• 2 randomized trials with available results included adults hospitalized with COVID-19 pneumonia
  • 1 multinational trial by the NIAID (ACTT-1; NEJM 2020) randomized 1,063 patients in 73 sites (in North America, Europe, and Asia)
  • 1 Chinese trial (Lancet 2020) randomized 236 patients
• Dose studied: remdesivir IV 200 mg then 100 mg once daily for 9 days
• Data regarding clinical efficacy
  • Mortality at 14 days might be reduced by absolute risk difference 4% (95% CI 1% to 8% (Low certainty)
  • Time to recovery or clinical improvement may be shortened by 2-4 days (Moderate certainty)
  • Mortality, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) at 2 weeks may be reduced by absolute risk difference 9% (95% CI 4% to 14%) (Moderate certainty)
• Adverse events not significantly different from placebo in ACTT-1 or Chinese trial
• NOTE: Remdesivir not FDA approved but has Emergency Use Authorization and US government coordinating with drug manufacturer (Gilead) to prioritize supply for areas with the greatest potential need
• The NIH COVID-19 Treatment Guidelines
  • recommend remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease (defined as having SpO₂ ≤94% on ambient air [at sea level], requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]) (BI).
  • do not recommend remdesivir for the treatment of mild or moderate COVID-19 outside of a clinical trial (AIII).
• Reference – NIH COVID-19 Treatment Guidelines – Remdesivir section

• 2 randomized trials with available results are limited:
  • 1 multinational trial by the NIAID (ACTT-1; NEJM 2020) randomized 1,063 patients in 73 sites (in North America, Europe, and Asia) but is limited by the preliminary state of reports: preliminary analysis reported but up to 28% of the data is not yet included in the analyses
  • 1 Chinese trial (Lancet 2020) randomized 236 patients but limited by early trial termination (attributed to the COVID-19 epidemic being controlled in China with no further cases eligible for study); proportion of people with symptom duration > 10 days at baseline was 54% in remdesivir group vs. 40% placebo group, but reason for 10-day dichotomization not clear; median time to initiation of therapy was 11 days (IQR 9 to 12 days) for remdesivir group and 10 days (IQR 9 to 12 days)
• Dose studied: remdesivir IV 200 mg then 100 mg once daily for 9 days
• Data regarding clinical efficacy
  • Mortality (Improved outcome, Low certainty)
    • nonsignificantly lower with remdesivir in ACTT-1 (estimated 7.1% vs. 11.9% at 14 days via Kaplan-Meier estimation; absolute risk difference -4.8%; hazard ratio 0.70 [95% CI 0.47 to 1.04])
    • effects less clear in Chinese trial, but Chinese trial has considerable imprecision
      • 9.8% vs. 9% at 14 days (absolute risk difference 0.8% [95% CI -8.4% to 8.2%])
      • 13.9% vs. 12.8% at 28 days (absolute risk difference 1.1% [95% CI -8.1% to 10.3%])
    • meta-analysis of trial data suggests mortality benefit for remdesivir at 14 days (see below for details of meta-analysis)
      • relative risk 0.65 (95% CI 0.45 to 0.94); absolute risk difference -4% (95% CI -1% to -8%)
    • Time to recovery or clinical improvement (Improved outcome, Moderate certainty)
      • significant benefit with remdesivir in ACTT-1 (median 11 vs. 15 days; rate ratio 1.32 [95% CI 1.12 to 1.55])
      • Chinese trial did not find a statistically-significant difference, but considerable imprecision in trial means it could not rule out important benefits (median 21 vs. 23 days; hazard ratio 1.23 [95% CI 0.87 to 1.75])
    • Mortality, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) at 2 weeks (Improved outcome, Moderate certainty)
      • significant benefit at 15 days with remdesivir in ACTT-1 (21.4% vs. 31%; absolute risk difference -9.6% [95% CI -3.6% to -15.4%])
      • Chinese trial did not find a statistically-significant difference, but considerable imprecision in trial means it could not rule out important benefits (12.4% vs. 17.9% at 14 days; absolute risk difference -5.5% [95% CI -16.4% to 3.8%])
      • meta-analysis of trial data suggests benefit for remdesivir at 14 to 15 days (see below for details of meta-analysis)
        • relative risk 0.69 (95% CI 0.56 to 0.86); absolute risk difference -9% (95% CI -4% to -14%)
• Adverse events not significantly different from placebo in ACTT-1 or Chinese trial
• NOTE: Remdesivir not FDA approved but has Emergency Use Authorization and US government coordinating with drug manufacturer (Gilead) to prioritize supply for areas with the greatest potential need
• Remdesivir is suggested for hospitalized patients with severe disease (Strength = Moderate recommendation) in NIH COVID-19 Treatment Guidelines
  • Based on May 19, 2020 view of NIH COVID-19 Treatment Guidelines last updated May 12, 2020
  • On the basis of preliminary clinical trial data (described below), the COVID-19 Treatment Guidelines Panel (the Panel) recommends the investigational antiviral agent remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease (defined as having SpO₂ ≤94% on ambient air [at sea level], requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]) (BI).
    • Remdesivir is not approved by the Food and Drug Administration (FDA); however, it is available through an FDA emergency use authorization (EUA) for the treatment of hospitalized adults and children with COVID-19 and is currently being investigated in clinical trials. Remdesivir is also available through an emergency access program for children (<18 years of age) and pregnant patients.
    • Additional data on the use of remdesivir for patients with COVID-19, including analyses of important patient subgroups, are expected soon and may further inform the Panel's recommendation.
• The Panel does not recommend remdesivir for the treatment of mild or moderate COVID-19 outside of a clinical trial (AIII).
• Reference – NIH COVID-19 Treatment Guidelines – Remdesivir section

Reasons for lower certainty

1. Preliminary results reported (may change with fuller data reporting) with 208 of 1,063 participants (19.6%) still receiving study treatment within the 28-day period or having missing treatment data at time of database freeze on April 28, 2020, and 301 (28.3%) who had not recovered and had not completed the day 29 follow-up visit as of April 28, 2020
2. One trial suggests benefit and one trial does not suggest a difference one way or the other. Although these findings could be consistent, this is essentially a failure to replicate results in a second trial.
3. Early trial termination (attributed to control of epidemic in China)
4. Proportion of people with symptom duration > 10 days at baseline was 54% in remdesivir group vs. 40% placebo group, but reason for 10-day dichotomization not clear; median time to initiation of therapy was 11 days (IQR 9 to 12 days) for remdesivir group and 10 days (IQR 9 to 12 days)
5. Imprecision (confidence intervals include important difference and no difference)

Details of meta-analyses

Meta-analytic results for the relative risk and risk difference are both from a fixed-effects model for the outcomes of 14-day mortality and death or need for invasive mechanical ventilation or ECMO at 14 or 15 days. Additionally, we note the risk difference is meta-analyzed directly (as opposed to using the relative risk in conjunction with a presumed baseline risk to estimate absolute treatment effects). Results for a random-effects model with a Paule-Mandel estimator yielded comparable findings, though we note that for the outcome of 14-day mortality, the findings no longer reached conventional statistical significance:

• Relative risk 0.71 (95% CI 0.39 to 1.28); I² = 43%, τ² = 0.0004
• Risk difference -3% (95% CI -8% to 1%); I² = 31%, τ² = 0.0891

Although some might lean toward a random-effects model given the values of I² and τ², we note that choosing between a fixed-effects and random-effects model based solely on these values is an ill-advised practice; additionally, it can be difficult to obtain a robust estimate of variance with only two trials. Considering more broadly the totality of the available evidence, the particularities of the trials included in these meta-analyses, and the consistency of the results between fixed- and random-effects models (other than wider confidence intervals for the random-effects model for 14-day mortality), we consider it reasonable to present the fixed-effects model as the primary results.

References

• Beigel JH et al, for the ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Preliminary Report. N Engl J Med. 2020 May 22. DOI: 10.156/NEJMoa2007764. https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
  • In computable form: Alper BS. Clinical Outcomes in NIAID ACTT Remdesivir RCT. COKA EvidenceReport 16. 2020 May 24. https://gps.health/coka/resources/EvidenceReport/16
• Wang Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020 Apr 29. https://doi.org/10.1016/S0140-6736(20)31022-9
  • In computable form: Alper BS. Clinical Outcomes in Lancet 2020 Apr 29 Remdesivir RCT. COKA EvidenceReport 4. 2020 Apr 30. https://gps.health/coka/resources/EvidenceReport/4