Trial NCT04403685
Publication Veiga VC, BMJ, 2021 (published paper)
Dates: 2020-05-08 to 2020-07-17
Funding: Mixed (The hospitals and research institutes participating in Coalition covid-19 Brazil; Fleury Laboratory (laboratory analysis); Instituto Votorantim (donation for drug provision))
Conflict of interest: Yes
| Methods | |
| RCT Blinding: Unblinded | |
| Location :
Multicenter / Brazil Follow-up duration (days): 29 | |
| Inclusion criteria | 1. Confirmed diagnosis of SARS-CoV-2 infection
2. Computed tomography (or chest X-ray) of the chest consistent with COVID-19 3. More than three days of symptoms related to COVID-19 4. 18 years or older; 5. Need for oxygen supplementation to maintain SpO2 > 93% OR need for mechanical ventilation less than 24 hours before the randomization 6. Two or more of the following inflammatory tests: i. D-dimer > 1,000 ng/mL ii. C reactive protein (CRP) > 5 mg/dL iii. Ferritin > 300 mg/dL iv. Lactate dehydrogenase (LDH) > upper limit of normal |
| Exclusion criteria | 1. Need for mechanical ventilation for 24 hours or more before the randomization
2. Hypersensitivity to tocilizumab 3. Patients without therapeutic perspective or in palliative care 4. Active non-controlled infections (other than COVID-19) 5. Neutrophil count < 0.5 x 109/L 6. Platelet count < 50 x 109/L 7. Liver disease, cirrhosis or elevated AST or ALT above 5 times the upper limit of normal 8. Renal disease with estimate glomerular filtration below 30 mL/min/1.72 m2 (MDRD or CKD-EPI scores) 9. Breastfeeding women 10. Pregnancy 11. Other clinical conditions that contraindicate tocilizumab, according to the attending physician |
| Interventions | |
| Treatment
Tocilizumab 8 mg/kg IV infusion once off, maximum 800 mg |
|
| Control
Standard care Definition of Standard care: Standard of care (Best supportive care), according to the local protocol. The concomitant use of hydroxychloroquine, azithromycin, corticosteroids, and antibiotics was allowed according to standard care per local institutional guidelines for patients with covid-19. Remdesivir was not available in Brazil. | |
| Participants | |
| Randomized 129 participants (n1=65 / n2= 64) | |
| Characteristics of participants N=129 Mean age : 57.4 88 males Severity : Mild: n=0 / Moderate: n=67/ Severe: n=41 Critical: n=21 | |
| Primary outcome | |
| In the register Evaluation of clinical status [Time Frame: Day 15 of the trial]: Evaluation of clinical status of patients on day 15 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score) | |
| In the report Clinical status at 15 days evaluated with the use of a seven level ordinal scale | |
| 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 the published article and its supplementary materials, the trial registry, published protocol and statistical analysis plan were used in data extraction and risk of bias assessment. Viral clearance was an exploratory outcome in the protocol but results were not reported. There were no other substantive differences between the protocol, registry and published report in study population, procedures or interventions. Unblinded study. The trial was terminated early after the first interim analysis owing to an excess number of deaths at 15 days in the tocilizumab group. Quote: "The trial registration on Clinicaltrials.gov was finalised only after enrolment of the first patient because of an administrative error by the research team. Thus, the study did not achieve the sample size recorded in the trial registry. On May 8th, an eligible patient was identified at our centre and enrolment offered to the patient. At the same day, the protocol was included in ClinicalTrials.gov but could not be registered. On May 11th, we received a response with a modified Protocol Registration and Results System for registration. On May 12th, we uploaded our protocol information in ClinicalTrials.gov as approved by the Brazilian Ethics authorities. As we did not receive a reply from ClinicalTrials.gov in subsequent days, a new contact was made on May 24th and the protocol as initially submitted was published." "In the first version of the trial protocol, need of mechanical ventilation was an exclusion criterion. On June 4th, 2020, after the study was initiated, an amendment was made to allow inclusion of patients under mechanical ventilation for less than 24 hours. On July 7th, 2020 chest X-ray evidence of COVID-19 was included as an alternative to computed tomography in the inclusion criteria" |