meta|Evidence - COVID-19
click on circles to display study description...
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
convalescent plasma treatment (n=4) vs. standard of care (n=8)
randomized controlled trial low risk of bias
Convalescent plasma
Standard of care
COVID 19 all comers
Open-label.
Italy.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
leflunomide (n=26) vs. interferon (n=24)
randomized controlled trial some concerns about risk of bias
Leflunomide
leflunomide (50 mgevery 12 hours, 3 consecutive times, orally; then 20 mg onc edaily for 8 days; a total course of 10 days) plus nebulized interferon alpha 2a (IFN-α-2a; 3 million IU each time, adding2 mL of sterilized water, atomization inhalation twice daily for10 days)
Interferon alpha 2a
IFN-α-2a, 3 million IU each time, twice daily for 10 days.
COVID 19 all comers
(1) age 18–70 years with a diagnosis of COVID-19 conforming to Chinese guidelines (2) hospitalized for prolonged postsymptomatic viral shedding; (3) able to orally take medication; (4) if female, not pregnant; and (5) effective contraception for 7 days after taking the last medication.
Open-label.
Single center, Renmin Hospital of Wuhan University, Wuhan, China.
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
acalabrutinib (n=70) vs. standard of care (n=70)
randomized controlled trial risk of bias NA
acalabrutinib
standard of care
COVID 19 hospitalized
open label
1 center, Argentina
acalabrutinib (n=31) vs. standard of care (n=31)
randomized controlled trial risk of bias NA
acalabrutinib
standard of care
COVID 19 hospitalized
open label
multicenters, USA
amubarvimab/romlusevimab (BRII-196 and BRII-198-Brii Biosciences) (n=179) vs. placebo (n=183)
randomized controlled trial low risk of bias
BRII-196 plus BRII-198
Placebo
Randomisation allocation was 2:1:2:1 to sotrovimab, matching placebo for sotrovimab, BRII-196 plus BRII-198, or matching placebo for BRII-196 plus BRII-198. The concurrent placebo groups were pooled for analyses, resulting in approximately a 1:1:1 allocation ofsotrovimab to BRII-196 plus BRII-198 to placebo. All patients received remdesivir. Other treatments for COVID-19, including oxygen, respiratory support, and corticosteroids, were administered at the discretion of the treating clinician per local standard of care.
COVID 19 hospitalized
Double-blind.
43 hospitals in the USA, Denmark, Switzerland, and Poland.
Prematurely discontinued for futility (based on pulmonary and pulmonary-plus ordinal outcome scale at day 5) after enrollment of 300 patients. *Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.*
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
bamlanivimab monotherapy (n=163) vs. placebo (n=151)
randomized controlled trial low risk of bias
LY-CoV555
LY-CoV555 at a dose of 7000 mg as a single intravenous infusion over a 1-hour period
placebo
supportive care as background therapy, including the antiviral drug remdesivir and,when indicated, supplemental oxygen and glucocorticoids
COVID 19 hospitalized
double-blind
31 sites in US, Denmark, Singapore
Study stopped for futility (seven-category ordinal scale on day 5). As of April 2021, regulatory authorities recommend that bamlanivumab no longer be used because of the potential risk of treatment failure due to the circulation of resistant variants of SARS-CoV-2.
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
casirivimab/imdevimab (Ronapreve) (n=4839) vs. standard of care (n=4946)
randomized controlled trial some concerns about risk of bias
REGEN-COV
Usual care plus single dose of REGEN-COV 8g (casirivimab 4g and imdevimab 4g) in 250ml 0.9% saline infused intravenously over 60 minutes as soon as possible after randomisation.
Usual care
Usual care alone
As a platform trial, and in a factorial design, patients could be simultaneously randomised to other treatment groups: i) azithromycin versus usual care, ii) colchicine versus usual care, iii) aspirin versus usual care, and iv) baricitinib versus usual care. Until 24 January 2021, the trial also allowed a subsequent randomisation for patients with progressive COVID-19 to tocilizumab versus usual care.
COVID 19 hospitalized
Pregnant or breastfeeding women were eligible for inclusion. For some patients, REGEN-COV was unavailable at the hospital at the time of enrolment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from the randomised comparison between REGEN-COV and usual care.
Open-label.
123 UK hospitals.
Prior to any unblinding of results, the trial steering committee specified that hypothesis-testing of the effect of allocation to REGEN-COV on 28-day mortality (and secondary outcomes) would first be done only in seronegative participants. All decisions about this modification to the analytical plan were made before recruitment was complete and before any members of the trial steering committee (who are responsible for drafting and approving the SAP) or investigators had access to any unblinded analyses of clinical outcome data for the REGN-COV2 comparison. No members of the independent Data Monitoring Committee (who are the only individuals who can review interim unblinded analyses) were involved in this change.
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.* 9785 patients including 3153 seronegative patients, 5272 seropositive patients, and 1360 patients with unknown baseline antibody status. Baseline presence of anti-SARS-CoV-2 antibodies was to be determined for each participant using serum samples taken at the time of randomisation.
cilgavimab and tixagevimab (Evusheld) (n=710) vs. placebo (n=707)
randomized controlled trial some concerns about risk of bias
intravenous tixagevimab 300 mg/cilgavimab 300 mg
placebo
in addition to remdesivir and other standard care
COVID 19 hospitalized
double-blind
81 sites on four continents
efficacy and safety analyses were performed in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab/cilgavimab or placebo
colchicine (n=19) vs. placebo (n=19)
randomized controlled trial high risk of bias
Colchicine
0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The first dose was 1.0 mg whether body weight was ≥ 80 kg.
Placebo
All participants received the institutional treatment for COVID-19 with azithromycin 500 mg once daily for up to 7 days, hydroxychloroquine 400 mg twice daily for 2 days, then 400 mg once daily for up to 8 days and unfractionated heparin 5000 UI thrice daily until the end of hospitalization. Methylprednisolone 0.5 mg/kg/day for 5 days could be added if the need for supplemental oxygen was 6 L/min or more.
COVID 19 hospitalized
Individuals hospitalized with moderate or severe forms of COVID-19 diagnosed by RT-PCR in nasopharyngeal swab specimens and lung computed tomography scan involvement compatible with COVID-19 pneumonia; older than 18 years; body weight > 50 kg; normal levels of serum Ca2 and K ; QT interval < 450 ms at 12 derivations electrocardiogram (according to the Bazett formula) and negative serum or urinary β-HCG if woman under 50. Patients with mild form of COVID-19 or in need for ICU admission were excluded.
Double-blind.
Single-center, Brazil.
Interim analysis. Neither protocol nor statistical plan available.
colchicine (n=50) vs. placebo (n=50)
randomized controlled trial some concerns about risk of bias
Colchicine
1 mg tablet of colchicine daily alongside the Hydroxychloroquine for 6 days.
Placebo
Similar tablet without therapeutic effects alongside the Hydroxychloroquine for 6 days.
HCQ in both groups.
COVID 19 hospitalized
Unclear
Single center, Imam Reza hospital in Ardabil city, Iran.
Blindness unclear: Prospective, open-label, randomized and double blind clinical trial. The participants of the placebo group were received a similar tablet without therapeutic effects.
None of the patients died or were readmitted.
colchicine (n=640) vs. standard of care (n=639)
randomized controlled trial some concerns about risk of bias
Colchicine
Usual care plus colchicine administered orally in a loading dose of 1.5mg immediately after randomization, followed by 0.5mg orally within 2 hours of the initial dose and 0.5mg orally twice a day for 14 days or discharge, whichever occurred first.
Usual care
local standard of care for COVID-19 SARS moderate /high-risk patients
COVID 19 hospitalized
Consented adults (age ≥18 years)COVID-19 suspicious andadmitted to hospital or already in hospital and fever (with or without at the time of randomization) andSARS (severe acute respiratory syndrome)-shortness of breath (dyspnea) or-image of typical or atypical pneumonia or-oxygen desaturation (spO2 ≤ 93)
Open-label.
42 centers in Argentina.
The original trial protocol included in-hospital mortality as the primary outcome and the composite of a new requirement for mechanical ventilation or death as a key secondaryoutcome. Due to low recruitment rate and low likelihood of reaching the original estimated sample size of 2500 patients, the executive committee decided to change the primary outcome in November 2020 prior to knowing the results to include 2 coprimary hierarchical outcomes with the aim of reducing the trial sample size and potentially getting an earlier result.
colchicine (n=55) vs. standard of care (n=50)
randomized controlled trial some concerns about risk of bias
Colchicine
1.5-mg loading dose followed by 0.5 mg after 60 min (in the case of azithromycin coadministration, a single 1.0-mg loading dose of colchicine was administered) and maintenance doses of 0.5 mg twice daily for as long as 3 weeks. Surveillance of gastrointestinal effects after the loading dose.
Standard treatment
Local protocols
Standard of care in both groups.
COVID 19 hospitalized
Patients >18 years old with laboratory confirmed SARS-CoV-2 infection (RT PCR) AND body temperature >37.5 degrees centigrade AND at least two of: i. sustained coughing, ii. sustained throat pain, iii. anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg, were considered eligible.Patients with clinical assessment indicating that ventilatory support would be inevitable in the following 24 hours because of rapidly declining respiratory status were excluded.
Open-label.
16 tertiary care hospitals in Greece.
Study end point analysis was planned to be performed in 2 phases, an early biochemical phase and a later clinical phase. The 7-grade ordinal scale consisted of the following levels: 1, ambulatory, normal activities; 2, ambulatory but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring extracorporeal membrane oxygenation, invasive mechanical ventilation, or both; and 7, death.
primary endpoints of low clinical relevence
colchicine (n=5610) vs. standard of care (n=5730)
randomized controlled trial some concerns about risk of bias
Colchicine
Usual care plus colchicine 1 mg after randomisation followed by 500 µg 12 h later and then 500 µg twice a day by mouth or nasogastric tube for 10 days in total or until discharge.
Usual care
94% of patients were being treated with a corticosteroid. As a platform trial, and in a factorial design, patients could be simultaneously randomly assigned to other treatment groups: 1) convalescent plasma versus casirivimab and imdevimab versus usual care, 2) aspirin versus usual care, and 3) baricitinib versus usual care. Until Jan 24, 2021, the trial also allowed a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia and a hyperinflammatory state) to receive usual care plus tocilizumab or usual care alone.
COVID 19 hospitalized
Patients admitted to hospital were eligible for the study if they had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Children and pregnant women were not eligible to receive colchicine.
Open-label.
177 hospitals in the UK, 2 hospitals in Indonesia, 2 hospitals in Nepal.
colchicine (n=5610) vs. standard of care (n=5730)
randomized controlled trial some concerns about risk of bias
colchicine twice daily for 10 days or until discharge plus usual standard of care
usual standard of care alone
COVID 19 hospitalized
open-label
UK
Colchicine plus rosuvastatin (n=161) vs. standard of care (n=162)
randomized controlled trial some concerns about risk of bias
Colchicine plus rosuvastatin
Standard of care
The standard of care follows the recommendations of the Colombian Consensus forCovid-19 Treatment in Hospitalized Patients,21 consisting of the use of dexamethasone,antiparasitic treatment (ivermectin or albendazole), enoxaparin, acetaminophen, oxygen asneeded, and supportive treatment for organ failure (i.e., use mechanical ventilation, ordialysis).
COVID 19 hospitalized
Adults aged 18 years or more, with a positive real-time polymerase chain reaction (RT-PCR) or with high suspicion of SARS CoV-2 by clinical criteria and a diagnosis of mild, severe, or critical pneumonia, requiring hospital management in six high complexity referral hospitals located in Bogota.
Open-label.
6 hospitals in Bogota, Colombia.
Relative Risks adjusted for age, sex, and severity of pneumonia using g Log-binomial General Estimating Equation models, assuming exchangeable correlation structure with each center as a cluster.
convalescent plasma treatment (n=468) vs. placebo (n=473)
randomized controlled trial some concerns about risk of bias
COVID-19 convalescent plasma (CCP)
A unit of approximately 250 mL of CCP infused within 24 hours of randomization at a rate of less than or equal to 500 mL/h.
Placebo
Equivalent volume of placebo (normal saline).
COVID 19 hospitalized
Eligible patients were adults aged 18 years or older hospitalized for 3 days or less or with symptoms of respiratory illness for 7 days or less (to include patients with presumably early phases of disease) who required noninvasive oxygen supplementation and had a positive nasopharyngeal SARS-CoV-2 reverse-transcriptase polymerase-chain-reaction test. Patients on mechanical ventilation or ECMO and patients who received a COVID-19 vaccine were excluded.
Double-blind.
21 US Hospitals at 7 centers.
WHO scale scores range from 0 to 10, with 0 indicating uninfected and no viral RNA detected and 10 indicating dead. Primary and secondary outcomes were analyzed with a bayesian proportional cumulative odds model with adjustment for the following prespecified covariates: age, sex, prerandomization WHO score, symptom duration, and the stratification variables: risk status (high vs average) and study site. CCP efficacy was defined as a cOR less than 1 and clinically meaningful effects were defined as cORs less than 0.8.
There were no prespecified stopping criteria for futility. However, after reviewing data on 920 participants on March 12, 2021, the DSMB recommended ceasing enrollment on March 15, 2021, based on slowing recruitment, the need for rapid reporting, and a 0.2% probability that the study would meet criteria for success if enrollment continued to 1000 participants.
convalescent plasma treatment (n=32) vs. placebo (n=11)
randomized controlled trial high risk of bias
Convalescent plasma
300 mL/day intravenously, on day one and day three
Placebo
Hartmann plus albumin
COVID 19 hospitalized
Double-blind.
1 center, Mexico
convalescent plasma treatment (n=8) vs. placebo (n=6)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Double-blind.
United States.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=59) vs. placebo (n=15)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
Single “dose” of 2 U of convalescent plasma (total volume approximately 480 mL). Each unit of plasma (approximately 240 mL) was administered over1–4 hours, using standard hospital procedures.
Standard plasma
Single “dose” of 2 U of standard plasma (total volume approximately 480 mL). Each unit of plasma (approximately 240 mL) was administered over1–4 hours, using standard hospital procedures.
4:1 ratio.
COVID 19 hospitalized
Inclusion criteria were adult patients hospitalized with a confirmed diagnosis of COVID-19 infection from SARS-CoV-2 RT-PCR testing. The patient (or Legally Authorized Representative) needed to be willing and able to provide written informed consent.
Double-blind.
Single center: hospital in New York, United States.
Subjects never requiring intubation were assigned a time of 28 days and those who died by day 28 were assigned 0 ventilator-free days.
Enrollment in the trial was stopped on August 24,2020, after FDA granted EUA for CP since it seemed unlikely that patients would wish to participate in a randomized trial for an “approved therapy.”
convalescent plasma treatment (n=11) vs. placebo (n=11)
randomized controlled trial risk of bias NA
placebo
normal saline
COVID 19 hospitalized
Double-blind.
Nigeria.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=98) vs. placebo (n=46)
randomized controlled trial low risk of bias
Convalescent plasma
Placebo
Normal saline
COVID 19 hospitalized
Double-blind.
Denmark.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.Study stopped for high probability of futility
convalescent plasma treatment (n=63) vs. placebo (n=95)
randomized controlled trial some concerns about risk of bias
convalescent plasma
5 mL/kg
placebo
non convalescent plasma
COVID 19 hospitalized
double-blind
3 centers, Ecuador
Study stopped after the second interim analysis due to futility
convalescent plasma treatment (n=43) vs. standard of care (n=43)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
300ml of convalescent plasma (with anti-SARSCoV-2 neutralizing antibody titers of at least 1:80) administered intravenously on the day of inclusion, plus standard of care. Patients without a clinical response and a persistently positive RT-PCR could receive a second plasma unit after five days.
Standard care
Off-label use of EMA-approved drugs (e.g. chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, anakinra) as a treatment for COVID-19 was allowed in hospitals were this was part of the standard of care.
All patients received standard of care.
COVID 19 hospitalized
Patients >= 18, admitted to a study site for COVID-19 and had clinical COVID-19 disease proven by a positive SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) test in the previous 96 hours.
Open-label.
14 secondary and academic hospitals in the Netherlands.
the trial was halted prematurely
convalescent plasma treatment (n=179) vs. standard of care (n=171)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
One dose (250-300 mL) of CP from donors with IgG anti-SARS-CoV-2 (ratio ≥1.1 with the Euroimmun ELISA test; Euroimmun,Lübeck, Germany)
Standard of care
Standard of care only ( including all supportive and specific treatments with off-label marketed medicines used according to local or national recommendations).
All patients in both groups received standard of care.
COVID 19 hospitalized
Patients hospitalized for laboratory-confirmed SARS-CoV-2 infection (RT-PCR) with either radiographic evidence of pulmonary infiltrates or clinical evidence plus SpO2 ≤94% on room air, and within 12 days from the onset of symptoms (fever or cough).
Open-label.
27 hospitals in Spain.
The patient’s clinical status was recorded using the seven-category ordinal COVID-19 scale: 1, not hospitalized, no limitations on activities; 2, not hospitalized, limitation on activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, on non-invasive ventilation or high flow oxygen devices; 6, hospitalized,on invasive mechanical ventilation or ECMO and 7, death.
The trial was temporarily stopped on July 10, 2020, after the first interim analysis, due to a drastic fall in recruitment (end of first wave in Spain), although prespecified futility or efficacy stop criteria had not been reached. The trial recruitment was resumed shortly after, with the surge of the second wave, and the trial was finally completed as planned.
convalescent plasma treatment (n=20) vs. standard of care (n=11)
randomized controlled trial some concerns about risk of bias
COVID 19 hospitalized
Double-blind.
Mexico.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=38) vs. standard of care (n=36)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Spain.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=41) vs. standard of care (n=39)
randomized controlled trial some concerns about risk of bias
convalescent plasma SOC
2 units of local convalescent plasma
soc
COVID 19 hospitalized
open- label
2 centers, USA
convalescent plasma treatment (n=60) vs. standard of care (n=60)
randomized controlled trial risk of bias NA
standard of care
COVID 19 hospitalized
Double-blind.
Italy.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=625) vs. standard of care (n=313)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
One or two units of apheresis plasma amounting to approximately 500 mL from one or two donors.
Standard of care
Usual medical care as per routine practices at each site.
COVID 19 hospitalized
Inclusion: 1. ≥16 years of age (≥18 years of age in the United States, Brazil, and Israel) 2. Admitted to hospital for confirmed COVID-19 respiratory illness3. Receiving supplemental oxygen4. 500 mL of ABO compatible CCP is available. Exclusion: 1. Onset of signs or symptoms of COVID-19 respiratory illness >12 days prior to randomization (eg. cough, chest pain,dyspnea, or hypoxia)2. Intubated or plan in place for intubation3. Plasma is contraindicated (e.g. history of anaphylaxis from transfusion)4. Decision in place for no active treatment.
Open-label.
72 hospital sites in Canada, US, and Brazil.
Trial was prematurely stopped at planned interim analysis for futility (see. concor1.ca web site)
convalescent plasma treatment (n=320) vs. standard of care (n=163)
randomized controlled trial some concerns about risk of bias
convalescent plasma
2 units of convalescent plasma (∼200–250 mL) were administered within 12 h after randomisation, with a second administration of 2 units24–36 h after the first administration
standard of care
COVID 19 hospitalized
open label
25 centers, Belgian
Phase 2
convalescent plasma treatment (n=20) vs. standard of care (n=10)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
United States.
Study not published yet. Results were extracetd from clinicaltrial sheets and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=200) vs. standard of care (n=200)
randomized controlled trial some concerns about risk of bias
Convalescent Plasma
Dose-250 ml Frequency - 2 doses on consecutive days Duration
Standard of care
COVID 19 hospitalized
open-labelled
2 centers, India
convalescent plasma treatment (n=40) vs. standard of care (n=20)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Bangladesh.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=15) vs. standard of care (n=18)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Australia and New Zealand.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=5795) vs. standard of care (n=5763)
randomized controlled trial some concerns about risk of bias
High titre convalescent plasma
plus usual care
Usual care
3 arms: usual care, usual care plus convalescent plasma or usual care plus REGN-COV2
COVID 19 hospitalized
clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put them at significant risk if they were to participate in the trial
Open-label.
177 National Health Service in UK.
very preliminary results. Preliminary analysis based on 10,406 randomised patients with 1873 reported deaths
convalescent plasma treatment (n=150) vs. standard of care (n=151)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=12) vs. standard of care (n=13)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Peru.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=15) vs. standard of care (n=15)
randomized controlled trial some concerns about risk of bias
Recovered COVID-19 plasma
Single dose of plasma of recovered COVID-19 individuals, 250 ml, plus standard COVID-19 therapy.
Standard of care
Available standard therapy included: supplemental oxygen, noninvasive and invasive ventilation, antibiotic medication, inotrope drugs, renal-replacement therapy, anticoagulants, glucocorticoids, intravenous fluids, interferon, and extracorporeal membrane oxygenation (ECMO).
COVID 19 hospitalized
Hospitalized patients ≥18 years, with confirmed positive nasopharyngeal/oropharyngeal covid-19 swab, and have two or more of a fourcategory illness-severity scale: 1. Respiratory frequency ≥24/min. 2. Blood oxygen saturation ≤ 93% on room air, 3. Partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300 mmHg, 4. Pulmonary infiltrates occupying more than 50% of both lungs. Any patient with prior allergic history to plasma or plasma products or septic shock or multiple organ failure was excluded from the study.
Open-label.
Single center, Qena University Hospital, Egypt.
50% Improvement of severity of illness was defined as achieving a minimum of two-point reduction on the four-category illnessseverity scale: Respiratory frequency ≥ 24/min; blood oxygen saturation ≤ 93% on room air; partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300 mmHg; pulmonary infiltrates occupying more than 50% of both lungs, during 5 days study period.
convalescent plasma treatment (n=67) vs. standard of care (n=69)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
Standard of care plus convalescent plasma administered over look 2-3 hours at a rate of 1.4-2mL/min and a second aliquot transfused at the same rate 3 hours after completion of the first one.
Standard of care
The SOC was according to the Uganda COVID-19 case management guidelines.
COVID 19 hospitalized
Open-label.
Single center: MNRH in Kampala, Uganda.
convalescent plasma treatment (n=13) vs. standard of care (n=12)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Philippines.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.May 24, 2022 terminated : unable to achieve target sample size
convalescent plasma treatment (n=9) vs. standard of care (n=8)
randomized controlled trial low risk of bias
COVID 19 hospitalized
Open-label.
Brazil.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=17) vs. standard of care (n=14)
randomized controlled trial some concerns about risk of bias
Convalescent plasma (CCP)
Standard of care plus 200–250 mL of CCP administered intravenously during 30 min on three consecutive days.
Standard of care
COVID 19 hospitalized
Patients admitted to the hospital with a nasopharyngeal swab positive for SARS-CoV-2 in RT-PCR no later than 4 days prior to inclusion and a need for supplemental oxygen treatment to keep peripheral oxygen saturation >93%.
Open-label.
Skåne University Hospital in Lund and Helsingborg Hospital, Sweden.
Unplanned interim analysis.
The study was prematurely terminated after an interim analysis that was carried out due to increasing evidence that this treatment modality was ineffective (thirty-one of 100 intended patients had been included).
convalescent plasma treatment (n=241) vs. standard of care (n=246)
randomized controlled trial some concerns about risk of bias
convalescent plasma
200 mL from 1 to a maximum of 3 infusions
SOC
COVID 19 hospitalized
open-label
27 centers, Italy
corticosteroids (n=35) vs. standard of care (n=29)
randomized controlled trial high risk of bias
Methylprednisolone
Intravenous methylprednisolone 40 mg every 12 hours for 3 days and then 20 mg every 12 hours for 3 days, plus standard of care.
Standard of care
Patients in both study groups received standard of care (SOC) therapy according to the local protocols. SOC included symptomatic treatment with acetaminophen, oxygen therapy, thrombosis prophylaxis with low molecular weight heparin, and antibiotics for co-infections. Azythromycin, hydroxychloroquine and lopinavir plus ritonavir were frequently prescribed. Azithromycin, hydroxychloroquine, and lopinavir plus ritonavir were frequently prescribed. In two patients in the SOC group but none in the MP group, clinicians prescribed MP boluses after initial allocation because of deterioration of the patient’s condition. One patient in SOC group received MP boluses before clinical deterioration.
COVID 19 hospitalized
Patients admitted to hospital with Covid-19, confirmed by microbiological tests or compatible clinical manifestations, with exclusion of other infections, Age: 18-85 years old, Time of evolution: more than 7 days since the beginning of symptoms, Evidence of inflammation, defined by: Lung infiltrates plus Gas exchange disturbance: PaO2 < 65 or Sat<93% (breathing air), or PAFI <300, or SAFI <440, or BCRSS ≥2 plus Elevated biomarkers: PCR >15, or DD>800, or Ferritin >1000, or IL6>20, Absence of bacterial infection or other disease that explains the lung disorder, Verbal informed consent, which will be recorded in history. Patients mechanically ventilated and/or hospitalized in the intensive care unit (ICU) were excluded.
Open-label.
Multicenter; 5 hospitals in Spain.
Partially randomized.
The study was interrupted in July 2020 after the publication of the RECOVERY trial. Results are from an interim analysis which was planned a priori after inclusion of 90 patients (supplementary material).
dexamethasone (n=2104) vs. standard of care (n=4321)
randomized controlled trial some concerns about risk of bias
Dexamethasone
Oral or intravenous dexamethasone at a dose of 6 mg once daily for up to 10 days (or until hospital discharge if sooner) plus standard of care.
Standard of care
Standard of care alone.
COVID 19 hospitalized
Hospitalized patients were eligible for the trial if they had clinically suspected or laboratoryconfirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attendingclinician, put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible.
Open-label.
175 NHS hospitals in UK
preliminary results
Early convalescent plasma. (n=28) vs. Deferred Convalescent plasma (n=30)
randomized controlled trial low risk of bias
Early plasma transfusion.
First plasma unit on the day of enrollment or 24h later.
Deferred plasma transfusion.
Only if a pre-specified worsening respiratory function criterion was met during hospitalization (Pa02/Fi02 <200) or if the patient still required hospitalization for symptomatic COVID-19 >7 days after enrollment.
Transfusions considered a total of 400 mL of ABO compatible convalescent plasma, infused as two 200 mL units, each separated by 24 hours. In both groups, cointerventions, including antibiotics, antivirals, heparin thromboprophylaxis, and immunomodulators, were allowed based on the hospital protocols. A total of 13 participants (43.3%) from the deferred plasma group received plasma
COVID 19 hospitalized
Patients over 18 years old, hospitalized, with COVID-19 symptoms present at enrollment and confirmed with a positive SARS-CoV-2 realtime PCR in nasopharyngeal swab, or pending PCR result and with imaging consistent with COVID-19 pneumonia and confirmed COVID-19 close contact, =< 7 days from COVID-19 symptom onset to enrollment, a CALL score >= 9 points at enrollment (predicts high risk of progression into respiratory failure, based on age, comorbidities, lactate dehydrogenase [LDH], and lymphocyte count); and Eastern Cooperative Oncology Group (ECOG) performance status before SARS-CoV-2 infection 0–2. Patients with PaO2/FiO2<200 or on mechanical ventilation at enrollment were excluded.
Open-label.
Single-center, Chilean medical center in Santiago, Chile.
Phase II.
Phase II.
high-dose IFN beta-1a (n=83) vs. IFN beta-1a (n=85)
randomized controlled trial some concerns about risk of bias
High-dose IFN-β 1a
IFN-β 1a (Recigen) subcutaneous injections of 88μg (24,000 IU) on days 1, 3, 6 plus lopinavir/ritonavir (Kaletra) 400mg/100 mg twice a day for 10 days, orally.
Low-dose IFN-β 1a
IFN-β 1a (Recigen) subcutaneous injections of 44μg (12,000 IU) on days 1, 3, 6 lopinavir/ritonavir (Kaletra) 400mg/100 mg twice a day for 10 days, orally.
Intervention and control groups received standards ofcare including necessary oxygen support and non-invasive or invasive mechanical ventilation.
COVID 19 hospitalized
Age >=18 years, oxygen saturation (SPO2) =< 93% or respiratory rate>= 24,presence of at least one of following manifestations on admission: Cough, shortness of breath,nasal congestion/ discharge, myalgia/arthralgia, radiation contactless body temperature >=37.8,diarrhea/vomiting and headache or fatigue. The patients’ symptoms must be in acute phase (=< 14 days).
Open-label
Single center, Loghman Hakim hospital.
The utilized seven-step ordinal scale consists of the subsequent categories: (I) Not hospitalized, and has no activity limitations; (II) Not hospitalized, but has activity limitations; (III) Hospitalized, but does not need any supplemental oxygen; (IV) Hospitalized, and needs supplemental oxygen; (V) Hospitalized, and needs either High-Flow Nasal Cannula (HFNC) or non-invasive ventilation;(VI) Hospitalized, and needs invasive ventilation; and (VII) Dead.
IFN beta-1a (n=2063) vs. control (n=2064)
randomized controlled trial some concerns about risk of bias
Interferon-ß1a
Interferon (mainly subcutaneous): Three doses over six days of 44µg subcutaneous Interferon-ß1a; where intravenous interferon was available, patients on high-flow oxygen, ventilators or ECMO were instead to be given 10µg intravenously once daily for six days
Control
Lopinavir or local standard of care
Five arms: hydroxychloroquine, interferon, remdesivir, lopinavir, or standard of care only. All patients were to receive the local standard of care.
COVID 19 hospitalized
Consenting adults (age ≥18) hospitalised with definite COVID-19, not already receiving any of the study drugs, without known allergy or contra-indications to any of them (in the view of the physician responsible for their care), and without anticipated transfer within 72 hours to a non-study hospital.
Open label.
Multicenter, 405 hospitals in 30 countries in all six WHO regions.
2,063 patients in the study group = 651 patients treated with Interferon plus Lopinavir and 1,412 patients treated with Interferon only. 2,064 control patients = 679 Lopinavir and 1,385 Local SoC.
IFN gamma (n=41) vs. standard of care (n=38)
randomized controlled trial high risk of bias
IFN alpha-2b plus IFN gamma (HeberFERON)
Subcutaneous treatment with a co-lyophilized combination of 3.0 MIU IFN-α2b and 0.5 MIU IFN-γ (HeberFERON, CIGB, Havana, Cuba), twice a week for two weeks,
IFN alpha-2b alone (Heberon)
Intramuscular injection of 3.0 MIU IFN-α2b (Heberon® Alpha R, CIGB, Havana, Cuba), thrice a week.
Additionally, all patients received lopinavir-ritonavir 200/50 mg every 12 h and chloroquine 250 mg every 12 h (standard of care).
COVID 19 hospitalized
Adult (≥19 years-old) patients with RT-PCR confirmed SARS-CoV-2, ECOG functional status ≥ 2 (Karnofsky ≥ 70%), and voluntariness by signing the informed consent.
Open-label
Single center, Military Central Hospital “Luis Diaz Soto”, Havana, Cuba.
Phase 2.
immunoglobulin therapy (n=17) vs. standard of care (n=17)
randomized controlled trial some concerns about risk of bias
IV immunoglobulin plus methylprednisolone
Standard of care plus IV immunoglobulin 0.5 g/kg/d with methylprednisolone 40 mg 30 minutes before infusion for 3 days.
Standard of care
All patients received standard of care.
COVID 19 hospitalized
Adult patients greater than 18 years of age hospitalized with COVID-19 infection confirmed by positive polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome in nasopharyngeal or oropharyngeal swab sample with moderate-to-severe hypoxia (sPo2 ≤ 96% on ≥ 4 L O2 by nasal cannula) but not on mechanical ventilation.
Open-label.
Multicenter, 2 hospitals in California, United States.
mavrilimumab (n=21) vs. placebo (n=19)
randomized controlled trial some concerns about risk of bias
Mavrilimumab
Single intravenous infusion of Mavrilimumab 6mg/kg
Placebo
Concomitant medications included antiviral drugs relatedto COVID-19, corticosteroids, convalescent plasma, otherimmunosuppressive agents, and antimicrobial drugsrelated to non-COVID-19 infections.
COVID 19 hospitalized
Patients with documented COVID19 pneumonia defined as positive SARS-CoV2 test AND abnormalities/infiltrates on chest x-ray or computed tomography AND active fever or documented fever within 24-48 hours or ongoing anti-pyretic use to suppress fever, hypoxia (Room air SpO2 <92% or requirement for supplemental oxygen), increased serum inflammatory marker (CRP > 5 mg/dL), severity of disease warrants inpatient hospitalization. Patients were excluded if they required mechanical ventilation.
Double-blind.
Multicenter, 7 hospitals in United States.
A trial of 60 patients was planned, but given slow enrolment, the study was stopped early toinform the natural history and potential treatment effect.
methylprednisolone (n=44) vs. dexamethasone (n=42)
randomized controlled trial some concerns about risk of bias
Methylprednisolone
2mg/kg/day of methylprednisolone intravenously daily infused over 60 minutes, which was tapered to half dosage every five days.
Dexamethasone
6 mg of dexamethasone intravenously daily for ten days.
All patients received standard care. Methylprednisolone treatment was stopped in any patient who faced severe elevations in blood pressure or uncontrolled blood sugar.
COVID 19 hospitalized
Hospitalized patients above 18 years of age with SARS-CoV-2 infection confirmed by real-time PCR, with an O2 saturation of less than 92 in room air.
Triple-blind.
Faghihi hospital in Shiraz, Iran.
9-point scale (WHO), ranging from 0 as no clinical or virological evidence of infection (uninfected) to 8 assigned as death. The patient, assessor, and analyzer in the two groupsdid not have access to the randomization list and type of administered drug (Triple blind).
methylprednisolone (n=43) vs. placebo (n=43)
randomized controlled trial some concerns about risk of bias
Methylprednisolone
IV Methylprednisolone 1mg/kg/day dissolved in 100 mL 0.9% normal saline for 7 days.
Placebo
IV 100 mL 0.9% normal saline for 7 days.
All the participants received standard therapy of COVID-19 according to the Chinese Diagnosis and Treatment Plan for COVID-19.
COVID 19 hospitalized
Patients who were laboratory confirmed of SARS-CoV-2 infection and had pneumonia confirmed by chest computed tomography were diagnosed with COVID-19 pneumonia. Patients with COVID-19 pneumonia aged 18 years or older, admitted to the general wards for less than 72 h, and able to sign informed consent.
Single-blind.
7 tertiary hospitals in Beijing and Hubei, China.
Physicians were aware of the treatment assignment, but the participants were blinded. The clinical deterioration fulfilled at least one of the following criteria: the clinical symptoms and signs continue to deteriorate, new pulmonary or extrapulmonary lesions appear, the chest computed tomography indicates the progress, or the patient is transferred to the ICU or is dead.
Trial terminated early because of the COVID-19 decrease in late March.
methylprednisolone (n=209) vs. placebo (n=207)
randomized controlled trial some concerns about risk of bias
Methylprednisolone
IV 0.5 mg/kg sodium succinate MP (0.5 mg/kg), twice daily for 5 days
Placebo
Saline solution twice daily for 5 days.
As per hospital protocol, all patients meeting ARDS criteria used pre-emptively intravenous ceftriaxone (1g 2x for 7 days) plus azithromycin (500 mg 1x for 5 days) or clarithromycin (500 mg 2x for 7 days), starting on day 1.
COVID 19 hospitalized
Hospitalized patients were included if they had clinical and/or radiological suspicion of COVID-19 (history of fever and any respiratory symptom; eg, cough or dyspnea and/or ground glass opacity or pulmonary consolidation on computed tomography [CT] scan), were aged 18 years or older at the time of inclusion,and either had SpO2 ≤ 94% with room air, required supplementary oxygen, or required IMV.
Double-blind.
Single center, Manaus, Brazil.
Phase IIb.
neutralizing antibody (n=301) vs. placebo (n=292)
randomized controlled trial some concerns about risk of bias
Hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2 derived from recovered donors
A dose of hIVIG of 400 mg/kg bodyweight, capped at 40g. Infusion of hIVIG was to commence at a rate of 0.5 mg/kg per min for approximately 30 min. If tolerated, the rate of infusion could be doubled after intervals of not less than 30 min up to a maximum of 4 mg/kg per min.
Placebo
Equivalent volume of saline.
All participants received supportive care reflecting local practice and national guidelines. Standard of care background therapy included up to 10 days of study provided remdesivir unless contraindicated. Other aspects of standard care including corticosteroids, prophylactic anti-coagulation, supplemental oxygen,and other end-organ support, as clinically indicated.
COVID 19 hospitalized
Double-blind.
63 sites in Argentina, Denmark, Germany, Greece, Indonesia, Israel, Japan, Nigeria, Spain, UK, USA.
Ordinal outcome is based on a seven-category ordinal scale (1=can independently undertake usual activities with minimal or no symptoms; 2=no supplemental oxygen, symptomatic and unable to undertake usual activities; 3=supplemental oxygen <4 L/min; 4=supplemental oxygen ≥4 L/min or symptoms/signs of extra-pulmonary conditions; 5=non-invasive ventilation, high-flow oxygen, or symptoms and signs of acute stroke (National Institute of Health Stroke Scale >14); 6=invasive ventilation, extracorporeal membrane oxygenation, mechanical circulatory support, vasopressor therapy or renal replacement therapy; 7=death)
recombinant super-compound interferon rSIFN-co (n=48) vs. IFN alpha (n=48)
randomized controlled trial some concerns about risk of bias
Nebulized rSIFN-co
12 IU, twice daily immediately after randomization until discharged from the hospital, but not more than 28 days.
Nebulized interferon-alpha
Interferon-alpha-2a or interferon-alpha-2b, 5 million IU, twice daily, immediately after randomization until discharged from thehospital, but not more than 28 days.
All patients received the standard care. The baseline antiviral agents were lopinavir-ritonavir (400mg and100 mg, orally, twice daily) or umifenovir (200 mg,orally, thrice daily).
COVID 19 hospitalized
1. Age over 18 years old; 2. Real-time fluorescent RT-PCR for respiratory or blood specimens to detect novel coronavirus nucleic acid positive; 3. The sequence of virus genes in respiratory or blood samples was highly homologous with the known novel coronavirus; 4. A common or severe type of new type of coronavirus pneumonia was diagnosed. The common patients diagnosed with novel coronavirus pneumonia that have fever, respiratory symptoms, and imaging shows pneumonia. Some severe patients could be included. Accord with any of the following: (1) Respiratory distress, RR >= 30 times / minute; (2) In resting state, means oxygen saturation <= 93%; (3) Arterial blood oxygen partial pressure (PaO2) / oxygen concentration (FiO2) <=300mmHg.
Single-blind.
Multicenter, five hospitals in Wuhan city and Chengdu city, China.
Patients were blinded to treatment allocation, whereas treating physicians were aware of group allocations.
This trial was designed as an exploratory one and was not powered statistically to measure a specific outcome,thus sample size estimates were not based on statistical power assessments.
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.
SNG001 inhaled interferon beta (n=50) vs. placebo (n=51)
randomized controlled trial some concerns about risk of bias
Interferon beta-1a (SNG001)
6 MIU interferon beta-1a (SNG001) for inhalation use via nebuliser, once daily for 14 days.
Placebo
Nebulisation solution for inhalation use, once daily for 14 days. Placebo had the same formulation as SNG001, excluding the active substance.
Local standard of care treatment in both groups. SNG001 and placebo were identical in appearance.
COVID 19 hospitalized
Adults aged 18 years or older, admitted to hospital with COVID-19 symptoms. Patients had to have a confirmed SARS-CoV-2test result in a UK National Health Service (NHS) diagnostic, qualitative RT-PCR assay or a positive point-of-care test (FebriDx, Lumos Diagnostics, Sarasota, FL,USA) within the previous 24 h.17 Patients unable to use a nebuliser with a mouthpiece (eg, ventilated patients and patients in intensive care); were ecluded.
Double-blind.
Multicentre, 9 specialist hospitals in United Kingdom.
Phase II pilot trial.The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death.
SNG001 inhaled interferon beta (n=309) vs. placebo (n=314)
randomized controlled trial risk of bias NA
SNG001
in addition to standard of care
placebo
COVID 19 hospitalized
double-blind
sotrovimab (Xevudy; VIR-7831) (n=184) vs. placebo (n=183)
randomized controlled trial low risk of bias
VIR-7831 Sotrovimab
Standard of care plus single intravenous dose of sotrovimab 500mg over 60 minutes as soon as possible after randomisation.
Placebo
Standard of care plus placebo (0.9% sodium chloride).
Randomisation allocation was 2:1:2:1 to sotrovimab, matching placebo for sotrovimab, BRII-196 plus BRII-198, or matching placebo for BRII-196 plus BRII-198. The concurrent placebo groups were pooled for analyses, resulting in approximately a 1:1:1 allocation ofsotrovimab to BRII-196 plus BRII-198 to placebo. All patients received remdesivir. Other treatments for COVID-19, including oxygen, respiratory support, and corticosteroids, were administered at the discretion of the treating clinician per local standard of care.
COVID 19 hospitalized
Patients with laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Patients were eligible for enrolment if they were receiving no oxygen therapy or standard oxygen therapy via a nasal cannula or mask, but were excluded if they were receiving high-flow oxygen via nasal cannula, non-invasive ventilation, or invasive mechanical ventilation, or met any of the other criteria for acute organ failure or major extrapulmonary manifestations of COVID-19.
Double-blind.
43 hospitals in the USA, Denmark, Switzerland, and Poland.
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.* Prematurely discontinued for futility (based on pulmonary and pulmonary-plus ordinal outcome scale at day 5) after enrollment of 300 patients.
stem cells (n=12) vs. placebo (n=12)
randomized controlled trial some concerns about risk of bias
Umbilical cord mesenchymal stem cell (UC-MSC)
Two intravenous infusions of 100 ± 20 × 106 UC-MSCs each, in 50 mL vehicle solution containing human serum albumin and heparin, infused over10 ± 5 minutes, at days 0 and 3.
Placebo
Two infusions of 50 mL vehicle solution, at day 0 and day 3.
Best standard of care was provided in both groups following the current institutional COVID-19 guidelines.
COVID 19 hospitalized
Patient hospitalized; age ≥ 18 years; peripheral capillary oxygen saturation (SpO2) ≤ 94% at room 134air, or requiring supplemental oxygen at screening; PaO2/FiO2 ratio < 300 mmHg; and bilateral infiltrates on frontal chest radiograph or bilateral ground glass opacities on a chest CT scan.
Double-blind.
Single-center, UHealth System/Jackson Health System (UHS/JHS), in Miami, Florida, United-States.
Phase 1/2a.
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=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=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=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
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=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=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=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.
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
casirivimab/imdevimab (Ronapreve) (n=912) vs. placebo (n=452)
randomized controlled trial some concerns about risk of bias
REGEN-COV Casirivimab and imdevimab
2.4 g or 8.0 gREGEN-COV (1.2 g casirivimab and1.2 g imdevimab)
Placebo
Single intravenous dose.
3 arms ratio 1:1:1 : 2.4 g REGEN-COV (1.2 g casirivimab and1.2 g imdevimab), 8.0 g REGEN-COV (4.0 g casirivimab and 4.0 g imdevimab), or placebo as a single intravenous dose. Standard-of-care treatments for Covid-19, per the investigator, were permitted.
COVID-19 mild to moderate
Double-blind.
103 sites in the United States, Brazil, Chile, Mexico, Moldova, and Romania
Primary endpoints were tested hierarchically.
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.* Trial was stopped earlier than planned (due to low enrollment prior to the surge associated with the Delta variant).
clarithromycine (n=99) vs. standard of care (n=99)
randomized controlled trial some concerns about risk of bias
clarithromycin
500mg /12 h for 7 days
standard of care
3 arms azithromycin, clarithromycin or standard of care
COVID-19 mild to moderate
open-label
1 centre, Egypt
colchicine (n=52) vs. standard of care (n=51)
randomized controlled trial some concerns about risk of bias
Colchicine
Standard of care plus initial dose of 1.5 mg (1 mg and 0.5 mg two hours after) of colchicine, followed by 0.5 mg every 12 hours during the next 7 days and 0.5 mg every 24 hours until the completion of 28 days of total treatment.
Standard of care
Both colchicine and control group patients received the recommended standard treatment in the study: dexamethasone (6 mg once a day for 10 days) in patients who required supplemental oxygen (WHO scale ≥4). Remdesivir was administered for 5 days following the Spanish Agency of Medications and Pharmaceutical Products recommendation which included: time from symptoms onset <7 days; two or more measurements of oxygen saturation below 94% on room air, respiratory rate >24 breaths/min without supplemental oxygen or Pa02/Fi02<300 (Kirby index). Tocilizumab was administered at a single dose of 600 mg and baricitinib at 4 mg/day for 14 days. The need for tocilizumab or baricitinib was established according to the physician on care criteria.
COVID-19 mild to moderate
Exclusion of patient needing mechanical ventilation, non-invasive or invasive, or extracorporeal membrane oxygenation support (ECMO).
Open-label, randomized.
Virgen de la Arrixaca University Clinical Hospital, Murcia, Spain.
multiple testing102 patients
convalescent plasma treatment (n=80) vs. placebo (n=80)
randomized controlled trial low risk of bias
Convalescent plasma
250 ml of convalescent plasma with an IgG titer greater than 1:1000 against SARS-CoV-2 spike (S) protein (COVIDAR IgG, Instituto Leloir, Argentina).
Placebo
250 ml of placebo (0.9% normal saline).
Convalescent plasma or placebo was administered less than 72 hours after the onset of symptoms, and the infusions were given over a period of 1.5 to 2.0 hours. None of the patients received any experimental therapy for Covid-19 besides convalescent plasma.
COVID-19 mild to moderate
Patients who were 75 years of age or older, irrespective of current coexisting conditions, or between 65 and 74 years of age with at least one coexisting condition were identified and assessed for eligibility. At the time of screening for SARS-CoV-2 by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, eligible patients had had at least one of each sign or symptom in the following two categories for less than 48 hours: a temperature of at least 37.5, unexplained sweating, or chills; and dry cough, dyspnea, fatigue, myalgia, anorexia, sore throat, dysgeusia, anosmia, or rhinorrhea.
Double-blind
Clinical sites and geriatric units in Argentina
The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.
convalescent plasma treatment (n=235) vs. standard of care (n=229)
randomized controlled trial high risk of bias
Convalescent plasma
Two doses of 200 mL CP was transfused 24 hours apart plus best standard of care
Standard of care
Best standard of care only
SoC in both groups
COVID-19 mild to moderate
The trial was conducted in 39 hospitals across India, with some level of heterogeneity across the trial sites for best standard of care and participantenrolment.
Open-label.
39 public and private hospitals across India.
Phase 2.
imatinib (n=55) vs. lopinavir/ritonavir plus chloroquine (n=-9)
randomized controlled trial risk of bias NA
-lopinavir/ ritonavir hydroxychloroquine-imatinib hydroxychloroquine-baricitinib hydroxychloroquine
no formal control groupcomparison between 3 active treatment groups
3 arms study
COVID-19 mild to moderate
open-label
madrid, spain
prospective, phase II, randomized, open-label, 3 parallel groups study
no formal control groupcomparison between 3 active treatment groups
Indomethacin (n=103) vs. paracetamol (n=107)
randomized controlled trial some concerns about risk of bias
Indomethacin
Standard of care plus indomethacin 75mg (once a day for BMI<30, twice a day for BMI>30). A proton pump inhibitor was also added along with indomethacin.
Paracetamol
Standard of care plus paracetamol 650mg four times a day.
All patients in both groups received standard of care (doxycycline, ivermectin, vitamin C, zinc, cough syrup).
COVID-19 mild to moderate
Hospitalized adult patients (20-90), with positive RT-PCR, normal KFT, normal LFT, oxygen saturation 94% or more.
Open-label.
Panimalar Medical College, Chennai, India.
Follow-up through a telephonic enquiry.
interferon / TFF2 (n=40) vs. standard of care (n=40)
randomized controlled trial some concerns about risk of bias
Interferon kappa plus TFF2
Both proteins (5 mg TFF2 plus 2 mg IFN-k) were dissolved in 5 mL sterilized water, and the combination aerosol was delivered to the patient for 20 to 30 min by a nasal mask driven by a medical compressed air atomizer (YUWELL, 403M). The aerosol inhalation treatment started from the first day of hospitalization and was administered 6 times every 24 h.
Standard care
Standard care alone. Standard care included symptomatic treatment with hydroxychloroquine, antibiotic agents, vasopressors, antifever medicine, vitamin C, immune enhancers, or traditional Chinese medicines.
Both groups received standard of care.
COVID-19 mild to moderate
Male and nonpregnant femalepatients at 18 years of age or older were eligible after they were confirmedas SARS-CoV-2 positive by RT-PCR. In addition, patients wereincluded if their peripheral capillary oxygen saturation (SpO2) was >94% on room air at screening. Symptoms of infection include fever,cough, and myalgia, with diarrhea, with the subsequent developmentof dyspnea or of pneumonia on chest CT. Patients with moderatepneumonia were then included following Diagnosis and TreatmentProtocol for Novel Coronavirus Pneumonia
Open-label.
Single center, Shanghai Public Health Clinical Center, Shanghai, China.
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.
peginterferon (n=60) vs. placebo (n=60)
randomized controlled trial some concerns about risk of bias
Peginterferon Lambda-1a
Peginterferon Lambda-1a (180 mcg subcutaneous injection) single dose alone with standard of care.
Placebo
Normal saline placebo subcutaneous injection along with standard of care Treatment for COVID-19 Infection.
COVID-19 mild to moderate
Age ≥ 18 years and ≤ 75 years at the time of the assessmentAble and willing to understand the study, adhere to all study procedures, and provide written informed consentDiagnosis of COVID-19 disease:If symptomatic, the presence of mild to moderate symptoms without signs of respiratory distress, with FDA-cleared molecular diagnostic assay positive for SARS-CoV-2 within 72 hours from swab to the time of commencing informed consent:If asymptomatic, initial diagnosis of SARS-CoV-2 infection with positive FDA-cleared molecular diagnostic assay obtained no more than 72 hours from initial swab to the time of commencing informed consent
Open-label.
Single-blind.
Phase II. Single-blind study in which only patients are blinded.
pegylated interferon-α2b (n=20) vs. standard of care (n=20)
randomized controlled trial some concerns about risk of bias
Single dose of PEG IFN-α2b
PEG IFN-α2b; 1 mg/kg subcutaneous injection, single dose, plus SOC.
Standard of care
SOC alone.
Antipyretics, cough suppressants, antibiotics, steroids, vitamins, anticoagulants, and hydroxychloroquine were administered as per regulatory recommendation and approval.
COVID-19 mild to moderate
1. Ability to comprehend and willingness to sign a written ICF for the study 2. Male or non-pregnant females, >= 18 years of age at the time of enrolment 3. Understands and agrees to comply with planned study procedures 4. Agrees to the collection of pharyngeal swabs and blood sample as per protocol 5. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen 6.Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study (acceptable methods will be determined by the site).
Open-label.
Multicenter, six study centers in India.
The primary efficacy endpoint was clinical status assessed onday 15 on a WHO 7-point ordinal scale consisting of the following categories: 1, not hospitalized, no limitations of activities; 2, not hospitalized, limitation on activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, on non-invasive ventilation or high flow oxygen devices; 6, hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 7, death.
Phase II. All patients were hospitalized.
pegylated interferon-α2b (n=120) vs. standard of care (n=130)
randomized controlled trial some concerns about risk of bias
Pegylated interferon-α2b
Standard of care plus a single dose of PEG IFN-α2b.
Standard of care
SOC treatments [i.e. antipyretics, cough suppressants, antibiotics, steroids, vitamins, anticoagulants, hydroxychloroquine and antivirals (e.g. remdesivir)] were administered as per the COVID-19 clinical management guidelines of the Ministry of Health, Government of India and the practices of the individual institutions.
COVID-19 mild to moderate
age ≥18 years, RT-PCR-confirmed SARS-CoV-2 infection, pneumonia with no signs of severe disease, respiratory rate ≥24 breaths/min, SpO2 90–94%, and a negative pregnancy test (for female patients of child-bearing potential).
Open-label.
Multicenter; 20 study centers across India.
The scale consists of the following categories: 1, not hospitalized, no limitation of activities; 2, not hospitalized, limitation of activities; 3, hospitalized, does not require supplemental oxygen; 4, hospitalized, requires supplemental oxygen; 5, hospitalized, requires noninvasive ventilation or on high flow oxygen devices; 6, hospitalized, requires invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 7, death.
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
colchicine (n=66) vs. placebo (n=60)
randomized controlled trial risk of bias NA
Colchicine
1.5 mg at baseline then, 0.5 mg PO BID for 10 days.
Placebo
COVID-19 severe or critically
excluded patients : - treated with antimalarial drugs, azithromycin, convalescent plasma, remdesivir, tocilizumab, or baricitinib- subjects over 70 years old,
triple blind
Mexico
After the second pre-specified interim analysis, the committee informed the research group that although the treatment was safe, itwas inefective to prevent the development of the primary outcome and we decided to suspend the trial.
convalescent plasma treatment (n=14) vs. placebo (n=15)
randomized controlled trial high risk of bias
Convalescent plasma (COPLA)
500 mL of convalescent plasma from recovered COVID-19 patients, in two divided doses on consecutive days to avoid transfusion-related volume overload.
Fresh Frozen Plasma (FFP)
FFP transfused in the study was collected before the emergence of the virus in India to avoid any chance of providing COVID-19 convalescent plasma in the SMT group. Transfusion of 500 mL of FFP in two divided doses on consecutive days to avoid transfusion-related volume overload.
Standard medical care in both groups: All the patients in the study were initiated on supplemental oxygen at five litter/min with target SpO2 being ≥94%. All patients received a course of Hydroxychloroquine 400 mg BD on Day1, followed by 200 mg BD for five days along with Oral Azithromycin 500 mg OD for five days.
COVID-19 severe or critically
Severe COVID -19 infections defined as WHO interim guidance and the guideline of diagnosis and treatment of COVID-19 of national health commission of china (version 5.0)
Open-label.
1 center, Lok Nayak Hospital, New Delhi, India.
Phase II.
phase 2
convalescent plasma treatment (n=150) vs. placebo (n=73)
randomized controlled trial low risk of bias
Convalescent plasma
Single unit of plasma (~200-250 milliliters) transfused over approximately 2 hours.
Normal control plasma
Single unit of plasma (~200-250 milliliters) transfused over approximately 2 hours.
Convalescent plasma collected from patients who had recovered from laboratory-confirmed COVID-19 with a minimum anti-SARS-CoV-2 total IgG antibody titer of ≥1:400. Control plasma consisted of oldest available plasma at each study site without prior testing for anti-SARS-CoV-2 antibodies and collected prior to January 1st, 2020 in Rio de Janeiro and February 20th, 2020 in New York City.
COVID-19 severe or critically
Hospitalized patients aged ≥18 years with laboratory-confirmed COVID-19, infiltrates on chest imaging and oxygen saturation ≤ 94% on room air or requirement for supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation
Double-blind.
5 hospitals in New York City, USA and Rio de Janeiro, Brazil.
The primary outcome was measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population. The ordinal scale is based on that recommended by the World Health Organization : 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring high-flow oxygen therapy or noninvasive mechanical ventilation; 6, hospitalized, requiring ECMO, IMV, or both; 7, death.
Phase II.
convalescent plasma treatment (n=228) vs. placebo (n=106)
randomized controlled trial low risk of bias
Convalescent plasma
Single administration of Covid-19 convalescent plasma in addition to standard treatment. The convalescent plasma infused volume was defined within the range of 5-10 ml/kg with aninferior limit around 400 ml for patients whose body weight was below 70 kg and a superior limitof 600 ml for those above 70 kg.
Placebo
Single dose of normal saline solution in addition to standard treatment.
2:1 ratio. Patients were allowed to receive antiviral agents, glucocorticoids, or both according to the standard of care at the provider health care institution.
COVID-19 severe or critically
Reverse-transcriptase–polymerase-chain-reaction (RT-PCR) positive for SARS-CoV-2, radiologically confirmed pneumonia, no previous directives rejecting advanced life support, and at least one of the following severity criteria: oxygen saturation (SaO2) below 93% while they were at rest and breathing ambient air, a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) below 300 mm Hg (PaO2 :FiO2), or a Sequential Organ Failure Assessment (SOFA) or modified SOFA (mSOFA) score of two or more points above baseline status.
Double blind.
12 clinical sites in Argentina (coordinated by Hospital Italiano de Buenos Aires).
Adapted version of the World Health Organization (WHO) clinical scale: 1 indicated death, 2 invasive ventilatory support, 3 hospitalized with supplemental oxygen requirement, 4 hospitalized without supplemental oxygen requirement, 5 discharged without full return to baseline physicalfunction, and 6 discharged with full return to baseline physical function.
convalescent plasma treatment (n=49) vs. standard of care (n=51)
randomized controlled trial some concerns about risk of bias
convalescent plasma hydroxychloroquine azithromycine
500 milliliters of convalescent plasma, distributed in two 250 milliliters transfusions on the first and second day. azithromycin (500 milligrams daily) and hydroxychloroquine (400 milligrams each 12 hours) for 10 days
hydroxychloroquine azithromycin
hydroxychloroquine 400 milligrams each 12 hours for 10 days ; azithromycin 500 milligrams daily for 10 days
COVID-19 severe or critically
open-label, randomized
3 centers, colombia
multiple testing estimated enrollment : 80 participants
convalescent plasma treatment (n=52) vs. standard of care (n=51)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
Thetransfusion dose of COVID-19 convalescent plasma was approximately 4 to 13 mL/kg of recipient bodyweight. Convalescent plasma transfusion was administered at approximately 10mLfor the first 15 minutes, which was then increased to approximately 100 mL per hour with close monitoring.
standard treatment alone.
Standard treatment consisted of symptomatic control and supportive care for COVID-19, mostly based on the evolving Chinese national COVID-19 treatment guidelines and hospital practice. Possible treatments included antiviral medications, antibacterial medications, steroids, human immunoglobulin, Chinese herbal medicines, and other medications.
SoC in both groups.
COVID-19 severe or critically
Open-label
7 medical centers in Wuhan, China,
Clinical improvement defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]).
convalescent plasma treatment (n=21) vs. standard of care (n=28)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
400 mL of frozen convalescent plasma transfused over 2 hours, The convalescent plasma was given only once for all of the patients in the CP group.
Standard of care
Included patients, whether in CP or control group, were exactly on the same protocol of therapy: hydroxychloquine 200 mg twice per day for at least 10 days plus azithromycin once 500 mg/day loading dose, followed by 250mg once per day for 5 days plus oxygen therapy plus methylprednisolone 40 mg per day after admissionto RCU.
COVID-19 severe or critically
Adult patients ≥18, with SpO2 <90% in resting state, affected by pneumonia at their first 3 days in RCU receiving O2 or on ventilators.
Open-label.
Multicenter, 3 hospitals in Baghdad, Iraq.
Recovery or death, length of stay inhospital, and improvement in the clinical course ofthe disease were monitored clinically.
convalescent plasma treatment (n=53) vs. standard of care (n=52)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
3 units of CCP: The administration of CCP should commence within 1 day after randomization, one transfusion unit each of CCP was given on day 1, 3 and 5.
Standard of care
Standard treatment alone.
Seven patients randomized to the control group crossed over to receive CCP after assessment on day 14 because of progressive COVID-19 (failure of primary outcome). Patients in the crossover group also received one unit of CCP on three days. Patients in both groups received other anti-viral treatment and/or supportive treatment according to institutional standard procedures.
COVID-19 severe or critically
(1) SARS CoV-2 infection confirmed by PCR (bronchoalveolar lavage, sputum, nasal and/or pharyngeal swap); (2) age ≥ 18 years and ≤ 75 years and (3) severe disease defined by at least one of the following: a)respiratory rate ≥ 30 breaths / minute under ambient air; b) requirement of any type of ventilation support (defined as supplemental oxygen or non-invasive ventilation or invasive ventilation or ECMO); c) needs treatment on ICU; (4) written informed consent by patient or representative.
Open-label.
Multicenter, 13 hospitals in Germany.
convalescent plasma treatment (n=20) vs. standard of care (n=20)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
400 mL of CP, given as 200ml over 2hrs over 2 successive days; the infusion rate was monitored and amended if there was a risk of fluid overload.
Standard of care
The standard supportive treatment included control of fever (paracetamol) and possible therapy including antiviral medications, Tocilizumab and antibacterial medication.
Patients prior to CP therapy were on standard supportive treatment including control of fever (paracetamol) and possible therapy including antiviral medications, Tocilizumab and antibacterial medication.
COVID-19 severe or critically
Patients with COVID-19 diagnosis based on polymerase chain reaction (PCR) testing, hypoxia (Oxygen saturation of less than or equal 92% on air, or PO2 < 60mmHg in arterial blood gas, or arterial partial pressure of oxygen (PaO )/fraction of inspired oxygen (FIO) of 300 or less) and patient requiring oxygen therapy, pneumonia confirmed by chest imaging. Patients requiring ventilatory support (invasive or non-invasive) were excluded.
Open-label.
Two medical centres in Bahrain.
Pilot trial.
convalescent plasma treatment (n=1095) vs. standard of care (n=916)
randomized controlled trial low risk of bias
Convalescent plasma
High-titer ABO compatible convalescent plasma (total volume approximately 550 /- 150 ml) within 48 hours of randomization
Standard of care
COVID-19 severe or critically
REMAP-CAP exclusion criteria included presumption that death was imminent with lack of commitment to full support, or participation in REMAP-CAP in the prior 90 days.
Open-label.
129 sites in UK, Australia, US, Canada.
In this composite ordinal outcome, all deaths within the hospital, up to day 90, are assigned the worst outcome (–1 day). Among survivors, respiratory and cardiovascular organ support-free days were calculated up to day 21, such that a higher number represents faster recovery.
The convalescent plasma intervention was stopped after pre-specified criteria for futility were met.
convalescent plasma treatment (n=43) vs. standard of care (n=47)
randomized controlled trial low risk of bias
A cross over from the standard arm into the experimental arm is possible after day 10 in case of not improving or worsening clinical condition.
COVID-19 severe or critically
Open-label.
Germany.
Study not published yet. Results and risk of bias assessment were extracted from Axfors C. et al meta-analysis https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06829-7?s=09.
convalescent plasma treatment (n=40) vs. standard of care (n=40)
randomized controlled trial high risk of bias
Convalescent plasma
Two consecutive doses of ABO-matched 200ml convalescent plasma on two consecutive days, the first transfusion being on the day of enrolment, in addition to standard of care.
Standard of care
Most of patients received Hydroxychloroquine 400 mg BD on first day followed by 400 mg OD for four days, Azithromycin 500mg OD for 5 days, Ivermectin 12 mg OD for 5days and Doxycyclin 100 mg BD for 10 days.
Standard of care in both groups. All patients with evidence for ARDS received O2 therapy as per requirement, either intravenous or oral corticosteroids. Prophylactic or therapeutic anticoagulation, appropriate broad-spectrum antibiotic, antidiabetic therapy and anti-hypertensive agents if needed.
COVID-19 severe or critically
COVID-19 patients with severe disease (fever or suspected respiratory infection, plus one of the following; respiratory rate >30 breaths/min, severe respiratory distress, SpO2< 90% at room air) with mild ARDS, defined as patients having partial pressure of oxygen in the arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio of 200-300 mmHg or moderate ARDS, defined as PaO2/FiO2 100-200 mmHg, not on mechanical ventilation.
Open-label.
Single center,
Phase II. No plan statistical available.
convalescent plasma treatment (n=31) vs. standard of care (n=31)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
One unit (500 mL) plasma on the admission day plus standard drugs. The first plasma unit was injected in the first 4 h after admission; according to the physician’s recommendation, the second unit was prescribed if no improvement was observed after 24 h.
Standard of care
Five patients required the administration of the second unit of plasma. All patients received similar antiviral therapy, including Ritonavir/Lopinavir, and chloroquine phosphate.
COVID-19 severe or critically
1- COVID-19 patients who had specifed COVID-19 symptoms (less than 7 days since the onset of the symptoms).2- The positive results of PCR test and CT scan.3- Severity WHO score>4.4- Blood oxygen saturation (SPO2) ≤93% in room air. 5- Individuals who no exhibit hypersensitivity to plasma intravenous administration.6- Those who voluntarily signed the informed consent.
Single-blind.
Single center: emergency departement in Razi hospital of Ahvaz, Iran.
In the register, primary endpoints were: Complete remission of clinical signs, negative qRT-PCR test, and improved CT scan. (7-14 days after starting the treatment).
convalescent plasma treatment (n=80) vs. standard of care (n=80)
randomized controlled trial some concerns about risk of bias
Convalescent plasma
Two infusions 48 hours apart of 300ml of CP plus Standard of Care (SOC).
Standard of care
Standard of care alone.
All patients in both groups received standard of care. The SOC for COVID-19 was at the discretion of the treating physicians. The use of glucocorticoids, other immunomodulators, antibiotic agents, and antiviral agents was allowed. Remdesivir was not available in Brazil during the trial period.
COVID-19 severe or critically
18 or older, positive reverse transcriptase polymerase chain reaction (RT-PCR) for SARSCoV-2, less than 15 days of initial symptoms onset, and severe respiratory disease, as defined by the presence of at least one of the following: respiratory rate >30 breaths per minute in room air; oxygen saturation (O2) ≤93% in room air; arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤ 300; need for supplemental O2 to maintain O2 saturation >95%; need for supplemental O2 by high flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation.
Open-label.
Single center: single COVID-19 reference hospital, Porto Alegre, Brazil.
Clinical improvement was defined as hospital discharge or reduction of 2 points in a 6-level ordinal scale defined as follows; 1, not hospitalized; 2, hospitalized and not receiving supplemental oxygen; 3, hospitalized and receiving supplemental oxygen; 4, hospitalized and receiving oxygen supplementation administered by a high-flow nasal cannula or noninvasive ventilation; 5, hospitalized and receiving mechanical ventilation or extracorporeal membrane oxygenation; and 6, death.
One pre-planned interim analysis for efficacy and safety evaluation after 80 patients with complete follow-up was conducted. The stopping rule for efficacy and safety was a P value<.05. There was no adjustment in the final threshold for statistical significance for sequential analysis.
dexamethasone (n=7) vs. standard of care (n=12)
randomized controlled trial low risk of bias
Dexamethasone
Dexamethasone 20 mg/iv/daily/from day 1 of randomization during 5 days, followed by 10 mg/iv/daily from day 6 to 10, plus standard of care.
Standard of care
Standard intensive care.
COVID-19 severe or critically
Age ≥ 18 years, positive reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay for SARS-CoV-2 in a respiratory tract sample, intubated and mechanically ventilated, acute onset of moderate-to-severe ARDS, as defined by Berlin criteria, which includes (i) having pneumonia, (ii) bilateralpulmonary infiltrates on chest imaging (x-ray or CTscan), (iii) absence of left atrial hypertension or no clinicalsigns of left heart failure, and (iv) hypoxemia, as defined by a PaO2/FiO2 ratio of ≤ 200 mmHg on positive end-expiratory pressure (PEEP) of ≥ 5 cmH2O, regardless of FiO2.
Open-label
Multicenter, ICUs in teaching hospitals, Spain.
Study not published yet. Data and results come from Sterne J et al. meta-analysis, trial protocol and statistical plan. Planned sample size: 200 patients.
dexamethasone (n=151) vs. standard of care (n=148)
randomized controlled trial some concerns about risk of bias
Dexamethasone
Dexamethasone 20mg intravenously once daily for 5 days, followed by 10 mg intravenously once daily for additional 5 days or until ICU discharge, whichever occurred first, plus standard care.
Standard care
Standard care alone.
Standard care in both groups. All clinical interventions, such as use of antibiotics, ventilatory strategy, laboratory testing, and hemodynamic management were left at thediscretion of the ICU team for both groups.
COVID-19 severe or critically
Patients age ≥18 years old, with probable or confirmed infection by SARS-CoV2, intubated and mechanically ventilated, moderate or severe ARDS according to Berlin criteria (partial pressure of arterial blood oxygen to fraction of inspired oxygen (PaO2:FIO2) ratio of 200 or less.), onset of moderate or severe ARDS in less than 48h before randomization.
Open-label.
Multicenter, 41 intensive care units (ICUs) in Brazil.
The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients
dexamethasone (n=25) vs. standard of care (n=25)
randomized controlled trial some concerns about risk of bias
Dexamethasone
intravenous dexamethasone at a dose of 20 mg/day from day 1–5 and then at 10 mg/day from day 6–10.
Control
No corticosteroids
Patients in both groups received oxygen support (CPAP with pressure of 5–10 cmH2O and FIO2 equal to 60 to achieve SPO2≥90% and the duration was different ac-cording to the monitoring of patients’ clinical status), fluid support, and lopinavir/ritonavir (200/50 mg, two tablets twice a day) according to the National Iranian Guidelines
COVID-19 severe or critically
(1) age >18 years; (2) SARS-CoV-2 infection confirmed by a reverse transcription-polymerase chain reac-tion test; (3) ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) between 100 and 300 mmHg; (4) bilateral lung infiltration; and (5) provision of written informed consent by the patient.
Open-label.
Single center, Dr. Masih Daneshvari Hospital, Tehran, Iran.
dexamethasone (n=75) vs. tocilizumab (n=74)
randomized controlled trial high risk of bias
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.
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.
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.
Dexamethasone 12mg (n=497) vs. dexamethasone 6mg (n=485)
randomized controlled trial low risk of bias
Dexamethasone 12mg
Standard of care plus intravenous bolus injection of dexamethasone 12 mg once daily for up to 10 days.
Dexamethasone 6mg
Standard of care plus intravenous bolus injection of dexamethasone 6 mg once daily for up to 10 days.
Betamethasone (12mg or 6mg) use was allowed at sites where dexamethasone was not available.
COVID-19 severe or critically
Aged 18 years or above AND confirmed SARS-CoV-2 (COVID-19) requiring hospitalisation AND use of one of the following: Invasive mechanical ventilation OR Non-invasive ventilation or continuous use of continuous positive airway pressure (CPAP) for hypoxia OR Oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system.
Double-blind.
Multicenter: 26 hospitals in Europe (Denmark, Sweden, Switzerland) and India.
equine polyclonal antibodies INM005 (n=118) vs. placebo (n=123)
randomized controlled trial some concerns about risk of bias
Equine polyclonal antibodies INM005
placebo
COVID-19 severe or critically
double-blind
19 hospitals of Argentina
Hydrocortisone (n=76) vs. placebo (n=73)
randomized controlled trial low risk of bias
Low-dose Hydrocortisone
Continuous intravenous infusion of hydrocortisone at an initial dose of 200mg/d. Treatment was continued at 200mg/d until day 7 and then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days, for a total of 14 days. If improvement by day 4, a short treatment regimen was used for a total of 8 days.
Placebo
Saline in a form guaranteeing double-blinding.
Patients received standard care for acute respiratory failure.
COVID-19 severe or critically
Patients aged at least 18 years admitted to 1 of the 9 participating French ICUs for acute respiratory failure with a biologically confirmed (reverse transcriptase–polymerase chain reaction) or suspected (suggestive chest computed tomography scan result in the absence of any other cause of pneumonia) COVID-19. The experimental treatment had to be administered within 24 hours of the onset of the first severity criterion (see below) or within 48 hours for patients referred from another hospital. One of 4 severity criteria had to be present: need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of 5 cm H20 or more; a ratio of PaO2 to fraction of inspired oxygen (FIo2) less than 300 on high-flow oxygen therapy with an FIO2 value of at least 50%; for patients receiving oxygen through a reservoir mask, a PaO2:FIO2 ratio less than 300, estimated using prespecified charts; or a Pulmonary Severity Index greater than 130.
Double-blind.
Multicenter, 9 ICUs in France.
The trial was stopped early following the recommendation of the data and safety monitoring board after the publication of RECOVERY's results.
Hydrocortisone (n=16) vs. placebo (n=14)
randomized controlled trial low risk of bias
Hydrocortisone
IV hydrocortisone 200mg/day for 7 days or until hospital discharge whichever came first. (Continuous infusion over 24 hours or bolus injections every 6 hours (50 mg per bolus)).
Placebo
Matching placebo IV for 7 days or until hospital discharge. (Continuous infusion over 24 hours or bolus injections every 6 hours).
The injections had identical appearances. All other interventions were given at the discretion of the treating clinicians.
COVID-19 severe or critically
Aged 18 years or above AND Confirmed SARS-CoV-2 (COVID-19) requiring hospitalisation ANDUse of one of the following: Invasive mechanical ventilation OR Non-invasive ventilation or continuous use of continuous positive airway pressure (CPAP) for hypoxia OR Oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system.
Double-blind.
Multicenter
The trial was terminated early when 30 out of 1,000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19.
Hydrocortisone (n=143) vs. standard of care (n=108)
randomized controlled trial high risk of bias
Hydrocortisone
Fixed 7-day course of intravenous hydrocortisone (50mg or 100mg every 6 hours).
Standard of care
No corticosteroids
COVID-19 severe or critically
1. Adult patient admitted to an ICU for acute severe CAP within 48 hours of hospital admission with a. symptoms or signs or both that are consistent with lower respiratory tract infection (for example, acute onset of dyspnea, cough, pleuritic chest pain) AND b. Radiological evidence of new onset infiltrate of infective origin (in patients with preexisting radiological changes, evidence of new infiltrate) 2. Up to 48 hours after ICU admission, receiving organ support with one or more of: a. Non-invasive or invasive ventilatory support; b. Receiving infusion of vasopressor or inotropes or both.
Open-label
121 sites in 8 countries (Australia, Canada, France, Ireland, Netherlands, New Zealand, UK, US).
Prematurely discontinuated due to external results
Hydrocortisone (n=152) vs. standard of care (n=108)
randomized controlled trial high risk of bias
Hydrocortisone
Shock-dependent course (50mg every 6 hours when shock was clinically evident).
Standard of care
No corticosteroids
COVID-19 severe or critically
1. Adult patient admitted to an ICU for acute severe CAP within 48 hours of hospital admission with a. symptoms or signs or both that are consistent with lower respiratory tract infection (for example, acute onset of dyspnea, cough, pleuritic chest pain) AND b. Radiological evidence of new onset infiltrate of infective origin (in patients with preexisting radiological changes, evidence of new infiltrate) 2. Up to 48 hours after ICU admission, receiving organ support with one or more of: a. Non-invasive or invasive ventilatory support; b. Receiving infusion of vasopressor or inotropes or both.
Open-label.
121 sites in 8 countries (Australia, Canada, France, Ireland, the Netherlands, New Zealand, UK, US).
Prematurely discontinuated due to external results
IFN beta-1a (n=487) vs. placebo (n=482)
randomized controlled trial some concerns about risk of bias
Interferon beta-1a
44 mcg of interferon beta-1a administered by a 0.5 mL subcutaneous injection on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses. plus remdesivir.
Placebo
0.5 mL placebo injection administered subcutaneously on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses plus remdesivir.
All hospitalized patients also received intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days. All patients received standard supportive care by the trial site hospital,including glucocorticoids, but other experimental treatments for COVID-19 were prohibited.
COVID-19 severe or critically
Patients already on mechanical ventilation were excluded.
Double-blind.
63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, USA).
Disease severity was defined according to the eight-category ordinal scale used in previous ACTT studies. Patients defined by a score of :1 were not hospitalised and had no limitations to theiractivities; 2 were not hospitalised but had limitations to their activities or required home oxygen supplementation,or both; 3 were hospitalised but did not require supplemental oxygen and no longer required ongoing medical care; 4 were hospitalised and did not require supplemental oxygen but did require ongoing medical care; 5 were hospitalised and required any supplemental oxygen;6 were hospitalised and required non-invasive ventilation or use of high-flow oxygen devices; 7 were hospitalised and receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; and 8 were those who had died.
IFN beta-1a (n=46) vs. standard of care (n=46)
randomized controlled trial high risk of bias
Interferon beta-1a
IFN β-1a in addition to the standard of care. Each 44 micrograms/ml (12 million IU/ml) of interferon β-1a (ReciGen®, CinnaGen Co., Iran) was subcutaneously injected three times weekly for two consecutive weeks.
Standard of care
Hydroxychloroquine (400 mg BD in first day and then 200 mg BD) plus lopinavir/ritonavir (400/100 mg BD) or atazanavir/ritonavir (300/100 mg daily) for 7-10 days (hospital protocol).
Both groups received standard of care. Primary care, respiratory support, fluid, electrolytes, analgesic, antipyretic, corticosteroid and antibiotic were recommended in the hospital protocol if indicated.
COVID-19 severe or critically
Adult patients (aged ≥ 18 years old) with the severe disease with following criteria: (1) hypoxemia (need for noninvasive or invasive respiratory support to provide capillary oxygen saturation above 90%) (2) Hypotension (systolic blood pressure less than 90 mmHg or vasopressor requirement) (3) renal failure secondary to COVID-19 (according to KDIGO definition) (4) neurologic disorder secondary to COVID-19 (decrease of 2 or more scores in Glasgow Coma Scale) (5) thrombocytopenia secondary to COVID-19 (platelet count less than 150000 /mm3) (6) severe gastrointestinal symptoms secondary to COVID-19 (vomiting/diarrhea that caused at least mild dehydration). The diagnosis of COVID-19 was according to either a positive Real-Time Polymerase Chain Reaction (RT-PCR) of the respiratory tract samples or clinical signs/symptoms and imaging findings highly suspicious for COVID-19.
Open-label.
Single center, Imam Khomeini Hospital Complex, Tehran, Iran.
Clinical response was defined according to the six-category ordinal scale. The six categories are: (1) discharge (2) hospital admission, not requiring oxygen (3) hospital admission, requiring oxygen (4) hospital admission, requiring non-invasive positive pressure ventilation (5) hospital admission requiring invasive mechanical ventilation (6) death.
IFN beta-1a (n=20) vs. standard of care (n=20)
randomized controlled trial some concerns about risk of bias
IFNβ1a
IFNβ1a (Recigen) (Subcutaneous injections of 44μg (12,000 IU) ondays 1, 3, 6) plus a single dose of hydroxychloroquine 400mg and Lopinavir/Ritonavir 400mg/100 mg twice a day for 10 days.
Standard of care
Hydroxychloroquine (Single dose of 400 mg on day1, orally) and Lopinavir/Ritonavir (Kaletra) (400mg/100 mg twice a day for 10 days) .
Three arms: IFNβ1a, IFNβ1b, control group. All three groups received standards of care consisting of the necessary oxygen support, non-invasive, or invasive mechanical ventilation.
COVID-19 severe or critically
Male, non-lactating, and non-pregnant female patients with at least 18 years of age who had confirmed COVID-19, defined as a positive test of Reverse Transcriptase Polymerase-Chain Reaction (RT-PCR) with peripheral capillary oxygen saturation level (SpO2) ≤ 93% on pulse oximetry OR a respiratory frequency ≥ 24/minute while breathing ambient air] AND at least one in every of the following: contactless infrared forehead thermometer temperature of ≥ 37·8, muscle ache, rhinitis, headache, cough or fatigue onadmission AND acute onset time for the symptoms (Days ≤ 14).
Open-label.
Single center, Loghman Hakim Hospital, a leading academic hospital of Shahid Beheshti ,Tehran, Iran.
Seven-step ordinal scale: (I) Not hospitalized, and has no activity limitations; (II) Not hospitalized, but has activity limitations; (III) Hospitalized, but does not need any supplemental oxygen; (IV) Hospitalized, and needs supplemental oxygen; (V) Hospitalized, and needs either High-Flow Nasal Cannula (HFNC) or non-invasive ventilation;(VI) Hospitalized, and needs invasive ventilation; and (VII) Dead.
IFN beta-1b (n=40) vs. standard of care (n=40)
randomized controlled trial some concerns about risk of bias
Interferon β-1b.
IFN β-1b (250 mcg subcutaneously every other day for two consecutive weeks) plus national protocol medications.
National protocol medications only.
National protocol medications (lopinavir/ritonavir (400/100 mg BD) or atazanavir/ritonavir (300/100 mg daily) plus hydroxychloroquine (400 mg BD in first day and then 200 mg BD) for 7-10 days).
Both groups received national protocol medications. The national protocol consisted lopinavir/ritonavir (400/100 mg BD) or atazanavir/ritonavir (300/100 mg daily) plus hydroxychloroquine (400 mg BD in first day and then 200 mg BD) for 7–10 days. Other supportive cares such as fluid therapy, stress ulcer prophylaxis, deep vein thrombosis, treatment of electrolyte disorders and antibiotic therapy were considered according to the hospital protocols.
COVID-19 severe or critically
Adult patients (≥18 years old) with positive PCR and clinical symptoms/signs of pneumonia (including dyspnea, cough and fever),peripheral oxygen saturation (SPO2) ≤ 93% in ambient air or arterial oxygen partial pressure to fractional inspired oxygen (PaO2/ FiO2) < 300 or SPO2/FiO2 < 315 and lung involvement in chest imaging.
Open-label.
Single-center, Imam Khomeini Hospital Center in Tehran, Iran.
Clinical improvement was defined as improvement of at least two points from the baseline status on the six-category ordinal scale. This scale contains the subsequent categories: (1) death (2) hospital admission requiring invasive mechanical ventilation (3) hospital admission, requiring non-invasive positive pressure ventilation (4) hospital admission, requiring oxygen (5) hospital admission, not requiring oxygen (6) discharge.
IFN beta-1b (n=20) vs. standard of care (n=20)
randomized controlled trial some concerns about risk of bias
IFNβ1b
IFNβ1b subcutaneous injections of 8,000,000 IU on days 1, 3, 6 plus a single dose of hydroxychloroquine 400mg on the first day and Lopinavir/Ritonavir 400mg/100 mg twice a day for ten days.
Standard of care.
Hydroxychloroquine: single dose of 400 mg on day1, orally, and Lopinavir/Ritonavir (Kaletra): 400mg/100 mg twice a day for 10 days, orally.
Three arms: IFNβ1a, IFNβ1b, control group. All three groups received standards of care consisting of the necessary oxygen support, non-invasive, or invasive mechanical ventilation.
COVID-19 severe or critically
Male, non-lactating, and non-pregnant female patients with at least 18 years of age who had confirmed COVID-19, defined as a positive test of Reverse Transcriptase Polymerase-Chain Reaction (RT-PCR) with peripheral capillary oxygen saturation level (SpO2) ≤ 93% on pulse oximetry OR a respiratory frequency ≥ 24/minute while breathing ambient air] AND at least one in every of the following: contactless infrared forehead thermometer temperature of ≥ 37·8, muscle ache, rhinitis, headache, cough or fatigue onadmission AND acute onset time for the symptoms (Days ≤ 14).
Open-label.
Single center, Loghman Hakim Hospital, a leading academic hospital of Shahid Beheshti ,Tehran, Iran.
Seven-step ordinal scale: (I) Not hospitalized, and has no activity limitations; (II) Not hospitalized, but has activity limitations; (III) Hospitalized, but does not need any supplemental oxygen; (IV) Hospitalized, and needs supplemental oxygen; (V) Hospitalized, and needs either High-Flow Nasal Cannula (HFNC) or non-invasive ventilation;(VI) Hospitalized, and needs invasive ventilation; and (VII) Dead.
immunoglobulin therapy (n=30) vs. placebo (n=29)
randomized controlled trial risk of bias NA
Intravenous immunoglobulin IVIg
Intravenous immunoglobulin IVIg (human) flebogamma 5%: four vials of 5 gm5 daily for 3 consecutive days, in addition to initial treatment.
Placebo
Saline solution. in addition to initial treatment.
Initial treatment including at least both one antiviral and one chloroquine-class drug.
COVID-19 severe or critically
> 18 years of age, PCR-confirmed COVID-19 diagnosis, involvement of > than 30% of both lungs (ground-glass opacity) in high-resolution computed tomography (HRCT) (confirmed by two radiologists), O2 saturation (satO2) of < 90%, and a lack of adequate response to initial treatment including at least both one antiviral and one chloroquine-class drug. Inadequate response to initial treatment was defined as the lack of improvement of dyspnea, fever, and hypoxemia (satO2 less than 90%), as well as the need for oxygenation to maintain satO2 above 90% after 48 h of commencing treatment.
Double-blind.
Single center, Ayatollah Talegani hospital, Iran.
In the registry, main outcome variables were: improvement in o2 saturation , dyspnea, shortening of hospital stay and decreased mortality.
immunoglobulin therapy (n=52) vs. standard of care (n=32)
randomized controlled trial some concerns about risk of bias
Intravenous immunoglobulin
400 mg/kg, IV, daily for 3 days, plus standard of care. All patients in the IVIg group were premedicated with 500 mg Acetaminophen, 100 mg Hydrocortisone, and 25 mg Diphenhydramine 30 min before the injection.
Standard of care.
Hydroxychloroquine 200 mg twice daily plus Lopinavir/Ritonavir 200-50 mg 2 Tab twice daily for 7 days.
Patients in both groups received oxygen and fluid support, lopinavir/ritonavir 200/50 mg, two tablets twice a day, and hydroxychloroquine 200 mg two times daily.
COVID-19 severe or critically
Patients who are diagnosed with COVID-19 by RT-PCR test, who are severely ill, and are between 18 to 65 years old. Patients with oxygen saturation <90% (at rest with nasal cannula 3-4 L/min and FIO2<30-40 L/min) with bilateral pulmonary infiltration. Severe pneumonia cases were determined based on World Health Organization (WHO) case definitions for COVID-19 consisting of the following: respiratory rates: ≥30 breaths/min, SpO2 ≤93%, and PaO2/ FiO2 ≤300 mmHg.
Open-label.
Single center, Dr. Masih Daneshvari Hospital, Tehran, Iran.
immunoglobulin therapy (n=50) vs. standard of care (n=50)
randomized controlled trial some concerns about risk of bias
Intravenous immunoglobulin
Daily IVIg 0.4 g/kg body weight for 5 days, plus standard of care.
Standard of care
Standard of care consisted of Azithromycin; Lopinavir/ritonavir; Piperacillin plus Tazobactam; Acetaminophen and Pantocid.
All patients received standard of care.
COVID-19 severe or critically
Male or female aged ≥18 years with RT-PCR confirmed COVID-19 illness; Patients with moderate pneumonia were defined as: body temperature ≥38.0℃ or PaO2/ FiO2 100-300 mmHg or respiratory rate >24/min and oxygen saturation 90-93% on room air or lung involvement confirmed with chest X-ray.
Open-label.
Multicenter, 4 centers across India.
Phase II.
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
methylprednisolone (n=14) vs. control (n=15)
randomized controlled trial risk of bias NA
Methylprednisolone pulse
Methylprednisolone (1000 mg/day for three days, IV), and oral prednisolone 1 mg/kg with tapering of dose within ten days
Standard of care only
Kaletra (lopinavir/ritonavir) daily, Hydroxychloroquine 400 mg daily, Azithromycin 500 mg daily.
Standard of care in both groups: Kaletra (lopinavir/ritonavir) daily, Hydroxychloroquine 400 mg daily, Azithromycin 500 mg daily, oxygen therapy, nutritional support.
COVID-19 severe or critically
Double-blind
Phase 2
methylprednisolone (n=24) vs. standard of care (n=23)
randomized controlled trial some concerns about risk of bias
Methylprednisolone (high dose)
Methylprednisolone 40 mg IV every 12h for 5 days plus standard of care.
Standard of care
Standard of care only.
COVID-19 severe or critically
Adult patients with PCR confirmed COVID-19 infection, symptoms developed more than 7 days, PaO2/FiO2 < 200 mmHg, positive pressure ventilation (non-invasive or invasive) or high flow nasal cannula (HFNC) higher than 45 L/min for less than 48 hours, and requiring ICU admission.
Open-label.
Medical ICU,peking union medical college hospital, China.
Data and results come from Sterne J et al. meta-analysis and study registry. Planned sample size: 80 patients.
methylprednisolone (n=34) vs. standard of care (n=34)
randomized controlled trial high risk of bias
Methylprednisolone pulse
Methylprednisolone pulse (intravenous injection, 250 mg/day for 3 days) plus standard care.
Standard care
Hydroxychloroquine sulfate, lopinavir, and naproxen. Patients did not receive methylprednisolone or other glucocorticoids.
All patients received standard care (Hydroxychloroquine sulfate, Lopinavir, and Naproxen) for COVID-19 according to the protocol for diagnosis and treatment of COVID-19 in Iran. In the standard care group, six patients received corticosteroids by the attending physician during treatment and excluded from the ITT population.
COVID-19 severe or critically
Aged 18 years or older, confirmed COVID-19 with blood oxygen saturation <90%, elevated C-reactive protein (CRP >10), and interleukin (IL)-6 (>6) at the early pulmonary phase of disease before connecting to the ventilator and intubation and agreed to give informed consent. The diagnosis of COVID-19 in subjects was performed based on the following criteria: 1. Identification of SARS-CoV-2 via reverse transcription-polymerase chain reaction (RT-PCR) in nasopharyngeal swab or sputum samples and 2. Abnormal computed tomography (CT) scan finding (bilateral, subpleural, peripheral ground-glass opacities) with oxygen saturation <90% at rest.
Single-blind.
2 centers: Imam Khomeini Hospital and Khorshid Hospital, Iran.
Improvement was defined as BORG score>3, improved dyspnea, stopped fever for 72 hours,SO2> 93%, tolerated oral regimen (PO), normal urinary output and reduced CRP levelwithout any treatment side effects.
Phase II.
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.
stem cells (n=66) vs. placebo (n=35)
randomized controlled trial some concerns about risk of bias
Human umbilical cord mesenchymal stem cells (UC-MSCs)
UC-MSCs (4 × 107 cells per infusion) on day 0, 3 and 6.
Placebo
Saline containing 1% Human serum albumin (solution without UC-MSCs). Infusion on day 0, 3, 6.
2:1 ratio. All patients received standard of care.
COVID-19 severe or critically
Hospitalized patients with severe COVID-19 with laboratory-confirmed SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) with severe COVID-19 diagnosed after onset of disease; or chest computed tomography (CT) imaging confirmed pneumonia combined with lung damage. Patients with shock or COVID-19 combined with any one of other organ failures or who received invasive ventilation were excluded.
Double-blind.
Wuhan, China.
Phase II.
stem cells (n=12) vs. standard of care (n=29)
randomized controlled trial some concerns about risk of bias
Umbilical cord mesenchymal stem cell infusion (hUC-MSCs)
Umbilical cord mesenchymal stem cell intravenous infusion plus standard of care. Before the intravenous drip, the MSCs were suspended in 100 ml of normal saline, and the total number of transplanted cells was calculated as 2 × 106 cells/kg. The infusion was from the patients’ right cubital veins and lasted approximately 1 h (35 drops/min).
Standard treatment
Supplemental oxygen (noninvasive or invasive ventilation); antiviral agents (abidor/oseltamivir); antibiotic agents (moxifloxacin is taken orally; if there is clear evidence of bacteriological infection, the choice of antibacterial drugs is based on a drug sensitivity test), and glucocorticoid therapy (1-2 mg/kg, less than a week).
Standard treatments in both groups.
COVID-19 severe or critically
Criteria for severe disease are A) an epidemiological history; B) etiological evidence (i.e., a positive SARS-CoV-2 nucleic acid test by the real time reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 RNA from the Chinese Center for Disease Control and Prevention); AND C) CT imaging indicators of pneumonia. In addition, these factors should coincide with any of the following criteria: (a) respiratory distress, respiration rate (RR) ≥ 30 times/min; (b) oxygen saturation ≤93% in the resting state; and (c) PaO2/FiO2 ≤ 300 mmHg (1 mmHg = 0.133 kPa).
Open-label.
Single-center, Huangshi Hospital of Traditional Chinese Medicine in Hubei Province, China.
NEWS2 score and seven category ordinal scale were used to assess the clinical symptoms and conditions of the enrolled patients.
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=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=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=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=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
powered by vis.js Network