Early treatment of Covid-19 with SARS-CoV-2 neutralizing antibody Sotrovimab

Trials and supervision

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 to prevent the progression of mild to moderate Covid-19 in high-risk, non-hospitalized patients. For this pre-specified interim analysis, patients were recruited from 27 August 2020 and were followed until 4 March 2021 at 37 trial sites in four countries (USA, Canada, Brazil and Spain). The protocol and the statistical analysis plan are available at NEJM.org, and changes made to these documents after the trial started 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 of International Organizations of Medical Sciences, applicable guidelines of the International Council for Harmonization of Good Clinical Practice, and applicable laws and rules. All patients gave 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 experiment to the protocol. Medical authors, funded by Vir Biotechnology, helped draft the manuscript under the authors’ guidance. All authors had confidentiality agreements with the sponsors.

Patients and procedures

Adult patients (≥18 years) who had a positive result on reverse transcriptase-polymerase chain reaction or antigen SARS-CoV-2 test and an onset of Covid-19 symptoms within the previous 5 days were screened for suitability; screening was performed within 24 hours prior to administration of sotrovimab or placebo. Patients were at high risk for progression of Covid-19 due to older age (≥55 years) or because they had at least one of the following risk factors: diabetes to which medication was eligible, 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 the body surface),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. Complete inclusion and exclusion criteria are described in the Supplementary Methods section of the Supplementary Appendix.

Sample design.

Patients were stratified by age (≤70 years or> 70 years), symptom duration (≤3 days or 4 or 5 days) and geographical region. The experimental pharmacists reconstituted and dispensed sotrovimab and placebo within equal time frames to maintain blindness.

Eligible patients were randomly assigned to a 1: 1 ratio using an interactive web-based response system to receive either a single 500 mg, 1-hour sotrovimab infusion, or an equivalent amount of saline placebo on day 1 (figure 1). The experimental design did not impose any other treatment for Covid-19 other than sotrovimab or placebo; as a result, patients received treatment at the discretion of their physician according to the local standard of care.

Impact assessments

The primary outcome was the percentage of patients who were hospitalized for more than 24 hours or who died of any cause through day 29 after randomization. Secondary efficacy outcomes included the percentage of patients with an emergency room visit, hospitalization, or death and the percentage of patients who had disease progression that warranted the use of supplemental oxygen.

Security assessments

The safety results included adverse reactions, serious adverse reactions and adverse reactions of particular interest, which were defined as infusion-related reactions (including hypersensitivity reactions). Immunogenicity testing for antibody antibodies was performed and antibody-dependent amplification was evaluated. All admissions, including those due to Covid-19, were considered as serious side effects.

Statistical analysis

A pre-specified interim analysis for safety, uselessness 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 analyzes to assess both uselessness due to lack of efficacy and efficacy. A Lan-DeMet alpha consumption function was used to control type I errors using a Pocock analog rule for uselessness and a Hwang-Shih-DeCani analog rule for efficiency (with the value γ = 1).25 The total sample of 1360 patients would have given approximately 90% power to detect a relative effect of 37.5% to reduce the progression of Covid-19 through day 29 at the overall two-sided significance level of 5%, with an assumed incidence of progression of 16% in the placebo group.

In the temporary analysis, the intention-to-treat population included all patients who underwent randomization through the predetermined interim analysis cut-off date of January 19, 2021, whether they received sotrovimab or placebo. The safety analysis population in the preliminary analysis included all patients who received sotrovimab or placebo and underwent randomization until 17 February 2021; patients were grouped according to the actual agent received. The primary outcome was analyzed in the intention-to-treat population using a Poisson regression model with robust sandwich estimators to adjust for test drug, duration of symptoms, age, and sex. Missing progression status was imputed under a lack of random assumption using multiple imputation. Based on 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 admission to the trial be stopped on March 10, 2021 due to the efficacy at which time 1057 patients had undergone randomization. Analyzes of all secondary and exploratory results are scheduled when all patients have completed day 29.

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