WHO Solidarity Trial - Solidarity

Contribution To Literature:

Highlighted text has been updated as of May 23, 2022.

Among patients admitted with COVID-19, none of the four tested drugs (remdesivir, hydroxychloroquine, lopinavir, interferon) demonstrated a mortality benefit compared with their respective controls.

Description:

The goal of the trial was to assess the safety and efficacy of four drugs (remdesivir, hydroxychloroquine, lopinavir, interferon) among patients hospitalized with coronavirus disease 2019 (COVID-19).

Study Design

Patients were randomized in an open-label fashion to either remdesivir (n = 2,750), hydroxychloroquine (n = 954), lopinavir without interferon (n = 1,411), interferon with or without lopinavir (n = 2,063), or no trial drug (n = 4,088). Participants were randomly assigned in equal proportions to receive no trial drug or one of the trial drug regimens that was locally available.

The regimen for remdesivir (intravenous) was 200 mg on day 0 and 100 mg on days 1-9. The regimen for hydroxychloroquine (oral) was four tablets at hour 0, four tablets at hour 6, and, starting at hour 12, two tablets twice daily for 10 days. Each tablet contained 200 mg of hydroxychloroquine sulfate. The regimen for lopinavir (oral) was two tablets twice daily for 14 days. Each tablet contained 200 mg of lopinavir (plus 50 mg of ritonavir, to slow hepatic lopinavir clearance). The regimen for interferon (mainly subcutaneous) was three doses over a period of 6 days (the day of randomization and days 3 and 6) of 44 μg of subcutaneous interferon beta-1; where intravenous interferon was available, patients receiving high-flow oxygen, ventilation, or extracorporeal membrane oxygenation (ECMO) were instead to be given 10 μg intravenously daily for 6 days.

  • Total number of enrollees: 11,266
  • Duration of follow-up: 28 days
  • Age: 81% were <70 years
  • Percentage female: 38%

Inclusion criteria:

  • Age ≥18 years
  • Hospitalization with COVID-19
  • Not known to have received any trial drug
  • Were not expected to be transferred elsewhere within 72 hours
  • No contraindications

Exclusion criteria:

  • Known hypersensitivity to tocilizumab
  • Pregnancy
  • Current documented bacterial infection
  • Patients with any of following laboratory results out of the ranges detailed below at screening: absolute neutrophil count 1.0 × 109/L or less or platelets <50 G /L

Other salient features/characteristics:

  • Diabetes: 25%
  • 8% on ventilation

Principal Findings:

The primary outcome was in-hospital mortality.

  • Remdesivir vs. control: 12.5% vs. 12.7%, risk ratio (RR) 0.95, 95% confidence interval (CI) 0.81-1.11 (p = 0.5)
  • Hydroxychloroquine vs. control: 10.2% vs. 8.9%, RR 1.19, 95% CI 0.89-1.59 (p = 0.23)
  • Lopinavir vs. control: 9.7% vs. 10.3%, RR 1.0, 95% CI 0.79-1.25 (p = 0.97)
  • Interferon vs. control: 12.9% vs. 11%, RR 1.16, 95% CI 0.96-1.39 (p = 0.11)

None of the subgroup analyses tested were significant.

Updated results: In-hospital mortality for remdesivir (n = 4,146) or control (n = 4,129): 14.5% vs. 15.6% (p = 0.12). Subgroups: No oxygen: 2.9% vs. 3.8% (p = 0.31); oxygen but not ventilated: 14.6% vs. 16.3% (p = 0.03); not on oxygen initially: 2.9% vs. 3.8% (p = 0.3); already ventilated: 42.1% vs. 38.6% (p = 0.32).

Non-prespecified composite outcome of death or progression to ventilation: 19.6% vs. 22.5% (RR 0.84, 95% CI 0.75-0.93, p = 0.001).

Interpretation:

The results of this trial indicate that among patients admitted with COVID-19, none of the four tested drugs (remdesivir, hydroxychloroquine, lopinavir, interferon) demonstrated a mortality benefit compared with their respective controls. Among the subset of patients who were hospitalized but not ventilated, there appeared to be a small benefit with remdesivir towards mortality/progression to ventilation.

A major limitation is that this was an open-label study with no placebo control. Longer-term data are awaited. Overall, the negative overall findings from the regimens tested are adequate to refute early hopes, based on smaller or nonrandomized studies, that any of these regimens will substantially reduce inpatient mortality, the initiation of mechanical ventilation, or hospitalization duration.

References:

WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalized patients with COVID-19: final results of the WHO Solidarity randomized trial and updated meta-analyses. Lancet 2022;May 2:[Epub ahead of print].

WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511.

Editorial: Harrington DP, Baden LR, Hogan JW. A Large, Simple Trial Leading to Complex Questions. N Engl J Med 2021;384:576-7.

Clinical Topics: Prevention, Novel Agents, Statins

Keywords: Antiviral Agents, Coronavirus, Coronavirus Infections, COVID-19, ACC COVID-19 Podcast, Extracorporeal Membrane Oxygenation, Hospital Mortality, Hydroxychloroquine, Inpatients, Interferons, Lopinavir, Primary Prevention, remdesivir, Respiration, Artificial, Ritonavir, severe acute respiratory syndrome coronavirus 2, Ventilation


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