Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia | Critical Care Medicine | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What is the effect of tocilizumab, an anti–interleukin-6 receptor antibody, in patients with COVID-19 and moderate-to-severe pneumonia?

Findings  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.

Meaning  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.


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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

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 (ohermine@gmail.com).

Correction: This article was corrected on January 4, 2021, to fix errors in the supplemental group member list and to add the collaborative group in the end matter. These collaborators were previously not indexed in PubMed, but the error has been resolved. It was corrected again on May 3, 2021, to correct the spelling of 2 names in the nonauthor collaborators list in the Supplement.

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 3.

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).

The CORIMUNO-19 Collaborative Group: The CORIMUNO-19 Collaborative Group members are listed in Supplement 4.

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 4) 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 (Supplement 4).

Wu  Z , McGoogan  JM .  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648 PubMedGoogle ScholarCrossref
Huang  C , Wang  Y , Li  X ,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5 PubMedGoogle ScholarCrossref
Chen  N , Zhou  M , Dong  X ,  et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.   Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7 PubMedGoogle ScholarCrossref
Guan  WJ , Ni  ZY , Hu  Y ,  et al; China Medical Treatment Expert Group for Covid-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032 PubMedGoogle ScholarCrossref
Team TNCPERE: The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team.  The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19).   China CDC Weekly. 2020;2(8):113-122. doi:10.46234/ccdcw2020.032 doi:10.46234/ccdcw2020.032Google ScholarCrossref
Yang  X , Yu  Y , Xu  J ,  et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.   Lancet Respir Med. 2020;8(5):475-481. doi:10.1016/S2213-2600(20)30079-5 PubMedGoogle ScholarCrossref
Wang  D , Hu  B , Hu  C ,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585 PubMedGoogle ScholarCrossref
Wu  J , Liu  J , Zhao  X ,  et al.  Clinical characteristics of imported cases of coronavirus disease 2019 (COVID-19) in Jiangsu province: a multicenter descriptive study.   Clin Infect Dis. 2020;71(15):706-712. doi:10.1093/cid/ciaa199 PubMedGoogle ScholarCrossref
Beigel  JH , Tomashek  KM , Dodd  LE ,  et al.  Remdesivir for the treatment of Covid-19: preliminary report.   N Engl J Med. 2020;NEJMoa2007764. doi:10.1056/NEJMoa2007764Google Scholar
Group  RC , Horby  P , Lim  WS ,  et al.  Dexamethasone in hospitalized patients with Covid-19: preliminary report.   N Engl J Med. 2020;NEJMoa2021436.Google Scholar
Mehta  P , McAuley  DF , Brown  M , Sanchez  E , Tattersall  RS , Manson  JJ ; HLH Across Speciality Collaboration, UK.  COVID-19: consider cytokine storm syndromes and immunosuppression.   Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0 PubMedGoogle ScholarCrossref
Ruan  Q , Yang  K , Wang  W , Jiang  L , Song  J .  Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.   Intensive Care Med. 2020;46(5):846-848. doi:10.1007/s00134-020-05991-x PubMedGoogle ScholarCrossref
Zhu  J , Pang  J , Ji  P ,  et al.  Elevated interleukin-6 is associated with severity of COVID-19: a meta-analysis.   J med virol. Published online May 29, 2020. doi:10.1002/jmv.26085Google Scholar
Del Valle  DM , Kim-Schulze  S , Huang  HH ,  et al.  An inflammatory cytokine signature predicts COVID-19 severity and survival.   Nat Med. 2020. doi:10.1038/s41591-020-1051-9 PubMedGoogle Scholar
Grifoni  E , Valoriani  A , Cei  F ,  et al.  Interleukin-6 as prognosticator in patients with COVID-19.   J Infect. 2020;81(3):452-482. doi:10.1016/j.jinf.2020.06.008 PubMedGoogle ScholarCrossref
Xu  X , Han  M , Li  T ,  et al.  Effective treatment of severe COVID-19 patients with tocilizumab.   Proc Natl Acad Sci U S A. 2020;117(20):10970-10975. doi:10.1073/pnas.2005615117 PubMedGoogle ScholarCrossref
Roumier  M , Paule  R , Groh  M , Vallee  A , Ackermann  F .  Interleukin-6 blockade for severe COVID-19.   medRxiv. Published online April 22, 2020. doi:10.1101/2020.04.20.20061861.Google Scholar
Guaraldi  G , Meschiari  M , Cozzi-Lepri  A ,  et al.  Tocilizumab in patients with severe COVID-19: a retrospective cohort study.   Lancet Rheumatol. 2020;2(8):e474-e484. doi:10.1016/S2665-9913(20)30173-9 PubMedGoogle ScholarCrossref
Working  WHO ; WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection.  A minimal common outcome measure set for COVID-19 clinical research.   Lancet Infect Dis. 2020;20(8):e192-e197. doi:10.1016/S1473-3099(20)30483-7 PubMedGoogle ScholarCrossref
Cook  DJ , Marshall  JC , Fowler  RA .  Critical illness in patients with COVID-19: mounting an effective clinical and research response.   JAMA. 2020;323(16):1559-1560. doi:10.1001/jama.2020.5775 PubMedGoogle ScholarCrossref
Angus  DC .  Optimizing the trade-off between learning and doing in a pandemic.   JAMA. 2020;323(19):1895-1896. doi:10.1001/jama.2020.4984 PubMedGoogle ScholarCrossref
Dechartres  A , Trinquart  L , Boutron  I , Ravaud  P .  Influence of trial sample size on treatment effect estimates: meta-epidemiological study.   BMJ. 2013;346:f2304. doi:10.1136/bmj.f2304 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity



My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right