Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Copyright © 2020 Massachusetts Medical Society.

Figures

Figure 1. Information to October 4, 2020, on Trial Entry, Follow-up, and Intention-to-Treat Analyses.

After it was determined which treatments were locally available, random assignment (with equal probability) was between the local standard of care and the available treatments. After the exclusion of 64 of 11,330 patients (0.6%) who had provided either no or uncertain consent regarding follow-up, 11,266 remained in the intention-to-treat analyses. Each pairwise intention-to-treat analysis was between a particular trial drug and its control (i.e., patients who could have been assigned to a particular trial drug but were concurrently assigned to the same care without it). There is partial overlap of each control group with other groups.

Figure 2. Effects of Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon on In-Hospital Mortality.

Shown are Kaplan–Meier graphs of in-hospital mortality at any time (the primary outcome), comparing each treatment with its control without standardization for any initial patient characteristics. Insets show the same data on an expanded y axis. The rate ratios for death were standardized for age and for ventilation status at entry. Denominators for the few events on day 0, but not thereafter, include patients with no follow-up. Numbers of deaths are by week, and then deaths after day 28. CI denotes confidence interval.

Figure 3. Rate Ratios for In-Hospital Death, Subdivided by Age and Respiratory Support at Trial Entry.

Analyses in subgroups of age are stratified according to respiratory status at trial entry and vice versa, so each total is stratified for both factors. The percentages show Kaplan–Meier 28-day mortality. O−E denotes the observed minus expected number of deaths in patients assigned to active treatment. Diamonds show 95% confidence intervals for treatment effects. Squares and horizontal lines show treatment effects in particular subgroups and their 99% confidence intervals, with an arrow if the upper 99% confidence limit is outside the range shown. The area of each square is proportional to the variance of O−E in the subgroup it describes..

Figure 4. Meta-Analysis of Mortality in Trials of Random Assignment of Remdesivir or Its Control to Hospitalized Patients with Covid-19.

Percentages show Kaplan–Meier 28-day mortality. Values for observed minus expected number of deaths (O−E) are log-rank O−E for the Solidarity trial, O−E from 2-by-2 tables for the Wuhan and international trials, and w.loge hazard ratio for each stratum in the Adaptive Covid-19 Treatment Trial (ACTT-1) (with the weight w being the inverse of the variance of the loge hazard ratio, which was calculated from the confidence interval of the hazard ratio). Rate ratios were calculated by taking the loge rate ratio to be (O−E)/V with a Normal distribution and variance 1/V. Subtotals or totals of (O−E) and of V yield inverse-variance–weighted averages of the loge rate ratios. For balance, controls in the 2:1 trials were counted twice in the control totals and subtotals. Diamonds show 95% confidence intervals for treatment effects. Squares and horizontal lines show treatment effects in particular subgroups and their 99% confidence intervals, with an arrow if the upper 99% confidence limit is outside the range shown. The area of each square is proportional to the variance of O−E in the subgroup it describes.