Abstract: Research JAMA | Original Investigation Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19 A Randomized Clinical Trial Anil Gupta, MD; Yaneicy Gonzalez-Rojas, MD; Erick Juarez, MD; Manuel Crespo Casal, MD; Jaynier Moya, MD; Diego Rodrigues Falci, MD, PhD; Elias Sarkis, MD; Joel Solis, MD; Hanzhe Zheng, PhD; Nicola Scott, MSc; Andrea L. Cathcart, PhD; Sergio Parra, MD, MSc; Jennifer E. Sager, PhD; Daren Austin, PhD; Amanda Peppercorn, MD; Elizabeth Alexander, MD, MSc; Wendy W. Yeh, MD; Cynthia Brinson, MD; Melissa Aldinger, PharmD; Adrienne E. Shapiro, MD, PhD; for the COMET-ICE Investigators Visual Abstract IMPORTANCE Older patients and those with comorbidities who are infected with SARS-CoV-2 Supplemental content may be at increased risk of hospitalization and death. Sotrovimab is a neutralizing antibody for the treatment of high-risk patients to prevent COVID-19 progression. OBJECTIVE To evaluate the efficacy and adverse events of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial including 1057 nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for progression conducted at 57 sites in Brazil, Canada, Peru, Spain, and the US from August 27, 2020, through March 11, 2021; follow-up data were collected through April 8, 2021. INTERVENTIONS Patients were randomized (1:1) to an intravenous infusion with 500 mg of sotrovimab (n = 528) or placebo (n = 529). MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients with COVID-19 progression through day 29 (all-cause hospitalization lasting >24 hours for acute illness management or death); 5 secondary outcomes were tested in hierarchal order, including a composite of all-cause emergency department (ED) visit, hospitalization of any duration for acute illness management, or death through day 29 and progression to severe or critical respiratory COVID-19 requiring supplemental oxygen or mechanical ventilation. RESULTS Enrollment was stopped early for efficacy at the prespecified interim analysis. Among 1057 patients randomized (median age, 53 years [IQR, 42-62], 20% were ⱖ65 years of age, and 65% Latinx), the median duration of follow-up was 103 days for sotrovimab and 102 days for placebo. All-cause hospitalization lasting longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) (adjusted relative risk [RR], 0.21 [95% CI, 0.09 to 0.50]; absolute difference, –4.53% [95% CI, –6.70% to –2.37%]; P < .001). Four of the 5 secondary outcomes were statistically significant in favor of sotrovimab, including reduced ED visit, hospitalization, or death (13/528 [2%] for sotrovimab vs 39/529 [7%] for placebo; adjusted RR, 0.34 [95% CI, 0.19 to 0.63]; absolute difference, –4.91% [95% CI, –7.50% to –2.32%]; P < .001) and progression to severe or critical respiratory COVID-19 (7/528 [1%] for sotrovimab vs 28/529 [5%] for placebo; adjusted RR, 0.26 [95% CI, 0.12 to 0.59]; absolute difference, –3.97% [95% CI, –6.11% to –1.82%]; P = .002). Adverse events were infrequent and similar between treatment groups (22% for sotrovimab vs 23% for placebo); the most common events were diarrhea with sotrovimab (n = 8; 2%) and COVID-19 pneumonia with placebo (n = 22; 4%). CONCLUSIONS AND RELEVANCE Among nonhospitalized patients with mild to moderate COVID-19 and..