Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial
Francesco Perrone, Maria Carmela Piccirillo, Paolo A. Ascierto, Carlo Salvarani, Roberto Parrella, Anna Maria Marata, Patrizia Popoli, Laurenzia Ferraris, Massimiliano M. Marrocco‐Trischitta, Diego Ripamonti, Francesca Binda, Paolo Bonfanti, Nicola Squillace, Francesco Castelli, Maria Lorenza Muiesan, Miriam Lichtner, Carlo Calzetti, Nicola Duccio Salerno, Luigi Atripaldi, Marco Cascella, Massimo Costantini, Giovanni Dolci, Nicola Facciolongo, Fiorentino Fraganza, Marco Massari, Vincenzo Montesarchio, Cristina Mussini, Emanuele Alberto Negri, Gerardo Botti, Claudia Cardone, Piera Gargiulo, Adriano Gravina, Clorinda Schettino, Laura Arenare, Paolo Chiodini, Ciro Gallo, the TOCIVID-19 investigators, Italy, Francesco Perrone, Maria Carmela Piccirillo, Clorinda Schettino, Adriano Gravina, Piera Gargiulo, Claudia Cardone, Laura Arenare, Paolo A. Ascierto, Maria Grazia Vitale, Claudia Trojaniello, Marco Palla, Attilio Antonio Montano Bianchi, Gerardo Botti, Gianfranco De Feo, Leonardo Miscio, Ciro Gallo, Paolo Chiodini, Laurenzia Ferraris, Massimiliano M. Marrocco‐Trischitta, M. Froldi, Lorenzo Menicanti, Maria Teresa Cuppone, Giulia Gobbo, Chiara Baldessari, Vincenzo Valenti, Serenella Castelvecchio, Federica Poli, Francesca Giacomazzi, Rosangela Piccinni, Maria Laura Annnunziata, Andrea Biondi, Cecilia Bussolari, Manuel Giovanni Mazzoleni, Andrea Giachi, Annalisa Filtz, Arianna Manini, Enrico Poletti, Federico Masserini, Francesco Conforti, Gianfranco Gaudiano, Vittoria Favero, Alice Moroni, Tommaso Viva, Fabiana Fancoli, Davide Ferrari, Dario Niro, Marco Resta, Andrea Ballotta, Marco Poli, Marco Ranucci, Diego Ripamonti, Francesca Binda, Alessandra Tebaldi, Giuseppe Gritti, L. Pasulo, Leonardo Gaglio, Roberto Del Fabbro, Leonardo Alborghetti, Paolo Bonfanti, Nicola Squillace, Giulia Giustinetti, Paola Columpsi, Marina Elena Cazzaniga
Abstract
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).