Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial
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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 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).
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SciScore for 10.1101/2020.06.01.20119149: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: TOCIVID-19, an academic multicentre clinical trial, was promoted by the National Cancer Institute of Naples and was approved for all Italian centres by the National Ethical Committee at the Lazzaro Spallanzani Institute on March 18th, 2020; two amendments followed on March 24th, 2020 and April 28th, 2020.
Consent: Informed consent for participation in the study could be oral if a written consent was unfeasible.Randomization not detected. Blinding not detected. Power Analysis Phase 2 study design and analysis: Sample size for the phase 2 study was initially calculated using 1-month lethality rate as the primary endpoint; based on March 10th daily report on … SciScore for 10.1101/2020.06.01.20119149: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: TOCIVID-19, an academic multicentre clinical trial, was promoted by the National Cancer Institute of Naples and was approved for all Italian centres by the National Ethical Committee at the Lazzaro Spallanzani Institute on March 18th, 2020; two amendments followed on March 24th, 2020 and April 28th, 2020.
Consent: Informed consent for participation in the study could be oral if a written consent was unfeasible.Randomization not detected. Blinding not detected. Power Analysis Phase 2 study design and analysis: Sample size for the phase 2 study was initially calculated using 1-month lethality rate as the primary endpoint; based on March 10th daily report on Italian breakout, 1-month mortality for the eligible population was estimated around 15%; 330 patients were planned to test the alternative hypothesis that tocilizumab may halve lethality rate (from 15% to 7.5%), with 99% power and 5% bilateral alpha error. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Mostly, retrospective or observational data have been reported so far, not based on prospective hypothesis testing, with prevalently positive results.[8, 16-25] However, our study has several limitations that deserve discussion for a better interpretation of findings. The first limitation is the single-arm study design, which prevents definitive conclusions.[26] However, we think that a randomised controlled trial was unfeasible for many reasons. There was a tremendous pressure to have the drug available, due to a widespread media diffusion of positive expectations and the increasing number of patients hospitalized for the disease, as confirmed by the massive registration of centres when the study began. Thus, obtaining a proper informed consent to randomization would have been extremely difficult also due to patients’ condition and clinical burden. Finally, developing a placebo was impossible, and, within a non-blind study, the risk of cross-over from the control to the experimental arm would have been high, reducing the validity of the randomised trial. Within this context, the problem of “learning while doing” was increased.[27] In our opinion, when the TOCIVID-19 trial started this protocol was the best trade-off between do-something and learn-something. A critical issue of the single-arm design was the definition of the null hypotheses to be tested, already acknowledged in the initial protocol where future modifications of study design were explicitly planned as an optio...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04317092 Active, not recruiting Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) NCT04320615 Completed A Study to Evaluate the Safety and Efficacy of Tocilizumab i… NCT04381936 Recruiting Randomised Evaluation of COVID-19 Therapy NCT04330638 Active, not recruiting Treatment of COVID-19 Patients With Anti-interleukin Drugs NCT04346355 Terminated Efficacy of Early Administration of Tocilizumab in COVID-19 … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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