Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial.
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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, TOCIVID-19 investigators, Italy
Аннотация
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).