Author: Dr Matthew Durie
Peer reviewer: Dr Vinodh Nanjayya
Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020, Apr 29. Doi: 10.1016/S0140-6736(20)31022-9.
In a multicentre, randomised, placebo-controlled trial, remdesivir did not significantly shorten the time to clinical improvement compared with placebo in patients hospitalised in with COVID-19.
This paper is notable for two reasons. It is the first placebo-controlled, double-blinded, multicentre, randomised controlled trial of this agent, an adenosine analogue, in COVID-19. Second, news of its findings were largely eclipsed by the widely publicised, but as yet unpublished positive results of an interim safety analysis of the similarly designed, but larger, US National Institute of Health (NIH) funded multicentre trial (Adaptive COVID-19 Treatment Trial; ACTT), which were released to the press on the same day as this trial was published in the Lancet (29 April).
In Wang et al’s trial, 237 hospitalised patients with PCR-confirmed COVID-19 at 10 sites in Wuhan, China, were randomly assigned in a 2:1 ratio to receive either remdesivir 200mg intravenously on day 1 followed by 100mg IV daily on day 2-10, or placebo. Patients had symptom onset within 12 days, radiographic features of pneumonia, and an oxygen saturation of <94% on room air, or a P:F ratio of <300mmHg. Patients who were pregnant, or with liver dysfunction or severe renal impairment were excluded. The primary outcome was time to clinical improvement of two points on a six-point ordinal scale, or hospital discharge, which is similar to the same group’s previous study of Lopinavir/Ritonavir, published one month earlier in NEJM and previously reviewed on INTENSIVE. Secondary outcomes included 28-day mortality, frequency of invasive ventilation, time to hospital discharge and viral load.
The trial was powered to detect a six-day reduction in time to clinical improvement following randomisation, assuming a 21-day time to improvement with placebo, and a study size of 453 patients was calculated. However, the study was terminated after recruiting 237 patients due to the falling incidence of new cases in Wuhan, China preventing recruitment. In total, 158 and 78 patients were assigned treatment with remdesivir and placebo, respectively. Most patients were receiving supplemental oxygen at the time of randomisation, with around 20% on high-flow, or non-invasive mechanical ventilation. Only one patient was invasively ventilated. Many patients received additional therapy with either lopinavir-ritonavir (28 vs. 29%) or interferon-alpha-2b (29 vs. 38%). Protocol violations were infrequent (8/158 and 3/79 in the remdesivir and placebo groups respectively).
The primary outcome, time to clinical improvement was 21 vs. 23 days with remdesivir and placebo, respectively (HR 1.23, 95% CI 0.87 to 1.75). 28-day mortality was similar 14 vs 13%, -1.1% (95% CI -8.1 to 10.3%). No statistically significant differences were observed in any of the secondary outcomes. The authors conclude that ‘intravenous remdesivir did not significantly improve the time to clinical improvement, mortality or time to viral clearance in patients with serious COVID-19, compared with placebo’.
This paper provides the first peer reviewed, scrutable, multicentre, randomised trial of remdesivir, and for patients with COVID-19 in hospital (but not necessarily intensive care), fails to demonstrate a clinically meaningful improvement. This is despite a plausible mechanism of action and in vitro evidence of its antiviral efficacy. There are a few possibilities for this result. The first is that despite in vitro efficacy, for reasons unknown remdesivir lacks in vivo efficacy against COVID-19. The second is that due to the truncated sample, the study lacks power to demonstrate a clinical benefit. However, given the close point estimates, it is unlikely that increasing the sample size would have demonstrated the six-day difference in time to clinical improvement proposed by the authors in their design. The third is that only a subset of COVID-19 patients benefit, for example, those who are earlier in their disease, as the authors suggest, or less severe, or more. A fourth is that there were confounders that persisted despite randomisation. In particular, most patients appear to have received one or more additional therapies, including corticosteroids, lopinavir-ritonavir or interferon alfa-2b, none of which are supported by high quality clinical evidence. The effect of these (if any) on the efficacy of remdesivir is unknown.
One can’t help comparing these results of this study with those announced by the NIH for the ACTT trial on the same day. This study of 1063 patients, similar in design, will purportedly show that remdesivir results an 11 vs 15 day time to clinical recovery (p < 0.001) using a three point ordinal scale, as well as a potential mortality benefit (8.0 vs. 11.6%, p=0.059). This ‘press before peer-review’ release strategy is atypical, and this author questions the timing of the announcement. While the world awaits an opportunity to compare the full ACTT paper with this study, we are left to ponder the negative results.
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- Durie, M. Cao et al, 2020 – “LOTUS China” trial of Lopinavir–Ritonavir for Covid-19 | INTENSIVE Review. INTENSIVEblog.com. March 20, 2020. [Accessed May 2,2020] Available at URL: https://intensiveblog.com/cao-et-al-2020-lotus-china-trial-of-lopinavir-ritonavir-for-covid-19/
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