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

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


Trial objectives 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 for the prevention of progression of mild to moderate Covid-19 in patients. at high risk. , outpatients. For this pre-defined interim analysis, patients were recruited from August 27, 2020 and were followed through March 4, 2021 at 37 trial sites in four countries (United States, Canada, Brazil and Spain). The protocol and statistical analysis plan are available at NEJM.org, and changes to these documents after the start of the trial are summarized in the supplemental 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 guidelines of the International Council for harmonization of good clinical practices, and applicable laws and regulations. All patients provided written informed consent. The sponsors designed the trial, and the trial sponsors and investigators were involved in data collection, analysis, and interpretation. The authors have made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data presented and the reliability of the trial to the protocol. Medical editors funded by Vir Biotechnology helped write the manuscript under the direction of the authors. All of the authors had confidentiality agreements with the sponsors.

Patients and procedures

Adult patients (≥ 18 years of age) who have tested positive for reverse transcriptase-polymerase chain reaction or SARS-CoV-2 antigen and onset of symptoms of Covid-19 within the previous 5 days have been screened for eligibility; screening was performed within 24 hours of administration of sotrovimab or placebo. Patients were at high risk of progression to Covid-19 because of their advanced age (≥ 55 years) or because they had at least one of the following risk factors: diabetes for which medication was warranted, obesity (index of body mass [BMI; the weight in kilograms divided by the square of the height in meters],> 30), chronic kidney disease (estimated glomerular filtration rate, 2 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, oxygen saturation below 94%, or use of supplemental oxygen, were excluded. The full inclusion and exclusion criteria are described in the Additional Methods section of the Additional Annex.

Trial design.

Patients were stratified by age (≤ 70 years or> 70 years), duration of symptoms (≤ 3 days or 4 or 5 days) and geographic region. Pharmacists in the trial reconstituted and dispensed sotrovimab and placebo on an equal time basis to maintain blinding.

Eligible patients were randomly assigned in a 1: 1 ratio using a web-based interactive response system to receive either a single infusion of 500 mg sotrovimab over 1 hour or an equal volume of placebo saline on day 1 (Figure 1). The trial design did not mandate any treatment for Covid-19 other than sotrovimab or placebo; as a result, patients received treatment at the discretion of their physicians according to local standards of care.

Effectiveness evaluations

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

Security Assessments

Safety results included adverse events, serious adverse events, and adverse events of special interest, which were defined as infusion-related reactions (including hypersensitivity reactions). Immunogenicity tests for anti-drug antibodies were performed and antibody-dependent improvement was assessed. All hospitalizations, including those due to Covid-19, were counted as serious adverse events.

Statistical analyzes

A pre-defined interim analysis for safety, futility, and efficacy was triggered when approximately 41% of the required number of patients in the trial reached day 29. The sample size calculations were based on a sequential group design with two interim analyzes to assess both futility due to ineffectiveness and inefficiency. A Lan-DeMets alpha spending function was used to control for Type I error, with the use of an analogous Pocock rule for futility and an analogous Hwang-Shih-DeCani rule for efficiency (with the value of γ = 1).25 The overall sample of 1360 patients would have provided approximately 90% power to detect a relative efficacy of 37.5% in reducing the progression of Covid-19 through day 29 at the overall bilateral significance level of 5% , with an assumed incidence of progression of 16% in the placebo group.

In the interim analysis, the intention-to-treat population included all patients who had been randomized up to the predefined interim analysis cut-off date of January 19, 2021, whether they received sotrovimab or placebo. The safety analysis population in the interim analysis included all patients who received sotrovimab or placebo and were randomized until February 17, 2021; the patients were grouped according to the agent actually received. The primary outcome was analyzed in the intention-to-treat population using a Poisson regression model with robust sandwich estimators to adjust the test agent, duration of symptoms, age, and sex. Missing progress status was imputed on an absence assumption at random with the use of multiple imputation. Based on this analysis model, the tests of statistical significance, the relative risk of progression and its appropriate confidence interval are provided with the level of significance adjusted for this interim analysis.

An independent data monitoring committee recommended that enrollment into the trial be stopped on March 10, 2021, due to efficacy, by which time 1,057 patients had been randomized. Analyzes for all secondary and exploratory results are scheduled when all patients have completed day 29.

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