key: cord-0983325-ccbbmtp3
authors: Shih, Richard D.; Maki, Dennis G.; Hennekens, Charles H.
title: Remdesivir for coronavirus 2019 (COVID-19): More promising but still unproven
date: 2020-10-07
journal: Contemp Clin Trials Commun
DOI: 10.1016/j.conctc.2020.100663
sha: 59472d6cdff2b739c3e558769b1598232b6d4764
doc_id: 983325
cord_uid: ccbbmtp3

From December 2019 to May 22, 2020 the emerging and ever-increasing pandemic of coronavirus 19 (COVID-19) had no effective and safe treatment. Not surprisingly, remdesivir attracted worldwide attention. In a trial published online ahead of print, of 1063 patients, 541 were assigned at random to remdesivir and 522 to placebo. The primary prespecified endpoint was mean recovery time and patients assigned to remdesivir had a mean recovery time of 11 days versus 15 days for those assigned a random to placebo. (p < 0.001). With respect to mortality, the prespecfied secondary endpoint, 34/538 patients in remdesivir and 54/521 in placebo died after 28 days, yielding a possible 31% reduction that approached but did not achieve statistical significance (p = 0.059). The only other published trial of remdesivir randomized 237 patients in China. In that trial, 178 patients were assigned at random to remdesivir compared to 79 assigned to placebo. Those assigned at random to remdesivir experienced a possible but nonsignificant 23% faster time to clinical improvement of 21 days compared with 23 for those assigned to placebo [hazard ratio 1.23 [95% CI, 0·87-1.75)]. With respect to mortality there was no suggestion of any benefit. In fact, the mortality rate in those receiving remdesivir was 15% (22/150) compared with 13% (10/77) for those assigned to placebo. Ongoing randomized trials should be designed, conducted and analyzed to provide the necessary reliable data on mortality to resolve the remaining clinical uncertainties.

Ongoing randomized trials should be designed, conducted and analyzed to provide the necessary reliable data on mortality to resolve the remaining clinical uncertainties.

Text (word count=1420 including text CRediT statement and Acknowledgements, limit=1500) From December 2019 to May 22, 2020, the emerging and ever-increasing pandemic of coronavirus 19 (COVID-19) had no effective and safe treatment. Not surprisingly, remdesivir has attracted worldwide attention.

In this Short Communication, we review the totality of available evidence, especially the reliable data from randomized trials to detect the plausible small to moderate effects. We conclude that the current totality of evidence on remdesivir supports an urgent necessity to obtain reliable data from randomized trials of sufficient size, dose and duration in order to distinguish reliably between the alternative hypothesis of a significant benefit on mortality and the null hypothesis.

Worldwide, from January to June 2020 over 7.1 million cases and over 400 thousand deaths from coronavirus 19 (COVID-19) have been reported. North and South America have reported over 3 million cases, with 2.0 million reported from Europe, over 1.3 million from Asia, over 189 thousand from Africa and over 8 thousand from Oceania.(1) These sobering statistics underscore the urgent need J o u r n a l P r e -p r o o f When the evidence is incomplete, it is appropriate for healthcare providers to remain uncertain. (4) The current alarming and ever-increasing pandemic of COVID-19, which has more than a 10fold higher mortality rate than influenza, (1) and, for which, dexamethasone is the only drug demonstrating a benefit on mortality, (5) has created a situation of dire need. In such circumstances, regulatory and public health authorities appropriately feel the need to take action with only incomplete evidence which ultimately may or may not turn out to justify the early actions. (6) In that regard, it should be noted that, to the best of our knowledge, no other regulatory body throughout the world except for the United 

Early in the epidemic of Acquired Immune Deficiency Syndrome (AIDS) despite the existence of any known effective treatments, there was substantial resistance to the conduct of placebo-controlled trial. A single, small, randomized and placebo-controlled trial demonstrated evidence for a survival benefit of azathioprine (AZT). Although this amount of information was less than would typically be needed to support approval of a new drug, an expanded access program was approved by the US FDA and implemented This action allowed many thousands of affected patients to receive this drug. Further evidence which accrued later, while not contradicting the initial short-term efficacy result, showed that the benefit was time-limited and that the initially studied dose was highly toxic and could be substantially reduced. (6) During the West African Ebola outbreak of 2014-15, there was also substantial resistance to the conduct of properly randomized trials. Fortunately, concomitant with numerous delays, the epidemic had waned so avoidable premature deaths did not occur.(6,11) During the 2009 H1N1 influenza ("swineflu") outbreak, the US FDA issued an Emergency Use Authorization for peramivir, an experimental antiviral drug, for the treatment of hospitalized patients. (12, 13) Within 24 hours, more than 1,100 critically ill patients with H1N1 were administered this agent. Although effectiveness of this agent was never clearly demonstrated, 31% of patients had an adverse event or medication error. (13) J o u r n a l P r e -p r o o f Randomized trials provide reliable results about small to moderate treatment effects because of their unique ability in large samples to distribute, on average, both known and unknown confounders equally between the groups. (4, 14) Thus, the current randomized evidence renders remdesivir to be more promising for the treatment of hospitalized COVID-19 patients, but still unproven because of remaining uncertainties about whether there is a clear benefit on mortality.

Fortunately, ongoing trials may provide the needed evidence. One such ongoing trial, sponsored by the World Health Organization, has a "best supportive care" arm as a control, and with mortality as the primary endpoint. (15) This trial is testing remdesivir as well as several other experimental treatments. In addition, the manufacturer of remdesivir is conducting another randomized trial comparing their drug to optimal standard of care in patients hospitalized for COVID-19. The primary endpoint of this trial is clinical improvement with mortality as a secondary endpoint. (16) We believe that the current evidence, albeit incomplete, justifies compassionate use of remdesivir for severely ill patients with COVID-19. We remain cautiously optimistic that further reliable randomized evidence that should be forthcoming soon will confirm or refute whether there is a mortality benefit of remdesivir for the treatment of COVID-19. At present, however, we must also remain cognizant of the alternative hypothesis. This is, to paraphrase Thomas J o u r n a l P r e -p r o o f

European Centre for Disease Prevention and Control: An agency of the European Union. Epidemiological Update Accessed on

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Compared to Standard of Care Treatment

We are indebted to Professor and Dean Susan Ellenberg, PhD, for advice and help.