Repurposed antiviral drugs – remdesivir, hydroxychloroquine, lopinavir and interferon – to treat COVID-19 appear to have little or no effect on patients hospitalised for the disease, in terms of overall mortality, initiation of ventilation and duration of hospital stay.
The interim findings from the WHO Solidarity trial, published in the New England Journal of Medicine (NEJM), followed 11,266 adults at 405 hospitals in 30 countries.
The study by an international team of scientists, which was co-ordinated by the World Health Organisation, compared the effects on major outcomes in hospital of the local standard of care alone (the care all patients usually receive) versus the local standard of care in addition to one of four potential drugs to treat COVID-19.
None of the study’s four repurposed antiviral drugs substantially reduced mortality (in unventilated patients or any other subgroup) or delayed the need for ventilation.
The global Solidarity trial is still recruiting about 2,000 patients per month, thanks to the contributions of nearly 500 hospitals, 1,500 clinicians and research staff and their patients. It will now rapidly evaluate promising new treatment options, such as new antivirals, immunomodulators and specific anti-SARS-Cov-2 monoclonal antibodies. Its primary objective is to provide reliable estimates on any effects of potential drugs to treat COVID-19 on in-hospital mortality in moderate and in severe COVID.
Jonathan Sterne, Professor of Medical Statistics and Epidemiology, University of Bristol and Deputy Director of the NIHR Bristol Biomedical Research Centre (NIHR Bristol BRC), said: “It’s disappointing the four treatments evaluated in the Solidarity trial did not substantially reduce mortality. But it is encouraging that the trial will continue to evaluate promising new treatment options.”
Chris Rogers, Professor of Medical Statistics and Clinical Trials and Director of the Bristol Trials Centre, added: “We are proud to have contributed to the rapid rollout of a large, international randomized trial during a public health emergency, in order to answer key public health questions. The findings give evidence to policy makers and clinicians worldwide in their fight against COVID-19.”
World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).
We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.
At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.
These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.
Full text in New England Journal of Medicine (Open access)