meta|Evidence - COVID-19
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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.
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.*
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.
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
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=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=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=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=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=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=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=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=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=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=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=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=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=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=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=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=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=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=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
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=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=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=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=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=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=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=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).
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.
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.
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
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.
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.
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).
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.
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.
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.
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=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=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=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=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=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=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=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=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.
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=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.
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
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=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.
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.
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=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.
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.
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