Abstract

Background

Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have but been proven to be efficacious.

Strategies

We performed a double-blind, randomized, placebo-managed trial of intravenous remdesivir in adults hospitalized with Covid-19 with proof of lower respiratory tract involvement. Patients have been randomly assigned to receive either remdesivir (200 mg loading dose on day 1, adopted by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary consequence was the time to restoration, defined by either discharge from the hospital or hospitalization for infection-catch watch over functions easiest.

Outcomes

A total of 1063 patients underwent randomization. The data and safety monitoring board urged early unblinding of the outcomes on the basis of findings from an analysis that confirmed shortened time to restoration in the remdesivir neighborhood. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that these that obtained remdesivir had a median restoration time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in these that obtained placebo (rate ratio for restoration, 1.32; 95% CI, 1.12 to 1.55; P

Conclusions

Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number,NCT04280705.)

Introduction

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 as the cause of a respiratory illness designated coronavirus disease 2019, or Covid-19.1Several therapeutic agents have been evaluated for the treatment of Covid-19, but none have yet been shown to be efficacious.2,3Remdesivir (GS-5734), an inhibitor of the viral RNA-dependent, RNA polymerase with inhibitory activity against SARS-CoV and the Middle East respiratory syndrome (MERS-CoV),4-7was identified early as a promising therapeutic candidate for Covid-19 because of its ability to inhibit SARS-CoV-2 in vitro.8In addition, in nonhuman primate studies, remdesivir initiated 12 hours after inoculation with MERS-CoV9,10reduced lung virus levels and lung damage.

To evaluate the clinical efficacy and safety of putative investigational therapeutic agents among hospitalized adults with laboratory-confirmed Covid-19, we designed an adaptive platform to rapidly conduct a series of phase 3, randomized, double-blind, placebo-controlled trials. Here, we describe the preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACTT-1), in which we evaluated treatment with remdesivir as compared with placebo.

Methods

Design

Enrollment for ACTT-1 began on February 21, 2020, and ended on April 19, 2020. There were 60 trial sites and 13 subsites in the United States (45 sites), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1). Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir or placebo. Randomization was stratified by study site and disease severity at enrollment (see theSupplementary Appendix, available with the full text of this article at NEJM.org, for details about stratification criteria). Remdesivir was administered intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death. A matching placebo was administered according to the same schedule and in the same volume as the active drug. A normal saline placebo was used at the European sites and at some non-European sites owing to a shortage of matching placebo; the infusions were masked with an opaque bag and tubing covers to maintain blinding. All patients received supportive care according to the standard of care for the trial site hospital. If a hospital had a written policy or guideline for use of other treatments for Covid-19, patients could receive those treatments. In the absence of a written policy or guideline, other experimental treatment or off-label use of marketed medications intended as specific treatment for Covid-19 were prohibited from day 1 through day 29 (though such medications could have been used before enrollment in this trial).

The trial protocol was approved by the institutional review board at each site (or by a centralized institutional review board as applicable) and was overseen by an independent data and safety monitoring board. Informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent. Full details of the trial design, conduct, oversight, and analyses can be found in theprotocoland statistical analysis plan (available at NEJM.org).

Procedures

Patients were assessed daily during their hospitalization, from day 1 through day 29. The patient’s clinical status on an eight-category ordinal scale (defined below) and the National Early Warning Score was recorded each day.11,12All serious adverse events and grade 3 or 4 adverse events that represented an increase in severity from day 1 and any grade 2 or higher suspected drug-related hypersensitivity reactions were recorded. (See the full description of trial procedures in theSupplementary Appendix.)

Statistical Analysis

The primary analysis was a stratified log-rank test of the time to recovery with remdesivir as compared with placebo, with stratification by disease severity. (See theSupplementary Appendixfor more information about the planned statistical analysis.)

The primary outcome measure was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient satisfied categories 1, 2, or 3 on the eight-category ordinal scale. The categories are as follows: 1, not hospitalized, no limitations of activities; 2, not hospitalized, limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (Covid-19–related or other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 8, death. Other outcomes included mortality at 14 and 28 days after enrollment and grade 3 and 4 adverse events and serious adverse events that occurred during the trial. Prespecified subgroups in these analyses were defined according to sex, disease severity (as defined for stratification and by ordinal scale at enrollment), age (18 to 39 years, 40 to 64 years, or 65 years of age or older), and duration of symptoms before randomization (≤10 days or>10 days). (Peek theprotocolfor more information about the trial methods.)

The primary consequence was initially defined as the variation in clinical status, defined by the eight-category ordinal scale, among patients treated with remdesivir as co

View Source