By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
Dr. Deresinski reports no financial relationships relevant to this field of study.
SYNOPSIS: None of the four drugs studied was superior to placebo.
SOURCE: WHO Solidarity Trial Consortium; Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed antiviral drugs for COVID-19 — Interim WHO Solidarity Trial Results. N Engl J Med 2020; Dec 2. doi: 10.1056/NEJMoa2023184. [Online ahead of print].
The World Health Organization (WHO) Solidarity Consortium performed a large, simple, randomized noninferiority trial of four proposed therapies and of local standard of care in adults with COVID-19. A total of 11,330 patients at 405 hospitals in 30 countries representing all WHO regions were randomized to receive either remdesivir (N = 2,750), hydroxychloroquine (954), lopinavir (1,411), interferon (2,063, 651 of whom also received lopinavir), or no trial drug (4,088). The primary endpoint was in-hospital mortality.
Each treatment was compared to standard of care. The rate ratios for death were:
- remdesivir: 0.95 (95% confidence interval [CI], 0.81 to 1.11);
- hydroxychloroquine: 1.19 (95% CI, 0.89 to 1.59);
- lopinavir: 1.00 (95% CI, 0.79 to 1.25);
- interferon beta-1a: 1.16 (95% CI, 0.96 to 1.39).
The investigators concluded that, “No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.”
This massive study was accomplished over a remarkably brief period of time. The tradeoff for speed and efficiency was the need to simplify enrollment and management and to accept a large degree of heterogeneity in patient management across a wide range of hospital settings. Although these and other factors may have affected the results, it seems clear that none of the therapies have a large effect on mortality, and this likely would be true no matter what the setting and standard clinical practice.
Perhaps the greatest controversy generated by these results revolves around the use of remdesivir, which was approved by the U.S. Food and Drug Administration (FDA) shortly before this information became available. That approval was based largely on the ACTT-1 trial in which the drug was compared to placebo and in which remdesivir use was associated with a shortened time to recovery and duration of hospitalization, but did not significantly affect mortality.1 The National Institutes of Health (NIH) guideline points out that remdesivir is recommended for use in patients requiring supplemental oxygen, but not in patients requiring mechanical ventilation (because of a lack of relevant data).2
These results of the Solidarity Trial were published in the New England Journal of Medicine shortly after the journal had published a study of the use of convalescent plasma in patients with severe COVID-19 that concluded that “no significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo.”3
Baricitinib has provided, at best, minimal benefit. In addition, monoclonal antibodies have not performed well. Unfortunately, negative or minimal results of therapy of COVID-19 (with the exception of dexamethasone) have become a theme.
- Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 - Final Report. N Engl J Med 2020;383:1813-1826.
- National Institutes of Health. COVID-19 Treatment Guidelines. Therapeutic management of patients with COVID-19.
- Simonovich VA, Burgos Pratx LD, Scibona P, et al; PlasmAr Study Group. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med 2020; Nov 24. doi: 10.1056/NEJMoa2031304. [Online ahead of print].