Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 | NEJM – nejm.org

Patients

We enrolled hospitalized patients who were at least 12 years of age who had SARS-CoV-2 infection confirmed by polymerase-chain-reaction assay within 4 days before randomization. Eligible patients had radiographic evidence of pulmonary infiltrates and either had oxygen saturation of 94% or less while they were breathing ambient air or were receiving supplemental oxygen. Patients who were receiving mechanical ventilation and extracorporeal membrane oxygenation (ECMO) at screening were excluded, as were patients with signs of multiorgan failure. Exclusion criteria included alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 5 times the upper limit of the normal range or estimated creatinine clearance of less than 50 ml per minute (by the Cockcroft–Gault formula). Patients receiving concurrent treatment (within 24 hours before the start of trial treatment) with other agents with putative activity against Covid-19 were excluded.

Trial Design and Oversight

For this ongoing phase 3 trial, patients were enrolled at 55 hospitals in the United States, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, and Taiwan between March 6 and March 26, 2020. Patients were randomly assigned in a 1:1 ratio to receive intravenous treatment with remdesivir for 5 days or 10 days. The randomization was not stratified. All the patients were to receive 200 mg of remdesivir on day 1, followed by 100 mg of remdesivir once daily for the subsequent 4 or 9 days. Both treatment groups continued supportive therapy at the discretion of the investigator throughout the duration of the trial. The protocol (available with the full text of this article at NEJM.org) did not mandate that patients whose condition improved enough to warrant hospital discharge complete the full course of assigned remdesivir treatment.

The protocol was amended on March 15, 2020, after the beginning of enrollment but before any results were available. The lower age limit for eligibility was reduced from 18 years to 12 years, and a requirement for an axillary temperature of at least 36.6°C at screening was eliminated. In addition, one of the primary efficacy assessments — the proportions of patients with normalization of temperature at day 14 — was changed to assessment of clinical status on a 7-point ordinal scale on day 14 (described below). This change was made in response to an evolving understanding of the signs and symptoms of Covid-19 during hospitalization and in recognition of emerging standards for assessment of Covid-19.19,20 The protocol was also amended to add an extension phase involving an additional 5600 patients, including a cohort of patients receiving mechanical ventilation (results of the extension phase are not reported here). All versions of the protocol and summaries of the amendments are available at NEJM.org.

The trial was approved by the institutional review board or ethics committee at each site and was conducted in compliance with the Declaration of Helsinki Good Clinical Practice guidelines and local regulatory requirements. 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 conduct of the trial, and performed the statistical analyses. An independent safety monitoring committee reviewed data on day 14 of the trial, when all the patients had reached the primary end point. They agreed that the 5-day and 10-day treatment groups had similar outcomes, and they unanimously recommended that the trial continue into the second part according to the protocol. The authors vouch for the integrity and completeness of the data and the fidelity of the trial to the protocol. The initial draft of the manuscript was prepared by a writer employed by Gilead Sciences, with input from all the authors.

Clinical and Laboratory Monitoring

Patients were assessed by physical examination and by documentation of respiratory status, adverse events, and concomitant medications. On trial days 1, 3, 5, 8, 10, and 14, blood samples were obtained for complete blood count and measurement of creatinine, glucose, total bilirubin, and liver aminotransferases.

The clinical status of patients was assessed daily on a 7-point ordinal scale (see below) from day 1 through 14 or until discharge. The worst (i.e., the lowest) score from each day was recorded.

End Points

The primary efficacy end point was clinical status assessed on day 14 on a 7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and 7, not hospitalized (see Table S1 in the Supplementary Appendix, available at NEJM.org).

The secondary end point of the trial was the proportion of patients with adverse events that occurred on or after the first dose of remdesivir for up to 30 days after the last dose. Prespecified exploratory end points included the time to clinical improvement (defined as an improvement of at least 2 points from baseline on the 7-point ordinal scale), the time to recovery (defined by the National Institute of Allergy and Infectious Diseases [NIAID] as an improvement from a baseline score of 2 to 5 to a score of 6 or 7), the time to modified recovery (defined as an improvement from a baseline score of 2 to 4 to a score of 5 to 7 or from a score of 5 to a score of 6 or 7), and death from any cause.

Statistical Analysis

We calculated that a sample size of 400 patients (200 in each group) would provide greater than 85% power to detect an odds ratio for improvement of 1.75, using a two-sided significance level of 0.05. All patients who were randomized and received at least one dose of remdesivir were assessed for efficacy and safety. If a patient died before day 14, the day 14 category on the ordinal scale was recorded as “died”; if a patient was discharged before day 14, the category was recorded as “not hospitalized”; otherwise, the most recent assessment was used for missing day 14 values. The prespecified primary analysis, performed after all patients completed 14 days in the trial, used the proportional odds model, including treatment as the independent variable and baseline clinical status as a continuous covariate. The conclusion would be that 10 days of treatment was superior to 5 days of treatment if the lower bound of the two-sided 95% confidence interval of the odds ratio (10 days to 5 days) on day 14 was greater than 1. The stratified Wilcoxon rank-sum test was prespecified to compare the treatment groups in case the proportional odds assumption was not met. For time-to-event end points (such as the time to clinical improvement, the time to recovery, and the time to modified recovery), the hazard ratio and its 95% confidence interval were estimated from a cause-specific proportional-hazards model that included treatment and baseline clinical status as covariates and treated death as the competing risk. For events associated with prespecified times (e.g., days 5, 7, 11, and 14), the difference in the proportion of patients with an event under evaluation (such as clinical improvement, recovery, and modified recovery) between treatment groups and its 95% confidence interval were estimated from the Mantel–Haenszel proportions, with adjustment according to baseline clinical status. For end points other than the primary end point, 95% confidence intervals have not been adjusted for multiplicity and should not be used to infer effects.

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