meta|Evidence - COVID-19
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baricitinib (n=4148) vs. standard of care (n=4008)
randomized controlled trial some concerns about risk of bias
baricitinib 4 mg once daily
baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner
usual standard of care alone
COVID 19 all comers
open-label
tocilizumab (n=161) vs. placebo (n=81)
randomized controlled trial low risk of bias
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=136) vs. standard of care (n=134)
randomized controlled trial risk of bias NA
experimental: intervention early administration of tocilizumab associated with hydroxychloroquine and azithromycin
tocilizumab 162 mg sc x 2 doses tocilizumab 162mg sc x 2 doses at 12 hours (day 1)hydroxychloroquine 400 mg / 12h v.o. day 1 followed by 200 mg / 12h v.o. for 6 days (7 days in total)azithromycin 500 mg / day v.o. for 3 days
hydroxychloroquine and azithromycin
hydroxychloroquine 400 mg / 12h v.o. day 1 followed by 200 mg / 12h v.o. for 6 days (7 days in total)azithromycin 500 mg / day v.o. for 3 days
COVID 19 all comers
open-label
Spain
pilot, randomized, multicenter, open-label clinical trial
anakinra (n=412) vs. placebo (n=194)
randomized controlled trial low risk of bias
100 mg anakinra once daily for 10 days
placebo
COVID 19 hospitalized
double-blind
12 patients withdrew consent and requested removal of alldata
baricitinib (n=764) vs. placebo (n=761)
randomized controlled trial low risk of bias
Once-daily baricitinib (4 mg) or up to 14 days
Placebo
Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir.
COVID 19 hospitalized
laboratory-confirmed SARS-CoV-2 infection, had evidence of pneumonia or active and symptomatic COVID-19, and had at least one elevated inflammatory marker (C-reactive protein, D-dimer, lactate dehydrogenase, or ferritin. were excluded if, at study entry, they required invasive mechanical ventilation (National Institute of Allergy and Infectious Disease Ordinal Scale [NIAID-OS] score 7); were receiving immunosuppressants (high-dose corticosteroids, biologics, T-cell-targeted or B-cell-targeted therapies, interferon, or JAK inhibitors); had ever received convalescent plasma or intravenous immunoglobulin for COVID-19; or had neutropenia (absolute neutrophil count <1000 cells per μL), lymphopenia (absolute lymphocyte count <200 cells per μL), alanine aminotransferase (ALT) or aspartate aminotransferase concentration greater than five times the upper limit of normal, or an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1·73 m2
Double-blind.
101 centres across 12 countries in Asia, Europe, North America, and South America.
according graphical testing procedure used to test results in a hierarchical manner for controlling the overall family-wise type I error rate (appendix 6 p 14), the twoprimary analyses were at the top of the hierarchy. Population 1 was tested at 99% of the total alpha (0.05) and Population 2 at 1% of 0.05.
because the primary outcome was not statistically significant in the prespecified hierarchical graphical testing procedure, none of the key secondary outcomes could be considered statistically significant using this same procedure.
baricitinib (n=515) vs. placebo (n=518)
randomized controlled trial low risk of bias
baricitinib (≤14 days) and remdesivir (≤10 days)
baricitinib 4-mg daily dose (either orally [two 2-mg tablets] or through a nasogastric tube) for 14 days or until hospital discharge
remdesivir (≤10 days) (and placebo)
remdesivir intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death
COVID 19 hospitalized
double-blind
67 trial sites in 8 countries
sarilumab (n=68) vs. standard of care (n=80)
randomized controlled trial some concerns about risk of bias
Sarilumab
sarilumab (an IV dose of 400 mg of sarilumab in a 1 hour-infusion at D1).
Standard care
COVID 19 hospitalized
Patients 18 years or older hospitalised with COVID-19 in six French centres, requiring at least 3L/min of oxygen but without ventilation assistance (that included high-flow oxygen, non-invasive ventilation, or mechanical ventilation) and a WHO Clinical Progression Scale [CPS] score of 5.
Open-label.
6 hospitals in France.
Type I error may be inflated due to multiple testing. Thus, results are exploratory.
Phase 2/3.
tocilizumab (n=10) vs. placebo (n=11)
randomized controlled trial low risk of bias
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=259) vs. placebo (n=129)
randomized controlled trial some concerns about risk of bias
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=90) vs. standard of care (n=90)
randomized controlled trial some concerns about risk of bias
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=114) vs. standard of care (n=115)
randomized controlled trial low risk of bias
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=26) vs. standard of care (n=13)
randomized controlled trial low risk of bias
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=174) vs. standard of care (n=180)
randomized controlled trial low risk of bias
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=33) vs. standard of care (n=32)
randomized controlled trial some concerns about risk of bias
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=174) vs. standard of care (n=180)
randomized controlled trial some concerns about risk of bias
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=22) vs. standard of care (n=27)
randomized controlled trial low risk of bias
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=20) vs. standard of care (n=8)
randomized controlled trial low risk of bias
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=17) vs. standard of care (n=9)
randomized controlled trial low risk of bias
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 some concerns about risk of bias
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=2022) vs. standard of care (n=2094)
randomized controlled trial some concerns about risk of bias
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
tofacitinib (n=144) vs. placebo (n=145)
randomized controlled trial low risk of bias
tofacitinib at a dose of 10 mg twice daily
for up to 14 days or until hospital discharge
placebo
COVID 19 hospitalized
patients 18 years of age or older who had laboratory-confirmed SARS-CoV-2 infection as determined on RT-PCR assay before randomization, who had evidence of Covid-19 pneumonia on radiographic imaging, and who had been hospitalized for less than 72 hours.The main exclusion criteria were the use of noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) on the day of randomization, a history of thrombosis or current thrombosis, known immunosuppression, and any current cancer for which the patient was receiving active treatment.
double blind
15 sites in Brazil
anakinra (n=59) vs. control (n=57)
randomized controlled trial some concerns about risk of bias
usual care plus anakinra (200 mg twice a day on days 1–3, 100 mg twice on day 4, 100 mg once on day 5)
usual care alone
COVID-19 mild to moderate
patients with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital
open-label
16 university hospitals in France
lenzilumab (n=261) vs. placebo (n=259)
randomized controlled trial some concerns about risk of bias
Lenzilumab
Standard of care plus three intravenous doses of lenzilumab (600 mg per dose) delivered 8h apart. Infusions beginning at day 0 within 12h of randomisation.
Placebo
Standard of care plus three doses of 0.9% saline for injection delivered 8h apart.
All patients received standard supportive care, including the use of remdesivir and corticosteroids. Paracetamol 500–1000 mg orally or intravenously and diphenhydramine 12.5–25 mg intravenously or 25 mg orally (or equivalent) were administered approximately 1h before lenzilumab or placebo infusion to prevent hypersensitivity reactions.
COVID-19 mild to moderate
At least 18 years of age; experienced blood oxygen saturation (SpO2) of less than or equal to 94%; or required low-flow supplemental oxygen, or high-flow oxygen support, or non-invasive positive pressure ventilation (NIPPV); and were hospitalized but did not require IMV. Patients were excluded if they required IMV or extracorporeal membrane oxygenation (ECMO).
Double-blind.
29 sites in the US and Brazil.
For the purposes of the survival analysis for the primary endpoint, an event was defined as mortality or the requirement for IMV.
tofacitinib (n=50) vs. standard of care (n=50)
randomized controlled trial risk of bias NA
COVID-19 mild to moderate
abatacept (n=509) vs. placebo (n=513)
randomized controlled trial risk of bias NA
abatacept
placebo
in addition to the standard of care, which may include remdesivir. About 90% received remdesivir, and about 85% received dexamethasone
COVID-19 severe or critically
46 in the United States and 23 in Latin America
preliminary results in a press release
adalimumab (n=34) vs. standard of care (n=34)
randomized controlled trial some concerns about risk of bias
Adalimumab
Standard of care plus adalimumab 40mg single dose subcutaneously.
Standard of care
SoC only.
Both groups received oxygen and fluid support, remdesivir 200 mg stat followed by 100 mg intravenously daily for five to ten days, and dexamethasone 6 mg intravenously daily for ten days or up to the point of discharge.
COVID-19 severe or critically
Open-label.
Dr. Masih, Daneshvari Hospital, Tehran, Iran.
baricitinib (n=51) vs. placebo (n=50)
randomized controlled trial low risk of bias
Baricitinib
Baricitinib 4mg once daily for up to 14 days, or until discharge from hospital, in combination with standard of care.
Placebo
Matched placebo once daily for up to 14 days in combination with standard of care.
All participants received standard of care in keeping with local clinical practice for COVID-19 management, which could include concomitant medications such as corticosteroids, antivirals, and other treatments, including vasopressors.
COVID-19 severe or critically
Double-blind.
18 hospitals in Argentina, Brazil, Mexico, and the USA.
As the cohort reported here was an addition to the parent trial study design, all endpointsare considered exploratory.
Exploratory trial which followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial.
canakinumab (n=227) vs. placebo (n=227)
randomized controlled trial some concerns about risk of bias
Canakinumab
Single dose of canakinumab (450mg for body weight of 40-<60 kg, 600mg for 60-80 kg, and 750 mg for >80 kg) in 250 mL of 5% dextrose infused intravenously over 2 hours.
Placebo
250 mL of 5% dextrose infused intravenously over 2 hours.
Use of glucocorticoids, convalescent serum or plasma, antivirals, and anticoagulants was permitted during the trial.
COVID-19 severe or critically
Diagnosis of infection with SARSCoV-2 within 7 days prior to randomization, diagnosis of pneumonia with pulmonary infiltrates on chest x-ray or computedtomographic scan within 5 days prior to randomization, peripheral capillary oxygen saturation of 93%or less on room air or arterial oxygen partial pressure/fraction of inspired oxygen less than 300mmHg, and blood levels of CRP of 20mg/L or greater or ferritin of 600 μg/L or greater.
Double-blind.
39 hospitals in Europe and the United States.
cenicriviroc (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
cenicriviroc
placebo
in addition to the standard of care, which may include remdesivir. About 90% received remdesivir, and about 85% received dexamethasone
COVID-19 severe or critically
46 in the United States and 23 in Latin America
preliminary results in a press release
infliximab (n=518) vs. placebo (n=519)
randomized controlled trial risk of bias NA
infliximab
placebo
in addition to the standard of care, which may include remdesivir. About 90% received remdesivir, and about 85% received dexamethasone
COVID-19 severe or critically
preliminary results in a press release
itolizumab (n=22) vs. standard of care (n=10)
randomized controlled trial high risk of bias
itolizumab
standard care
COVID-19 severe or critically
open-label
ruxolitinib (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
ruxolitinib 5mg and 15mg plus standard of care
placebo plus standard of care
COVID-19 severe or critically
double-blind
very preliminary results from a press release. Trial did not meet its primary endpoint due to lack of statistically significant differences for each of the both doses (given that an overall type 1 error risk is needed)
ruxolitinib (n=21) vs. vitamin C (n=21)
randomized controlled trial some concerns about risk of bias
Ruxolitinib
Oral intake of ruxolitinib 5mg twice a day plus standard-of-care.
Vitamin C
100 mg vitamin C twice a day with SoC treatment.
Standard of care in both groups. The SoC treatment included antiviral therapy, supplemental oxygen, noninvasive and invasive ventilation, corticosteroid, antibiotic agents,vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation.
COVID-19 severe or critically
(1) met the diagnostic criteria for COVID-19; (2) 18 years or older and younger than 75 years; (3) severe cases. patients in need of invasive mechanic ventilation at recruitment were ecluded.
Single-blind.
Multicenter, 3 hospitals in China.
Phase II.
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.
TD-0903 10mg (n=6) vs. placebo (n=6)
randomized controlled trial some concerns about risk of bias
TD-0903 10mg
Once-daily inhalation of TD-0903 10 mg (no loading dose) for up to 7 days.
Placebo
Matched placebo via inhalation for up to 7 days.
Phase IIa 4 arms: 3 different doses of TD-0903 (1mg, 3mg, 10mg) and placebo.
COVID-19 severe or critically
Patients 18 to 80 years of age with PCR confirmed, symptomatic COVID-19 (symptoms for 3–14 days) who were hospitalized and required supplemental oxygen to maintain saturation >90%.
Double-blind.
Multicenter: UK, Moldova, Ukraine.
Key safety outcomes were change from baseline in vital signs and clinical laboratory results, and incidence and severity of treatment-emergent AEs; key pharmacokinetic (PK) endpoints were plasma PK parameters on Days 1 and 7, and the key pharmacodynamic outcome was change from baseline SaO2/FiO2 ratio. Other clinical outcomes were considered exploratory.
Phase IIa (ascending-dose study).
TD-0903 1mg (n=6) vs. placebo (n=6)
randomized controlled trial some concerns about risk of bias
TD-0903 1mg
Once-daily inhalation of TD-0903 1 mg (Day 1 loading dose 2mg) for up to 7 days
Placebo
Matched placebo via inhalation for up to 7 days.
Phase IIa 4 arms: 3 different doses of TD-0903 (1mg, 3mg, 10mg) and placebo.
COVID-19 severe or critically
Patients 18 to 80 years of age with PCR confirmed, symptomatic COVID-19 (symptoms for 3–14 days) who were hospitalized and required supplemental oxygen to maintain saturation >90%.
Double-blind.
Multicenter: UK, Moldova, Ukraine.
Key safety outcomes were change frombaseline in vital signs and clinical laboratory results, and incidence and severity of treatment-emergent AEs; key pharmacokinetic (PK) endpoints were plasma PK parameters on Days 1 and 7, and the key pharmacodynamic outcome was change from baseline SaO2/FiO2 ratio. Other clinical outcomes were considered exploratory.
Phase IIa (ascending-dose study).
TD-0903 3mg (n=7) vs. placebo (n=6)
randomized controlled trial some concerns about risk of bias
TD-0903 3mg
Once-daily inhalation of TD-0903 3mg (Day 1 loading dose 6mg) for up to 7 days.
Placebo
Matched placebo via inhalation for up to 7 days.
Phase IIa 4 arms: 3 different doses of TD-0903 (1mg, 3mg, 10mg) and placebo.
COVID-19 severe or critically
Patients 18 to 80 years of age with PCR confirmed, symptomatic COVID-19 (symptoms for 3–14 days) who were hospitalized and required supplemental oxygen to maintain saturation >90%.
Double-blind.
Multicenter: UK, Moldova, Ukraine.
Key safety outcomes were change from baseline in vital signs and clinical laboratory results, and incidence and severity of treatment-emergent AEs; key pharmacokinetic (PK) endpoints were plasma PK parameters on Days 1 and 7, and the key pharmacodynamic outcome was change from baseline SaO2/FiO2 ratio. Other clinical outcomes were considered exploratory.
Phase IIa (ascending-dose study).
thalidomide (n=30) vs. standard of care (n=30)
randomized controlled trial high risk of bias
Thalidomide
Thalidomide tablets 100 mg daily for 14 days added to the usual treatment
Usual care
Patients in both groups received methylprednisolone 50 mg intravenously every 12 hours for 3 days andthen daily for 7 days, hydroxychloroquine 200 mg orally every 12 hours for 5 days. Antibiotics were administered based on physician choice (Ceftriaxone, Azithromycin, and Vancomycin). All patients received enoxaparin 40 mg subcutaneously daily during hospitalization.
COVID-19 severe or critically
1- 18-75 year old men and 50-75 year old women admitted in hospital 2-Spo2 less than 85% in admission 3-Clinical symptoms and signs compatible with COVID19 infection and positive PCR test or lung HRCT abnormalities compatible with COVID19 pneumonia 4-No need to intubation in first 24 hour of admission 5-No multiorgan failure at presentation 6- No shock state at presentation 7- Obtained informed consent Exclusion criteria: 1. Hepatic failure (Child Pugh score ≥ C, AST> 5 times of the upper limit normal) 2. Severe renal dysfunction (GFR less than 30cc per min)
Open-label.
Single center, Khorshid hopsital, Isfahan, Iran.
All patients were visited daily by an Internist or Pulmonologist and were followed weekly for 4 weeks using phone calls.
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=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=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=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=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=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=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=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=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=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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