Background
The Solidarity trial among hospitalized COVID-19 patients previously reported interim mortality analyzes for four repurposed antiviral drugs.
Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued due to futility , but randomization to remdesivir continued.
Here we report the final results from Solidarity and meta-analyses of mortality in all relevant trials to date.
Methods
Solidarity enrolled consenting adults (≥18 years) recently hospitalized with, in the opinion of their physician, definite COVID-19 and no contraindication to any of the study medications, regardless of any other patient characteristics.
Participants were randomly assigned, in equal proportions among locally available options, to receive any of the four study medications (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) that were locally available at the time or no study medication (controls). ).
All patients also received the local standard of care. No placebos were administered. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity.
Secondary endpoints were progression to ventilation if not already ventilated and time to hospital discharge. Final log-rank and Kaplan-Meier analyzes are presented for remdesivir and are attached for all four study drugs.
Meta -analyses provide weighted averages of mortality findings in this and all other randomized trials of these drugs among hospitalized patients.
Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.
Results
Between March 22, 2020 and January 29, 2021, 14,304 potentially eligible patients were recruited from 454 hospitals in 35 countries across the six WHO regions.
After exclusion of 83 (0.6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14,221 patients, including 8,275 randomly assigned (1:1) to remdesivir ( ten infusions daily, unless discharged earlier) or to your follow-up (you were not assigned any study drug although remdesivir was available locally).
Compliance was high in both groups.
Overall, 602 (14.5%) of 4146 patients assigned to remdesivir died versus 643 (15.6%) of 4129 assigned to control (mortality rate ratio [RR] 0.91 [95% CI 0. 82–1.02 ], p=0·12).
Of those already ventilated, 151 (42.1%) of 359 assigned to remdesivir died compared to 134 (38.6%) of 347 assigned to control (RR 1.13 [0.89–1.42], p=0 · 32).
Of those not ventilated but given oxygen, 14.6% assigned to remdesivir died versus 16.3% assigned to control (RR 0.87 [0.76–0.99], p=0.03). Of 1730 initially not receiving oxygen, 2.9% assigned to remdesivir died versus 3.8% assigned to control (RR 0.76 [0.46–1.28], p=0.30).
Combining all those not initially ventilated, 11.9% assigned to remdesivir died versus 13.5% assigned to control (RR 0.86 [0.76–0.98], p=0.02) and 14.1% versus 15.7% progressed to ventilation (RR 0.88 [0.77-1.00], p=0.04).
The non-prespecified composite outcome of death or progression to ventilation occurred in 19.6% assigned to remdesivir versus 22.5% assigned to control (RR 0.84 [0.75–0.93], p=0.001).
Assignment to daily remdesivir infusions (vs. open-label control) delayed discharge by approximately 1 day during the 10-day treatment period. A meta-analysis of mortality across all randomized trials of remdesivir versus non-remdesivir yielded similar findings.
Interpretation Remdesivir has no significant effect on COVID-19 patients who are already being ventilated. Among other hospitalized patients, it has a small effect against death or progression to ventilation (or both). |
Implications of all available evidence
Solidarity alone, or meta-analyses of all trials, do not suggest a reduction in mortality in patients who are already ventilated, but a reduction in mortality (with a wide confidence interval) in patients who receive oxygen but are not ventilated.
However, since high- and low-flow oxygen were not recorded separately when enrolling in Solidarity, it is not known whether any protective effect in unventilated patients extends to those receiving high-flow oxygen.
In Solidarity and in the meta-analyses, there was low mortality (3%) in hospitalized patients with COVID-19 who were not receiving oxygen.
Daily infusions of open-label remdesivir could slightly delay hospital discharge in those who would have been discharged earlier, as hospitalized patients could remain in the hospital to continue their remdesivir treatment.
