Strategies used for the COVID-OUT decentralized trial of outpatient treatment of SARS-CoV-2
BA Nandini Avula, Dustin Kakach, Christopher J Tignanelli, David M Liebovitz, Jacinda M Nicklas, Kenneth Cohen, Michael A Puskarich, Hrishikesh K Belani, John B Buse, Nichole R Klatt, Blake Anderson, Amy B Karger, Katrina M Hartman, Barkha Patel, Sarah L Fenno, Neha V Reddy, Spencer M Erickson, David R Boulware, Thomas A Murray, Carolyn T Bramante
Journal of Clinical and Translational Science, doi:10.1017/cts.2023.668
The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT's are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participantreported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.
JBB reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by Dexcom, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion Inc., Boehringer-Ingelheim, CeQur, Cirius Therapeutics Inc., Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns Inc., Valo and Zealand Pharma; and stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health. Dr Puskarich receives consulting fees from Opticyte and Cytovale. The trial was funded by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and the UnitedHealth Group Foundation. Competing interests. The fluvoxamine placebo tablets were donated by the Apotex pharmacy. The ivermectin placebo and active tablets were donated by the Edenbridge pharmacy. The funders had no influence on the design or conduct of the trial and were not involved in data collection or analysis, writing of the manuscript, or decision to submit for publication. The authors assume responsibility for trial fidelity and the accuracy and completeness of the data and analyses.
References
Adepoju, Ojinnaka, Shetty, Angelocci, Utilization gaps during the COVID-19 pandemic: racial and ethnic disparities in Telemedicine Uptake in federally qualified health center clinics, J Gen Intern Med,
doi:10.1007/s11606-021-07304-4Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19, N Engl J Med,
doi:10.1056/NEJMoa2016638Bramante, Buse, Liebovitz, Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial, Lancet Infect Dis,
doi:10.1016/S1473-3099(23)00299-2Bramante, Huling, Tignanelli, Randomized trial of metformin, ivermectin, and fluvoxamine for covid-19, N Engl J Med,
doi:10.1056/NEJMoa2201662Chiamulera, Mantovani, Tamburin, Remote clinical trials: a timely opportunity for a virtual reality approach and its potential application in neurology, Br J Clin Pharmacol,
doi:10.1111/bcp.14922Ely, Ramanan, Kartman, Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial, Lancet Respir Med,
doi:10.1016/S2213-2600(22)00006-6Hammond, Leister-Tebbe, Gardner, Oral nirmatrelvir for high-risk, nonhospitalized adults with covid-19, N Engl J Med,
doi:10.1056/NEJMoa2118542Kjerpeseth, Cesta, Furu, Metformin versus insulin and risk of major congenital malformations in pregnancies with Type 2 Diabetes: a nordic register-based cohort study, Diabetes Care,
doi:10.2337/dc23-0256Schuchat, Walensky, Agency Guidance Review
Simmons, Phipps, Whipps, From hybrid to fully remote clinical trial amidst the COVID-19 pandemic: strategies to promote recruitment, retention, and engagement in a randomized mHealth trial, Digit Health,
doi:10.1177/20552076221129065Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial, Ann Intern Med,
doi:10.7326/M20-4207Spiegel, Hays, Bolus, Development of the NIH patientreported outcomes measurement information system (PROMIS) gastrointestinal symptom scales, Am J Gastroenterol,
doi:10.1038/ajg.2014.237Stewart, Krows, Schaafsma, Comparison of racial, ethnic, and geographic location diversity of participants enrolled in clinic-based vs 2 remote COVID-19 clinical trials, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2021.48325Tarry-Adkins, Ozanne, Aiken, Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/metaanalysis, Sci Rep,
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'\t <jats:p>The COVID-19 pandemic accelerated the development of decentralized clinical '
'trials (DCT). DCT’s are an important and pragmatic method for assessing health outcomes yet '
'comprise only a minority of clinical trials, and few published methodologies exist. In this '
'report, we detail the operational components of COVID-OUT, a decentralized, multicenter, '
'quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial '
'examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment '
'of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized '
'strategies included HIPAA-compliant electronic screening and consenting, prepacking '
'investigational product to accelerate delivery after randomization, and remotely confirming '
'participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, '
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'which was the a priori primary study sample. Only 1.4% of participants were lost to '
'follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT '
'trial without any in-person contact by expediting intervention delivery, expanding trial '
'access geographically, limiting contagion exposure, and making it easy for participants to '
'complete follow-up visits. Remotely completed consent and follow-up facilitated '
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'https://greenphire.com/participant-payments/clincard-participant-support/. '
'Accessed June 11, 2023.'},
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'Adolescent Subjects in Clinical Trials of Drugs and Biological Products '
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'https://www.fda.gov/media/142143/download. Accessed March 27, 2023.'},
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