Table 3

Potential effect modulators for anti-interleukin 6 in large-scale studies of tocilizumab for COVID-19

Trial	Enrollment criteria	Timing of tocilizumab	Concomitant medications (tocilizumab and placebo arms)
Positive trials
EMPACTA123	PCR and radiographically confirmed COVID-19. Blood O₂<94% not requiring invasive ventiliation. Emphasis on high-risk racial and ethnic minorities.	Not specified. If clinical signs or symptoms worsened or did not improve, an additional infusion could be administered 8–24 hours after the first.	Corticosteroids: (200 patients (80.3%) and 112 (87.5%)). Antivirals (196 (78.7%) and 102 (79.7%)).
CORIMUNO-TOCI-1121	Confirmed SARS-CoV-2 infection (PCR and/or typical chest CT). Moderate, severe, or criticalpneumonia (O₂ >3 L/min, WHO-CSP score ≥5) without NIV or MV.	First dose on day 1. Additional fixed dose of 400 mg intravenous on day 3 recommended if O₂ not decreased by more than 50%, but decision was left to the treating physician.	Corticosteroids (21 (33%) and 41 (61%)). Antivirals (7 (11%) and 16 (24%)). Preventative or therapeutic anticoagulants (59 (94%) and 61 (91%)).
STOP-COVID126	Laboratory-confirmed COVID-19. Admitted to ICU.	2 days after ICU admission	Corticosteroids (81 (18.7%) and 440 (12.6%)).
REMAP-CAP124	Clinically suspected or confirmed SARS-CoV-2 infection. Receiving respiratory or cardiovascular organ failure support.	Within 24 hours of starting organ support.	Corticosteroids (50 (14.2%) and 52 (12.9%)). Antivirals (169 (47.9%) and 217 (54.0%)). Anticoagulants (119 (33.7%) and 146 (36.3%)). Anti-SARS-CoV-2 IgG (175 (49.6%) and 202 (50.3%)).*
RECOVERY125	Clinically suspected or confirmed SARS-CoV-2 infection. O₂ saturation <92% on room air or requiring supplemental O₂. Evidence of systemic inflammation (CRP ≥75 mg/L).	Not specified. A second dose could be given 12–24 hours later if the patient’s condition had not improved.	Corticosteroids (1664 (82%) and 1721 (82%)). Antivirals (51 (3%) and 64 (3%)). Hydroxychloroquine (37 (2%) and 38 (2%)). Azithromicin (197 (10%) and 177 (8%)).
Negative trials
COVACTA127	PCR confirmed SARS-CoV-2 infection. Bilateral chest infiltrates on chest X-ray or CT. O₂ saturation ≤93% or Pao₂/Fio₂ ratio <300 mm Hg.	Not specified. If clinical signs or symptoms worsened or did not improve, an additional infusion could be administered 8–24 hours after the first.	Corticosteroids (106 (36.1%) and 79 (54.9%)). Antivirals (87 (29.6%) and 51 (35.4%)). Convalescent plasma (10 (3.4%) and 6 (4.2%)).
RCT-TCZ-COVID-19137	PCR-confirmed COVID-19. Pao₂/Fio₂ ratio between 200 and 300 mm Hg. Inflammatory phenotype: Temperature >38°C during the last 2 days. -OR- CRP ≥10 mg/dL and/or at least twice admission measurement.	Within 8 hours of randomization followed by a second dose after 12 hours.	Only in cases documented clinical worsening. In tocilizumab arm: one patient received steroids on day 4 after. In the standard care arm: two patients received tocilizumab intravenous plus steroids, one received tocilizumab subcutaneously, two received steroids, and one received canakinumab.
TOCIBRAS129 †	PCR-confirmed SARS-CoV-2. Symptoms for >3 days. Pulmonary infiltrates by chest CT or X-ray. Need for supplemental O₂ to maintain SpO2 >93% OR need for mechanical ventilation for <24 hours before randomization. Two or more inflammatory parameters: D dimer >1000 ng/mL). CRP >50 mg/L. Ferritin >300 µg/L. LDH >ULN.	Not specified. Single infusion.	Corticosteroids (45 (69%) and 47 (73%)). Heparin (53 (81%) and 54 (84%)).
BACC Bay128	Laboratory confirmed SARS-CoV-2 infection (nasopharyngeal swab PCR or serum IgM). At least two signs: Fever (>38°C) within 72 hours before enrollment. Pulmonary infiltrates. Need for supplemental O₂ to maintain an O₂ saturation >92%. At least one laboratory criteria: CRP >50 mg/L. Ferritin >500 ng/mL. d-dimer >1000 ng/mL. LDH >250 U/L.	Within 3 hours after informed consent was obtained.	Corticosteroids (18 (11%) and 5 (6%)). Remdesivir (53 (33%) and 24 (29%)). Hydroxychloroquine (6 (4%) and 3 (4)).

*Antivirals, anticoagulants, and anti-SARS-CoV-2 were also given to 26 (54.2%), 31 (64.6%), and 41 (85.4) patients, respectively, in the sarilumab group.
†Remdesivir was not available in Brazil during the TOCIBRAS study.
CRP, C reactive protein; ICU, intensive care unit; LDH, lactate dehydrogenase; MV, mechanical ventilation; NIV, non-invasive ventilation; ULN, upper limit of normal; WHO-CPS, WHO-Clinical Progression Scale.