Trial NCT04320615
Publication Rosas I, N Engl J Med, 2021 (published paper)
Dates: 2020-04-03 to 2020-07-28
Funding: Mixed (F. Hoffmann-La Roche Ltd; Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority)
Conflict of interest: Yes
| Methods | |
| RCT Blinding: | |
| Location :
Multicenter / Canada, Denmark, France, Germany, Italy, Netherlands, Spain, UK, USA Follow-up duration (days): 60 | |
| Inclusion criteria | Patients 18 years or older with severe COVID-19 pneumonia confirmed by positive polymerase chain reaction test in any body fluid and evidenced by bilateral chest infiltrates on chest x-ray or computed tomography were enrolled. Eligible patients had blood oxygen saturation ≤93% or partial pressure of oxygen/fraction of inspired oxygen <300 mm/Hg. Informed consent was obtained for all enrolled patients. |
| Exclusion criteria | Report:
Patients were excluded if the treating physician determined that death was imminent and inevitable within 24 hours or if they had active tuberculosis or bacterial, fungal, or viral infection other than SARS-CoV-2. Protocol: Known severe allergic reactions to TCZ or other monoclonal antibodies Active tuberculosis (TB) infection Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Have received oral anti-rejection or immunomodulatory drugs (including TCZ) with the past 3 months Participating in other drug clinical trials (participation in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor) Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization (investigational COVID-19 antivirals may be permitted if approved by Medial Monitor) Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 10 x upper limit of normal (ULN) detected within 24 hours at screening (per local lab) Absolute neutrophil count (ANC) < 1000/mL at screening (per local lab) Platelet count < 50,000/mL at screening (per local lab) |
| Interventions | |
| Treatment
Tocilizumab 8mg/kg IV infusion, maximum 800 mg.A second infusion could be administered 8 to 24 hours after the first |
|
| Control
Placebo Duration : 1 day | |
| Participants | |
| Randomized 452 participants (n1=301 / n2= 151) | |
| Characteristics of participants N=452 Mean age : 60.8 306 males Severity : Mild: n=15 / Moderate: n=122/ Severe: n=133 Critical: n=168 | |
| Primary outcome | |
| In the register Clinical Status Assessed Using a 7-Category Ordinal Scale [ Time Frame: Day 28 ] | |
| In the report Clinical status assessed on a 7-category ordinal scale at day 28 | |
| Documents available |
Protocol Yes. In English Statistical plan Yes Data-sharing stated Yes |
| Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review |
Some concerns |
| General comment |
In addition to all available versions of the pre-print article, the protocol, statistical analysis plan, study registry and supplementary appendix, as well as responses from contact with authors were used in data extraction and risk of bias assessment. Patients in the Tocilizumab group received a second dose only if their condition did not improve or worsened. The study achieved the target sample size prespecified in the registry. There is no change from the trial registration in the intervention and control treatments as well as primary outcome. Some secondary outcomes in the registry were not reported in the pre-print article, particularly regarding the 60-day timepoint as well. For safety data, a longer follow up to June 24, 2020 was used. The sponsor (Hoffman-La Roche Ltd.) played a prominent role, with writing support for the authors provided by Sara Duggan, Ph.D., of ApotheCom, funded by F. Hoffmann-La Roche Ltd. Three authors were employees of Roche Products Ltd. On December 7th, 2020, we received additional information from authors on this study. This study was updated with data from contact with authors on January 13th, 2021. This trial was updated on March 1st, 2021 after the publication of the study report. |