All Studies Meta Analysis

Metformin on Time to Sustained Recovery in Adults with COVID-19: The ACTIV-6 Randomized Clinical Trial

Bramante et al., medRxiv, doi:10.1101/2025.01.13.25320485, ACTIV-6, NCT04885530

Jan 2025

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Metformin for COVID-19

3rd treatment shown to reduce risk in July 2020, now with p < 0.00000000001 from 102 studies.

Lower risk for mortality, ventilation, ICU, hospitalization, progression, and recovery.

No treatment is 100% effective. Protocols combine treatments.

5,200+ studies for 112 treatments. c19early.org

RCT 2,991 outpatient adults with mild to moderate COVID-19 showing no significant difference in time to sustained recovery with metformin compared to placebo. Median days to symptom resolution was 9 days vs. 10 days for placebo, without statistical significance. There was a median 5 day delay for drug receipt (treatment delay is unspecified but may be greater).

eFigure 5 shows HR 0.40 [0.28-0.58], p = 0.000001, for patients that had recovered by the time of drug receipt and had no symptoms on that day. This result suggests a major confounding factor or flaw in the study leading to very unreliable results and a strong bias towards the placebo group. A likely possible cause is the inclusion of metformin side effects as COVID-19 symptoms. Authors include many side effects of metformin as COVID-19 symptoms: diarrhea: a common side effect of metformin, especially in the initial days of treatment; nausea: frequently reported with metformin use, vomiting: less common but a documented side effect of metformin; fatigue: metformin may cause mild fatigue or malaise in some individuals, and headache: rare but also a possible side effect of metformin. Authors do a sensitivity analysis using day 1 vs. baseline symptoms, however they do not provide details of this analysis. The text suggests authors only used diarrhea, and the day 1 focus would also result in only partial correction.

Note that it would be simple for authors to perform an analysis focusing on more COVID-19 specific and/or serious symptoms.

Trial designs favoring placebo/no effect were likely done to minimize efficacy of an earlier treatment in the trial - for example the wide inclusion of non-COVID-19 specific symptoms, inclusion of typical side-effect symptoms, use of the last of 3 days instead of the first of 3 days for sustained recovery, very slow shipping, and inclusion of patients up to 12 days from onset.

Patients with symptoms ≤7 days from onset were eligible, however eFigure 1 shows there were patients with up to 12 days from symptoms to drug receipt, suggesting up to 5 days shipping delay. Trial operation is not logical for an acute condition like COVID-19. Table 1 shows 48 hours delay between enrollment and receipt of medication (treatment time is not reported and may be even later - patients may not be at the location at delivery time). It is unclear why authors would not use overnight shipping as a worst case, widely available for the study population, for <24 hours delivery (other than designing the trial to favor finding no effect).

The study period was September 2023 - May 2024, by which time SARS-CoV-2 variants resulted in signficantly fewer serious outcomes, reducing the potential for a treatment to show a significant affect on serious outcomes.

There is an extensive list of major conflicts of interest reported (any many unreported).

ACTIV trial authors have reported a number of issues that may affect the reliability of the results in ACTIV trials including participant fraud1, biased participant demographics2, resource issues that may have led to protocol deviations2, differences in trial design including inconsistent inclusion/exclusion criteria2, participant self-selection bias1,2, underrepresentation of older patients due to web-based recruitment2, changes in treatment and public health policies during trials2, treatment delay determination from shipping logs and delivery that may not be directly to the patient1, variable placebo responses (e.g., oral vs. inhaled)3, logistical challenges maintaining blinding3, errors from complex data collection systems3, unplanned design changes including endpoint changes3, and inconsistent SoC across trial sites and time periods3.

Important missing comments or errors? Let us know.

risk of hospitalization, 43.0% higher, HR 1.43, p = 0.65, treatment 4 of 1,443 (0.3%), control 3 of 1,548 (0.2%), day 28.

risk of progression, 24.0% higher, HR 1.24, p = 0.28, treatment 58 of 1,443 (4.0%), control 53 of 1,548 (3.4%), adjusted per study, hospitalization, clinic visit, ER visit, or death, day 28.

risk of progression, 8.0% higher, HR 1.08, p = 0.62, treatment 1,443, control 1,548, adjusted per study, ordinal scale, day 28.

risk of progression, 4.0% lower, HR 0.96, p = 0.87, treatment 1,443, control 1,548, adjusted per study, ordinal scale, day 14.

risk of progression, no change, HR 1.00, p = 1.00, treatment 1,443, control 1,548, adjusted per study, ordinal scale, day 7.

risk of no recovery, 4.2% higher, HR 1.04, p = 0.28, treatment 58 of 1,443 (4.0%), control 53 of 1,548 (3.4%), adjusted per study, inverted to make HR<1 favor treatment, skeptical prior.

risk of no recovery, 10.0% lower, RR 0.90, p = 0.006, treatment mean 9.0 (±9.69) n=1,443, control mean 10.0 (±10.0) n=1,548, relative median days to sustained recovery, last of three days.

risk of no recovery, 12.5% lower, RR 0.88, p = 0.006, treatment mean 7.0 (±9.69) n=1,443, control mean 8.0 (±10.0) n=1,548, relative median days to sustained recovery, first of three days.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Lindsell et al., ACTIV-6: Operationalizing a decentralized, outpatient randomized platform trial to evaluate efficacy of repurposed medicines for COVID-19, Journal of Clinical and Translational Science, doi:10.1017/cts.2023.644.cambridge.org, doi.org.

2. Wohl et al., Engaging communities in therapeutics clinical research during pandemics: Experiences and lessons from the ACTIV COVID-19 therapeutics research initiative, Journal of Clinical and Translational Science, doi:10.1017/cts.2024.561.cambridge.org, doi.org.

3. Lindsell (B) et al., The statistical design and analysis of pandemic platform trials: Implications for the future, Journal of Clinical and Translational Science, doi:10.1017/cts.2024.514.cambridge.org, doi.org.

Bramante et al., 14 Jan 2025, Double Blind Randomized Controlled Trial, placebo-controlled, USA, preprint, median age 47.0, 28 authors, study period 19 September, 2023 - 1 May, 2024, trial NCT04885530 (history) (ACTIV-6). Contact: susanna.naggie@duke.edu.

This Paper Metformin All

Metformin on Time to Sustained Recovery in Adults with COVID-19: The ACTIV-6 Randomized Clinical Trial

MD, MPH Carolyn T Bramante, PhD Thomas G Stewart, MD, MPH David R Boulware, MD Matthew W Mccarthy, MS, Med Yue Gao, MD, MPP Russell L Rothman, MD Ahmad Mourad, Florence Thicklin, MD Jonathan B Cohen, Idania T Garcia Del Sol, MD Juan Ruiz-Unger, MD, MPH Nirav S Shah, DPM Manisha Mehta, MD Orlando Quintero Cardona, MD Jake Scott, MD, MPH Adit A Ginde, MD, MPH Mario Castro, MD Dushyantha Jayaweera, MD Mark Sulkowski, MD Nina Gentile, MD Kathleen Mctigue, MD G Michael Felker, MD, MSci Sean Collins, PhD Sarah E Dunsmore, PhD Stacey J Adam, PhD Christopher J Lindsell, MD, MHS Adrian F Hernandez, MD, MHS Susanna Naggie

doi:10.1101/2025.01.13.25320485

Importance: The effect of metformin on reducing symptom duration among outpatient adults with coronavirus disease 2019 (COVID-19) has not been studied. Objective: Assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. Design , Setting, and Participants: The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, 2991 participants age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days, were included at 90 US sites. Interventions: Participants were randomized to receive metformin (titrated to 1500 mg daily) or placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving study drug. Secondary outcomes included time to hospitalization or death; time to healthcare utilization (clinic visit, emergency department visit, hospitalization, or death). Safety events of special interest were hypoglycemia and lactic acidosis. Results: Among 2991 participants who were randomized and received study drug, the median age was 47 years (IQR 38-58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 1443 participants who received metformin and 1548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR] 0.96; 95% credible interval [CrI] 0.89-1.03; P(efficacy)=0.11). For participants enrolled during current variants, the aHR was 1.19 (95% CrI 1.05-1.34). The median time to sustained recovery was 9 days (95% confidence interval [CI] 9-10) for metformin and 10 days (95% CI 9-10) for placebo. No deaths were reported; 111 participants reported healthcare utilization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81-1.75; P(efficacy)=0.135). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. Five participants in each group reported having hypoglycemia.

Author Contributions Drs Naggie, Hernandez, and Lindsell had full access to all the blinded data in the study. Dr Stewart was provided curated study data and takes responsibility for the integrity of the data analysis. All authors contributed to the drafting and review of the manuscript and agreed to submit for publication.

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Late treatment
is less effective

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