Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial
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).
| Errataetall: |
ErratumIn: J Transl Med. 2021 Oct 21;19(1):442. - PMID 34674735 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
|---|---|
| Enthalten in: |
Journal of translational medicine - 18(2020), 1 vom: 21. Okt., Seite 405 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Perrone, Francesco [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Monoclonal, Humanized |
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| Anmerkungen: |
Date Completed 30.10.2020 Date Revised 03.01.2023 published: Electronic ClinicalTrials.gov: NCT04317092 ErratumIn: J Transl Med. 2021 Oct 21;19(1):442. - PMID 34674735 Citation Status MEDLINE |
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| doi: |
10.1186/s12967-020-02573-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316561843 |
|---|
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| 100 | 1 | |a Perrone, Francesco |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 30.10.2020 | ||
| 500 | |a Date Revised 03.01.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT04317092 | ||
| 500 | |a ErratumIn: J Transl Med. 2021 Oct 21;19(1):442. - PMID 34674735 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Coronavirus | |
| 650 | 4 | |a IL-6 | |
| 650 | 4 | |a Mortality | |
| 650 | 4 | |a Phase 2 | |
| 650 | 4 | |a Pneumonia | |
| 650 | 4 | |a Safety | |
| 650 | 4 | |a Tocilizumab | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 650 | 7 | |a tocilizumab |2 NLM | |
| 650 | 7 | |a I031V2H011 |2 NLM | |
| 700 | 1 | |a Piccirillo, Maria Carmela |e verfasserin |4 aut | |
| 700 | 1 | |a Ascierto, Paolo Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Salvarani, Carlo |e verfasserin |4 aut | |
| 700 | 1 | |a Parrella, Roberto |e verfasserin |4 aut | |
| 700 | 1 | |a Marata, Anna Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Popoli, Patrizia |e verfasserin |4 aut | |
| 700 | 1 | |a Ferraris, Laurenzia |e verfasserin |4 aut | |
| 700 | 1 | |a Marrocco-Trischitta, Massimiliano M |e verfasserin |4 aut | |
| 700 | 1 | |a Ripamonti, Diego |e verfasserin |4 aut | |
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| 700 | 1 | |a Bonfanti, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Squillace, Nicola |e verfasserin |4 aut | |
| 700 | 1 | |a Castelli, Francesco |e verfasserin |4 aut | |
| 700 | 1 | |a Muiesan, Maria Lorenza |e verfasserin |4 aut | |
| 700 | 1 | |a Lichtner, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Calzetti, Carlo |e verfasserin |4 aut | |
| 700 | 1 | |a Salerno, Nicola Duccio |e verfasserin |4 aut | |
| 700 | 1 | |a Atripaldi, Luigi |e verfasserin |4 aut | |
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| 700 | 1 | |a Costantini, Massimo |e verfasserin |4 aut | |
| 700 | 1 | |a Dolci, Giovanni |e verfasserin |4 aut | |
| 700 | 1 | |a Facciolongo, Nicola Cosimo |e verfasserin |4 aut | |
| 700 | 1 | |a Fraganza, Fiorentino |e verfasserin |4 aut | |
| 700 | 1 | |a Massari, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Montesarchio, Vincenzo |e verfasserin |4 aut | |
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| 700 | 1 | |a Negri, Emanuele Alberto |e verfasserin |4 aut | |
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| 700 | 0 | |a TOCIVID-19 investigators, Italy |e verfasserin |4 aut | |
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| 700 | 1 | |a Gravina, Adriano |e investigator |4 oth | |
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| 700 | 1 | |a Cardone, Claudia |e investigator |4 oth | |
| 700 | 1 | |a Arenare, Laura |e investigator |4 oth | |
| 700 | 1 | |a Ascierto, Paolo Antonio |e investigator |4 oth | |
| 700 | 1 | |a Vitale, Maria Grazia |e investigator |4 oth | |
| 700 | 1 | |a Trojaniello, Claudia |e investigator |4 oth | |
| 700 | 1 | |a Palla, Marco |e investigator |4 oth | |
| 700 | 1 | |a Bianchi, Attilio Antonio Montano |e investigator |4 oth | |
| 700 | 1 | |a Botti, Gerardo |e investigator |4 oth | |
| 700 | 1 | |a De Feo, Gianfranco |e investigator |4 oth | |
| 700 | 1 | |a Miscio, Leonardo |e investigator |4 oth | |
| 700 | 1 | |a Gallo, Ciro |e investigator |4 oth | |
| 700 | 1 | |a Chiodini, Paolo |e investigator |4 oth | |
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| 700 | 1 | |a Froldi, Marco |e investigator |4 oth | |
| 700 | 1 | |a Menicanti, Lorenzo |e investigator |4 oth | |
| 700 | 1 | |a Cuppone, Maria Teresa |e investigator |4 oth | |
| 700 | 1 | |a Gobbo, Giulia |e investigator |4 oth | |
| 700 | 1 | |a Baldessari, Chiara |e investigator |4 oth | |
| 700 | 1 | |a Valenti, Vincenzo |e investigator |4 oth | |
| 700 | 1 | |a Castelvecchio, Serenella |e investigator |4 oth | |
| 700 | 1 | |a Poli, Federica |e investigator |4 oth | |
| 700 | 1 | |a Giacomazzi, Francesca |e investigator |4 oth | |
| 700 | 1 | |a Piccinni, Rosangela |e investigator |4 oth | |
| 700 | 1 | |a Annnunziata, Maria Laura |e investigator |4 oth | |
| 700 | 1 | |a Biondi, Andrea |e investigator |4 oth | |
| 700 | 1 | |a Bussolari, Cecilia |e investigator |4 oth | |
| 700 | 1 | |a Mazzoleni, Manuel |e investigator |4 oth | |
| 700 | 1 | |a Giachi, Andrea |e investigator |4 oth | |
| 700 | 1 | |a Filtz, Annalisa |e investigator |4 oth | |
| 700 | 1 | |a Manini, Arianna |e investigator |4 oth | |
| 700 | 1 | |a Poletti, Enrico |e investigator |4 oth | |
| 700 | 1 | |a Masserini, Federico |e investigator |4 oth | |
| 700 | 1 | |a Conforti, Francesco |e investigator |4 oth | |
| 700 | 1 | |a Gaudiano, Gianfranco |e investigator |4 oth | |
| 700 | 1 | |a Favero, Vittoria |e investigator |4 oth | |
| 700 | 1 | |a Moroni, Alice |e investigator |4 oth | |
| 700 | 1 | |a Viva, Tommaso |e investigator |4 oth | |
| 700 | 1 | |a Fancoli, Fabiana |e investigator |4 oth | |
| 700 | 1 | |a Ferrari, Davide |e investigator |4 oth | |
| 700 | 1 | |a Niro, Dario |e investigator |4 oth | |
| 700 | 1 | |a Resta, Marco |e investigator |4 oth | |
| 700 | 1 | |a Ballotta, Andrea |e investigator |4 oth | |
| 700 | 1 | |a Poli, Marco Dei |e investigator |4 oth | |
| 700 | 1 | |a Ranucci, Marco |e investigator |4 oth | |
| 700 | 1 | |a Ripamonti, Diego |e investigator |4 oth | |
| 700 | 1 | |a Binda, Francesca |e investigator |4 oth | |
| 700 | 1 | |a Tebaldi, Alessandra |e investigator |4 oth | |
| 700 | 1 | |a Gritti, Giuseppe |e investigator |4 oth | |
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| 700 | 1 | |a Cazzaniga, Marina |e investigator |4 oth | |
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| 700 | 1 | |a Franceschini, Franco |e investigator |4 oth | |
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| 700 | 1 | |a Tieghi, Tiziana |e investigator |4 oth | |
| 700 | 1 | |a De Masi, Margherita |e investigator |4 oth | |
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