Suitable individuals had been 12 decades of age or older and experienced at minimum 1 preexisting chance aspect for development to significant Covid-19 or were 60 years of age or more mature, no matter of no matter if they experienced other possibility things. Danger factors integrated hypertension, cardiovascular or cerebrovascular sickness, diabetes mellitus, obesity (a physique-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30), immune compromise, long-term gentle or reasonable kidney sickness, serious liver illness, long-term lung sickness, existing cancer, or sickle mobile disease. Eligible sufferers had at minimum 1 ongoing symptom steady with Covid-19, with onset of the 1st symptom in 7 days in advance of randomization (given that hospitalization typically takes place at or soon after 7 times of indicators).13,14 Suitable sufferers had SARS-CoV-2 infection confirmed by a molecular diagnostic assay within just 4 times ahead of screening (which corresponds with the time period characterised by the maximum viral loads).15
Patients had been ineligible if they ended up getting or have been envisioned to get supplemental oxygen or healthcare facility treatment at the time of screening. Clients have been also ineligible if they experienced had a earlier hospitalization for Covid-19, experienced previously received cure for Covid-19 (which include investigational agents), or had been given a SARS-CoV-2 vaccine. Complete information are delivered in the protocol and the statistical analysis prepare (offered with the full textual content of this report at NEJM.org).
Demo Style and design and Oversight
From September 18, 2020, by way of April 8, 2021, clients were enrolled at 64 websites in the United States, Spain, Denmark, and the United Kingdom. Demo internet sites included outpatient infusion services and experienced nursing facilities, and some participants acquired infusions at residence. Clients ended up randomly assigned in a 1:1 ratio to get intravenous remdesivir (200 mg on working day 1 adopted by 100 mg on times 2 and 3) or placebo. Randomization was stratified in accordance to residence in a competent 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.