Remdesivir in COVID-19 – ACCT Trial

Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report.

New England Journal of Medicine doi:10.1056/NEJMoa2007764

Setting:

73 sites including United States (45), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1). Enrollment between February 21, 2020, and April 19, 2020.

844/1059 patients (79.8%) of patients were enrolled at sites in North America. [15.3% in Europe, and 4.9% in Asia). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported; 249 (23.4%)]

Design:

Randomly assigned in a 1:1 ratio to receive either Remdesivir or placebo. Randomization was stratified by study site and disease severity at enrollment

Intervention: Remdesivir 200 mg IV loading dose on day 1, followed by a 100-mg daily on days 2 through 10 or until hospital discharge or death.

Control: Placebo

Common: Supportive care according to local standard of care. If a hospital had a written policy or guideline for use of other treatments for Covid-19, these were administered. In the absence of a written policy or guideline, other experimental treatments were prohibited through the study period.

Patients were evaluated daily during hospitalization, from day 1 to day 29. The clinical status was evaluated using an eight-category ordinal scale (defined below) and the National Early Warning Score was recorded each day.

1. Not hospitalized, no limitations of activities
2. Not hospitalized, limitation of activities, home oxygen requirement
3. Hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (only for isolation)
4. Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care
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 ECMO
8. Death

On April 27, 2020, the data and safety monitoring board reviewed the results.

A total of 482 recoveries and 81 deaths, more than estimated for trial completion

They 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.

As of April 28, 2020, a total of 391 patients in the Remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died; 272 (25.6%) patients met category 7 criteria.

Primary outcome:

The primary outcome measure was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient was within categories 1, 2, or 3

Secondary outcomes:

Mortality at day 14 (overall)

Results –  

• With Remdesivir, the time to recovery was lower, but not mortality, although there was a trend towards improved survival
• Unclear if a shorter time to recovery translates to the recovery of a larger number of patients
• Does not seem to have an impact in the more severely ill patients; Kaplan Meir mortality estimate at 14 days among patients on NIV or HFNC: 15.2 vs. 14.7%; invasive ventilation: 11.3 vs. 14.1%
• Safety outcomes and adverse events no different

Strengths – 

Well-conducted RCT.

Limitations – 

• the effect on time to recovery was observed largely in patients who entered the study in the severe disease spectrum but not in those with the mild-to-moderate disease
• Remdesivir did not appear to improve outcomes in patients who required mechanical ventilation or extracorporeal membrane oxygenation — Need more data
• No mention of Co-therapies that patients received as a part of adaptive randomisation.
• No information on organ failures, baseline severity
• No information on ventilation parameters
• Is accelerated recovery only for less severely ill patients, who would recover even otherwise (albeit over a longer period of time)?

• Quantitative analyses of virus specimens collected sequentially from different geographic sites and from multiple anatomical locations

• Cost-effective analyses will be interested to see the real benefit of the treatment.

Summary —

An informative study which has asked more questions than giving all answers.

Remdesivir seems to be beneficial in a selective cohort of patients with COVID-19.