Bayesian adaptive designs with response adaptive randomization (RAR) have the potential to benefit more participants in a clinical trial. While there are many papers that describe RAR designs and results, there is a scarcity of works reporting the details of RAR implementation from a statistical point exclusively. In this paper, we introduce the statistical methodology and implementation of the trial Changing the Default (CTD). CTD is a single-center prospective RAR comparative effectiveness trial to compare opt-in to opt-out tobacco treatment approaches for hospitalized patients. The design assumed an uninformative prior, conservative initial allocation ratio, and a higher threshold for stopping for success to protect results from statistical bias. A particular emerging concern of RAR designs is the possibility that time trends will occur during the implementation of a trial. If there is a time trend and the analytic plan does not prespecify an appropriate model, this could lead to a biased trial. Adjustment for time trend was not pre-specified in CTD, but post hoc time-adjusted analysis showed no presence of influential drift. This trial was an example of a successful two-armed confirmatory trial with a Bayesian adaptive design using response adaptive randomization.

BACKGROUND: To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075).
METHODS: We used data (n = 55) from our recent double-blind, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin.
RESULTS: Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm.
CONCLUSIONS: Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.

Clinicians report primarily using functional behavioral assessment (FBA) methods that do not include functional analyses. However, studies examining the correspondence between functional analyses and other types of FBAs have produced inconsistent results. In addition, although functional analyses are considered the gold standard, their contribution toward successful treatment compared with other FBA methods remains unclear. This comparative effectiveness study, conducted with 57 young children with autism spectrum disorder, evaluated the results of FBAs that did (n = 26) and did not (n = 31) include a functional analysis. Results of FBAs with and without functional analyses showed modest correspondence. All participants who completed functional communication training achieved successful outcomes regardless of the type of FBA conducted.

Rural residents generally lack adequate physical activity to benefit health and reduce disparities in chronic diseases, such as cardiovascular disease and certain cancers. The Socioecological Model describes physical activity as involving a dynamic and reciprocal interaction between individual, social, and community factors. Community group-based walking programs and civic engagement interventions aimed at enhancing physical activity have been successful in rural communities but have not targeted all three socioecological levels. Public libraries can act as innovative public health partners in rural communities. However, challenges remain because rural libraries often lack the capacity to implement evidence-based health promotion programming. The goals of this study are (1) build the capacity for rural libraries to implement evidence-based health promotion programs, (2) compare changes in physical activity between a group-based walking program and a combined group-based walking and civic engagement program with rural residents, and (3) conduct an implementation evaluation.
We will conduct a comparative effectiveness study of a group-based walking (standard approach) versus a group-based walking plus civic engagement program (combined approach) aimed at enhancing walkability to increase physical activity among rural adults. Key mediators between the program effects and change in outcomes will also be identified. Finally, we will evaluate program implementation, conduct a cost effectiveness evaluation, and use a positive deviance analysis to understand experiences of high and low changers on key outcomes. Twenty towns will be matched and randomized to one of the two conditions and our aim is to enroll a total of 350-400 rural residents (15-20 per town). Study outcomes will be assessed at baseline, and 6, 12, and 24 months.
This study will build the capacity of rural libraries to implement evidence-based walking programs as well as other health promotion programs in their communities. The study results will answer questions regarding the relative effectiveness and cost effectiveness of two multilevel physical activity interventions targeting rural communities. We will learn what works and how these multilevel interventions can be implemented in rural populations.
ClinicalTrials.gov Identifier: NCT05677906.

To address the US opioid epidemic, there is an urgent clinical need to provide persons with opioid use disorder (OUD) with effective medication treatments for OUD (MOUD). Formulations of sublingual buprenorphine/naloxone (SL-BUP/NLX) are considered the standard of care for OUD including within the Veterans Healthcare Administration (VHA). However, poor retention on MOUD undermines its effectiveness. Long-acting injectable monthly buprenorphine (INJ-BUP) (e.g., Sublocade®) has the potential to improve retention and therefore reduce opioid use and overdose. Designing and conducting studies for OUD pose unique challenges. The strategies and solutions to some of these considerations in designing Cooperative Studies Program (CSP) 2014, Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE), a randomized, 20-site, clinical effectiveness trial comparing INJ-BUP to SL-BUP/NLX conducted within the VHA may provide valuable guidance for others confronted with similar investigation challenges.
This 52-week, parallel group, open-label, randomized controlled trial (RCT) evaluates the comparative effectiveness of two current FDA-approved formulations of buprenorphine: (1) daily SL-BUP/NLX vs. (2) monthly (28-day) INJ-BUP for Veterans with moderate to severe OUD (n = 952). The primary outcomes are (1) retention in MOUD and (2) opioid abstinence. Secondary outcomes include measures of other drug use, psychiatric symptoms, medical outcomes including prevalence rates of HIV, hepatitis B and C as well as social outcomes (housing instability, criminal justice involvement), service utilization and cost-effectiveness. Special considerations in conducting a comparative effectiveness trial with this population and during COVID-19 pandemic were also included.
The evaluation of the extended-release formulation of buprenorphine compared to the standard sublingual formulation in real-world VHA settings is of paramount importance in addressing the opioid epidemic. The extent to which this new treatment facilitates retention, decreases opioid use, and prevents severe sequelae of OUD has not been studied in any long-term trial to date. Positive findings in this trial could lead to widespread adoption of MOUD, and, if proven superior INJ-BUP, by clinicians throughout the VHA and beyond. This treatment has the potential to reduce opioid use among Veterans, improve medical, psychological, and social outcomes, and save lives at justifiable cost. Trial registration Registered at Clinicaltrials.gov NCT04375033.

We examine recruitment processes for 71 pragmatic and comparative effectiveness trials identified in a systematic review, using path analysis to examine rates of refusal to screen, test, and consent to trial participation. Our analysis suggests that refusal rates might be on net slightly higher if potential subjects are screened or asked to undergo physical eligibility tests, but this was not significant in our sample of trials (p = .11 by Mann-Whitney test). We find that rates of refusing to provide informed consent are much lower for trials in which subjects have agreed to screening or testing (odds ratio = 0.40, Wilcoxon rank-sum z = 2.67, p = .008). We also observe that the overwhelming majority of trials examined secured consent after determining eligibility, even in trials involving screening or testing activities. The ethical implications and areas for future research are discussed.

The Patient-Centered Outcomes Research Institute (PCORI) defines engagement in research as the meaningful involvement of patients, caregivers, clinicians, insurers, and others throughout the entire research process-from planning to conducting the study to disseminating study results. The purposes of this paper are to (a) describe methods used to engage community members across the various phases of a PCORI-funded comparative effectiveness trial to increase colorectal cancer screening; and (b) report results of qualitative and quantitative evaluations of community advisory board members\' experiences on this project. Decisions to join and stay engaged with the study included feeling valued and appreciated, being compensated, the opportunity to contribute to research based on their skills and expertise, and being committed to colon cancer prevention efforts. Challenges identified by advisory board members included the significant time commitment, transportation, and meeting location. Lessons learned and guidance for researchers committed to patient and community engagement are described.

This comparative effectiveness trial compared the longer-term effectiveness (12 and 18 months) of the standard Fit & Strong! physical activity program to Fit & Strong! Plus, which combined physical activity and dietary weight loss. Outcomes were weight, diet quality, physical activity, osteoarthritis symptoms, performance measures, and anxiety/depression. In this study, 413 overweight/obese participants with OA, ≥60 years old and primarily African American, were randomly assigned to Fit & Strong! (F&S!) or Fit & Strong! Plus (F&S! Plus), with outcomes assessed at 2, 6, 12, and 18 months. 356 (86%) participants completed the 18-month visit. Compared with participants randomized to standard F&S!, F&S! Plus participants maintained longer-term benefits at 12 months in weight (mean change ± SE: -1.7 ± 0.3 kg for F&S! Plus vs -0.9 ± 0.3 kg for F&S!, p = 0.049), BMI (-0.6 ± 0.1 vs -0.3 ± 0.1 kg/m2, p = 0.04), waist circumference (-2.7 ± 0.6 vs -0.4 ± 0.6 cm, p = 0.004), and lower extremity strength (1.6 ± 0.2 vs 1.0 ± 0.2 chair stands, p = 0.046). At 18 months, F&S! Plus participants showed improved lower extremity strength (1.4 ± 0.2 vs. 0.7 ± 0.2 chair stands, p = 0.045. African American older adults in the F&S! Plus arm showed sustained modest improvements in weight, waist circumference, and lower extremity strength at 12 months and in lower extremity strength at 18 months compared to F&S!. Implications for the translation of evidence-based programs into community settings to support healthy behaviors in older adults are discussed.

BACKGROUND: For loco-regionally advanced, but transorally resectable oropharyngeal cancer (OPSCC), the current standard of care includes surgical resection and risk-adapted adjuvant (chemo) radiotherapy, or definite chemoradiation with or without salvage surgery. While transoral surgery for OPSCC has increased over the last decade for example in the United States due to transoral robotic surgery, this treatment approach has a long history in Germany. In contrast to Anglo-Saxon countries, transoral surgical approaches have been used frequently in Germany to treat patients with oro-, hypopharyngeal and laryngeal cancer. Transoral laser microsurgery (TLM) has had a long tradition since its introduction in the early 70s. To date, the different therapeutic approaches to transorally resectable OPSCC have not been directly compared to each other in a randomized trial concerning disease control and survival. The goal of this study is to compare initial transoral surgery to definitive chemoradiation for resectable OPSCC, especially with regards to local and regional control.
METHODS: TopROC is a prospective, two-arm, open label, multicenter, randomized, and controlled comparative effectiveness study. Eligible patients are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1-2c, M0; T3, N0-2c, M0 UICC vers. 7) which are amenable to transoral resection. Two hundred eighty patients will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be performed according to daily routine practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant therapy. Patients treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits for 3 years are planned. Primary endpoint is time to local or locoregional failure (LRF). Secondary endpoints include overall and disease free survival, toxicity, and patient reported outcomes. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a scientific support program.
CONCLUSIONS: This study will shed light on an urgently-needed randomized comparison of the strategy of primary chemoradiation vs. primary surgical approach. As a comparative effectiveness trial, it is designed to provide data based on two established regimens in daily clinical routine.
BACKGROUND: NCT03691441 Registered 1 October 2018 - Retrospectively registered.

BACKGROUND: We designed and initiated a pilot comparative effectiveness study for juvenile localized scleroderma (jLS), for which there is limited evidence on best therapy. We evaluated the process we used, in relation to the specific protocol and to the general task of identifying strategies for implementing studies in rare pediatric diseases.
METHODS: This was a prospective, multi-center, observational cohort study of 50 jLS patients initiating treatment, designed and conducted by the jLS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) from 2012 to 2015. A series of virtual and physical meetings were held to design the study, standardize clinical assessments, generate and refine disease activity and damage measures, and monitor the study. Patients were initiated on one of three standardized methotrexate-based treatment regimens (consensus treatment plans, CTPs) and monitored for 1 year. An optional bio-banking sub-study was included.
RESULTS: The target enrollment of 50 patients was achieved over 26 months at 10 sites, with patients enrolled into all CTPs. Enrolled patients were typical for jLS. Study eligibility criteria were found to perform well, capturing patients thought appropriate for treatment studies. Minor modifications to the eligibility criteria, primarily to facilitate recruitment for future studies, were discussed with consensus agreement reached on them by the jLS group. There were marked differences in site preferences for specific CTPs, with half the sites treating all their patients with the same CTP. Most patients (88%) completed the study, and 68% participated in the bio-banking substudy.
CONCLUSIONS: We demonstrate the feasibility of our approach for conducting comparative effectiveness research in a rare pediatric disease. Multi-center collaboration by dedicated investigators who met regularly was a key factor in the success of this project. Other factors that facilitate these studies include having a sufficient number of investigators to enroll in each regimen, and streamlining study approval and management.