Veiga TOCIBRAS 2021.

Study characteristics
Methods	RCT Blinding: unblinded Date of study: from 8 May 2020 to 17 July 2020 Location: multicentre (9 centres) / Brazil Follow‐up duration (days): 29
Participants	Population: patients with confirmed COVID‐19 (moderate‐critical) Randomised: 129 participants (n1 tocilizumab arm = 65 / n2 control arm = 64) Characteristics of participants N= 129 Mean age: 57.4 years 88 Males Admitted to ICU: n = NR Severity: mild: n = 0 / moderate: n = 67/ severe: n = 41 / critical = 21 Patients on oxygen without intubation: n = 108 (84%); intubated: n = 21(16%) C‐reactive protein (mean): 160 to 193 mg/L Inclusion criteria Confirmed diagnosis of SARS‐CoV‐2 infection CT (or chest X‐ray) of the chest consistent with COVID‐19 More than 3 days of symptoms related to COVID‐19 18 years or older; Need for oxygen supplementation to maintain SpO2 > 93% OR need for mechanical ventilation less than 24 hours before the randomisation 2 or more of the following inflammatory tests: D‐dimer > 1000 ng/mL; C reactive protein (CRP) > 5 mg/dL; ferritin > 300 mg/dL; lactate dehydrogenase (LDH) > upper limit of normal. Exclusion criteria Need for mechanical ventilation for 24 hours or more before the randomisation Hypersensitivity to tocilizumab Patients without therapeutic perspective or in palliative care Active non‐controlled infections (other than COVID‐19) Neutrophil count < 0.5 x 109/L Platelet count < 50 x 109/L Liver disease, cirrhosis or elevated AST or ALT above 5 times the upper limit of normal Renal disease with estimate glomerular filtration below 30 mL/min/1.72 m2 (MDRD or CKD‐EPI scores) Breastfeeding women Pregnancy Other clinical conditions that contraindicate tocilizumab, according to the attending physician Dropouts and withdrawals: (0%); 0 withdrawal due to AEs
Interventions	Intervention: tocilizumab (8 mg/kg, IV) on day 1 up to a maximum of 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. Co‐interventions Steroid use at baseline or any time during the study Tocilizumab: 56 (86%) Standard care: 55 (86%)
Outcomes	Primary outcome of the trial Clinical status at 15 days evaluated with the use of a 7‐level ordinal scale Note: the definition of clinical improvement extracted is discharge alive
Notes	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, declared. "Support from hospitals and research institutes participating in the Coalition covid‐19 Brazil, Fleury Laboratory in São Paulo, Brazil, and Instituto Votorantim for the submitted work. JAGGP reports support from Pfizer, Jansen, Sanofi,..." Protocol: yes, available. Statistical plan: yes, available. Data‐sharing stated: yes, 3 months after publication. Request to the corresponding author at viviane.veiga@bp.org.br Overall 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." Quote. "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"