Author:
,Pan Hongchao,Peto Richard,Karim Quarraisha Abdool,Alejandria Marissa,Henao-Restrepo Ana Maria,García César Hernández,Kieny Marie-Paule,Malekzadeh Reza,Murthy Srinivas,Preziosi Marie-Pierre,Reddy Srinath,Periago Mirta Roses,Sathiyamoorthy Vasee,Røttingen John-Arne,Swaminathan Soumya,
Abstract
ABSTRACTBACKGROUNDWHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs.METHODSStudy 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.RESULTSIn 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.CONCLUSIONSThese 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)
Publisher
Cold Spring Harbor Laboratory
Reference17 articles.
1. World Health Organization, R&D Blueprint. A coordinated global research roadmap: 2019 novel coronavirus. Geneva, Switzerland March 2020 https://www.who.int/docs/default-source/coronaviruse/coordinated-global-research-roadmap.pdf?sfvrsn=21b0f5c4_1&download=true (Accessed October 3, 2020).
2. World Health Organization, R&D Blueprint. Informal consultation on prioritization of candidate therapeutic agents for use in novel coronavirus 2019 infection https://www.who.int/teams/blueprint/covid-19 (Accessed October 3, 2020).
3. World Health Organization, R&D Blueprint. An international randomised trial of additional treatments for COVID-19 in hospitalised patients who are all receiving the local standard of care https://www.who.int/publications/m/item/an-international-randomised-trial-of-additional-treatments-for-covid-19-in-hospitalised-patients-who-are-all-receiving-the-local-standard-of-care (Accessed October 3, 2020).
4. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology;PLoS Med,2020
5. Remdesivir for the Treatment of Covid-19 — Preliminary Report