setting of the clinical trial can be applied to other projects to decrease costs, enhance the quality of the data, and minimize time to analysis. [Copyright &y& Elsevier]

Colonial historical trauma and ongoing structural racism have impacted Indigenous peoples for generations and explain the ongoing health disparities. However, Indigenous peoples have been engaging in multilevel, clinical trial interventions with Indigenous and allied research scientists resulting in promising success. In this paper, National Institutes of Health funded scientists in the field of Indigenous health have sought to describe the utility and need for multilevel interventions across Indigenous communities (Jernigan et al., 2020). We posit limitations to the existing socioecological, multilevel frameworks and propose a dynamic, interrelated heuristic framework, which focuses on the inter-relationships of the collective within the environment and de-centers the individual. We conclude with identified calls for action within multilevel clinical trial research. [ABSTRACT FROM AUTHOR]

In oncology, dose-finding studies are largely performed only in Phase I clinical trials and the maximum tolerated dose (MTD), a dose initially developed for systemic chemotherapies, is by default selected for the Phase 3 confirmatory trial. With the advent of anti-cancer therapies such as molecular targeted agents and immunotherapies, a paradigm shift is underway from the use of conventional MTD approaches to improved dose selection strategies for oncology programs. In response to this new challenge, new study designs are needed to optimize dose selection while still bring life-changing new therapies to patients as soon as possible. In this paper, we propose a 2-in-1 adaptive design starting with a Phase 2 trial with randomized evaluation of multiple doses and only select one dose to expand to a Phase 3 trial if efficacy evidence is observed based on an interim evaluation. The lowest dose will be selected if multiple doses show promising efficacy unless the higher dose demonstrates a more compelling treatment effect, and study will be seamlessly expanded to a Phase 3 trial with the selected dose with patients enrolled in the Phase 2 portion also used for the statistical inference in the Phase 3 portion. The overall Type I error can be controlled under a mild assumption. Simulation studies are conducted to confirm the control of Type I error and to demonstrate the desirable operating characteristics of the proposed design. [ABSTRACT FROM AUTHOR]

While comorbidity between posttraumatic stress disorder (PTSD) and substance use disorders (SUD) is common among veterans, there is debate regarding how to best treat individuals suffering from both conditions. Despite data supporting the effectiveness of integrated treatments that simultaneously address both disorders, due to concerns that an early focus on trauma may increase dropout and reduce the likelihood of achieving SUD-related goals, providers continue to prefer a sequential approach, where the addiction is treated first and PTSD treatment is instituted following sustained abstinence or reduced use. This project is designed to directly examine these provider concerns by evaluating the benefits and harms of an integrated versus a sequential approach to treating comorbid PTSD and SUD. This paper reviews the study's methodology, treatment approaches, and baseline participant characteristics. In this randomized clinical trial, one hundred eighty-three veterans with co-occurring PTSD and SUD have been randomized to one of two psychotherapies that include the same treatment components for SUD and PTSD (Motivational Enhancement Therapy and Prolonged Exposure respectively), but differ by whether the components are delivered sequentially or are integrated such that PTSD and SUD symptoms are addressed concurrently. We hypothesize that veterans assigned to integrated treatment will show greater improvement in PTSD and SUD symptoms than veterans assigned to sequential treatment. If this hypothesis is supported, the findings have the potential to change clinicians' beliefs and challenge long-standing practice patterns that require participation in SUD treatment prior to initiating trauma-focused therapies for PTSD. [ABSTRACT FROM AUTHOR]

Background Many of the health behaviors known to contribute to cardiometabolic risk and disease (CMRD), including physical activity, diet, sleep, and screen time, begin during childhood. Given the population-wide burden of CMRD, novel ways of assessing risk and providing feedback to support behavior change are needed. Purpose This paper describes the design and rationale for the Study for using Technology to Reach Individual Excellence (STRIVE), a randomized controlled trial testing the use of an integrated, closed-loop feedback system that incorporates longitudinal, patient-generated, mobile health technology (mHealth) data on health behaviors and provides clinical recommendations to help manage CMRD among at-risk families. Methods STRIVE is a 6-month trial among 68 children, ages 6–12 year olds with a body mass index ≥ 85th percentile from Massachusetts with at least one parent with CMRD. Data on several health behaviors will be collected daily over 6 months. Children and parents will each wear wristbands that collect objective physical activity, sleep, and screen time data via accelerometry, noise, and infrared detection. Sugar sweetened beverage consumption will be assessed by self-report via a smartphone application. Weight will be collected using a wireless scale. Intervention group parents receive feedback on their child's health behaviors and personalized CMRD counseling via mobile messaging. Control parents receive standard of care recommendations and weekly health behavior reports for self-guided care. Conclusion The STRIVE trial will test the use of mHealth and closed-loop feedback systems to improve health behaviors among families at-risk for or with established CMRD. [ABSTRACT FROM AUTHOR]

Understanding the human experience is no longer an outcome explored strictly by social and behavioral researchers. Increasingly, biomedical researchers are also including patient reported outcomes (PROs) in their clinical research studies not only due to calls for increased patient engagement in research but also healthcare. Collecting PROs in clinical research studies offers a lens into the patient's unique perspective providing important information to industry sponsors and the FDA. Approximately 30% of trials include PROs as primary or secondary endpoints and a quarter of FDA new drug, device and biologic applications include PRO data to support labeling claims. In this paper PRO, represents any information obtained directly from the patient or their proxy, without interpretation by another individual to ascertain their health, evaluate symptoms or conditions and extends the reference of PRO, as defined by the FDA, to include other sources such as patient diaries. Consumers and clinicians consistently report that PRO data are valued, and can aide when deciding between treatment options; therefore an integral part of clinical research. However, little guidance exists for clinical research professionals (CRPs) responsible for collecting PRO data on the best practices to ensure quality data collection so that an accurate assessment of the patient's view is collected. Therefore the purpose of this work was to develop and validate a checklist to guide quality collection of PRO data. The checklist synthesizes best practices from published literature and expert opinions addressing practical and methodological challenges CRPs often encounter when collecting PRO data in research settings. [ABSTRACT FROM AUTHOR]