Review 2: "Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results"

Marie Warrer Munch

doi:doi:10.1162/2e3983f5.0067288a

Review 2: "Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results"

This reliable study suggests four antivirals have no effect on important clinical outcomes in hospitalized COVID-19 patients. While the randomized control trial is thorough, reviewers note missing descriptions of study protocol, patient eligibility, & adverse reactions.

by Marie Warrer Munch

Published onNov 11, 2020

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This Pub is a Review of

Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results

by WHO Solidarity trial consortium, Hongchao Pan, Richard Peto, Quarraisha Abdool Karim, Marissa Alejandria, Ana Maria Henao-Restrepo, César Hernández García, Marie-Paule Kieny, Reza Malekzadeh, Srinivas Murthy, Marie-Pierre Preziosi, Srinath Reddy, Mirta Roses Periago, Vasee Sathiyamoorthy, John-Arne Røttingen, Soumya Swaminathan, and as the members of the Writing Committee, assume responsibility for the content and integrity of this article

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Published on Oct 15, 2020
www.medrxiv.org

Description

BACKGROUND WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs. METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-β1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry. RESULTS In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration. CONCLUSIONS These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151, NCT04315948)

RR:C19 Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

This large, multi-country, randomized evaluation of remdesivir, hydroxychloroquine, lopinavir, and interferon is highly important evidence. The trial comes with several strengths, including 1) randomized evaluation of treatment effects, 2) large sample size, 3) web-based randomization and concealed allocation, 4) assessment of patient-important outcomes in the ITT population, 5) primary analysis supplemented with subgroup analysis and sensitivity analyses, 6) trial design and reporting independent of funders, and 7) high external validity due to participation of both low- and high-income countries. The trial reporting is supplemented with a meta-analysis of all current trials. The mortality findings of the SOLIDARITY trial are in general in accordance with findings from other trials.

The trial also comes with some limitations, 1) open-labelled trial design, 2) no formal sample size calculation, 3) unstratified randomization (ideally stratified for age and mechanical ventilation), 4) unclear or at least not fully presented eligibility criteria (according to trial registration, exclusion criteria changed during course of trial), 5) full protocol not available online, only trial registration and protocol for DISCOVERY (not able to see what analyses were prespecified and post hoc), 6) only recording of SUSARs, these are not reported, no formal recording or reporting of SAR, which is highly relevant, 7) only short-term follow-up, ideally also follow-up on longer-term mortality (i.e. 90 days) and quality of life.

Suggested revisions include 1) full presentation of eligibility criteria, including changes during the trial, 2) link to full protocol, 3) applying which analysis were pre-specified and which were post hoc with reference to the protocol and statistical analysis plan, and 4) reporting of SUSARs (and SARs if recorded).

Based upon the above-mentioned strengths and limitations and considering the large sample size and multi-country design, my recommendation regarding strength of evidence in the preprint is ‘reliable.’