Mary Wilson
Well-known member
Published: June 08, 2023
DOI: https://doi.org/10.1016/S1473-3099(23)00299-2
Carolyn T Bramante, MD, Prof John B Buse, PhD, David M Liebovitz, MD, Jacinda M Nicklas, MD, Michael A Puskarich, MD, Ken Cohen, MD, et al.
Summary
Background
Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially a ecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or uvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID.
Methods
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 uvoxamine, metformin plus placebo, ivermectin plus placebo, uvoxamine 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 modi ed 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 prespeci ed, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194.
Findings
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 modi ed 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 uvoxamine). 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
0·59, 95% CI 0·39–0·89; p=0·012). The metformin bene cial e ect was consistent across prespeci ed 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 e ect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or uvoxamine (1·36, 0·78–2·34) compared with placebo.
Interpretation
Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin
https://www.thelancet.com/action/showPdf?pii=S1473-3099(23)00299-2
DOI: https://doi.org/10.1016/S1473-3099(23)00299-2
Carolyn T Bramante, MD, Prof John B Buse, PhD, David M Liebovitz, MD, Jacinda M Nicklas, MD, Michael A Puskarich, MD, Ken Cohen, MD, et al.
Summary
Background
Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially a ecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or uvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID.
Methods
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 uvoxamine, metformin plus placebo, ivermectin plus placebo, uvoxamine 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 modi ed 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 prespeci ed, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194.
Findings
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 modi ed 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 uvoxamine). 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
0·59, 95% CI 0·39–0·89; p=0·012). The metformin bene cial e ect was consistent across prespeci ed 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 e ect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or uvoxamine (1·36, 0·78–2·34) compared with placebo.
Interpretation
Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin
https://www.thelancet.com/action/showPdf?pii=S1473-3099(23)00299-2