meta|Evidence - COVID-19
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sarilumab (n=-9) vs. control (n=-9)
randomized controlled trial risk of bias NA
sarilumab IV 400 mg
placebo
A second cohort, which was partially recruited (n=27), compared Kevzara 800 mg versus placebo
COVID-19 severe or critically
double-blind
US
sarilumab (n=334) vs. placebo (n=86)
randomized controlled trial low risk of bias
sarilumab IV 400 mg (n=173) or 200mg (n=161)
placebo
COVID-19 severe or critically
Severe disease: requires oxygen by nasal cannula, simple face mask, or other similar oxygen delivery device. Critical disease: requires oxygen by non-rebreather mask or high-flow nasal cannula, or use of invasive or non-invasive ventilation, or treatment in an intensive care unit.
double-blind
Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia and Spain
sarilumab (n=48) vs. standard of care (n=402)
randomized controlled trial high risk of bias
sarilumab (400mg)
standard care
3 arms : tocilizumab (8mg/kg), 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
sarilumab high dose (400mg) (n=173) vs. placebo (n=86)
randomized controlled trial some concerns about risk of bias
Sarilumab
Prefilled syringes (PFS) of sarilumab 200mg solution for subcutaneous injection into a specified volume of 0,9% NaCl solution for IV infusion (two syringe for the 400-mg dose). An option for a second dose existed (within the assigned treatment arm) within 24–48 hours of the first dose, based on the investigator’s benefit-risk assessment.
Placebo
0,9% NaCl solution for IV infusion.
Phase 2/3, 3 arms: Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo.
COVID-19 severe or critically
Patients aged 18 years or older at the time of signing informed consent who had been hospitalised for laboratory-confirmed SARS-CoV-2 infection in any specimenwithin 2 weeks prior to randomisation and with evidence of pneumonia by chest imaging orchest auscultation and no alternative explanation for current clinical presentation. Patientsalso had to meet criteria for severe disease (defined as administration of supplemental oxygenby nasal cannula, simple face mask, or another similar device) or critical disease (defined asneed for supplemental oxygen delivered by nonrebreather mask or high-flow nasal cannula,use of invasive or noninvasive ventilation, or treatment in an intensive care unit).
Double-blind.
45 sites in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Spain.
1—Death; 2—Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3—Hospitalised, on noninvasive ventilation or high-flow oxygen devices; 4—Hospitalised, requiring supplemental oxygen; 5—Hospitalised, not requiring supplemental oxygen –requiring ongoing medical care (COVID-19 related or otherwise); 6—Hospitalised, notrequiring supplemental oxygen – no longer requiring ongoing medical care; 7—Not hospitalised.
sarilumab low dose (200mg) (n=161) vs. placebo (n=86)
randomized controlled trial some concerns about risk of bias
Sarilumab
Prefilled syringes (PFS) of sarilumab 200mg solution for subcutaneous injection into a specified volume of 0,9% NaCl solution for IV infusion (one syringe for the 200-mg dose). An option for a second dose existed (within the assigned treatment arm) within 24–48 hours of the first dose, based on the investigator’s benefit-risk assessment.
Placebo
0,9% NaCl solution for IV infusion.
Phase 2/3, 3 arms: Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo.
COVID-19 severe or critically
Patients aged 18 years or older at the time of signing informed consent who had been hospitalised for laboratory-confirmed SARS-CoV-2 infection in any specimenwithin 2 weeks prior to randomisation and with evidence of pneumonia by chest imaging orchest auscultation and no alternative explanation for current clinical presentation. Patientsalso had to meet criteria for severe disease (defined as administration of supplemental oxygenby nasal cannula, simple face mask, or another similar device) or critical disease (defined asneed for supplemental oxygen delivered by nonrebreather mask or high-flow nasal cannula,use of invasive or noninvasive ventilation, or treatment in an intensive care unit).
Double-blind.
45 sites in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Spain.
1—Death; 2—Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3—Hospitalised, on noninvasive ventilation or high-flow oxygen devices; 4—Hospitalised, requiring supplemental oxygen; 5—Hospitalised, not requiring supplemental oxygen –requiring ongoing medical care (COVID-19 related or otherwise); 6—Hospitalised, notrequiring supplemental oxygen – no longer requiring ongoing medical care; 7—Not hospitalised.
tocilizumab (n=74) vs. dexamethasone (n=75)
randomized controlled trial high risk of bias
Tocilizumab
Standard of care plus tocilizumab 4 mg/kg/dose in 100 cc normal saline over one hour repeated afer 24 h, then patient continue symptomatic treatment and oxygen therapy and/or assisted ventilation as needed.
Dexamethasone
Standard of care plus pulse Dexamethasone 4 mg/kg/day in an infusion form for 3 days,followed by a maintenance dose of 8 mg/day for ten days.
All patients received standard of care.
COVID-19 severe or critically
Patients with signifcant deterioration in respiratory clinical status with respiratory rate>30 cycle/minute, Bilateral ChestmL) computed tomography (CT) infltration>30%, PaO2/FiO2 ratio<150 or saturation<90 on>6 L/min, Two positive laboratory tests of the following: (CRP>10 g/L, lymphocytes<600/mm3, D-dimer>500 ng/mL , ferritin>500 ng/mL). Patients who were not requiring supplemental oxygen were excluded from the study.
Open-label.
ICU of ESNA hospital, Egypt.
tocilizumab (n=37) vs. placebo (n=17)
randomized controlled trial high risk of bias
Tocilizumab
Single dose: 8mg/kg (maximum dose 800mg).
Placebo
COVID-19 severe or critically
Hospitalized patients with confirmed COVID-19 with acute respiratory failure, radiographic pneumonia, defined as any/ changing new lung infiltrate. Patient breathing spontaneously, required more than 50% oxygen and MEWS score > 7. If intubated, intubated less than 24 hours with PaO2/Fio2 ratio ≤ 200 andPEEP ≥ 5 cm H2O.
Open-label.
Israel
tocilizumab (n=434) vs. placebo (n=215)
randomized controlled trial some concerns about risk of bias
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 some concerns about risk of bias
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=353) vs. standard of care (n=402)
randomized controlled trial some concerns about risk of bias
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=49) vs. standard of care (n=43)
randomized controlled trial some concerns about risk of bias
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=65) vs. standard of care (n=64)
randomized controlled trial some concerns about risk of bias
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 some concerns about risk of bias
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 some concerns about risk of bias
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=26) vs. standard of care (n=23)
randomized controlled trial high risk of bias
Tocilizumab plus methylprednisolone
Single dose of intravenous tocilizumab (400mg) plus intravenous methylprednisolone 40mg twice daily for 7 days.
Methylprednisolone
Intravenous methylprednisolone 40mg twice daily for 7 days.
Patients could receive concomitant antiviral and other usual care.3 arms: tocilizumab plus methylprednisolone, methylprednisolone only, and control. Control arm consisted of historical controls (retrospective review of medical records). Thus, control arm results were not included.
COVID-19 severe or critically
Patients aged ≥18 years were deemed eligible if they were hospitalized at Rashid Hospital, Dubai, with clinically and laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection, as shown by positive results on real-time PCR (RT-PCR) of nasopharyngeal swab samples. Other eligibility criteria included the development lung infiltrates involving >50% of the lung fields, as shown on chest X-rays, within 48 h of admission; and O2 saturation <93% at rest on room air.
Open-label.
Rashid Hospital, Dubai.
tocilizumab (n=48) vs. tocilizumab (n=49)
randomized controlled trial some concerns about risk of bias
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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