BACKGROUND
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.
METHODS
We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
RESULTS
A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
CONCLUSIONS
Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others;
This double-blind, randomized, placebo-controlled trial identified an antiviral therapy as beneficial in the treatment of Covid-19. Our overall findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with Covid-19. Patients who received remdesivir had a shorter time to recovery (the primary end point) than those who received placebo (median, 10 days vs. 15 days; rate ratio for recovery, 1.29 [95% CI, 1.12 to 1.49]) and were more likely to have improvement in the ordinal scale score at day 15 (key secondary end point; odds ratio, 1.5; 95% CI, 1.2 to 1.9). Additional secondary end points supporting these findings include remdesivir treatment resulting in a shorter time to improvement of one and of two ordinal scale categories, a shorter time to discharge or to a sustained National Early Warning Score of 2 or lower, and a shorter length of initial hospital stay (median, 12 days vs. 17 days). All-cause mortality was 11.4% with remdesivir and 15.2% with placebo (hazard ratio, 0.73; 95% CI, 0.52 to 1.03).
Our data also suggest that treatment with remdesivir may have prevented the progression to more severe respiratory disease, as shown by the lower proportion of serious adverse events due to respiratory failure among patients in the remdesivir group, as well as a lower incidence of new oxygen use among patients who were not receiving oxygen at enrollment and a lower proportion of patients needing higher levels of respiratory support during the study. Treatment with remdesivir was associated with fewer days of subsequent oxygen use for patients receiving oxygen at enrollment and shorter subsequent duration of mechanical ventilation or ECMO for those receiving these interventions at enrollment. Cumulatively, these findings suggest that treatment with remdesivir may not only reduce the disease burden but may also decrease the use of scarce health care resources during this pandemic. The benefit in recovery persisted when adjustment was made for glucocorticoid use, which suggests that the benefit of dexamethasone as shown in the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial4 may be additive to that of remdesivir.
The benefit of remdesivir was most apparent in patients with a baseline ordinal score of 5 (receiving low-flow oxygen). Some of this difference may be due to the larger sample size in this category since confidence intervals for baseline ordinal scores of 4 (not receiving oxygen), 6 (receiving high-flow oxygen), and 7 (receiving ECMO or mechanical ventilation) were wide. However, the interaction tests suggest greater benefit (with respect to recovery and mortality) in lower ordinal score categories. This should not be interpreted as conclusively showing a lack of efficacy in higher ordinal score categories. The median recovery time for patients in category 7 could not be estimated, which suggests that the follow-up time may have been too short to evaluate that subgroup.
The findings in our trial should be compared with those observed in other randomized trials of remdesivir. Wang et al. enrolled 237 patients (158 assigned to remdesivir and 79 to placebo) in China early in the pandemic and showed a shorter time to improvement (a two-point improvement) with remdesivir: 21.0 days (95% CI, 13.0 to 28.0) in the remdesivir group and 23.0 days (95% CI, 15.0 to 28.0) in the placebo group (hazard ratio for clinical improvement, 1.23; 95% CI, 0.87 to 1.75).14 That trial did not complete full enrollment owing to local control of the outbreak, had lower power than ACTT-1 owing to the smaller sample size and a 2:1 randomization, and was unable to demonstrate any statistically significant clinical benefits of remdesivir. In the recently published, open-label, randomized study of remdesivir in hospitalized patients with moderate-severity Covid-19 (83% were not receiving oxygen at baseline), patients who received remdesivir for 5 days had higher odds of clinical improvement than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09 to 2.48; P=0.02). This benefit was not seen with the 10-day course (P=0.18).15 We believe that these other studies support our findings regarding the efficacy of remdesivir; however, our study was larger, blinded, and fully enrolled.
The primary outcome of the current trial was changed early in the trial, from a comparison of the eight-category ordinal scale scores on day 15 to a comparison of time to recovery up to day 29. Little was known about the natural clinical course of Covid-19 when the trial was designed in February 2020. Emerging data suggested that Covid-19 had a more protracted course than was previously known, which aroused concern that a difference in outcome after day 15 would have been missed by a single assessment at day 15. The amendment was proposed on March 22, 2020, by trial statisticians who were unaware of treatment assignment and had no knowledge of outcome data; when this change was proposed 72 patients had been enrolled. Although changes in the primary outcome are not common in trials for diseases that are well understood, it is recognized that in some trials, such as those involving poorly understood diseases, circumstances may require a change in the way an outcome is assessed or may necessitate a different outcome.16 The original primary outcome became the key secondary end point. In the end, findings for both primary and key secondary end points were significantly different between the remdesivir and placebo groups.
Numerous challenges were encountered during this trial. The trial was implemented during a time of restricted travel, and hospitals restricted the entrance of nonessential personnel. Training, site initiation visits, and monitoring visits often were performed remotely. Research staff were often assigned other clinical duties, and staff illnesses strained research resources. Many sites did not have adequate supplies of personal protective equipment and trial-related supplies, such as swabs. However, research teams were motivated to find creative solutions to overcome these challenges. Throughout the trial, we were able to enroll a diverse population, similar to the population that was being infected with SARS-CoV-2 during that period.
Given the preliminary results about remdesivir, the Food and Drug Administration issued an Emergency Use Authorization on May 1, 2020 (modified on August 28, 2020), to permit the use of remdesivir for treatment in adults and children hospitalized with suspected or laboratory-confirmed Covid-19. Remdesivir has also received full or conditional approval in several other countries since that time. However, given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient for all patients. Current strategies are evaluating remdesivir in combination with modifiers of the immune response (e.g., the Janus kinase [JAK] inhibitor baricitinib in ACTT-2, and interferon beta-1a in ACTT-3). A variety of therapeutic approaches including novel antivirals, modifiers of the immune response or other intrinsic pathways, and combination approaches are needed to continue to improve outcomes in patients with Covid-19
Reference & Source information: https://www.nejm.org/
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