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What is the effect of tocilizumab, an anti–interleukin-6 receptor antibody, in patients with COVID-19 and moderate-to-severe pneumonia?
In this randomized clinical trial that included 130 patients hospitalized with COVID-19 and moderate-to-severe pneumonia, tocilizumab did not reduce the World Health Organization 10-point Clinical Progression Scale scores lower than 5 at day 4, and the proportion of patients with noninvasive ventilation, intubation, or death at day 14 was 36% with usual care and 24% with tocilizumab. No difference in mortality over 28 days was found between the 2 groups.
Tocilizumab may reduce the need for mechanical and noninvasive ventilation or death by day 14 but not mortality by day 28; further studies are necessary to confirm these preliminary results.
Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).
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.
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.
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.
ClinicalTrials.gov Identifier: NCT04331808
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Accepted for Publication: October 1, 2020.
Published Online: October 20, 2020. doi:10.1001/jamainternmed.2020.6820
Corresponding author: Olivier Hermine, MD, PhD, Université de Paris, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker, INSERM, Imagine Institute, 149-161 rue de Sèvres, Paris 75743, France (email@example.com).
Author Contributions: Drs Resche-Rigon and Porcher had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors contributed equally to this study.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Hermine, Mariette, Tharaux, Resche-Rigon.
Statistical analysis: Porcher, Ravaud.
Obtained funding: Hermine, Mariette, Resche-Rigon, Ravaud.
Administrative, technical, or material support: Hermine, Mariette, Resche-Rigon, Ravaud.
Supervision: Hermine, Mariette, Tharaux, Ravaud.
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.
Data Sharing Statement: See Supplement 4.
Funding/Support: This trial was publicly funded (Ministry of Health, Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0143, PHRC COVID-19-20-0029], Foundation for Medical Research (FRM), AP-HP Foundation and the Reacting program).
Role of the Funder/Sponsor: The funding agencies had no access to the trial data and had no role in the design, conduct or reporting of the trial. Roche donated TCZ in unrestricted grant, and had no role in the trial design or conduct; the collection, management, analysis, interpretation of the data; or in the preparation, review of the manuscript or the approval of the manuscript for submission.
Additional Contributions: We are grateful to all patients who participated in the CORIMUNO study, and their families. The authors also thank Pr Maxime Dougados, MD, in charge of the logistics, as well as the investigators who collaborated in this study (Supplement) and Universities of Paris, Paris-Saclay, Paris-Sorbonne, Paris-Nord Sorbonne, Paris-Est Créteil, Versailles-Saint Quentin, Strasbourg and Lille (Medical Students support), INSERM, and Reacting.
Additional Information: A coordination committee was responsible for the design, conduct, and reporting of the trial, and an independent data and safety monitoring board (DSMB) oversees all CORIMUNO trials (see eAppendix 1 in Supplement 1).
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