Table of Contents
Suitable patients were being 12 yrs of age or more mature and experienced at the very least one particular preexisting possibility variable for development to severe Covid-19 or have been 60 many years of age or older, irrespective of whether or not they experienced other hazard components. Chance elements included hypertension, cardiovascular or cerebrovascular sickness, diabetic issues mellitus, being overweight (a entire body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30), immune compromise, persistent gentle or reasonable kidney ailment, persistent liver disease, persistent lung disease, recent cancer, or sickle cell sickness. Qualified people had at minimum one ongoing symptom reliable with Covid-19, with onset of the to start with symptom in just 7 days just before randomization (offered that hospitalization generally takes place at or immediately after 7 times of indicators).13,14 Qualified clients had SARS-CoV-2 an infection confirmed by a molecular diagnostic assay in just 4 days just before screening (which corresponds with the period of time characterised by the maximum viral loads).15
Clients were being ineligible if they were getting or had been expected to receive supplemental oxygen or healthcare facility treatment at the time of screening. Clients have been also ineligible if they experienced experienced a preceding hospitalization for Covid-19, had formerly acquired treatment for Covid-19 (including investigational agents), or had obtained a SARS-CoV-2 vaccine. Comprehensive specifics are furnished in the protocol and the statistical examination prepare (available with the full textual content of this article at NEJM.org).
Trial Design and style and Oversight
From September 18, 2020, by way of April 8, 2021, sufferers were enrolled at 64 web pages in the United States, Spain, Denmark, and the United Kingdom. Demo web-sites integrated outpatient infusion services and skilled nursing facilities, and some contributors gained infusions at house. Sufferers were randomly assigned in a 1:1 ratio to obtain intravenous remdesivir (200 mg on working day 1 followed by 100 mg on days 2 and 3) or placebo. Randomization was stratified in accordance to residence in a expert nursing facility (of course or no), age (<60 years or ≥60 years), and country (United States or outside the United States). All patients and trial personnel were unaware of the trial-group assignments. Before undergoing trial procedures, the patients provided written informed consent. Assent and parental or guardian consent were obtained if the patients were younger than 18 years of age.
The trial was approved by the institutional review board or ethics committee at each trial site and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulations. The trial was designed and conducted by the sponsor (Gilead Sciences) in collaboration with the principal investigators and in accordance with the protocol and amendments. The sponsor collected the data, monitored the trial conduct, and performed the statistical analyses. An interim analysis to be performed by the data and safety monitoring board was planned for when 50% enrollment was reached. The manuscript was prepared by a writer who was employed by Gilead Sciences, with input from all authors. All the authors had data confidentiality agreements with the sponsor. All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.
Assessments included physical examinations, reporting of adverse events, blood testing, and the collection of nasopharyngeal swabs to quantify the SARS-CoV-2 viral load with the use of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay at prespecified intervals. The electronic Covid-19–adapted Influenza Patient-Reported Outcome (FLU-PRO) Plus questionnaire (Evidera–PPD) was used to assess patient-reported symptoms. Patients completed the first questionnaire before the first infusion on day 1 and then daily through day 14. The symptom questionnaire was first available on October 21, 2020 (1 month after the start of enrollment). The full schedule of trial procedures is provided in the protocol.
The primary efficacy end point was a composite of hospitalization related to Covid-19 (as determined by site investigators, who were unaware of trial-group assignments, and defined as ≥24 hours of acute care) or death from any cause by day 28. The primary efficacy end point was initially a composite of hospitalization for any cause or death from any cause by day 14 and was modified on January 14, 2021, in response to comments from the Food and Drug Administration trial blinding was maintained. The primary safety end point was any adverse event.
Secondary end points included the composite of Covid-19–related medically attended visits or death from any cause by days 14 and 28, Covid-19–related hospitalization by days 14 and 28, the time-weighted average change in nasopharyngeal SARS-CoV-2 viral load from baseline to day 7, and the time to alleviation of baseline Covid-19 symptoms (with alleviation defined as mild or absent symptoms) as compared with those reported on the baseline FLU-PRO Plus questionnaire completed before the first infusion. Post hoc analyses were also conducted of hospitalization for any cause by day 28 and time to alleviation of baseline Covid-19 symptoms as reported on the FLU-PRO Plus questionnaire completed on the day of the first infusion, either before or after the infusion.
Assuming that 9.3% of patients would die or have a Covid-19–related hospitalization and 5% would drop out of the trial, we determined that a sample of 1264 patients would provide the trial with more than 90% power to detect a hazard ratio for Covid-19–related hospitalization or death from any cause of 0.55 for the comparison of remdesivir with placebo, with a two-sided significance level of 0.05. All patients who underwent randomization and received at least one infusion were included in the analyses (the full analysis set). Demographic characteristics, baseline measurements, adverse events, and laboratory abnormalities were summarized descriptively.
Hazard ratios, rate ratios, and two-sided 95% confidence intervals for the primary and secondary end points were calculated with the use of a Cox proportional-hazards model adjusted for the stratification factors of residence in a skilled nursing facility (yes or no), age (<60 years or ≥60 years), and country (United States or outside the United States). The P value for the primary efficacy end point was calculated with the use of the same method. The percentage of patients who were hospitalized with Covid-19 by day 28 was estimated with the use of a Kaplan–Meier analysis. The time to alleviation of baseline Covid-19 symptoms in the prespecified and post hoc analyses was estimated with the use of the Kaplan–Meier product-limit method. The time-weighted average change in viral load from baseline to day 7 was assessed with the use of analysis-of-covariance, with baseline viral load as a covariate. The widths of all calculated confidence intervals were not adjusted for multiplicity.
On April 6, 2021, an orderly closure of trial enrollment was announced by the sponsor because of administrative reasons related to a decrease in the incidence of SARS-CoV-2 infections, ethical concerns regarding assigning patients to placebo in the context of increased access to emergency-use–authorized treatments such as monoclonal antibodies, and increasing vaccination rates among high-risk persons. The last patient was enrolled on April 8, 2021. Of the 1264 patients who were expected to enroll, 562 (44.5%) had undergone randomization and had begun the trial regimen by the time enrollment was stopped. The data and safety monitoring board was informed that the trial had been stopped, and no interim analyses were performed before trial discontinuation. Double blinding was maintained until finalization of the data.