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

F. Perrone, M.C. Piccirillo, P.A. Ascierto, C. Salvarani, R. Parrella, A.M. Marata, P. Popoli, L. Ferraris, M.M. Marrocco-Trischitta, D. Ripamonti, F. Binda, P. Bonfanti, N. Squillace, F. Castelli, M.L. Muiesan, M. Lichtner, C. Calzetti, N.D. Salerno, L. Atripaldi, M. CascellaM. Costantini, G. Dolci, N.C. Facciolongo, F. Fraganza, M. Massari, V. Montesarchio, C. Mussini, E.A. Negri, G. Botti, C. Cardone, P. Gargiulo, A. Gravina, C. Schettino, L. Arenare, P. Chiodini, C. Gallo, Italy the TOCIVID-19 investigators

Research output: Contribution to journalArticlepeer-review

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). © 2020, The Author(s).
Original languageEnglish
Article number405
JournalJ. Transl. Med.
Volume18
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • Coronavirus
  • COVID-19
  • IL-6
  • Mortality
  • Phase 2
  • Pneumonia
  • Safety
  • Tocilizumab
  • tocilizumab
  • monoclonal antibody
  • adult
  • aged
  • Article
  • assisted ventilation
  • cancer survival
  • cohort analysis
  • coronavirus disease 2019
  • drug effect
  • drug safety
  • female
  • groups by age
  • human
  • intention to treat analysis
  • lethality
  • major clinical study
  • male
  • mortality
  • multicenter study
  • phase 2 clinical trial
  • pneumonia
  • treatment planning
  • validation process
  • Betacoronavirus
  • clinical trial
  • Coronavirus infection
  • immunology
  • Italy
  • middle aged
  • off label drug use
  • pandemic
  • treatment outcome
  • validation study
  • very elderly
  • virus pneumonia
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized
  • Cohort Studies
  • Coronavirus Infections
  • Female
  • Humans
  • Male
  • Middle Aged
  • Off-Label Use
  • Pandemics
  • Pneumonia, Viral
  • Treatment Outcome
  • Validation Studies as Topic

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