Even as the coronavirus disease 2019 (COVID-19) continues to cause thousands of new cases and dozens of deaths each day, research findings highlight the inadequacy of most current drug approaches to treating this potentially deadly condition. A recent study published in the journal The Lancet summarized the final results of the Solidarity trial which aimed at finding out which drugs were most effective at reducing the severity of the disease among hospitalized patients.
Study: Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Image Credit: ker_vii / Shutterstock
The Solidarity trial aimed to discover the efficacy of several different therapies used in patients hospitalized with COVID-19.
All patients in the trial had a diagnosis of COVID-19 made by their physicians and received whichever of four drugs were available locally at the time of their entry into the trial – lopinavir, hydroxychloroquine, the interferon IFN-β1a, or remdesivir – while, in addition, a control group received none of these drugs. Whatever other therapies were locally being given at the time were also used in addition to the study drug or control.
In this arm of the study, patients were randomly assigned to receive remdesivir or control. It covered the period from March 22, 2020, to January 29, 2021, including over 14,000 patients from 35 countries worldwide.
What Did the Study Show?
The study's findings show that while compliance with either remdesivir or control drug was high in both groups, there was no benefit in terms of reduced mortality from remdesivir. In both groups, the mortality was about 15%.
Among patients who were already on mechanical ventilation, death occurred in 42% of remdesivir recipients vs. 39% of controls. Again, of patients who did not receive mechanical ventilation but were on supplementary oxygen, deaths occurred in 15% of the remdesivir group but 16% of the controls.
With low-risk patients who did not initially require oxygen supplementation, there was a mortality toll of 3% in the remdesivir group and 4% among the controls. If all the patients who did not have to be put on ventilation at admission are considered, the mortality outcomes were 12% vs 14% in the remdesivir and control groups.
Moreover, while 16% of the former eventually required ventilation, this occurred in 16% of the control group. When both death and the need for ventilation at some point are combined to form one outcome, this affected 20% of the remdesivir group vs 23% of controls.
The remdesivir group received daily infusions of the drug for ten days unless they were discharged earlier than this. This protocol prolonged the duration of hospitalization to discharge by one day during the treatment period.
These findings mirrored those found in a meta-analysis of mortality data in all earlier randomized trials of the drug as against no-remdesivir protocols. This indicates that "Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated." In others, it has a negligible effect in preventing death or the need for ventilation, or both.
What Are the Implications?
The study brought up more evidence about the effects of this drug in treating moderate to severe COVID-19 than its earlier interim findings could supply. However, the trend remains the same – both overall, and in different subgroups, such as those on oxygen, those on ventilation, or others, the use of remdesivir failed to bring about any significant reduction in mortality rates. The value of this additional evidence is in the certainty it provides that the trend is not a statistical artifact, while giving more insight into the effect of the drug on the duration of hospitalization to discharge and the incidence of ventilation after admission, as compared to at the time of admission.
This contradicts the earlier claims by the manufacturer of the drug, based on raw analyses from the earlier ACTT-1 trial that remdesivir saved money spent on healthcare by reducing the hospitalization duration by some days. Even the use of open-label remdesivir failed to do this, thus negating both pharmacological and non-pharmacological, or placebo, effects on the time to discharge except that within the 10-day period required for a full course of the drug, discharge was delayed by one day.
"Delays in the discharge of patients who would be discharged within the first 5 or 10 days does not mean remdesivir has no pharmacological effect on time to fitness for discharge, but any such effect is not large and was outweighed by the non-pharmacological effect of patients remaining in hospital to continue remdesivir infusions."
This corroborates the findings from other trials, showing that the use of the drug delays discharges within the remdesivir treatment period, but this vanishes once this period is over.
These trials showed that while low-risk patients recovered faster with the drug, those who were on supplemental high-flow oxygen or ventilation were not affected favorably. Since high-risk COVID-19 patients succumb largely to the cytokine storm and related systemic hyper-inflammatory responses rather than to the presence of the virus, it might be expected that remdesivir, which inhibits viral replication, would be relatively ineffective. The principal contributor to the difference in outcome is, in fact, the degree of respiratory distress when the patient is admitted.
Patients who did not require oxygen at admission had a mortality of 3%, compared to 15% in those with oxygen supplementation but not ventilation and 30% in the ventilated group. Thus, the mortality increased ten-fold between cohorts when these entry criteria were applied to the whole set of patients.
However, further examination of all available evidence, including that of other trials, seems to indicate that remdesivir may reduce the severity of disease in non-hospitalized patients or those with mild disease at admission (receiving no oxygen, or low-flow oxygen, at entry). More research will be needed on a larger scale to reduce the scale of uncertainty about the results.
WHO Solidarity Trial Consortium (2022). Remdesivir and Three Other Drugs for Hospitalized Patients With COVID-19: Final Results Of The WHO Solidarity Randomized Trial And Updated Meta-Analyses. The Lancet. https://doi.org/10.1016/S0140-6736(22)00519-0. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00519-0/fulltext