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Remdesivir for 5 or 10 Days in Patients with Severe Covid-19


Patients

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

Trial Design and Oversight

For this phase 3 trial, patients were recruited from March 6 to March 26, 2020 in 55 hospitals in the United States, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, and Taiwan. Patients were randomly assigned in 1. : 1 ratio for receiving intravenous treatment with remedisvir for 5 days or 10 days. Randomization was not stratified. All patients were to receive 200 mg of Remedisvir in 1 day, followed by 100 mg of Remedisvir daily for the next 4 or 9 days. Both treatment groups continued adjuvant therapy at the investigator’s discretion throughout the duration of the trial. Draft a contract (Available with the full text of this article at NEJM.org) did not mention that patients whose conditions improved improved to warrant hospital discharge with a full schedule of remediesvir treatment.

The protocol was amended after the start of enrollment on March 15, 2020, but before any results were available. The lower age limit for eligibility was reduced from 18 years to 12 years, and the need for an axial temperature of at least 36.6 ° C was eliminated in screening. In addition, one of the assessments of primary efficacy – the proportion of patients with temperature normalization on day 14 – on day 7 (described below) was changed to assess clinical status on a 7-point ordinal scale. This change was made in response to an emerging understanding of the signs and symptoms of Kovid-19 during hospitalization and the recognition of emerging standards for evaluation of Kovid-19.19,20 The protocol was amended to add an expansion phase involving an additional 5600 patients, including covalents of patients receiving mechanical ventilation (results of the expansion phase are not reported here). All versions of Draft a contract And a summary of the amendments is available at NEJM.org.

The trial was approved by the institutional review board or ethical committee at each site and was conducted in compliance with the Declaration of Helsinki Good Clinical Practice Guidelines and local regulatory requirements. The test was designed and conducted by the sponsor (Gilead Sciences) in collaboration with the principal investigators and according to protocols and modifications. The sponsor collected data, supervised the operation of the test, and performed statistical analysis. An independent safety monitoring committee reviewed the data on day 14 of the trial, when all patients had reached the primary end point. They agreed that there were similar results in the 5-day and 10-day treatment groups, and they unanimously recommended that the trial continue in the second part according to the protocol. The authors pledge for the integrity and completeness of the data and the integrity of the test for the protocol. The initial draft of the manuscript was prepared by an author appointed by Gilead Sciences with input from all authors.

Clinical and laboratory monitoring

Patients were evaluated by physical examination and documentation of respiratory status, adverse events, and concomitant medications. On test 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 aminotransferase.

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

Finish points

The end point of primary efficacy was assessed clinical status 14 on a 7-point scale consisting of the following categories: 1, death; 2, hospitalization, receiving aggressive mechanical ventilation or ECMO; 3, hospitalization, non-ventilation ventilation or receiving high-flow oxygen equipment; 4, hospitalization, low flow supplemental oxygen required; 5, hospitalization, not requiring supplemental oxygen but receiving ongoing medical care (related to or not related to Kovid-19); 6, hospitalization, requiring neither supplemental oxygen nor medical care (except as specified in the protocol for remediesvir administration); And 7, not hospitalized (see Table S1) Supplementary appendix, Available at NEJM.org).

The secondary end point of the trial was the proportion of patients with adverse events, which occurred at or after the first dose of Remedisvir up to 30 days after the last dose. Prespected Explosive End Points included time to clinical improvement (defined as improvement of at least 2 points from baseline on a 7-point ordinal scale), recovery time (defined by the National Institute of Allergy and Infectious Disease). [NIAID] Modified recovery time (defined as an improvement from a score of 5 to 7 or a baseline score of 5 to 4) as an improvement in baseline score of 2 to 5 based on a score of 6 or 7 5 on 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 more than 85% power to detect barriers to improvement of 1.75, using a two-sided significance level of 0.05. All patients who were randomly received and in at least one dose of remedesvir were evaluated for efficacy and safety. If a patient died before day 14, then the day 14 category was recorded as “death” on a gradual scale; If a patient was discharged before 14 days, the category was recorded as “not hospitalized”; Otherwise, the most recent evaluation was used for the missing day 14 values. Pre-determined primary analysis, performed after 14 days of completion to all patients in the trial, used a proportional odds model, including independent variables as a continuous covalent and treatment as a baseline clinical condition. The conclusion would be that the 10-day treatment was better than the 5-day treatment if the two-way 95% confidence interval of the 14-day odds ratio (10 days to 5 days) was greater than 1 at the bottom. The Wilconon rank-even test was determined to compare treatment groups in the event that stratified proportional odds were not met. For time-to-end endpoints (such as clinical recovery time, recovery time, and modified recovery time), the hazard ratio and its 95% confidence interval were estimated from the cause-specific proportional-risk model Was that included treatment as covariates and a baseline clinical condition and treated death as a competitive risk. For scheduled time-associated events (eg, days 5, 7, 11 and 14), the proportion of patients with an event under evaluation (eg clinical improvement, recovery, and revised recovery) between treatment groups and 95 The% confidence interval was estimated from the Mantel – Haensel ratio with adjustment according to differential baseline clinical status. For endpoints other than the primary end point, the 95% confidence interval has not been adjusted for plurality and should not be used for estimation effects.



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