Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Abstract

Background: Lopinavir-ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity, preclinical studies, and observational studies. Here, we report the results of a randomised trial to assess whether lopinavir-ritonavir improves outcomes in patients admitted to hospital with COVID-19.

Methods: In this randomised, controlled, open-label, platform trial, a range of possible treatments was compared with usual care in patients admitted to hospital with COVID-19. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus lopinavir-ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge (or one of the other RECOVERY treatment groups: hydroxychloroquine, dexamethasone, or azithromycin) using web-based simple (unstratified) randomisation with allocation concealment. Randomisation to usual care was twice that of any of the active treatment groups (eg, 2:1 in favour of usual care if the patient was eligible for only one active group, 2:1:1 if the patient was eligible for two active groups). The primary outcome was 28-day all-cause mortality. Analyses were done on an intention-to-treat basis in all randomly assigned participants. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.

Findings: Between March 19, 2020, and June 29, 2020, 1616 patients were randomly allocated to receive lopinavir-ritonavir and 3424 patients to receive usual care. Overall, 374 (23%) patients allocated to lopinavir-ritonavir and 767 (22%) patients allocated to usual care died within 28 days (rate ratio 1·03, 95% CI 0·91-1·17; p=0·60). Results were consistent across all prespecified subgroups of patients. We observed no significant difference in time until discharge alive from hospital (median 11 days [IQR 5 to >28] in both groups) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 0·98, 95% CI 0·91-1·05; p=0·53). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion who met the composite endpoint of invasive mechanical ventilation or death (risk ratio 1·09, 95% CI 0·99-1·20; p=0·092).

Interpretation: In patients admitted to hospital with COVID-19, lopinavir-ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir-ritonavir for treatment of patients admitted to hospital with COVID-19.

Funding: Medical Research Council and National Institute for Health Research.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile *Number recruited overall during the period that participants could be recruited into lopinavir–ritonavir comparison. †Some patients were included in both of the below groups. ‡A second randomisation to tocilizumab versus usual care in patients with hypoxia and C-reactive protein ≥75 mg/L was introduced in protocol version 4.0.

Figure 2

Effect of allocation to lopinavir–ritonavir on 28-day mortality

Figure 3

Effect of allocation to lopinavir–ritonavir on 28-day mortality by baseline characteristics Subgroup-specific rate ratio estimates are represented by squares (with areas of the squares proportional to the amount of statistical information) and the lines through them correspond to the 95% CIs. The ethnicity and days since onset subgroups exclude those with missing data, but these patients are included in the overall summary diamond. The method used to calculate baseline predicted risk is described in the appendix (p 23)). The χ2 statistics correspond to tests for trend (or heterogeneity) in the log rate ratios across the levels of each subgroup. *Includes patients receiving non-invasive ventilation.