The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care.

INTRODUCTION: The COVID-19 pandemic had significant impact on clinical care and clinical trial operations, but the impact on decentralized pragmatic trials is unclear. The Diuretic Comparison Project (DCP) is a Point-of Care (POC) pragmatic trial testing whether chlorthalidone is superior to hydrochlorothiazide in preventing major cardiovascular (CV) events and non-cancer death. DCP utilized telephone consent, data collection from the electronic health record and Medicare, forwent study visits, and limited provider commitment beyond usual care. We assessed the impact of COVID-19 on recruitment, follow-up, data collection, and outcome ascertainment in DCP. METHODS: We compared data from two 8-month periods: Pre-Pandemic (July 2019-February 2020) and Mid-Pandemic (July 2020-February 2021). Consent and randomization rates, diuretic adherence, blood pressure (BP) and electrolyte follow-up rates, records of CV events, hospitalization, and death rates were compared. RESULTS: Providers participated at a lower rate mid-pandemic (65%) than pre-pandemic (71%), but more patients were contacted (7622 vs. 5363) and consented (3718 vs. 3048) mid-pandemic than pre-pandemic. Patients refilled medications and remained on their randomized diuretic equally (90%) in both periods. Overall, rates of BP, electrolyte measurements, and hospitalizations decreased mid-pandemic while deaths increased. CONCLUSIONS: While recruitment, enrollment, and adherence did not suffer during the pandemic, documented blood pressure checks and laboratory evaluations decreased, likely due to fewer in-person visits. VA hospitalizations decreased, despite a considerable number of COVID-related hospitalizations. This suggests changes in clinical care during the pandemic, but the limited impact on DCP's operations during a global pandemic is an important strength of POC trials. CLINICAL TRIAL REGISTRATION: NCT02185417.

Patient- reported reasons for non-participation in a COVID-19 therapeutics clinical trial: Findings from a multi-center investigation.

BACKGROUND: Early in the pandemic, there were no evidence-based treatments for SARS-CoV-2, creating an urgent need to identify effective therapeutics. However, public participation in medical research is low; trial enrollment in the US is typically 10-20%. Thus, the aim of this study was to identify common themes underpinning patient reasons to decline participation and evaluate the impact of specific contextual factors. METHODS: This sub-study was conducted in five VISN-1 Clinical Trials Network participating facilities from 4/10/2020-2/3/2021. The trial evaluated the addition of the IL-6-inhibitor, Sarilumab, to the current standard of care for inpatients with moderate-to-severe SARS-CoV-2. Consent procedures varied by site and included fully in-person and fully remote processes. Reasons for declining enrollment were collected among eligible patients who declined to participate but agreed to answer a short follow-up question. Qualitative data were analyzed using directed content analysis. Enrollment rates were assessed using simple, descriptive statistics. RESULTS: N = 417 COVID-19 positive inpatients were screened and 53/162 eligible patients enrolled. Enrollment varied across study sites and by study period. Prior to identification of effective treatment, the enrollment rate was 10/11 (91%) versus 43/144 (30%) during the later period of the study. N = 85/102 patients who did not enroll answered the follow-up question. The most commonly reported responses were: concerns about the study drug and participation in clinical research in general, comorbidity concerns, competing priorities, external factors, and external advice and influence from family members and clinicians. CONCLUSIONS: Identifying reasons behind declining to enroll may help investigators develop strategies to increase research participation.

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Rationale, design and methods of VA-BRAVE: a randomized comparative effectiveness trial of two formulations of buprenorphine for treatment of opioid use disorder in veterans.

BACKGROUND: 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. METHODS: 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. DISCUSSION: 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.

Rapid implementation of a modular clinical trial informatics solution for COVID-19 research.

Veterans Health Administration (VHA) services are most frequently used by patients 65 years and older, an age group that is disproportionally affected by COVID-19. Here we describe a modular Clinical Trial Informatics Solution (CTIS) that was rapidly developed and deployed to support a multi-hospital embedded pragmatic clinical trial in COVID-19 patients within the VHA. Our CTIS includes tools for patient eligibility screening, informed consent tracking, treatment randomization, EHR data transformation for reporting and interfaces for patient outcome and adverse event tracking. We hope our CTIS component descriptions and practical lessons learned will serve as a useful building block for others creating their own clinical trial tools and have made application and database code publicly available.

Implementation of documented and written informed consent for clinical trials of communicable diseases: Lessons learned, barriers, solutions, future directions identified during the conduct of a COVID-19 clinical trial.

BACKGROUND AND OBJECTIVE: The communicable nature of many infectious diseases, including SARS-CoV-2, creates challenges for implementing and obtaining regulatory-compliant written informed consent. The goal of this project was to identify and evaluate processes that address these barriers while maintaining clinical and research staff safety. METHODS: We reviewed Federal Drug Administration (FDA), World Health Organization (WHO), and VA Office of Research and Development (ORD) guidance about informed consent during the COVID-19 pandemic, and identified and pilot-tested several mechanisms for obtaining regulatory-compliant consent during our COVID-19 therapeutics clinical trial. RESULTS: Several processes were identified. These included a standard face-to-face consent with a plan for maintaining a paper copy of the signed consent form, a phone or video chat consent process that included taking a picture of the signed consent form or a screen shot of the signed document during a video chat, integration of the consent forms into software embedded within the electronic health record, and secure software programs with electronic signature. These processes are FDA-compliant but time-intensive, often requiring four or more hours of coordination between the clinical team, research staff, patients, and legally authorized representatives. CONCLUSIONS: Future studies could evaluate how to improve efficiency, and whether some elements of the consenting process, such as the requirement for documented written signed consent, rather than a witnessed oral consent, is an acceptable standard for research participants with communicable diseases.

Pragmatic, adaptive clinical trials: Is 2020 the dawning of a new age?

Given the high case fatality rate of SARS-CoV-2, for which there is no cure and no vaccine, clinicians are forced to make decisions about how best to manage patients with limited high-quality evidence to guide treatment. Traditional randomized controlled trials provide strong experimental evidence, however, tend to be slow, inflexible, and have limited generalizability. Adaptive and pragmatic designs are an attractive alternative, which meet our ethical obligation during the SARS-CoV-2 pandemic to balance speed, agility, and generalizability with both prospective study and scientific rigor.