Report on the operation of the COVID-OUT trial noting several issues affecting the reliability of the results:
- Use of home pulse oximeters for measuring oxygen saturation: authors note that the FDA warned about inaccuracies with home pulse oximeters during the trial. A single low reading <94% was part of the composite primary outcome for severe COVID-19. However, home devices can give falsely low readings for various reasons, so basing part of the primary outcome on a single home reading likely introduced significant error.
- Self-reported data: most of the data collected, including symptoms, medication adherence, oxygen levels, etc., was self-reported by participants. Self-reported data is subject to recall bias and other issues that could affect accuracy.
- No objective measurement of medication adherence: the authors note that medication adherence was assessed via self-report in the symptom logs. Without an objective measure like pill counts, actual adherence is uncertain.
- Limited verification of reported medical events/medications: while reported emergency room visits and hospitalizations were verified with records, new medications and medical events outside of participating health systems were not verified, relying only on participant self-report.
- Missing symptom data due to non-returned paper logs: the use of paper symptom logs meant that data was missing if participants did not mail the logs back, hampering data completeness.
- Inaccuracies in sample collection labeling early on: initially some patient samples were missing ID labels, creating challenges for connecting samples to the right patients. This may have led to unusable or mismatched samples.
Avula et al., 7 Nov 2023, peer-reviewed, 21 authors.
Contact:
avula010@umn.edu.
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.
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