Remdesivir

The primary analysis was a stratified log-rank test of time to recovery with remdesivir as compared with placebo, with stratification by disease severity (the actual severity at baseline). (See the Supplementary Appendix for more information about the planned statistical analysis.) For time-to-recovery and time-to-improvement analyses, data for patients who did not recover and data for patients who died were censored at day 29.
Prespecified subgroups in these analyses were defined according to sex, baseline disease severity (according to stratification criteria and on the basis of the ordinal scale), age (18 to 39 years, 40 to 64 years, or ≥65 years), race, ethnic group, duration of symptoms before randomization (measured as ≤10 days or >10 days, in quartiles, and as the median), site location, and presence of coexisting conditions. (See the protocol for more information about the trial methods.) To assess the effect of disease severity on treatment benefit (recovery and mortality), post hoc analyses evaluated interactions of efficacy with baseline ordinal score (as a continuous variable).
The primary outcome was initially a comparison of clinical status at day 15 on the eight-category ordinal scale. However, the primary outcome was changed to a comparison of time to recovery by day 29 in response to evolving information, external to the trial, indicating that Covid-19 may have a more protracted course than previously anticipated. The change was proposed on March 22, 2020 (after 72 patients had been enrolled), by trial statisticians who were unaware of treatment assignments and had no knowledge of outcome data. The amendment was finalized on April 2, 2020, and the initial primary outcome was retained as the key secondary outcome.
On April 27, 2020, the data and safety monitoring board reviewed efficacy results. Although this review was originally planned as an interim analysis, because of the rapid pace of enrollment, the review occurred after completion of enrollment while follow-up was still ongoing. At the time of the data and safety monitoring board report, which was based on data cutoff date of April 22, 2020, a total of 482 recoveries (exceeding the estimated number of recoveries needed for the trial) and 81 deaths had been entered in the database. At that time, the data and safety monitoring board recommended that the preliminary primary analysis report and mortality data from the closed safety report be provided to trial team members from the National Institute of Allergy and Infectious Diseases (NIAID). These results were subsequently made public. The treating physician could request to be made aware of the treatment assignment of patients who had not completed day 29 if clinically indicated (e.g., because of worsening clinical status), and patients originally in the placebo group could be given remdesivir.

The primary outcome was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient met the criteria for category 1, 2, or 3 on the eight-category ordinal scale. The categories are as follows: 1, not hospitalized and no limitations of activities; 2, not hospitalized, with 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 or other nonmedical reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to 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.
The key secondary outcome was clinical status at day 15, as assessed on the ordinal scale. Other secondary outcomes included the time to improvement of one category and of two categories from the baseline ordinal score; clinical status as assessed on the ordinal scale at days 3, 5, 8, 11, 15, 22, and 29; mean change in status on the ordinal scale from day 1 to days 3, 5, 8, 11, 15, 22, and 29; time to discharge or National Early Warning Score of 2 or less (maintained for 24 hours), whichever occurred first; change in the National Early Warning Score from day 1 to days 3, 5, 8, 11, 15, 22, and 29; number of days with supplemental oxygen, with noninvasive ventilation or high-flow oxygen, and with invasive ventilation or ECMO up to day 29 (if these were being used at baseline); the incidence and duration of new oxygen use, of noninvasive ventilation or high-flow oxygen, and of invasive ventilation or ECMO; number of days of hospitalization up to day 29; and mortality at 14 and 28 days after enrollment. Secondary safety outcome measures included grade 3 and 4 adverse events and serious adverse events that occurred during the trial, discontinuation or temporary suspension of infusions, and changes in assessed laboratory values over time.

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. Patients were considered to have severe disease if they required mechanical ventilation, if they required supplemental oxygen, if the oxygen saturation as measured by pulse oximetry (Spo₂) was 94% or lower while they were breathing ambient air, or if they had tachypnea (respiratory rate ≥24 breaths per minute). 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; for these sites, the remdesivir and placebo 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. Written informed consent (or consent by other institutional review board-approved process) 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 the protocol and statistical analysis plan (available with the full text of this article at NEJM.org).