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

Abstract

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.

Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg-800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).

Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77-0·92; p<0·0001).

Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.

Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Conflict of interest statement

Declaration of interests The authors have no conflict of interest or financial relationships relevant to the submitted work to disclose. No form of payment was given to anyone to produce the manuscript. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. The Nuffield Department of Population Health at the University of Oxford has a staff policy of not accepting honoraria or consultancy fees directly or indirectly from industry.

Copyright © 2021 Published by Elsevier Ltd. All rights reserved. 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 REGN-COV2=a combination of two monoclonal antibodies directed against SARS-CoV-2 spike protein. *Number of adult patients recruited at a site activated for the tocilizumab comparison. †The first randomisation comprised up to three factorial elements such that an eligible patient could be entered into between one and three randomised comparisons, depending on the then current protocol, the patient's suitability for particular treatments, and the availability of the treatment at the site. Median time between first and second randomisation was 0·3 h (IQR 0·1−25·3). ‡1964 (97%) of 2022 patients of those allocated to tocilizumab and 2049 (98%) of 2094 of those allocated to usual care had a completed follow-up form at time of analysis.

Figure 2

Effect of allocation to tocilizumab on 28-day mortality (A) and discharge from hospital within 28 days of randomisation (B)

Figure 3

Effect of allocation to tocilizumab 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. *Includes nine patients not receiving any oxygen and 1859 patients receiving simple oxygen only. †Includes patients receiving high-flow nasal oxygen, continuous positive airway pressure ventilation, and other non-invasive ventilation. ‡Includes patients receiving invasive mechanical ventilation and extracorporeal membranous oxygenation. §Information on use of corticosteroids was collected from June 18, 2020, onwards following announcement of the results of the dexamethasone comparison from the RECOVERY trial. Participants undergoing first randomisation before this date (and who were not allocated to dexamethasone) are assumed not to be receiving systemic corticosteroids. In a model adjusted for all six baseline subgroups (in the categories shown) the overall rate ratio was 0·88 (95% CI 0·79−0·98).

Figure 4

Meta-analysis of mortality in randomised, controlled trials of tocilizumab in patients hospitalised with COVID-19 O–E=observed–expected. Var=variance. *Log–rank O–E for RECOVERY, O–E from 2 × 2 contingency tables for the other trials. Rate ratio is calculated by taking ln rate ratio to be (O–E)/V with normal variance 1/V, where V=Var (O–E). Subtotals or totals of (O–E) and of V yield inverse-variance weighted averages of the ln rate ratio values. †For balance, controls in the 2:1 studies count twice in the control totals and subtotals, but do not count twice when calculating their O–E or V values. Heterogeneity between RECOVERY and eight previous trials combined, χ12=0·2 (p=0·7).