[Summary text]
Parallel RCT
Randomised: 131 patients with moderate or severe pneumonia requiring at least 3 L/min oxygen but not ventilation or admission to ICU
Age (median [IQR]): 64 years [57.1-74.3] tocilizumab; 63.3 years [57.1-72.3]) usual care
Male (n %): 44/63 (70%) tocilizumab; 44/67 (66%) usual care
Confirmed SARS-CoV-2 infection: 56/63 (89%) tocilizumab; 61/67 (100%) usual care
Respiratory rate (median [IQR]): 24 [22-300 tocilizumab; 26 [24-30] usual care
Comorbidities:
Chronic cardiac disease: 20/61 (33%) tocilizumab; 20.67 (30%) usual care
Diabetes: 20/61 (33%) tocilizumab; 23/67 (34%) usual care
Chronic kidney disease: 5/61 (8%) tocilizumab; 13/67 (19%) usual care
Asthma: 5/61 (8%) tocilizumab; 3/67 (5%) usual care
Tocilizumab was administered intravenously at 8 mg/kg on day 1. Administration of an additional fixed dose of tocilizumab, 400 mg IV on day 3 was recommended if oxygen requirement was not decreased by more than 50%, but decision was left to the treating physician.
Usual care was provided at the discretion of the clinicians, and included antibiotic agents, antiviral agents, corticosteroids, vasopressor support and anticoagulants.
All-cause mortality; respiratory failure or ARDS; admission to ICU; serious averse events; adverse events; discharge from hospital
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
All cause morality (day 28) [critical]
All cause mortality [subgrouped]
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
All cause mortality (day 28) [moderate-severe]
All cause mortality [subgrouped]
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Parallel RCT (n=4116)
Baseline characteristics
Intervention
Age: 63.3
Feamle (%): 34
Diabetes (%):28
Heart disease (%):22
Chronic lung disease (%):23
Control
Age:63.9
Feamle (%): 31
Diabetes (%): 29
Heart disease (%): 24
Chronic lung disease (%): 23
Incusion criteria:
Exclusion criteria:
Intervention: usual standard of care plus tocilizumab single intravenous infusion over 60 min. The dose of tocilizumab was established by bodyweight (800 mg if weight >90 kg; 600 mg if weight >65 and ≤90 kg; 400 mg if weight >40 and ≤65 kg; and 8 mg/kg if weight ≤40 kg). A second dose could be given 12–24 h later if, in the opinion of the attending clinician, the patient’s condition had not improved.
Control: usual standard of care alone
All cause mortality (day 21-28) [All patients]
Mechanical ventilation
No. of patients discharged from hospital
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
N/A
All cause mortality (day 21-28) [All IL6 Ag]
All cause mortality (day 21-28) [critilcal IL6 Ag]
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
N/A
All cause mortality (21 days) [critical]
Serious adverse events
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
randomised multifactorial, adaptive platform trial
Baseline
Age (Mean SD): 61.5 (12.5) TCZ; 61.1 (12.8) Control
Male (n %): 261/353 (73.9%) TCZ; 283/402 (73.8%) Control
Confirmed SARS-CoV-2: 284/345 (82.3%) TCZ; 334/394 (84.8%) Control
Comorbidities:
Diabetes: 123/349 (35.2%) TCZ; 150/401 (37.4%) Control
Kidney disease: 30/312 (9.6%) TCZ; 43/372 (11.6%) Control
Severe cardiovascular disease: 34/339 (10%) TCZ; 47/395 (11.9%) Control
Inclusion criteria: critically ill patients, aged 18 years or over, with suspected or confirmed COVID-19, admitted to an intensive care unit and receiving respiratory or cardiovascular organ support.
Exclusion criteira: presumption that death was imminent with lack of commitment to full support, prior participation in REMAP-CAP within 90 days.
Intervention: Tocilizumab, at a dose of 8mg/kg of actual body weight (up to a maximum of 800mg), was administered as an intravenous infusion over 1 hour. Dose could be repeated 12-24 hours later at the discretion of treating clinician.
All cause mortality at day 21, serious adverse events, discharge from ICU (day 30)
NB: most patients recruited after publication of RECOVERY trial results (610/654; 93.3%) also received corticosteroids; 107/158 patients enrolled prior to publication received corticosteroids.
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
N/A
All cause mortality (day 21-28) [critical]
All cause mortality [subgrouped]
All cause mortality [undergrouped]
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
N/A
All cause mortality (day 21-280 [moderate-severe]
All cause mortality [subgrouped]
All cause mortality [undergrouped]
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Parallel RCT
Randomised: 452 patients hospitalised with COVID-19
mITT population: n=294 (TCZ); n=144 (SC)
Age (Mean SD): 60.9 (14.6) TCZ; 60.6 (13.7) SC
Male (n %): 205/295 (69.7%) TCZ; 101/144 (70.1%) SC
Disease severity (see notes):
Ordinal scale [2]: 9 (3.1%) TCZ; 6 (4.2%) SC [Mild]
Ordinal scale [3]: 78 (26.5%) TCZ; 44 (30.6%) SC [Moderate]
Ordinal scale [4]: 94 (32%) TCZ; 39 (27.1%) SC [Moderate/Severe]
Ordinal scale [5]: 45 (15.3%) TCZ; 15 (10.4%) SC [Severe]
Ordinal scale [6]: 68 (23.1%) TCZ; 40 (27.8%) SC [Critical]
Comorbidities:
Cardiovascular impairment: 88 (29/9%) TCZ; 35 (24.3%) SC
Diabetes: 105 (35.7%) TCZ; 62 (43.1%) SC
Obesity: 63 (21.4%) TCZ; 27 (18.8%) SC
Hypertension: 178 (60.5%) TCZ; 94 (65.3%) SC
Intervention: intravenous tocilizumab (8 mg/kg infusion, maximum 800 mg); if clinical signs or symptoms did not improve or worsened (defined as sustained fever or worsened ordinal scale clinical status), a second infusion could be administered 8 to 24 hours after the first.
Standard care: NR; however authors report that the 'lack of standardised treatment across study sites and countries is an important limitation of this study'.
All cause mortality day 28, mechanical ventilation, admission to ICU, serious adverse events, adverse events, septic shock,
NB: within 'Trial Design and Oversight', authors specify "Patients 18 years or older wth severe COVID-19 pneumonia...... were enrolled"; however table 1 demonstrates that ~30% of patients (categories 2 and 3) only had mild or moderate disease.
7-category ordinal scale: 1, discharged or ready for discharge; 2, non–ICU hospital ward, not requiring supplemental oxygen; 3, non–ICU hospital ward requiring supplemental oxygen; 4, ICU or non–ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death.
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
RCT (n=649)
Baseline Characteristics
[Remdesivir plus Tocilizumab]No. randomised (N): 434
[Remdesivir ]No. randomised (N): 215
Remdesivir plus Tocilizumab
Participants with laboratory confirmed COVID-19 (%) 100
Participants with severe or critical illness (%) 100
Age (mean [SD]) 60.1 [13.3]
Female participants (%) 38.1
Paediatric participants (%)
Pregnant participants (%)0
Pregnant and/or breastfeeding participants (%)0
Frailty index or similar
Participants with hypertension (%) 62.1
Participants with diabetes (%) 40
Participants with chronic heart disease (%) 24.4
Tocilizumab
Participants with laboratory confirmed COVID-19 (%) 100
Participants with severe or critical illness (%) 100
Age (mean [SD]) 58.2 [13.3]
Female participants (%) 33.8
Paediatric participants (%)
Pregnant participants (%) 0
Pregnant and/or breastfeeding participants (%)0
Frailty index or similar
Participants with hypertension (%) 61
Participants with diabetes (%) 38.6
Participants with chronic heart disease (%) 21.4
Included criteria:
Aged 12 years and older
hospitalized with severe COVID-19 pneumonia
Positive SARS-CoV-2 polymerase chain reaction test result within 7 days of randomization
Pneumonia confrmed by chest x-ray or computed tomography
Hypoxemia requiring>6 L/min supplemental oxygen
Excluded criteria:
Estimated glomerular fltration rate was5Ãthe upper limit of normal within 24 h of screening
Suspected active bacterial, fungal, viral, or other infection except COVID19 were excluded
Corticosteroids for treatment of COVID-19 pneumonia were permitted
Treatment with convalescent plasma, chloroquine or hydroxychloroquine, antivirals, biologics, and Janus kinase inhibitors during the trial was prohibited.
Remdesivir was administered intravenously as a 200 mg IV loading dose followed by 100 mg once-daily IV maintenance dose of remdesivir from Days 2 to 10. Remdesivir will be discontinued at the time of hospital discharge even if 10 days of remdesivir dosing have not been completed. Tocilizumab 8 mg/kg (maximum, 800 mg) or placebo on day 1. Patients with sustained fever or clinically signifcant worsening of signs and symptoms of COVID-19 (e.g., increased supplemental oxygen requirement) could receive a second infusion of blinded tocilizumab or placebo within 8 to 24 h of the frst infusion.
All-cause mortality (day 28)
All-casue mortality (day 60)
Adverse events
Serious adverse events
Hospital discharge (day 28)
Parallel RCT
Baseline
Age (Mean SD): 56.0 (14.3) TCZ; 55.6 (14.9) Placebo
Male (n %): 150/249 (60.2%) TCZ; 73/128 (57%) Placebo
Disease severity (see notes):
Ordinal scale [2]: 24 (9.6%) TCZ; 11 (8.6%) Placebo
Ordinal scale [3]: 161 (64.7%) TCZ; 81 (63.3%) Placebo
Ordinal scale [4]: 64 (25.7%) TCZ; 36 (28.1) Placebo
Comorbidities:
Asthma: 27 (10.8%) TCZ; 16 (12.6%) Placebo
COPD: 12 (4.8%) TCZ; 5 (3.9%) Placebo
Diabetes: 105 (42%) TCZ; 48 (37.8%) Placebo
Hypertension: 119 (47.6%) TCZ; 63 (49.6%) Placebo
Inclusion criteria: Patients 18 years of age or older, hospitalised with COVID-19 pneumonia confirmed by positive PCR and radiographic imaging, blood oxygen saturation <94% on ambient air.
Exclusion criteria: Patients that required continuous positive airway pressure, bilevel positive airway pressure, or mechanical ventilation.
Randomised: 389 nonventilated patients hospitalised with COVID-19 pneumonia
Intervention: Tocilizumab, 8 mg/kg (maximum 800 mg)
Standard care: as per local practice, which could include antiviral treatment, limited systemic corticosteroids and supportive care.
All cause mortality day 28, serious advserse events, adverse events, septic shock
7 category ordinal scale: 2 - non-ICU hospital ward (or ready for hospital ward), not requiring supplemental oxygen; 3 - non-ICU hospital ward (or ready for hospital ward), requiring supplemental oxygen; 4 - ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen.
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Parallel RCT
Baseline
Randomised: 126 adults hospitalised with COVID-19 pneumonia.
Age (Median [IQR]): 61.5 [51.5-73.5] TCZ; 60.0 [54.0-69.0] Standard care
Male (n %): 40/60 (66.7%) TCZ; 37/66 (56.1%) Standard care
Days from symptom onset to randomization (median [IQR]): 7 days [4-11] TCZ; 8 days [6-11] Standard care
Comorbidities:
Diabetes: 10/60 (16.7%) TCZ; 9/66 (13.6%) Standard care
Hypertension: 27/60 (45%) TCZ; 29/66 (43.9%) Standard care
COPD: 2/60 (3.3%) TCZ; 2/66 (3%) Standard care
Inclusion criteria: Confirmed COVID-19 by RT-PCR; presence of acute respiratory failure with partial pressure of arterial oxygen to fraction of inspired oxygen ratio between 200 and 300 mm/Hg; an inflammatory phenotype defined by a temperature greater than 38 degrees celsius during the last two days.
Exclusion criteria: ICU admission, known hypersensitivity to tocilizumab, any condition preventing future admission to ICU, such as advanced age with multiple comorbidities.
Intervention: 8 mg/kg tocilizumab intravenously administered within 8 hours of randomisation, up to a maximum of 800 mg, followed by a second dose after 12 hours.
Standard care: all drugs were allowed but IL-1 blockers, ak inhibitors, and tumor necrosis factor inhibitors. Steroids were allowed if already taken before hospitalisation.
All cause mortality day 28, Admission to ICU, clinical progression, discharge from hospital,
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
All cause mortality (day 21-28) [All patients]
Mechanical ventialtion
Admission to ICU
Serious adverse events
Adverse events
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Parallel RCT
Randomised: 243 adults hospitalised with confirmed COVID-19 in a hyperinflammatory state.
Age (Median [IQR]): 61.6 years [46.4-69.7] TCZ; 56.5 years [44.7-67.8] Placebo
Men (n %) 96/161 {60%) TCZ; 45/82 (55%) Placebo
Disease severity (see notes):
Ordinal scale [2]: 23/161 (14%) TCZ; 15/82 (18%) Placebo
Ordinal scale [3]: 133/161 (83%) TCZ; 61/82 (74%) Placebo
Ordinal scale [4]: 5/161 (3%) TCZ; 5/82 (6%) Placebo
Ordinal scale [5]: 0 TCZ; 1/82 (1%) Placebo
Comorbidities:
Diabetes: 45/161 (28%) TCZ; 30/82 (37%) Placebo
Hypertension: 80/161 (50%) TCZ; 38/82 (46%) Placebo
Asthma: 15/161 (9%) TCZ; 7/82 (9%) Placebo
Intervention: tocilizumab 8 mg/kg body weight, administered intravenously.
Comparator: placebo
All-cause mortality at day 28, mechanical ventilation, serious adverse events, adverse events, clinical improvement, clinical progression, discharge from hospital
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Study design: Randomized controlled trial
Study grouping:
Baseline Characteristics
Tocilizumab
Standard of Care
Included criteria: Inclusion Criteria:Male and females with 18 years and olderConfirmed diagnosis of SARS-CoV 2 infectionMore than 3 days of symptoms related to COVID-19Computed tomography (or Chest X-Ray) with COVID-19 alterationsBoth of the criteriaNeed for oxygen supplementation to keep SPO2 > 93% OR need for mechanical ventilation for less than 24 hours before the randomizationAt least two of the following inflammatory tests above the cutoff :D-dimer > 1,000 ng/mLReactive C protein > 5 mg/dLFerritin > 300 mg/dLLactate dehydrogenase > upper level limit
Excluded criteria: Exclusion Criteria:Need for mechanical ventilation for 24 hours or more before the randomizationHypersensitivity to tocilizumabPatients without therapeutic perspective or in palliative careActive non controlled infectionsOther clinical conditions that contraindicate tocilizumab, according to the assistant physicianLow neutrophils count (< 0.5 x 109/L)Low platelets count (< 50 x 109/L)Liver disease, cirrhosis or elevated AST or ALT above 5 times the upper level limitRenal disease with estimate glomerular filtration below 30 mL/min/1.72 m2 (MDRD or CKD-EPI scores)Active diverticulitisBreastfeeding womenPregnancy
Intervention Characteristics
Tocilizumab
Standard of Care
All cause mortality day 28, duration of hospital stay (days), serious adverse events, adverse events, all-cause mortality or mechanical ventilation (composite)
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Parallel RCT
Baseline Characteristics
Randomised: 65 hospitalised adults with confirmed COVID-19 and moderate to severe illness.
Age (Median [IQR]): 63.5 years [58-71] TCZ; 63 years [54-69] Control
Males (n %): 18/34 (53%) TCZ; 15/31 (48%) Control
Disease severity:
Moderate: 20/34 (58.8%) TCZ; 17/31 (54.8%) Control
Severe: 14/34 (41.2%) TCZ; 14/31 (45.2%) Control
Comorbidities:
Hypertension: 10/34 (29.4%) TCZ; 10/31 (32.3%) Control
Diabetes: 4/34 (11.8%) TCZ; 6/31 (19.4%) Control
Inclusion criteria: Adults aged 18-85 years old, elevated plasma IL-6 levels, moderate (with bilateral pulmonary lesions) or severe in disease degree.
Exclusion criteria: pregnant or lactating women, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal; people diagnosed with rheumatism; allergic to tocilizumab or any excipients; organ transplantation and mental disorders.
Intervention: The first dose of tocilizumab was 400 mg, diluted in 100 ml 0.9% saline, and intravenous dripped for more than 1 hour. A second dose was given if a patient remained febrile for 24 hours after the first dose.
Control: Standard care was given according to the "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th or update version)"
Serious adverse events, adverse events, length of hospitalisation
We have used version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for this study. Refer to Main text > Published notes for more details.
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Detection bias due to knowledge of the allocated interventions by outcome assessors
Attrition bias due to amount, nature or handling of incomplete outcome data
Reporting bias due to selective outcome reporting
Bias due to problems not covered elsewhere in the table