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

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

Pilot targets and supervision

In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, 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 patients. , non-hospitalized patients. For this pre-specified interim analysis, patients were recruited from August 27, 2020 and followed through March 4, 2021 at 37 study 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 papers after the trial began are summarized in the Supplementary Appendix.

The study, 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, the applicable guidelines of the International Council for Harmonization Good Clinical Practice, and applicable laws and regulations. All patients gave written informed consent. The sponsors designed the study, and the study sponsors and researchers participated in data collection, analysis, and interpretation. The authors have made the decision to submit the manuscript for publication and warrant the accuracy and completeness of the data presented and the study’s fidelity to the protocol. Medical writers funded by Vir Biotechnology helped prepare the manuscript under the direction of the authors. All authors had confidentiality agreements with the sponsors.

Patients and procedures

Adult patients (≥18 years) who had a positive result for reverse transcriptase polymerase chain reaction or antigen SARS-CoV-2 testing and onset of Covid-19 symptoms within the past 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 of progression of Covid-19 because of their older age (≥55 years) or because they had at least one of the following risk factors: diabetes requiring medication, 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 m22 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 of less than 94% or the use of supplemental oxygen, were excluded. Full inclusion and exclusion criteria are described in the Additional Methods section in the Supplementary Appendix.

Trial design.

Patients were stratified by 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 to maintain blinding.

Eligible patients were randomly assigned in a 1:1 ratio using 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 study design mandated no treatment for Covid-19 other than sotrovimab or placebo; as a result, the patients received treatment at the discretion of their physician according to the local standard of care.

Efficacy assessment

The primary outcome measure was the proportion 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 emergency department visits, hospitalization, or death and the percentage of patients with disease progression who warranted supplemental oxygen use.

Safety Ratings

The safety results included adverse reactions, serious adverse reactions and adverse reactions of special concern, which were defined as infusion-related reactions (including hypersensitivity reactions). Immunogenicity testing for anti-drug antibodies was performed and antibody-dependent enhancement was evaluated. All hospitalizations, including those due to Covid-19, were counted as serious side effects.

Static analysis

A pre-specified interim analysis for safety, futility and efficacy was activated when approximately 41% of the required number of subjects reached Day 29. lack of efficacy and efficacy. A Lan-DeMets alpha spend function was used to check for type I errors, using a Pocock analog rule for futility and a Hwang-Shih-DeCani analog rule for efficacy (with the value of γ = 1).25 The total 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 to day 29 at the overall two-sided significance level of 5%, with a assumed incidence of progression of 16% in the placebo group.

In the interim analysis, the intention-to-treat population included all patients who underwent randomization up to the pre-specified cut-off date of the interim analysis of January 19, 2021, regardless of 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 through February 17, 2021; patients were grouped according to the drug actually received. The primary outcome measure was analyzed in the intention-to-treat population using a Poisson regression model with robust sandwich estimators to adjust for study drug, duration of symptoms, age, and gender. Missing progression status was imputed based on a missing-at-random assumption using multiple imputation. Based on this analysis model, the statistical significance test, the relative risk of progression and the associated confidence interval are provided with the adjusted significance level for this interim analysis.

An independent data review committee recommended that the study be discontinued on March 10, 2021 due to efficacy, at which time 1057 patients were randomized. Analyzes of all secondary and exploratory outcomes are scheduled when all patients have completed Day 29.