CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

this result needs further study. Well-designed studies in this patient group are urgently needed to compare watchful waiting with different (combinations) of drugs as well as treatment durations.

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Metformin on Time to Sustained Recovery in Adults With COVID-19: ACTIV-6 Randomized Clinical Trial Carolyn Bramante 1 , Thomas Stewart 2 , David R. Boulware 1 , Matthew McCarthy 3 , Russell Rothman 4 , Ahmad Mourad 5 , Florence Thicklin 6 , Yue Gao 4 , Michael Felker 7 , Sean Collins 4 , Sarah Dunsmore 8 , Stacey Adam 9 , Christopher Lindsell 7 , Adrian Hernandez 7 , Susanna Naggie 7 , for the ACTIV-6 Study Group 1 University of Minnesota, Minneapolis, MN, USA, 2 University of Virginia, Charlottesville, VA, USA, 3 Weill Cornell Medicine, New York, NY, USA, 4 Vanderbilt University Medical Center, Nashville, TN, USA, 5 Duke University School of Medicine, Durham, NC, USA, 6 Stakeholder Advisory Committee, Pittsburgh, PA, USA, 7 Duke Clinical Research Institute, Durham, NC, USA, 8 National Center for Advancing Translational Science, Bethesda, MD, USA, 9 National Institutes of Health, Bethesda, MD, USA Background: The effect of metformin on reducing symptom duration among low-risk, outpatient adults with mild to moderate coronavirus disease 2019 (COVID-19) has not been studied. Our objective was to test metformin compared to placebo for symptom resolution during acute infection with SARS-CoV-2. Methods: The ACTIV-6 platform clinical trial evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023 and May 1, 2024, 3,214 participants were enrolled at 110 US sites to evaluate metformin. Participants were age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days. Participants were randomized to receive 14 days of metformin (titrated to 1,500mg daily) or placebo. 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 healthcare utilization (clinic visit, emergency department visit, hospitalization or death). Safety events of special interest included hypoglycemia and lactic acidosis. Results: Among randomized participants who received study drug, the median age was 47 years (IQR 38-58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.4% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 1,443 participants who received metformin and 1,548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR], 0.96 [95% credible interval, 0.89-1.03; P(efficacy) = 0.11]). The median time to sustained recovery was 9 days (95% CI 9 to 10) in the metformin group and 10 days (95% CI 9-10) in the placebo group. No deaths were reported; 111 participants reported a clinic visit, emergency department visit, or hospitalization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81, 1.75; P(efficacy)=0.135). There were no episodes of lactic acidosis, and 5 participants in each group reported that they had hypoglycemia. Prespecified analyses support hypotheses about early initiation and use with current variants. Conclusions: Metformin was not shown to shorten the time to symptom resolution in adults with mild to moderate COVID-19; the median days to symptom resolution was numerically but not significantly lower for metformin than placebo. Emergency department visits and hospitalizations were too infrequent to draw conclusions. This was the first phase 3 trial to randomize adults without chronic disease or disease risk to metformin, and there were no safety concerns.

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Synergistic Effect of NMV/r and Acquired Immunity in Reducing Severe COVID-19 Warren Bao 1 , Wayne Wisemandle 2 , Heidi Leister-Tebbe 3 , Romina Quercia 4 , Jennifer Hammond 3 1 Pfizer Biostatistics, New York, NY, USA, 2 Pfizer Biostatistics, Collegeville, PA, USA, 3 Pfizer R&D, Collegeville, PA, USA, 4 Pfizer Medical Affairs, Edison, NJ, USA Background: Both immunization and nirmatrelvir-ritonavir treatment (NMV-r) are known to lower the risk of severe COVID-19 including hospitalization or death. However, it is unclear whether the effect of NMV-r and acquired immunity (via vaccination or prior viral exposure indicated as serologic positivity) are additive or synergistic. Methods: Non-hospitalized symptomatic adults infected with COVID-19 were enrolled into two similarly designed double-blind clinical trials, EPIC-HR and EPIC-SR, and randomized (1:1) to receive NMV-r or placebo for 5 days. All participants with risk factors for severe COVID-19 from these two published trials were included to evaluate synergy between NMV-r and acquired immunity, with synergy assessed as Relative Excess Risk due to Interaction (RERI) and Attributable Proportion (AP). Results: 2572 participants were divided into 4 groups based on acquired immunity (vaccinated/sero-positivity) and NMV-r (or placebo). Relative to the group with no acquired immunity and treated with placebo, the risk of COVID-19 related hospitalization or all-cause death was reduced (95% CI) by 83% (71-90%) with acquired immunity alone, 85% (69-93%) with NMV-r alone, and 96% (88-98%) when both were present. To assess the presence of synergistic effect, comparisons were made with reference to the group with greatest risk prevention, participants with both acquired immunity and NMV-r. The risk increased significantly (p<0.0001) to 3.4-fold without acquired immunity, 3.82-fold without NMV-r, and to 22.73-fold in the absence of both (Figure 1). This indicated that 16.5-fold risk increase was due to synergy (RERI), accounting for 72.7% of total risk (AP). The synergy was seen both in men and in women, and regardless of whether immunity was acquired through vaccination or due to prior viral exposure. Furthermore, the synergistic effect was reflected in the clearance pattern of SARS-CoV-2 and was supported by similar synergy observed in the proportion of participants with any COVID-related medical visits or in the proportion with severe COVID-19 symptoms post treatment. Conclusions: Among participants at high risk to develop severe COVID-19, NMV-r and acquired immunity provided incremental protection against severe COVID including hospitalization or death in the presence of each other. More significantly, because of the synergistic effect between NMV-r and acquired immunity, participants with neither immunization nor treatment saw a deleterious risk increase in severe COVID of more than 20-fold.

Poster Abstracts

CROI 2025 207