Tocilizumab for patients with COVID-19 pneumonia. The TOCIVID-19 prospective phase 2 trial

  1. Francesco Perrone
  2. Maria Carmela Piccirillo
  3. Paolo Antonio Ascierto
  4. Carlo Salvarani
  5. Roberto Parrella
  6. Anna Maria Marata
  7. Patrizia Popoli
  8. Laurenzia Ferraris
  9. Massimiliano M. Marrocco-Trischitta
  10. Diego Ripamonti
  11. Francesca Binda
  12. Paolo Bonfanti
  13. Nicola Squillace
  14. Francesco Castelli
  15. Maria Lorenza Muiesan
  16. Miriam Lichtner
  17. Carlo Calzetti
  18. Nicola Duccio Salerno
  19. Luigi Atripaldi
  20. Marco Cascella
  21. Massimo Costantini
  22. Giovanni Dolci
  23. Nicola Cosimo Facciolongo
  24. Fiorentino Fraganza
  25. Marco Massari
  26. Vincenzo Montesarchio
  27. Cristina Mussini
  28. Emanuele Alberto Negri
  29. Gerardo Botti
  30. Claudia Cardone
  31. Piera Gargiulo
  32. Adriano Gravina
  33. Clorinda Schettino
  34. Laura Arenare
  35. Paolo Chiodini
  36. Ciro Gallo
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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 multicentre, single-arm, hypothesis-driven phase 2 trial was planned to study the effect of Tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints). A cohort of patients consecutively enrolled after phase 2 was used as a validation dataset. A multivariable logistic regression was performed to generate hypotheses, while controlling for possible confounders.

Results

out of 301 patients in phase 2 intention-to-treat (ITT) analysis, 180 (59.8%) received tocilizumab. With 67 death events, lethality rates were 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. Lethality rates were lower in the validation dataset, including 920 patients. No signal of specific drug toxicity was reported. The multivariable logistic regression suggests tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Also, it supports a positive effect on lethality rate of the use of corticosteroids.

Conclusions

Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Such result support the use of tocilizumab while waiting for ongoing phase 3 trials.

Registration

EudraCT (2020-001110-38); <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov</ext-link> ( <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04317092">NCT04317092</ext-link> )

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