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

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).

• Authors: Francesco Perrone, Maria Carmela Piccirillo, Paolo Antonio 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 Cosimo 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, TOCIVID-19 investigators, Italy
• Journal: Journal of translational medicine (J Transl Med) Vol. 18 Issue 1 Pg. 405 (10 21 2020) ISSN: 1479-5876 [Electronic] England
• PMID: 33087150 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Monoclonal, Humanized
• tocilizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Betacoronavirus (drug effects, immunology)
• COVID-19
• Cohort Studies
• Coronavirus Infections (drug therapy, epidemiology)
• Female
• Humans
• Italy (epidemiology)
• Male
• Middle Aged
• Mortality
• Off-Label Use
• Pandemics
• Pneumonia, Viral (drug therapy, epidemiology)
• SARS-CoV-2
• Treatment Outcome
• Validation Studies as Topic