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ACTIV-6: Operationalizing a decentralized, outpatient randomized platform trial to evaluate efficacy of repurposed medicines for COVID-19

Lindsell et al., Journal of Clinical and Translational Science, doi:10.1017/cts.2023.644, NCT04885530
Oct 2023  
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Discussion of the operation of ACTIV-6 Naggie revealing participant fraud - authors identified participants that signed up repeatedly, and participants that withdrew when not randomized to their preferred arm. Authors indicate that they tried to prevent repeat signups but provide no details on the algorithms or the evaluation thereof. It is possible that they only caught a small fraction of the fraud, and possible that improvements to detection were added only later in the trial.
It is likely that individuals were gaming the system related to politicized treatments with extreme financial implications. This information was not disclosed previously.
Authors note that delivery was increasingly made to centralized pickup locations and not directly to the participant. Authors indicate they use shipping logs and participant notification of drug receipt. This is unclear because if delivery was based on participant confirmation there would be no need to determine delivery based on shipping logs. This suggests that in at least some cases, delivery time may not have accounted for the time for participant pickup. Therefore the actual treatment delay may be even longer than reported.
Lindsell et al., 31 Oct 2023, USA, peer-reviewed, 1 author, trial NCT04885530 (history).
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ACTIV-6: Operationalizing a decentralized, outpatient randomized platform trial to evaluate efficacy of repurposed medicines for COVID-19
PhD C J Lindsell
Journal of Clinical and Translational Science, doi:10.1017/cts.2023.644
Despite the availability of vaccinations, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause Coronavirus Disease 2019 (COVID-19) infection with a spectrum of disease in the acute setting. Transmission, infection, and severe disease remain common. There is a critical need to establish treatment regimens in the ambulatory setting that can reduce symptom burden and potentially prevent progression to severe disease and death. Many existing medicines previously approved for other uses may have benefit but remain unproven in informative clinical trials. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 is a decentralized, placebo-controlled, double-blind, randomized, platform trial that has now enrolled more than 7500 participants and has reported on the effectiveness of ivermectin at two doses, fluticasone, and fluvoxamine for helping people with COVID-19. With additional repurposed therapies added to the platform, ACTIV-6 continues to enroll symptomatic outpatients aged ≥ 30 years with a confirmed positive PCR or antigen test for SARS-CoV-2. Potential participants are screened and enrolled online, through a call center, or facilitated by local study sites. Participants consent electronically and are randomized to placebo or to one of the open study drugs for which they are eligible at the time of enrollment. A shared, contemporary placebo approach is used. Participants receive study drug in the mail and remain on study for up to 180 days. While enrolled, electronic patient-reported outcome assessments are used to monitor symptoms, healthcare utilization, and mortality. The primary endpoint is time to recovery or a composite of hospitalization and mortality within 28 days. Symptoms, acute healthcare utilization, and the Patient-Reported Outcomes Measurement Information System-29 are collected for up to 180 days. Using a decentralized trial approach allowed the ACTIV-6 platform to increase both reach and rate of enrollment. The decentralized approach did not simplify regulatory oversight, and we found unanticipated challenges in patient behavior and the study drug delivery process. Despite challenges, ACTIV-6 has enrolled thousands of participants from across the USA and continues to test the effectiveness of repurposed medicines for treating COVID-19. Our lessons learned contribute to the emerging understanding of how to optimize decentralized trials.
Competing interests. Dr Lindsell reported receiving grants to the institution from the National Center for Advancing Translational Sciences (NCATS) to the institution during the conduct of the study and grants to the institution from NIH and Department of Defense and research funds to the institution from the CDC, bioMerieux, AstraZeneca, AbbVie, Entegrion Inc., and Endpoint Health outside the submitted work; having a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center; and having stock options in Bioscape Digital unrelated to the current work. Dr Naggie reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and receiving grants from Gilead Sciences and AbbVie; receiving personal fees from Pardes Biosciences and Silverback Therapeutics for consulting; serving as a scientific advisor for and having stock options in Vir Biotechnology; receiving personal fees from and serving on a data and safety monitoring board for Personal Health Insights; and serving on an event adjudication committee for Bristol Myers Squibb/PRA Health Sciences outside the submitted work. Dr Hernandez reported receiving grants from AstraZeneca, Merck, and Pfizer outside the submitted work. No other disclosures were reported. Dr Stewart reported receiving grants from Duke University as a subaward for ACTIV-6 from NIH during the conduct of the study and grants from NIH supported by grants from NCATS..
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