COVID-19 research briefs: flawed trial of 10-day and 5-day remdesivir and retraction of Lancet trial of hydroxychloroquine

Daily POEMs

Published: 2020-06-13 © 2020 John Wiley & Sons, Inc.

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Clinical question
How does 10-day compare with 5-day treatment with remdesivir in people with COVD-19? Can hydroxychloroquine, chloroquine, or azithromycin improve outcomes for patients with SARS-CoV-2 infection?

Bottom line
Outcomes similar for 5 vs 10 days remdesivir but trial had flaws. Retraction of Lancet trial of hydroxychloroquine or chloroquine with or without a macrolide for treament of COVID-19 does not affect overall POEM conclusions. (LOE = 1b)

Reference
Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 [published online ahead of print, 2020 May 27]. N Engl J Med. 2020;10.1056/NEJMoa2015301. doi:10.1056/NEJMoa201530.

Study design: Randomized controlled trial (nonblinded)

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis
Research Brief #34: The results of the ACTT-1 trial suggest that remdesivir for 10 days rather than than 5 days is more effectivefor reducing the time to recovery and possibly mortality in patients with COVID-19. In this study sponsored by Gilead, 397 hospitalized patients were randomized to 5 vs 10 days of remdesivir (200 mg loading dose on day 1 followed by 100 mg daily). The study had two major flaws that limit our ability to interpret its conclusion that results were similar for the two groups. First, this was an open label trial, so patients and physicians knew who was getting the medication and for how long. Second, there were clinically important differences between groups at baseline, with more patients requiring high flow oxygen, mechanical ventilation, or ECMO in the 10-day group at baseline (69 vs 53). In the ACTT-1 trial, those patients appeared to benefit less from remdesivir. There is also no description of how randomization was performed or whether allocation to groups was concealed, so it seems likely that sicker patients were non-randomly allocated to the 10 day group. The primary outcome was improvement of at least 2 grades on a 7 point scale ranging from death (grade 1) to - not hospitalized - (grade 7); all patients started at grades 2 to 5. Improvement occurred more often in those in the 5 day group (65% vs 54%), but this difference was no longer statistically significant after adjustment for baseline differences. The final assessment of the authors is that there is no difference in outcomes between 5 and 10 days, so 5 days should be considered, especially if supplies are limited. IMPORTANT UPDATE RE POEM PUBLISHED 30 MAY 2020: This POEM contained two COVID-19 research briefs assessing hydroxychloroquine, chloroquine and azithromycin. It has been brought to our attention that the Lancet paper referenced in Research brief #27 (Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis) has been withdrawn owing to the fact that 'several concerns were raised with respect to the veracity of the data and analyses'. This retraction in no way reflects on the veracity of the JAMA paper cited in Research brief #26 by Rosenberg et al and the conclusions drawn by this paper that hydroxychloroquine (HCQ) and azithromycin, used alone or in combination, do not reduce mortality in patients with COVID-19 and increase the risk of serious cardiac-related adverse events remain valid.

Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA

Copyright © 2020 John Wiley & Sons, Inc.