Remdesivir for COVID-19: Imperfect but better than nothing?

Contributed by Dr Chintan Kaswala, Dr Ram Gopalakrishnan

Remdesivir, a nucleoside analog of adenosine, exhibits anti-viral properties against SARS-CoV-2 by inhibiting RNA dependent RNA polymerase. The first randomized data for remdesivir in humans was published in The Lancet on April 29,2020 (Wang et al. 2020). The investigators couldn’t enroll the pre-specified number of patients as the outbreak was controlled by then in China. This underpowered trial didn’t show any difference in clinical improvement or 29 days mortality between two groups.

For the second RCT (ACTT-1) which had enrolled 1063 patients from 68 sites from Americas, Europe and Asia, the preliminary report has recently been published. Participants were randomized 1:1 to receive up to 10 days of remdesivir versus placebo. The trial enrolled adults with COVID-19 with lower respiratory involvement with varying degress of oxyen support. The primary endpoint in this adaptive design was “time to recovery,” defined as the first day of reaching a score of 1, 2, or 3 on the ordinal scale. Out of 538 patients in the treatment arm and 522 patients in placebo arm included in the interim analysis 391 in the former and 340 in the latter group had completed 29 days followup. In the interim analysis, the median days to recovery in Remdesivir group was 11 as compared to 15 days with placebo with rate ratio for recovery, 1.32 [95% CI, 1.12 to 1.55]. In subgroup analysis, the maximum benefit was seen in the patient receiving supplemental oxygen at baseline. This probably the first RCT showing a clear cut beneft of an antiviral in COVID 19.

The third is a randomized controlled trial evaluating the superiority of 10 days of Remdesivir to 5 days of therapyin the the patients infected with SARS-CoV-2. Here, they had exluded the patients receiving mechanical ventilation, ECMO or those with signs of multi organ failure. In this study, a large proportion of the participants, mainly in the 10 days arm, discontinued the treatment. However almost all of them were included in the intention to treat analysis provided they had received at least one dose of the trial treatment. The final analysis didn’t show any superiority in the clinical improvement at day 14. There was no significant mortality difference in the two arms as well. However, in the subgroup analysis, in those requiring invasive ventilation at day 5, mortality was significantly high in the 5 days arm. To conclude, remdesivir appears to accelerate recovery in patients requiring supplemental oxygen. However, benefit of evidence in patients requiring mechanical ventilation or ECMO is lacking. In the patient with moderate disease, a shorter duration of 5 days may be considered.

References

  1. 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 May 16;395(10236):1569-1578
  2. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — preliminary report. N Engl J Med. 2020 May 22
  3. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020 May 27