Table of Contents
Trial Objectives and Oversight
In this phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we evaluated a single intravenous infusion of sotrovimab at a dose of 500 mg for the prevention of progression of mild-to-moderate Covid-19 in high-risk, nonhospitalized patients. For this prespecified interim analysis, patients were recruited beginning on August 27, 2020, and were followed through March 4, 2021, at 37 trial sites in four countries (the United States, Canada, Brazil, and Spain). The protocol and statistical analysis plan are available at NEJM.org, and changes made to these documents after the trial began are summarized in the Supplementary Appendix.
The trial, which was sponsored by Vir Biotechnology in collaboration with GlaxoSmithKline, was conducted in accordance with the principles of the Declaration of Helsinki and the ethical guidelines of the Council for International Organizations of Medical Sciences, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations. All the patients provided written informed consent. The sponsors designed the trial, and the sponsors and trial investigators participated in data collection, analysis, and interpretation. The authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data presented and for the fidelity of the trial to the protocol. Medical writers who were funded by Vir Biotechnology assisted in drafting the manuscript under the authors’ direction. All the authors had confidentiality agreements with the sponsors.
Patients and Procedures
Adult patients (≥18 years of age) who had a positive result on reverse-transcriptase–polymerase-chain-reaction or antigen SARS-CoV-2 testing and an onset of Covid-19 symptoms within the previous 5 days were screened for eligibility; screening was performed within 24 hours before the administration of sotrovimab or placebo. The patients were at high risk for progression of Covid-19 because of older age (≥55 years) or because they had at least one of the following risk factors: diabetes for which medication was warranted, obesity (body-mass index [BMI; the weight in kilograms divided by the square of the height in meters], >30), chronic kidney disease (estimated glomerular filtration rate, <60 ml per minute per 1.73 m2 of body-surface area),23 congestive heart failure (New York Heart Association class II, III, or IV), chronic obstructive pulmonary disease, and moderate-to-severe asthma.24 Patients with already severe Covid-19, defined as shortness of breath at rest, an oxygen saturation below 94%, or the use of supplemental oxygen, were excluded. Full inclusion and exclusion criteria are described in the Supplementary Methods section in the Supplementary Appendix.
Patients were stratified according to age (≤70 years or >70 years), symptom duration (≤3 days or 4 or 5 days), and geographic region. The trial pharmacists reconstituted and dispensed sotrovimab and placebo within equal time frames in order to maintain blinding.
Eligible patients were randomly assigned in a 1:1 ratio with the use of an interactive Web-based response system to receive either a single 500-mg, 1-hour infusion of sotrovimab or an equal volume of saline placebo on day 1 (Figure 1). The trial design did not mandate any treatment for Covid-19 other than sotrovimab or placebo; as a result, the patients received treatment at the discretion of their physicians according to the local standard of care.
The primary outcome was the percentage of patients who were hospitalized for more than 24 hours or who died from any cause through day 29 after randomization. Secondary efficacy outcomes included the percentage of patients with an emergency department visit, hospitalization, or death and the percentage of patients who had disease progression that warranted the use of supplemental oxygen.
The safety outcomes included adverse events, serious adverse events, and adverse events of special interest, which were defined as infusion-related reactions (including hypersensitivity reactions). Immunogenicity testing for antidrug antibodies was performed, and antibody-dependent enhancement was evaluated. All hospitalizations, including those due to Covid-19, were counted as serious adverse events.
A prespecified interim analysis for safety, futility, and efficacy was triggered when approximately 41% of the required number of trial patients reached day 29. Sample-size calculations were based on a group-sequential design with two interim analyses to assess both futility due to lack of efficacy and efficacy. A Lan–DeMets alpha-spending function was used to control type I error, with the use of a Pocock analogue rule for futility and a Hwang–Shih–DeCani analogue rule for efficacy (with the value of γ=1).25 The overall sample of 1360 patients would have provided approximately 90% power to detect a 37.5% relative efficacy in reducing progression of Covid-19 through day 29 at the overall two-sided 5% significance level, with an assumed incidence of progression of 16% in the placebo group.
In the interim analysis, the intention-to-treat population included all the patients who underwent randomization through the prespecified interim analysis cutoff date of January 19, 2021, irrespective of whether they received sotrovimab or placebo. The safety analysis population in the interim analysis included all the patients who received sotrovimab or placebo and underwent randomization through February 17, 2021; patients were grouped according to the actual agent received. The primary outcome was analyzed in the intention-to-treat population with the use of a Poisson regression model with robust sandwich estimators to adjust for trial agent, duration of symptoms, age, and sex. Missing progression status was imputed under a missing-at-random assumption with the use of multiple imputation. On the basis of this analysis model, the statistical significance testing, the relative risk of progression, and its appropriate confidence interval are provided with the adjusted significance level for this interim analysis.
An independent data monitoring committee recommended that enrollment in the trial be stopped on March 10, 2021, because of efficacy, at which time 1057 patients had undergone randomization. Analyses of all secondary and exploratory outcomes are planned when all the patients have completed day 29.