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Cited by 734COVID-19 Clinical Research StudiesRespiratory Support and MechanismsSARS-CoV-2 and COVID-19 Research

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

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Hermine, Olivier, Mariette, Xavier, Tharaux, Pierre-Louis, Resche-Rigon, Matthieu, Porcher, Raphaël, Ravaud, Philippe, CORIMUNO-19 Collaborative Group, Bureau, Serge +586 more·2021·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2020.6820PMC PMC7577198
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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.

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  • Two large, randomized, controlled trials of anti-interleukin-6 receptor antibody therapies did not show a survival benefit in hospitalized patients with Covid-19.

    “Despite positive anecdotal reports, two large, randomized, controlled trials of anti–interleukin-6 receptor antibody therapies did not show a survival benefit in hospitalized patients with Covid-19.97,98”

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Hermine, O., Mariette, X., Tharaux, P.-L., Resche-Rigon, M., Porcher, R., Ravaud, P., CORIMUNO-19 Collaborative Group, Bureau, S., Dougados, M., Tibi, A., Azoulay, E., Cadranel, J., Emmerich, J., Fartoukh, M., Guidet, B., Humbert, M., Lacombe, K., Mahevas, M., Pene, F., Pourchet-Martinez, V., Schlemmer, F., Yazdanpanah, Y., Baron, G., Perrodeau, E., Vanhoye, D., Kedzia, C., Demerville, L., Gysembergh-Houal, A., Bourgoin, A., Dalibey, S., Resche-Rigon, M., Raked, N., Mameri, L., Alary, S., Hamiria, S., Bariz, T., Semri, H., Hai, D. M., Benafla, M., Belloul, M., Vauboin, P., Flamand, S., Pacheco, C., Walter-Petrich, A., Stan, E., Benarab, S., Nyanou, C., Montlahuc, C., Biard, L., Charreteur, R., Dupré, C., Cardet, K., Lehmann, B., Baghli, K., Madeleine, C., D'Ortenzio, E., Puéchal, O., Semaille, C., Savale, L., Harrois, A., Figueiredo, S., Duranteau, J., Anguel, N., Monnet, X., Richard, C., Teboul, J.-L., Durand, P., Tissieres, P., Jevnikar, M., Montani, D., Pavy, S., Noel, N., Lambotte, O., Escaut, L., Jauréguiberry, S., Baudry, E., Verny, C., Lefèvre, E., Zaidan, M., Le Tiec, C. L. T., Verstuyft, C. V., Roques, A.-M., Grimaldi, L., Molinari, D., Leprun, G., Fourreau, A., Cylly, L., Virlouvet, M., Meftali, R., Fabre, S., Licois, M., Mamoune, A., Boudali, Y., Georgin-Lavialle, S., Senet, P., Soria, A., Parrot, A., François, H., Rozensztajn, N., Blin, E., Choinier, P., Camuset, J., Rech, J.-S., Canellas, A., Rolland-Debord, C., Lemarié, N., Belaube, N., Nadal, M., Siguier, M., Petit-Hoang, C., Chas, J., Drouet, E., Lemoine, M., Phibel, A., Aunay, L., Bertrand, E., Ravato, S., Vayssettes, M., Adda, A., Wilpotte, C., Thibaut, P., Fillon, J., Debrix, I., Fellahi, S., Bastard, J.-P., Lefèvre, G., Fallet, V., Gottenberg, J.-E., Hansmann, Y., Andres, E., Bayer, S., Becker, G., Blanc, F., Brin, S., Castelain, V., Chatelus, E., Chatron, E., Collange, O., Danion, F., De Blay, F., Demonsant, E., Diemunsch, P., Diemunsch, S., Felten, R., Goichot, B., Greigert, V., Guffroy, A., Heger, B., Hutt, A., Kaeuffer, C., Kassegne, L., Korganow, A. S., Le Borgne, P., Lefebvre, N., Martin, T., Mertes, P. M., Metzger, C., Meyer, N., Nisand, G., Noll, E., Oberlin, M., Ohlmann-Caillard, S., Poindron, V., Pottecher, J., Ruch, Y., Sublon, C., Tayebi, H., Weill, F., Mekinian, A., Chopin, D., Fain, O., Garnier, M., Krause Le Garrec, J., Morgand, M., Pacanowski, J., Urbina, T., Mcavoy, C., Pereira, M., Aratus, G., Berard, L., Simon, T., Daguenel Nguyen, A., Antignac, M., Leplay, C., Arlet, J.-B., Diehl, J.-L., Bellenfant, F., Blanchard, A., Buffet, A., Cholley, B., Fayol, A., Flamarion, E., Godier, A., Gorget, T., Hamada, S.-R., Hauw-Berlemont, C., Hulot, J. S., Lebeaux, D., Livrozet, M., Michon, A., Neuschwander, A., Penet, M.-A., Planquette, B., Ranque, B., Sanchez, O., Volle, G., Briois, S., Cornic, M., Elisee, V., Jesuthasan, D., Djadi-Prat, J., Jouany, P., Junquera, R., Henriques, M., Kebir, A., Lehir, I., Meunier, J., Patin, F., Paquet, V., TréHan, A., Vigna, V., Sabatier, B., Bergerot, D., Jouve, C., Knosp, C., Lenoir, O., Mahtal, N., Resmini, L., Lescure, X., Ghosn, J., Bachelard, A., Bironne, T., Borie, R., Bounhiol, A., Boussard, C., Chauffier, J., Chalal, S., Chalal, L., Chansombat, M., Crespin, P., Crestani, B., Daconceicao, O., Deconinck, L., Dieude, H., Dossier, A., Dubert, M., Ducrocq, G., Fuentes, A., Gervais, A., Gilbert, M., Isernia, V., Ismael, S., Joly, V., Julia, Z., Lariven, S., Le Gac, S., Le Pluart, D., Louni, F., Ndiaye, A., Papo, T., Parisey, M., Phung, B., Pourbaix, A., Rachline, A., Rioux, C., Sautereau, A., Steg, G., Tharini, H., Valayer, S., Vallois, D., Vermes, P., Volpe, T., Nguyen, Y., Honsel, V., Weiss, E., Codorniu, A., Zarrouk, V., De Lastours, V., Uzzan, M., Gamany, N., Rahli, R., Louis, Z., Boutboul, D., Galicier, L., Amara, Y., Archer, G., Benattia, A., Bergeron, A., Bondeelle, L., De Castro, N., Clément, M., Darmont, M., Denis, B., Dupin, C., Feredj, E., Feyeux, D., Joseph, A., Lengliné, E., Le Guen, P., Liégeon, G., Lorillon, G., Mabrouki, A., Mariotte, E., Martin De Frémont, G., Mirouse, A., Molina, J.-M., Peffault De Latour, R., Oksenhendler, E., Saussereau, J., Tazi, A., Tudesq, J.-J., Zafrani, L., Brindele, I., Bugnet, E., Celli Lebras, K., Chabert, J., Djaghout, L., Fauvaux, C., Jegu, A. L., Kozaliewicz, E., Meunier, M., Tremorin, M.-T., Davoine, C., Madeleine, I., Caillat-Zucman, S., Delaugerre, C., Morin, F., Sene, D., Burlacu, R., Chousterman, B., Megarbane, B., Richette, P., Riveline, J.-P., Frazier, A., Vicaut, E., Berton, L., Hadjam, T., Vasquez-Ibarra, M. A., Jourdaine, C., Jacob, A., Smati, J., Renaud, S., Manivet, P., Pernin, C., Suarez, L., Semerano, L., Abad, S., Benainous, R., Bloch Queyrat, C., Bonnet, N., Brahmi, S., Cailhol, J., Cohen, Y., Comparon, C., Cordel, H., Dhote, R., Dournon, N., Duchemann, B., Ebstein, N., Giroux-Leprieur, B., Goupil De Bouille, J., Jacolot, A., Nunes, H., Oziel, J., Rathouin, V., Rigal, M., Roulot, D., Tantet, C., Uzunhan, Y., Costedoat-Chalumeau, N., Ait Hamou, Z., Benghanem, S., Blanche, P., Canoui, E., Carlier, N., Chaigne, B., Contejean, A., Dunogue, B., Dupland, P., Durel - Maurisse, A., Gauzit, R., Jaubert, P., Joumaa, H., Jozwiak, M., Kerneis, S., Lachatre, M., Lafoeste, H., Legendre, P., Luong Nguyen, L. 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S., Clarke, A., Clavere, G., Dusanter, I., Gaudefroy, C., Jallouli, M., Kolta, S., Le Bourlout, C., Marin, N., Menage, N., Moores, A., Peigney, I., Pierron, C., Saleh-Mghir, S., Vallet, M., Michel, M., Melica, G., Lelievre, J.-D., Fois, E., Lim, P., Matignon, M., Guillaud, C., Thiemele, A., Schmitz, D., Bouhris, M., Belazouz, S., Languille, L., Mekontso-Dessaps, A., Sadaoui, T., Mayaux, J., Cacoub, P., Corvol, J.-C., Louapre, C., Sambin, S., Mariani, L.-L., Karachi, C., Tubach, F., Estellat, C., Gimeno, L., Martin, K., Bah, A., Keo, V., Ouamri, S., Messaoudi, Y., Yelles, N., Faye, P., Cavelot, S., Larcheveque, C., Annonay, L., Benhida, J., Zahrate-Ghoul, A., Hammal, S., Belilita, R., Lecronier, M., Beurton, A., Haudebourg, L., Deleris, R., Le Marec, J., Virolle, S., Nemlaghi, S., Bureau, C., Mora, P., De Sarcus, M., Clovet, O., Duceau, B., Grisot, P. H., Pari, M. 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Affiliations
  • Hôpital Necker-Enfants Malades (FR)
  • Department of Rheumatology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, France
  • Inserm (FR)
  • for the CORIMUNO-19 Collaborative Group
Corresponding author
Hermine, Olivier
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2021-01-01
Volume
181
Issue
1
Pages
32
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2020.6820
PMC
PMC7577198
OpenAlex
W3094609299
Cited by
734
References
26
Citations by year
2026: 7 · 2025: 14 · 2024: 37 · 2023: 85 · 2022: 186 · 2021: 363 · 2020: 42
FWCI
22.14
Type
journal article
Language
en
Open access
Locations
  • JAMA Internal Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-21-COVR-0024)
  • Institut National de la Santé et de la Recherche Médicale
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
tocilizumab, COVID-19 pandemic, severe pneumonia, interleukin-6, hyperinflammation, cytokine inhibition, hospitalization, survival, WHO Clinical Progression Scale, C-reactive protein, oxygen requirement, discharge time, adverse events, usual care, SARS-CoV-2, hospitalized adults, non-invasive ventilation, corticosteroids
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Adrenal Cortex Hormones, Aged, Anti-Bacterial Agents, Anticoagulants, Antiviral Agents, Female, Hospitalization, Humans, Intubation, Intratracheal, Male, Middle Aged, Mortality, Oxygen Inhalation Therapy, Respiration, Artificial, Respiratory Insufficiency, Severity of Illness Index, Vasoconstrictor Agents, Hospital Mortality, Disease Progression, Receptors, Interleukin-6, Antibodies, Monoclonal, Humanized, Noninvasive Ventilation

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