Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial
Viviane C Veiga, João A G G Prats, Danielle L C Farias, Regis G Rosa, Leticia K Dourado, Fernando G Zampieri, Flávia R Machado, Renato D Lopes, Otavio Berwanger, Luciano C P Azevedo, Álvaro Avezum, Thiago C Lisboa, Salomón S O Rojas, Juliana C Coelho, Rodrigo T Leite, Júlio C Carvalho, Luis E C Andrade, Alex F Sandes, Maria C T Pintão, Claudio G Castro Jr, Sueli V Santos, Thiago M L De Almeida, André N Costa, Otávio C E Gebara, Flávio G Rezende De Freitas, Eduardo S Pacheco, David J B Machado, Josiane Martin, Fábio G Conceição, Suellen R R Siqueira, Lucas P Damiani, Luciana M Ishihara, Daniel Schneider, Denise De Souza, Alexandre B Cavalcanti, Phillip Scheinberg
BMJ, doi:10.1136/bmj.n84
Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).
Design Randomised, open label trial. setting Nine hospitals in Brazil, 8 May to 17 July 2020. cOnclusiOns In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. trial registratiOn ClinicalTrials.gov NCT04403685.
conclusions In this trial including patients admitted to hospital with severe or critical covid-19, the use of tocilizumab plus standard care was not superior to standard care alone in improving patients' clinical status at 15 days, and might have increased mortality. The collaborators are listed in the supplementary file. The trial was designed by the executive committee (see supplementary file). The executive committee vouches for the completeness and accuracy of the data and for the fidelity of the trial to the protocol. Contributors: ABC, DLCF, JP, PS, and VCV conceived the study, wrote the protocol, recruited patients, and drafted the manuscript. ABC, RGR, FRM, FGZ, OB, LCPA, RDL, AA, LKD, and CGC developed the protocol and approved the final version for the Coalition covid-19 Brazil Group, recruited patients, participated in interim discussions, and reviewed the manuscript. CZO developed the REDCap database and attended to all data collection related issues. LPD and LMI performed the statistical analysis. LECA, AFS, and MCP coordinated exploratory sample collection and will be performing the exploratory analysis, participated in the protocol development an interim discussion and reviewed the manuscript. VCV, ABC, DLCF, JP, and PS act as guarantors, accept full responsibility for the work, had access to the data, and controlled the decision to publish. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the..
References
Campochiaro, Della-Torre, Cavalli, Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study, Eur J Intern Med,
doi:10.1016/j.ejim.2020.05.021Canziani, Trovati, Brunetta, -19 Task Forces. Interleukin-6 receptor blocking with intravenous tocilizumab in COVID-19 severe acute respiratory distress syndrome: A retrospective case-control survival analysis of 128 patients, J Autoimmun,
doi:10.1016/j.jaut.2020.102511Capra, Rossi, Mattioli, Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia, Eur J Intern Med,
doi:10.1016/j.ejim.2020.05.009Cavalcanti, Zampieri, Rosa, Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2019014Chen, Wu, Guo, Clinical and immunological features of severe and moderate coronavirus disease 2019, J Clin Invest,
doi:10.1172/JCI137244Colaneri, Bogliolo, Valsecchi, The Covid Irccs San Matteo Pavia Task Force. Tocilizumab for Treatment of Severe COVID-19 Patients: Preliminary Results from SMAtteo COvid19 REgistry (SMACORE), Microorganisms,
doi:10.3390/microorganisms8050695Core, R: a language and environmnet for statistical computing
Farias, Prats, Cavalcanti, Rationale and design of tocilizumab in patients with moderate to severe COVID-19: an open label multicentre randomised controlled trial (TOCIBRAS). Revista Brasileira de terapia intensiva, Rev Bras Ter Intensiva,
doi:10.5935/0103-507X.20200060Furtado, Berwanger, Fonseca, COALITION COVID-19 Brazil II Investigators. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial, Lancet,
doi:10.1016/S0140-6736(20)31862-6Gupta, Wang, Hayek, Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.6252Hermine, Tharaux, Effect of Tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.6820Herold, Jurinovic, Arnreich, Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19, J Allergy Clin Immunol,
doi:10.1016/j.jaci.2020.05.008Horby, Lim, Emberson, Dexamethasone in Hospitalised Patients with Covid-19 -Preliminary Report, N Engl J Med,
doi:10.1056/NEJMoa2021436Horby, Roddick, Spata, Azithromycin in hospitalized patients with covid-19 (RECOVERY): a randomized, controlled, openlabel, platform trial,
doi:10.1101/2020.12.10.20245944Jones, Palumbo, Brown, Coronavirus: A visual guide to the economic impact, BBC News
Kewan, Covut, Mj, Rose, Gopalakrishna et al., Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study, EClinicalMedicine,
doi:10.1016/j.eclinm.2020.100418Klopfenstein, Zayet, Lohse, Tocilizumab multidisciplinary team. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients, Med Mal Infect,
doi:10.1016/j.medmal.2020.05.001Laguna-Goya, Utrero-Rico, Talayero, IL-6-based mortality risk model for hospitalized patients with COVID-19, J Allergy Clin Immunol,
doi:10.1016/j.jaci.2020.07.009Langer-Gould, Smith, Gonzales, Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab, Int J Infect Dis,
doi:10.1016/j.ijid.2020.07.081Merad, Martin, Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages, Nat Rev Immunol,
doi:10.1038/s41577-020-0331-4Moreno-Pérez, Andres, Experience with tocilizumab in severe COVID-19 pneumonia after 80 days of followup: A retrospective cohort study, J Autoimmun,
doi:10.1016/j.jaut.2020.102523Nishimoto, Terao, Mima, Nakahara, Takagi et al., Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease, Blood,
doi:10.1182/blood-2008-05-155846Petrak, Van Hise, Skorodin, Early tocilizumab dosing is associated with improved survival in critically ill patients infected with SARS-COV-2, medRxiv,
doi:10.1101/2020.10.27.20211433Quartuccio, Sonaglia, Pecori, Higher levels of IL-6 early after tocilizumab distinguish survivors from nonsurvivors in COVID-19 pneumonia: A possible indication for deeper targeting of IL-6, J Med Virol,
doi:10.1002/jmv.26149Rose-John, Winthrop, Calabrese, The role of IL-6 in host defence against infections: immunobiology and clinical implications, Nat Rev Rheumatol,
doi:10.1038/nrrheum.2017.83Rossotti, Travi, Ughi, Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis, J Infect,
doi:10.1016/j.jinf.2020.07.008Salvarani, Dolci, Massari, RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.6615Siemieniuk, Rochwerg, Agoritsas, A living WHO guideline on drugs for covid-19, BMJ,
doi:10.1136/bmj.m3379Somers, Eschenauer, Troost, Tocilizumab for treatment of mechanically ventilated patients with COVID-19, Clin Infect Dis,
doi:10.1093/cid/ciaa954Tomasiewicz, Piekarska, Stempkowska-Rejek, Tocilizumab for patients with severe COVID-19: a retrospective, multi-center study, Expert Rev Anti Infect Ther,
doi:10.1080/14787210.2020.1800453Wu, Mcgoogan, 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,
doi:10.1001/jama.2020.2648DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Objective</jats:title>\n <jats:p>To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Design</jats:title>\n <jats:p>Randomised, open label trial.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Setting</jats:title>\n <jats:p>Nine hospitals in Brazil, 8 May to 17 July 2020.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Participants</jats:title>\n <jats:p>Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Interventions</jats:title>\n <jats:p>Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Main outcome measure</jats:title>\n <jats:p>The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Trial registration</jats:title>\n <jats:p>\n ClinicalTrials.gov\n <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"NCT04403685\" ext-link-type=\"clintrialgov\">NCT04403685</jats:ext-link>\n .\n </jats:p>\n </jats:sec>",
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