Article
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of COVID-19 — Preliminary Report. N Engl J Med. 2020 (ACTT-1).
OBJECTIVE
To evaluate the effect of remdesivir on time to recovery in patients with COVID-19
BACKGROUND
Remdesivir, a viral RNA polymerase inhibitor, has garnered a great deal of international attention as a possible COVID-19 therapy after showing some promise in in-vitro studies with SARS, MERS, and SARS-CoV-2 viruses. However, it has not yet shown any benefit to human patients with respiratory virus infections. Just 2 weeks before the publication of this study, Wang et. al published the first major study of remdesivir in COVID-19 patients in The Lancet. Wang et. al found no benefit to receiving remdesivir, though the study was underpowered to detect a difference due to low enrollment. Notably, Wang et. al also found no effect of remdesivir on viral load, though the significance of the quantitative PCR-measured viral loads used in the study on disease severity is unknown.
It should be mentioned that there has been significant controversy around the publication of the preliminary results of this new trial. The primary outcome had been changed mid-trial, and these results were announced by Dr. Anthony Fauci in advance of publication. These unpublished results had been a major reason for the FDA's Emergency Use Authorization of remdesivir for the treatment of COVID-19. With the publication of this paper, the authors needed to provide a convincing, unbiased justification for changing the primary outcome during the trial.
DESIGN
This paper describes the preliminary results of the Adaptive COVID-19 Treatment Trial (ACTT), an international platform for conducting a series of phase 3, randomized, double-blind, placebo-controlled trials on potential therapeutic targets for COVID-19. Randomization of this particular trial was stratified by study site and disease severity at enrollment. Patients were followed for 29 days.
POPULATION
Hospitalized adults (>18 years old) with laboratory-confirmed COVID-19 (by RT-PCR)
Exclusion criteria included AST or ALT > 5 times upper limit of normal, impared renal function, need for hemodialysis, pregnancy or breastfeeding, or anticipated hospital discharge or transfer within 72 hours.
INTERVENTION
IV remdesivir 200 mg loading dose on day 1, followed by 100 mg maintenance dose daily from day 2 to day 10 or until hospital discharge or death
CONTROL
Placebo infusion plus usual supportive care
OUTCOMES
Primary
The primary outcome was changed in the middle of the trial to time to recovery, as defined by the first day after enrollment that the patient met category 1-3 on an eight-point ordinal scale (below). The original primary outcome had been the difference in clinical status on the eight-point ordinal scale at day 15, and this outcome subsequently became a key secondary outcome.
Eight Point Ordinal Scale
- Not hospitalized, no limitations of activities
- Not hospitalized, limitation of activities or home oxygen requirement
- Hospitalized for infection control reasons, but no need for oxygen or ongoing medical care
- Hospitalized, no oxygen requirement but ongoing medical care
- Hospitalized, requiring oxygen
- Hospitalized, requiring high flow oxygen devices or NIV
- Hospitalized, receiving mechanical ventilation or ECMO
- Death
This change in primary outcome was made by trial statisticians blinded to outcome data based upon an evolving global understanding of the protracted time course of COVID-19. Due to the protracted time course, they were concerned that any benefits of remdesivir may not be revealed within the originally planned 15 dayss
Secondary
The key secondary outcome, as noted above, was difference in clinical status on the ordinal scale at day 15.
Other secondary outcomes included mortality at day 14 and day 28, and adverse events.
KEY RESULTS
A total of 1063 patients were enrolled, and the data and safety monitoring board conducted an interim analysis on April 27, 2020. Based on their interim analysis, they decided to release the results to the National Institute of Allergy and Infectious Disease (NIAID), which subsequently made them public. This paper presents the results of this preliminary analysis, with data recorded up to April 28, 2020. By that date, 391 patients assigned to remdesivir and 340 assigned to placebo had completed the 29-day follow-up period, recovered, or died, while 132 remdesivir patients and 169 placebo patients had not yet completed the 29-day follow-up and thus provided incomplete results. The treatment assignment of patients was unblinded to treating physicians at this time, meaning that future follow up data will not be double blinded.
On average, patients were randomized 9 days after symptom onset. The primary outcome, time to recovery, was significantly reduced in the remdesivir group (11 days vs 15 days, rate ratio: 1.32, 95% CI: 1.12-1.55), with a similar result when adjusted for baseline ordinal score. The key secondary outcome, improvement on the ordinal scale, was also significantly better in the remdesivir group (odds ratio for improvement: 1.50, 95% CI: 1.18-1.91). Mortality at 14 days was 7.1% in the remdesivir group vs 11.9% in the placebo group but nonsignificant (hazard ratio: 0.70, 95% CI: 0.47-1.04). Mortality at 28 days was not reported due to the high number of patients who had not yet been followed for the complete 29-day enrollment period. Adverse events were not worse in the remdesivir group.
STRENGTHS
• International randomized controlled trial
• Larger enrollment than previous trials
• Patient-oriented outcomes
LIMITATIONS
• Primary outcome changed mid-trial (more discussion to follow)
• Preliminary results of an interim analysis without full follow-up data
• Significant variation in health system response to the COVID-19 crisis may raise questions about external validity.
EM TAKE-AWAYS
This is the first major trial to suggest benefit from remdesivir for hospitalized COVID-19 patients. The authors provide sufficient justification for the change in primary outcome, and the original primary outcome also showed a benefit in the remdesivir group. Mortality difference was close to significant, which has generated a lot of press, but conclusions should not be drawn until we see the results of complete follow up for all trial patients. It is possible that remdesivir could delay death in patients past the 14-day mark but not actually improve overall mortality, and full follow up will be needed to answer this question. It is unfortunate that the treatment assignment was unblinded to physicians after these results were released, as it will raise otherwise unnecessary questions about the validity of the full results of the study.
Finally, the study's authors point out that despite any benefits, mortality is still very high in the remdesivir group. Though remdesivir should be incorporated as a treatment in hospitals, it should not be considered a silver bullet but should instead be thoughtfully incorporated into a broader response to the pandemic.
References
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of COVID-19 — Preliminary Report. N Engl J Med. 2020 (ACTT-1).
- Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020.