By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
Dr. Deresinski reports no financial relationships relevant to this field of study.
SYNOPSIS: Remdesivir is safe and moderately effective in the treatment of patients with COVID-19.
SOURCES: Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 - Preliminary report. N Engl J Med 2020 May 22;NEJMoa2007764. doi:10.1056/NEJMoa2007764. [Online ahead of print].
Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020 May 27. doi:10.1056/NEJMoa2015301 [Online ahead of print].
Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir in Covid-19. N Engl J Med 2020;382:10.1056/NEJMc2015312#sa4. [Online ahead of print].
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Erratum. Lancet 2020;395:1694.
Gilead Sciences Inc. Gilead announces results from Phase 3 trial of remdesivir in patients with moderate COVID-19. Press Release. June 1, 2020.
Wang and colleagues randomized adults with moderate-to-severe COVID-19 to treatment to receive remdesivir or placebo in a 2:1 ratio. Many patients also received one or more of the following: lopinavir-ritonavir, interferon alfa-2b, and corticosteroids. The median interval from symptom onset to study enrollment was 10-11 days. The study found no statistically significant improvement with the use of remdesivir. However, it was significantly underpowered as a result of premature termination because of an inability to enroll patients as the outbreak came under control in Wuhan (236 of a planned 325 were enrolled), reducing the power to detect a significant difference in their targeted improvement from a planned 80% to 58%. This meant that no firm conclusion could be drawn from this study. However, it did suggest that, if remdesivir was effective, its impact would not be huge.
Beigel and colleagues reported the preliminary results of a larger international, multicenter National Institute of Allergy and Infectious Diseases (NIAID)-sponsored trial (ACTT-1) in which adults with severe COVID-19 were randomized (1:1) to up to 10 days of treatment with remdesivir or placebo. Entry requirements included hospitalization, polymerase chain reaction (PCR)-confirmed infection, pulmonary infiltrates on chest radiography, or SpO2 < 94% on room air or requirement for supplemental oxygen or need for mechanical ventilation. Among the exclusion criteria were pregnancy and creatinine clearance < 30 mL/min. The analysis included 1,059 patients.
Patients were enrolled a median of nine days after symptom onset. The median time to recovery was 11 days (95% confidence interval [CI], 9 to 12 days) in remdesivir recipients and 15 days (95% CI, 13 to 19 days) in those assigned placebo. The calculated rate ratio for recovery was 1.32 (95% CI, 1.12 to 1.55; P < 0.001). The median time to recovery was calculated from the day of enrollment to the first day when one of the following occurred: the patient was hospitalized but no longer required oxygen or the patient was not hospitalized either with or without a supplemental oxygen requirement and/or activity limitation.
The day 14 Kaplan-Meier mortality estimates for those receiving remdesivir was 7.1%, while it was 11.9% among placebo recipients, giving a hazard ratio for death of 0.70 (95% CI, 0.47 to 1.04). Remdesivir was well tolerated. Further analysis through day 28 is pending.
In a separate trial, Goldman and colleagues examined whether 10 days of remdesivir administration was superior to five days of therapy in an open-label, randomized trial in 397 hospitalized patients with confirmed infection, radiological evidence of pneumonia, and SpO2 < 94% on room air. After adjustments for imbalances in illness severity at randomization, there was no overall significant difference in outcomes between the two durations of therapy.
On June 1, 2020, the pharmaceutical sponsor, Gilead, announced the results of a yet unpublished trial in which 584 patients with moderate disease (X-ray evidence of pneumonia and SpO2 > 94%) were randomized (1:1:1) to standard of care, or to five days or 10 days of remdesivir treatment. They reported that “compared with those who received standard care, patients in the five-day remdesivir group were 65% more likely to show clinical improvement at day 11 (OR [odds ratio] = 1.65; 95% CI, 1.09-2.48). They also determined that patients in the 10-day remdesivir treatment group had increased odds of clinical improvement at day 11 compared to those who received usual care, but the observed increase was not statistically significant (OR = 1.31; 95% CI, 0.88-1.95).”
Finally, Grein and colleagues reported the results of the Gilead remdesivir compassionate use program for patients with severe disease (57% receiving mechanical ventilation) and noted clinical improvement in 36 of 53 (68%). The mortality rate was 13%, with six of 34 (18%) patients receiving invasive ventilation dying, while only one of 19 (5%) not requiring mechanical ventilation died. The drug was well tolerated.
All of these reports indicate that remdesivir is well tolerated, but only two compared treatment with this drug to placebo, thus allowing an assessment of efficacy. The study by Wang and colleagues failed to find benefit of remdesivir, but the study’s power (58%) was severely limited because of its early discontinuation because of a lack of enrollment. Thus, it failed to answer the question of efficacy. The NIAID trial by Beigel and colleagues demonstrated a significant, albeit moderate, benefit of remdesivir relative to placebo in patients with severe disease. While the drug’s use hastened time to recovery by approximately 30%, its effect on mortality failed to achieve statistical significance, although it came close, with the upper limit of the 95% confidence interval being 1.04. However, this study was analyzed before all the data were available, and there will be further word on this trial.
The randomized trial by Goldman and colleagues contributed useful information in demonstrating that, overall, there was not a significant benefit of 10 vs. five days of therapy (although there was a hint that 10 days may have been better in patients receiving extracorporeal membrane oxygenation or mechanical ventilation). Remdesivir was well tolerated in all the studies. Finally, the unpublished randomized trial noted earlier is reported to have found a benefit from remdesivir treatment in patients with moderately severe COVID-19. However, the reason for possibly greater benefit from a five-day treatment course relative to 10 days of therapy is puzzling.
Thus, the efficacy and safety of remdesivir in the treatment of COVID-19 patients has been demonstrated. Although the effect was perhaps more modest than one might hope, this nucleotide analog is, at least for now, the (only) treatment of choice for patients with this infection. It also should be kept in mind that earlier initiation of treatment may prove more beneficial — the median intervals from symptom onset in the two placebo-controlled trials were 10 and nine days.
The current formulation of remdesivir must be administered intravenously, and, apparently, there is no plan for an oral formulation for technical reasons. However, Gilead has indicated that they are developing a formulation suitable for inhalation, which will be the subject of future studies.