Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of...

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Published in:	Journal of translational medicine Vol. 18; no. 1; pp. 405 - 11
Main Authors:	Perrone, Francesco, Piccirillo, Maria Carmela, Ascierto, Paolo Antonio, Salvarani, Carlo, Parrella, Roberto, Marata, Anna Maria, Popoli, Patrizia, Ferraris, Laurenzia, Marrocco-Trischitta, Massimiliano M., Ripamonti, Diego, Binda, Francesca, Bonfanti, Paolo, Squillace, Nicola, Castelli, Francesco, Muiesan, Maria Lorenza, Lichtner, Miriam, Calzetti, Carlo, Salerno, Nicola Duccio, Atripaldi, Luigi, Cascella, Marco, Costantini, Massimo, Dolci, Giovanni, Facciolongo, Nicola Cosimo, Fraganza, Fiorentino, Massari, Marco, Montesarchio, Vincenzo, Mussini, Cristina, Negri, Emanuele Alberto, Botti, Gerardo, Cardone, Claudia, Gargiulo, Piera, Gravina, Adriano, Schettino, Clorinda, Arenare, Laura, Chiodini, Paolo, Gallo, Ciro
Format:	Journal Article
Language:	English
Published:	London BioMed Central 21.10.2020 BioMed Central Ltd Springer Nature B.V BMC
Subjects:	Adult Aged Aged, 80 and over Antibodies, Monoclonal, Humanized - therapeutic use Betacoronavirus - drug effects Betacoronavirus - immunology Biomedical and Life Sciences Biomedicine Care and treatment Clinical trials Cohort Studies Combination strategies Consent Coronavirus Coronavirus Infections - drug therapy Coronavirus Infections - epidemiology Coronaviruses COVID-19 Cytokines Drug dosages Female Humans Hypotheses IL-6 Immunosuppressive agents Inflammation Interleukin 6 Interleukins Italy - epidemiology Lethality Male Medicine/Public Health Middle Aged Monoclonal antibodies Mortality Off-Label Use Pandemics Phase 2 Pneumonia Pneumonia, Viral - drug therapy Pneumonia, Viral - epidemiology Population Registration SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 Statistical analysis Steroid hormones Survival Tocilizumab Toxicity Treatment Outcome Validation Studies as Topic Variables Ventilation Italy COVID-19 Pneumonia Coronavirus Tocilizumab Mortality Phase 2 Safety IL-6
ISSN:	1479-5876, 1479-5876
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Summary:	Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
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ISSN:	1479-5876 1479-5876
DOI:	10.1186/s12967-020-02573-9