None of the four once-promising drugs evaluated for the treatment of COVID-19 in the ongoing World Health Organization (WHO) Solidarity Trial—remdesivir, hydroxychloroquine, lopinavir, or interferon-beta-1a—prevented in-hospital death, reduced the need for ventilation, or shortened the duration of hospitalization.
The interim results of the open-label study, published yesterday in the New England Journal of Medicine, involved randomly assigning hospitalized COVID-19 patients equally to whichever trial drugs were available locally or to a control group from Mar 22 to Oct 4.
All four drugs were already in use for other indications and had been repurposed as potential treatments for the novel coronavirus.
Advanced age, early need for ventilation
The study involved 11,226 patients in 405 hospitals in 30 countries in all six WHO regions assigned to receive one of the four drugs or to be part of a control group. Some patients assigned to interferon also received the HIV antiviral drug lopinavir. The control group received hospital-specific standard care. Adherence to the regimens was 94% to 96% halfway through the treatment period.
A total of 1,253 patients (11.2%) died after a median of 8 days. The Kaplan-Meier 28-day death rate was 11.8% but rose to 20.4% in patients older than 70 years and 39.0% in patients already receiving ventilation at study arm assignment.
Of the 2,743 patients who received remdesivir, 301 died, as did 303 of the 2,708 patients in its control group (rate ratio, 0.95). Of the 947 patients in the hydroxychloroquine group, 104 died, as did 84 of the 906 in its control group (rate ratio, 1.19).
Of the 1,399 patients in the lopinavir group, 148 died, while 146 of 1,372 in its control group did so (rate ratio, 1.00). Among the 2,050 patients receiving interferon, 243 died, as did 216 of the 2,050 in its control group (rate ratio, 1.16).
"No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration," the authors wrote.
The vast majority (81%) of patients were younger than 70 years, 62% were male, and 25% had diabetes.
Hydroxychloroquine, lopinavir, and interferon were dropped from the Solidarity trial on Jun 19, Jul 4, and Oct 16, respectively, after they were deemed of no benefit, but other possible treatments are still being added. "The Solidarity trial has been recruiting approximately 2,000 patients per month, and efficient factorial designs may allow it to assess further treatments, such as immune modulators or anti–SARS-CoV-2 monoclonal antibodies," the authors said.
Remnants of hope for remdesivir
In a commentary in the same journal, David Harrington, PhD, of Harvard University; Lindsey Baden, MD, of Brigham and Women's Hospital; and Joseph Hogan, ScD, of Brown University; said that the results of the Solidarity trial, when combined with those of previous studies, clearly show that hydroxychloroquine, lopinavir, and interferon beta-1a have no place in the treatment of COVID-19.
Remdesivir might still be useful, though, the authors said, in light of the results of the Adaptive COVID-19 Treatment Trial, which suggested that the drug sped the time to recovery of COVID-19 patients (10 days vs 15 for a placebo) and reduced the length of hospitalization to 12 days, down from 17 with placebo, but found no benefit in terms of preventing death.
Two previous trials of remdesivir also showed some benefit in terms of time to recovery, with one showing that a 5-day regimen of remdesivir resulted in clinical improvement after 11 days but that a 10-day course did not, and the other finding reduced time to recovery with remdesivir, but only in patients who started treatment less than 10 days after diagnosis.
However, "even without a reduction in in-hospital mortality, reducing the time to recovery and hospital discharge among patients who survive is important, both for patients and for stressed health care systems, and was the basis for the recent approval of remdesivir by the Food and Drug Administration," Harrington and colleagues wrote, adding that the Solidarity trial results temper expectations for substantially reduced death rates with the drug. Remdesivir was approved for treatment of COVID-19 on Oct 22.
The commentary authors called for placebo-controlled trials with complex data to determine whether remdesivir is best reserved for patients with certain risk factors, identify the most effective timing for dosing, and determine whether outcomes can be improved if remdesivir is combined with other drugs.
"Detailed examination of these questions within the Solidarity trial would have undermined the very simplicity that made it possible," they said. "How to answer these more complicated and nuanced questions quickly remains a challenge for the scientific community. It will not be simple to achieve clarity on when and how—or even whether—to use remdesivir."
See also:
Oct 9 CIDRAP News story "New COVID studies: Remdesivir yes, hydroxychloroquine no"
Aug 21 CIDRAP News story "Remdesivir of scant benefit in hospitalized COVID patients, study finds"
