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

Horby et al., The Lancet, doi:10.1016/S0140-6736(20)32013-4, RECOVERY, NCT04381936
Oct 2020  
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Mortality -3% Improvement Relative Risk Ventilation -15% Discharge -2% Lopinavir/ritonavir  RECOVERY  LATE TREATMENT  RCT Is late treatment with lopinavir/ritonavir beneficial for COVID-19? RCT 5,040 patients in the United Kingdom (March - June 2020) No significant difference in outcomes seen c19early.org Horby et al., The Lancet, October 2020 Favorslopinavir/ritonavir Favorscontrol 0 0.5 1 1.5 2+
RCT with 1,616 hospitalized COVID-19 patients showing no significant differences with lopinavir-ritonavir treatment compared to usual care.
Standard of Care (SOC): SOC for COVID-19 in the study country, the United Kingdom, is poor with low average efficacy for approved treatments1. The United Kingdom focused on expensive high-profit treatments, approving only one low-cost treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of treatment—especially early—due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments. This may explain in part the very high mortality seen in this study. Results may differ in countries with improved SOC.
risk of death, 3.0% higher, RR 1.03, p = 0.60, treatment 374 of 1,616 (23.1%), control 767 of 3,424 (22.4%).
risk of mechanical ventilation, 15.0% higher, RR 1.15, p = 0.15, treatment 152 of 1,556 (9.8%), control 279 of 3,280 (8.5%).
risk of no hospital discharge, 2.0% higher, RR 1.02, p = 0.53, treatment 1,616, control 3,424, inverted to make RR<1 favor treatment.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Horby et al., 31 Oct 2020, Randomized Controlled Trial, United Kingdom, peer-reviewed, mean age 66.2, 26 authors, study period 19 March, 2020 - 29 June, 2020, trial NCT04381936 (history) (RECOVERY). Contact: recoverytrial@ndph.ox.ac.uk.
This PaperMiscellaneousAll
Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Peter W Horby, Marion Mafham, Jennifer L Bell, Louise Linsell, Natalie Staplin, Jonathan R Emberson, Adrian Palfreeman, Jason Raw, Einas Elmahi, Benjamin Prudon, Christopher Green, Simon Carley, David Chadwick, Matthew Davies, Matthew P Wise, J Kenneth Baillie, Lucy C Chappell, Saul N Faust, Thomas Jaki, Katie Jefferey, Wei Shen Lim, Alan Montgomery, Kathryn Rowan, Edmund Juszczak, Richard Haynes, Martin J Landray
The Lancet, doi:10.1016/s0140-6736(20)32013-4
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 lopinavirritonavir 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.
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Late treatment
is less effective
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