Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial

Abstract

Importance: Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).

Objective: To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.

Design, setting, and particpants: This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.

Interventions: Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

Main outcomes and measures: Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.

Results: Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] -9.0%; 90% credible interval [CrI], -21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI -28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).

Conclusions and relevance: In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.

Trial registration: ClinicalTrials.gov Identifier: NCT04331808.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tharaux has received honorarium fees for participation on advisory boards for Retrophin Inc not related to this work. No other disclosures are reported.

Figures

Figure 1.. Study Flowcharta

aOne patient withdrew consent and asked data to be erased. According to European regulation, no data were analyzed for this patient.

Figure 2.. Occurrence of Primary Outcome Events During Follow-up

Kaplan-Meier cumulative estimates of probability of (A) the primary outcome, death or ventilation support (mechanical ventilation, high-flow or noninvasive ventilation); B, death or mechanical ventilation; (C) overall survival in the tocilizumab arm compared with the usual care arm. In panel A, events occurring on day 1 occurred on the same day as but after randomization. For the primary event and death or mechanical ventilation, data are analyzed in a bayesian framework, and median posterior HR and 90% credible intervals (CrIs) are presented, together with posterior probabilities of achieving specified effects, in the tables on the right. Overall survival was analyzed in a frequentist framework, so these probabilities were not relevant. HFO indicates high-flow oxygen; MV, mechanical ventilation; NIV, noninvasive ventilation.