Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.
Commentary
Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.
The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.3 The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.
Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.
While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.4 The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.5 While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.