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Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial.
JAMA Intern Med. 2021 01 01; 181(1):32-40.JIM

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.

Authors+Show Affiliations

Department of Hematology, Hôpital Necker, Assistance Publique - Hôpitaux de Paris, France. Institut Imagine, Université de Paris, INSERM UMR1183, Paris France.Department of Rheumatology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, France. Université Paris-Saclay, INSERM UMR1184, Le Kremlin Bicêtre, France.Paris Cardiovascular Center-PARCC, Université de Paris, INSERM, F-75015 Paris, France.Université de Paris, ECSTRRA Team-CRESS-UMR 1153, INSERM, 75010, Paris, France. URC Saint-Louis, AP-HP, Hôpital Saint-Louis, 75010, France.Université de Paris, Centre of Research Epidemiology and Statistics (CRESS), INSERM U1153, Paris, France.Université de Paris, Centre of Research Epidemiology and Statistics (CRESS), INSERM U1153, Paris, France. Centre d'Epidémiologie Clinique, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Hôtel Dieu, Paris, France.No affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33080017

Citation

Hermine, Olivier, et al. "Effect of Tocilizumab Vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: a Randomized Clinical Trial." JAMA Internal Medicine, vol. 181, no. 1, 2021, pp. 32-40.
Hermine O, Mariette X, Tharaux PL, et al. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(1):32-40.
Hermine, O., Mariette, X., Tharaux, P. L., Resche-Rigon, M., Porcher, R., & Ravaud, P. (2021). Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Internal Medicine, 181(1), 32-40. https://doi.org/10.1001/jamainternmed.2020.6820
Hermine O, et al. Effect of Tocilizumab Vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: a Randomized Clinical Trial. JAMA Intern Med. 2021 01 1;181(1):32-40. PubMed PMID: 33080017.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. AU - Hermine,Olivier, AU - Mariette,Xavier, AU - Tharaux,Pierre-Louis, AU - Resche-Rigon,Matthieu, AU - Porcher,Raphaël, AU - Ravaud,Philippe, AU - ,, PY - 2020/10/21/pubmed PY - 2021/1/16/medline PY - 2020/10/20/entrez SP - 32 EP - 40 JF - JAMA internal medicine JO - JAMA Intern Med VL - 181 IS - 1 N2 - 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. SN - 2168-6114 UR - https://www.unboundmedicine.com/medline/citation/33080017/Effect_of_Tocilizumab_vs_Usual_Care_in_Adults_Hospitalized_With_COVID_19_and_Moderate_or_Severe_Pneumonia:_A_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamainternmed.2020.6820 DB - PRIME DP - Unbound Medicine ER -