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

Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. We co...

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Published in:	The Lancet infectious diseases Vol. 23; no. 10; pp. 1119 - 1129
Main Authors:	Bramante, Carolyn T, Buse, John B, Liebovitz, David M, Nicklas, Jacinda M, Puskarich, Michael A, Cohen, Ken, Belani, Hrishikesh K, Anderson, Blake J, Tignanelli, Christopher J, Thompson, Jennifer L, Pullen, Matthew, Wirtz, Esteban Lemus, Siegel, Lianne K, Proper, Jennifer L, Odde, David J, Klatt, Nichole R, Lindberg, Sarah M, Karger, Amy B, Erickson, Spencer M, Fenno, Sarah L, Hartman, Katrina M, Rose, Michael R, Mehta, Tanvi, Patel, Barkha, Griffiths, Gwendolyn, Bhat, Neeta S, Murray, Thomas A, Boulware, David R, Anderson, Blake, Atwater, Riannon C, Avula, Nandini, Beckman, Kenny B, Brea, Jannis, Broedlow, Courtney A, Campora, Paula, Challa, Anup, Charles, Jill, Christensen, Grace, Christiansen, Theresa, Connelly, Bo, Datta, Srijani, Deng, Nikita, Dunn, Alex T, Fairbairn, Faith M, Fraser, Daniel J, Fricton, Regina D, Griffiths, Gwen, Hagen, Aubrey A, Hendrickson, Audrey F, Huling, Jared D, Ingraham, Nicholas E, Jeng, Arthur C, Johnson, Darrell M, LaBar, Derek D, Lee, Samuel, Lindberg, Sarah, Luke, Darlette G, Machicado, Rosario, Mohamud, Zeinab, Ngonyama, Rumbidzai, Parrens, Elliott, Parra, Daniela, Pullen, Matthew F, Rao, Via, Reddy, Neha V, Reddy, Naveen, Rypka, Katelyn J, Saveraid, Hanna G, Seloadji, Paula, Shahriar, Arman, Sherwood, Nancy, Siegart, Jamie L, Simmons, Lucas, Sinelli, Isabella, Snyder, Andrew, Stauffer, Maxwell T, Watson, Ray HB, Wu, Beiqing, Zaman, Adnin, Zolik, Madeline R, Zinkl, Lena
Format:	Journal Article
Language:	English
Published:	United States Elsevier Ltd 01-10-2023 Elsevier Limited
Subjects:	Adult Antigens Breastfeeding & lactation Clinical trials Consent COVID-19 COVID-19 Drug Treatment Diabetes mellitus Diagnosis Double-Blind Method Drug dosages Drug stores Electronic health records Female Fluvoxamine Health services Humans Incidence Infections Infectious diseases Ivermectin Ivermectin - therapeutic use Kidney diseases Male Metformin Metformin - therapeutic use Middle Aged Oral administration Outpatients Placebos Post-Acute COVID-19 Syndrome Pregnancy Prevention Public health Rain water Randomization SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 Signs and symptoms Subgroups Treatment Outcome Viral diseases Web portals Womens health United States > US
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Summary:	Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30–85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo. Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.
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ISSN:	1473-3099 1474-4457 1474-4457
DOI:	10.1016/S1473-3099(23)00299-2