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tocilizumab (n=161) vs. placebo (n=81)
randomized controlled trial
Tocilizumab
Tocilizumab single dose (8 mg per kilogram of body weight administered intravenously, not to exceed 800 mg) plus standard of care.
Placebo
COVID 19 all comers
Age > 18 and < 80 years old, Male or female gender, Confirmed SARS-CoV-2 infection by NP swab PCR, Admitted to non-ICU level care at MGH WITH evidence of severe COVID-19 (at least 2 of the following): Fever > 38C, Pulmonary infiltrates on chest X ray, Need for supplemental O2 to maintain saturation > 92% AND at least 1 of the following: Ferritin > 500 ng/ml, CRP > 50 mg/L, LDH >250 U/L, D-dimer > 1000 ng/mL.
Double-blind.
7 Boston hospitals, United States.
tocilizumab (n=259) vs. placebo (n=129)
randomized controlled trial
tocilizumab
tocilizumab (8 mg/kg intravenous) plus standard care
placebo
COVID 19 hospitalized
hospitalized patients older than 18 years with confirmed SARS-CoV-2 (COVID-19) infection with SpO2 <94% while on ambient air who did not require noninvasive or invasive mechanical ventilation.
double-blind
United States, South Africa, Kenya, Brazil, Mexico and Peru
tocilizumab (n=10) vs. placebo (n=11)
randomized controlled trial
Tocilizumab
Single dose: 8 mg/kg IV (max 800mg). 1 additional dose may be given.
Placebo
Usual care plus placebo.
COVID 19 hospitalized
Hospitalized adult patients (18-95) with COVID-19 pneumonia, based on chest X-ray or CT scan AND evidence of hyperinflammation: IL-6>40pg/mL (if available) OR CRP >2 mg/dL OR ferritin >2000 ng/mL AND one or more of the: impending need for requiring invasive or non-invasive mechanical ventilation OR shock requiring vasopressor (without evidence of bacterial/fungal infection) OR need for extracorporeal membrane oxygenation (ECMO) OR severe, refractor ARDS (PaO2/FiO2<200 mmHg).
Double-blind.
USA.
Data from the study registry. Clinical Status 7-point ordinal scale: Not hospitalized, no limitations on activities, not hospitalized, limitation on activities hospitalized, not requiring supplemental oxygen, hospitalized, requiring supplemental oxygen hospitalized, on non-invasive ventilation or high flow oxygen devices, hospitalized, on invasive mechanical ventilation or ECMO, death.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=114) vs. standard of care (n=115)
randomized controlled trial
Tocilizumab
Single dose: 8 mg/kg IV (max 800mg).
Usual care
COVID 19 hospitalized
Hospitalised patients with Covid-19 infection, presence of hypoxia requiring supplemental oxygen and /or mechanical ventilation, signs of cytokine release syndrome, bilateral pulmonary infiltrates.
Open-label.
Belgium.
TTCI defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital: 1=death; 2=hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3=hospitalised, on non-invasive ventilation or high-flow oxygen devices; 4=hospitalised,requiring supplemental oxygen; 5=hospitalised, not requiring supplemental oxygen; 6=not hospitalised.
tocilizumab (n=2022) vs. standard of care (n=2094)
randomized controlled trial
Tocilizumab
tocilizumab at a dose of 400 mg to 800 mg (depending on weight) given intravenously. A second dose could be given 35 12 to 24 hours later if the patient’s condition had not improved
usual standard of care
COVID 19 hospitalized
Open-label.
Platform trial
tocilizumab (n=26) vs. standard of care (n=13)
randomized controlled trial
Tocilizumab
Single dose: 8mg/kg (max dose 800mg).
Usual care
COVID 19 hospitalized
Hospitalized Patients With COVID-19 Pneumonitis, not Requiring Invasive Ventilation, with radiographic evidence of pulmonary infiltrates, fever (≥ 38 degrees C).
Open-label.
USA.
Clinical status at day 28 assessed using 7-category ordinal scale: 7 death 6 in ICU with ECMO/ mechanical ventilation 5 in ICU, no ECMO/ mechanical ventilation 4 in hospital, not ICU, needs supplementary oxygen 3 in hospital, not ICU, no supplementary oxygen 2 not in hospital, but not back to normal 1 not in hospital, back to normal.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=90) vs. standard of care (n=90)
randomized controlled trial
Tocilizumab
1 intravenous infusion of Tocilizumab, dosed at 6 mg/kg, up to a maximum dose 480 mg. Up to 1 additional dose may be given 12 hours to day 7th, if clinical symptoms worsen or show no improvement.
Standard of care
Standard of care alone
Cross-over: 1 patient from SoC to Tocilizumab group. Standard care was provided according to the protocols at the individual study sites.
COVID 19 hospitalized
Patients aged 18 years or older admitted to hospital with SARS-CoV-2 infection confirmed by WHO criteria (positive PCR test on any specimen) and moderate to severe disease defined according to the Indian MoHFW clinical management protocol for COVID-19 (moderate defined as respiratory rate 15–30 per min [revised to 24 per min on June 13, 2020] and blood oxygen saturation [SpO2] 90–94%; and severe defined as respiratory rate ≥30 per min or SpO2 <90% in ambient air, or ARDS or septic shock.
Open-label.
Multicenter, 12 public and private hospitals across India.
tocilizumab (n=174) vs. standard of care (n=180)
randomized controlled trial
Tocilizumab
Single dose of 8mg/kg (maximum dose 800mg).
Usual care
COVID 19 hospitalized
Patients with a diagnosis of COVID-19 based on a compatible clinical presentation AND a positive SARS-CoV-2 PCR, clinical features compatible with hyperinflammation: Hypoxia, without other explanation for hypoxia than COVID-19 OR ferritin >2000 μg/L or doubling of serum ferritin in 20-48 hours. Inclusion of patients already requiring oxygen administration prior to COVID19 should be discussed with the study team.
Open-label.
Netherlands.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=22) vs. standard of care (n=27)
randomized controlled trial
Tocilizumab
Single dose of 8mg/kg (maximum dose 800mg).
Usual care
COVID 19 hospitalized
Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay < 3 days prior to screening SARS-CoV-2 infection with duration at least 7 days (as determined by onset of symptoms) 5l/min Oxygen for at least 8 hours to maintain SpO2 at ≥93% . (Shorter duration is also accepted if patient needs > 10l/min to maintain SpO2 at ≥93%. CRP > 70 mg/L with no non-SARS-Cov2 infections. Ferritin > 500 µg/L At least two of; lymphocytes < 1x 10(9)/L; D-dimer ≥ 0.5 mg/L; Lactate Dehydrogenase ≥ 8 microkatal/L.
Open-label.
Sweden.
Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale:1) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 1;2) Not hospitalized, limitation on activities and/or requiring home oxygen;3) Not hospitalized, no limitations on activities.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=33) vs. standard of care (n=32)
randomized controlled trial
Tocilizumab
The first dose of tocilizumab was 400 mg, diluted in 100 ml 0.9% saline, and intravenous dripped in more than 1 h. A second dose was given if a patient remained febrile for 24 hours after the first dose.
Standard care
Standard care alone
Standard of care in both groups. One patient in the control group, who aggravated severely 3 days after randomization, wastransferred to the tocilizumab group.
COVID 19 hospitalized
1) 18-85 years old; 2) plasma IL-6 levels elevated; 3) moderate (with bilateral pulmonary lesions) or severe in disease degree.
Open-label.
Multicenter, 6 hospitals in Anhui and Hubei, China.
The definition for cure followed the standard given by the “Diagnosis and Treatment Protocol for Novel CoronavirusPneumonia (5th or update version)” as 1) fever attenuated for continuously 7 days, 2) twice COVD-19 nucleolus acid detections negative, 3) CT scan shows chest effusion absorbed more than 50% percent when the patient is discharged from hospital.
tocilizumab (n=20) vs. standard of care (n=8)
randomized controlled trial
Tocilizumab
Single dose: 120mg or 40mg.
Usual care
3 arms: Tocilizumab 120mg, tocilizumab 40mg and usual care.
COVID 19 hospitalized
Hospitalized adult patients (>= 18) with COVID-19 pneumonitis, not requiring invasive ventilation, with radiographic evidence of pulmonary infiltrates and fever (≥ 38 degrees C).
Open-label.
USA.
Day of recovery is defined as the first day on which the patient achieves one of the following two categories from the seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=174) vs. standard of care (n=180)
randomized controlled trial
Tocilizumab
Standard of care plus single dose of tocilizumab (8 mg per kilogram of body weight administered intravenously, maximal 800 mg). A second dose of tocilizumab was permitted after 8 hours if hypoxia was not resolved (persisting at grade II or more according to CRS scale).
Standard of care
Standard of care alone.
The majority of patients (88%) received dexamethasone as a concomitant treatment. All other concomitants were permitted, including remdesivir and hydroxychloroquine.
COVID 19 hospitalized
Patients were eligible if they were18 years or older, capable of providing informed consent and had SARS-CoV-2 infection confirmed by nasopharyngeal swab polymerase chain reaction. Additionally, patients were required to be admitted to a ward and have at least one of the following signs compatible with hyperinflammation: 1) a need for supplemental oxygen (inspired by the ASTCT consensus grade 2 for CRS, generally matching a saturation < 94%) and/or 2) ferritin >2000ug/l or a doubling of serum ferritin in 20-48 hrs.
Open-label.
11 hospitals in Netherlands.
Phase II.
Phase II.
tocilizumab (n=17) vs. standard of care (n=9)
randomized controlled trial
Tocilizumab
Usual care 8mg/kg (maximum 800mg) single or double dose.
Usual care
Usual care only.
3 arms: Tocilizumab single dose, tocilizumab double dose, usual care. All patients received usual care.
COVID 19 hospitalized
Hospitalised adult patients (or patients meeting hospital admission criteria) with confirmed COVID-19 and: Basal oxygen saturation> 90%, CURB-65 ≤1, PaO2 / FiO2≥300 or SatO2 / FiO2≥315, and not expected to enter the ICU or die within 24 hours.
Open-label.
Single center in Spain.
Phase 2.
The trial was stopped for futility (unpublished). Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=60) vs. standard of care (n=66)
randomized controlled trial
tocilizumab
8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours
standard of care
COVID 19 hospitalized
COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein
open label, randomized
italy, 24 centers
398 participants
trial was prematurely interrupted after an interim analysis for futility
tocilizumab (n=434) vs. placebo (n=215)
randomized controlled trial
Tocilizumab
Remdesivir intravenously followed by a single intravenous dose of tocilizumab 8 mg/kg (maximum, 800 mg) on day 1.
Placebo
Remdesivir intravenously followed by a single intravenous dose of placebo on day 1.
Patients with sustained fever or clinically significant 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 first infusion. Systemic 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.
COVID-19 severe or critically
Patients were required tohave a positive SARS-CoV-2 polymerase chain reactiontest result within 7 days of randomization, pneumoniaconfrmed by chest x-ray or computed tomography, andhypoxemia requiring>6 L/min supplemental oxygen.
Double-blind.
Multicenter; 53 sites across Brazil, Russia, Spain, United States.
Ordinal scale categories are as follows: 1, discharged or “ready for discharge” (as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2 L/min supplemental oxygen); 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-fow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death.
tocilizumab (n=301) vs. placebo (n=151)
randomized controlled trial
Tocilizumab
Single intravenous infusion of tocilizumab at a dose of 8 mg per kilogram of body weight with a maximum dose of 800 mg.
Placebo
A second dose of tocilizumab or placebo was administered to 65 patients(22.1%) in the tocilizumab group and 43 patients (29.9%) in the placebo group. All patients received standard of care.
COVID-19 severe or critically
Age >= 18 years at time of signing Informed Consent Form, hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan, SpO2 =< 93% or PaO2/FiO2 < 300 mmHg.
Double-blind.
62 hospitals in Canada, Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom, US.
The patients’ clinical status was assessed on an ordinal scale according to the following categories: 1, discharged or ready for discharge;2, hospitalization in a non–intensive care unit(ICU) without supplemental oxygen; 3, non–ICU hospitalization with supplemental oxygen; 4, ICU or non–ICU hospitalization with noninvasive ventilation or high-flow oxygen; 5, ICU hospitalization with intubation and mechanical ventilation;6, ICU hospitalization with extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; and 7, death.
tocilizumab (n=65) vs. standard of care (n=64)
randomized controlled trial
Tocilizumab
Standard care plus tocilizumab (single intravenous infusion of 8 mg/kg: maximum 800 mg).
Standard care alone
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.
COVID-19 severe or critically
Severe or critical covid-19, with evidence of pulmonary infiltrates confirmed by chest computed tomography or radiography, and were receiving supplemental oxygen to maintain oxygen saturation greater than 93% or had been receiving mechanical ventilation for less than 24 hours before analysis. In addition, at least two of the following criteria had to be met: D dimer >2.74 nmol/L (>1000 ng/mL), C reactive protein >50 mg/L (>5 mg/dL), ferritin >300 μg/L, or lactate dehydrogenase greater than the upper limit of normal.
Open-label
9 hospitals in Brazil.
The seven level ordinal scale was defined as: level 1—not admitted to hospital and with no limitation in activities, level 2—not admitted to hospital but with limitation in activities, level 3—admitted to hospital and not receiving supplemental oxygen, level 4—admitted to hospital and receiving supplemental oxygen, level 5—admitted to hospital and receiving non-invasive positive pressure ventilation or high flow oxygen through a nasal cannula, level 6—admitted to hospital and receiving mechanical ventilation, and level 7—death.
data monitoring committee recommended stopping the trial early because of an increase of deaths at 15 days in the tocilizumab group
tocilizumab (n=20) vs. standard of care (n=20)
randomized controlled trial
Tocilizumab
Usual care plus tocilizumab 8mg/kg, 1 or 2 dosages (if the patient’s conditions were not stable, 2 doses by 12 hours were administrated, maximum dose: 800 mg).
Usual care
Usual care alone.
All patients received usual care for the disease based on the Iranian protocol for diagnosis and treatment of COVID-19
COVID-19 severe or critically
COVID-19 patients confirmed by positive PCR test for SARS-CoV-19 or confirmed by abnormal CT scan finding (bilateral, sub pleural, peripheral ground glass opacities), With blood oxygen saturation <93%, or respiratory rate> 24 high CRP rate, lymphopenia < 1100 not responding to standard COVID-19 treatment and not connecting to the mechanical ventilator.
Double-blind.
2 centers; Imam Khomeini and Shariati Hospital, Tehran University of Medical Sciences, Iran.
Phase II
tocilizumab (n=64) vs. standard of care (n=67)
randomized controlled trial
Tocilizumab
Single intravenous infusion of Tocilizumab (at a dose of 8 mg per kilogram of body weight), plus usual care, on day 1 and on day 3 if clinically indicated.
usual care alone
usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants
COVID-19 severe or critically
patients withCOVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen butwithout ventilation or admission to the intensive care unit
Open-label.
9 university hospitals in France
tocilizumab (n=49) vs. standard of care (n=43)
randomized controlled trial
Tocilizumab
Single intravenous infusion of Tocilizumab (at a dose of 8 mg per kilogram of body weight), plus usual care, on day 1 and on day 3 if clinically indicated.
usual care alone
usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants
COVID-19 severe or critically
Adults (18 and older) with respiratory failure AND (requiring mechanical ventilation OR NIV OR High flow), WHO progression scale >=6, No do-not-resuscitate order (DNR order).
Open-label.
9 university hospitals in France.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=353) vs. standard of care (n=402)
randomized controlled trial
tocilizumab (8mg/kg)
standard care
3 arms : tocilizumab (8mg/kg) or sarilumab (400mg) and control (standard care)
COVID-19 severe or critically
open-label
bayesian trial with a neurol prior (not necessary uninformative) and borrowing between the two tested treatment
tocilizumab (n=48) vs. tocilizumab (n=49)
randomized controlled trial
1 dose tocilizumab 4 mg/kg SOC
1 dose tocilizumab 8 mg/kg SOC
standard of car : antiviral treatment, low-dose corticosteroids, and supportive care
An additional infusion (same as initial dose) could be administered 8 to 24 hours after the first if a patient had a sustained fever or clinically significantworsening of signs or symptoms, such as an increased supplemental oxygen requirement
COVID-19 severe or critically
Patients who were on invasive ventilation >24 hours, on ECMO, in shock, or with multiorgan failure requiring treatment in an intensive care unit were excluded.
open-label
24 centers, USA
phase 2 study. Randomization was stratified by pneumonia severity (moderate or severe). Efficacy outcomes were exploratory
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