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adalimumab (n=34) vs. standard of care (n=34)
randomized controlled trial
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
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
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.
convalescent plasma treatment (n=150) vs. placebo (n=73)
randomized controlled trial
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
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=21) vs. standard of care (n=28)
randomized controlled trial
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
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
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
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=52) vs. standard of care (n=51)
randomized controlled trial
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=31) vs. standard of care (n=31)
randomized controlled trial
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
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=49) vs. standard of care (n=51)
randomized controlled trial
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=53) vs. standard of care (n=52)
randomized controlled trial
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.
dexamethasone (n=25) vs. standard of care (n=25)
randomized controlled trial
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=7) vs. standard of care (n=12)
randomized controlled trial
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
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 12mg (n=497) vs. dexamethasone 6mg (n=485)
randomized controlled trial
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
Equine polyclonal antibodies INM005
placebo
COVID-19 severe or critically
double-blind
19 hospitals of Argentina
Hydrocortisone (n=16) vs. placebo (n=14)
randomized controlled trial
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=76) vs. placebo (n=73)
randomized controlled trial
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.
IFN beta-1a (n=487) vs. placebo (n=482)
randomized controlled trial
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=20) vs. standard of care (n=20)
randomized controlled trial
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
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
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=52) vs. standard of care (n=32)
randomized controlled trial
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
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.
methylprednisolone (n=24) vs. standard of care (n=23)
randomized controlled trial
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.
ruxolitinib (n=21) vs. vitamin C (n=21)
randomized controlled trial
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=334) vs. placebo (n=86)
randomized controlled trial
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 high dose (400mg) (n=173) vs. placebo (n=86)
randomized controlled trial
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
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
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
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
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
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
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).
tocilizumab (n=301) vs. placebo (n=151)
randomized controlled trial
Tocilizumab
Single intravenous infusion of tocilizumab at a dose of 8 mg per kilogram of body weight with a maximum dose of 800 mg.
Placebo
A second dose of tocilizumab or placebo was administered to 65 patients(22.1%) in the tocilizumab group and 43 patients (29.9%) in the placebo group. All patients received standard of care.
COVID-19 severe or critically
Age >= 18 years at time of signing Informed Consent Form, hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan, SpO2 =< 93% or PaO2/FiO2 < 300 mmHg.
Double-blind.
62 hospitals in Canada, Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom, US.
The patients’ clinical status was assessed on an ordinal scale according to the following categories: 1, discharged or ready for discharge;2, hospitalization in a non–intensive care unit(ICU) without supplemental oxygen; 3, non–ICU hospitalization with supplemental oxygen; 4, ICU or non–ICU hospitalization with noninvasive ventilation or high-flow oxygen; 5, ICU hospitalization with intubation and mechanical ventilation;6, ICU hospitalization with extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; and 7, death.
tocilizumab (n=434) vs. placebo (n=215)
randomized controlled trial
Tocilizumab
Remdesivir intravenously followed by a single intravenous dose of tocilizumab 8 mg/kg (maximum, 800 mg) on day 1.
Placebo
Remdesivir intravenously followed by a single intravenous dose of placebo on day 1.
Patients with sustained fever or clinically significant worsening of signs and symptoms of COVID-19 (e.g., increased supplemental oxygen requirement) could receive a second infusion of blinded tocilizumab or placebo within 8 to 24 h of the first infusion. Systemic corticosteroids for treatment of COVID-19 pneumonia were permitted. Treatment with convalescent plasma, chloroquine or hydroxychloroquine, antivirals, biologics, and Janus kinase inhibitors during the trial was prohibited.
COVID-19 severe or critically
Patients were required tohave a positive SARS-CoV-2 polymerase chain reactiontest result within 7 days of randomization, pneumoniaconfrmed by chest x-ray or computed tomography, andhypoxemia requiring>6 L/min supplemental oxygen.
Double-blind.
Multicenter; 53 sites across Brazil, Russia, Spain, United States.
Ordinal scale categories are as follows: 1, discharged or “ready for discharge” (as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2 L/min supplemental oxygen); 2, non–ICU hospital ward, not requiring supplemental oxygen; 3, non–ICU hospital ward, requiring supplemental oxygen; 4, ICU or non–ICU hospital ward, requiring noninvasive ventilation or high-fow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; 7, death.
tocilizumab (n=65) vs. standard of care (n=64)
randomized controlled trial
Tocilizumab
Standard care plus tocilizumab (single intravenous infusion of 8 mg/kg: maximum 800 mg).
Standard care alone
The concomitant use of hydroxychloroquine, azithromycin, corticosteroids, and antibiotics was allowed according to standard care per local institutional guidelines for patients with covid-19. Remdesivir was not available in Brazil.
COVID-19 severe or critically
Severe or critical covid-19, with evidence of pulmonary infiltrates confirmed by chest computed tomography or radiography, and were receiving supplemental oxygen to maintain oxygen saturation greater than 93% or had been receiving mechanical ventilation for less than 24 hours before analysis. In addition, at least two of the following criteria had to be met: D dimer >2.74 nmol/L (>1000 ng/mL), C reactive protein >50 mg/L (>5 mg/dL), ferritin >300 μg/L, or lactate dehydrogenase greater than the upper limit of normal.
Open-label
9 hospitals in Brazil.
The seven level ordinal scale was defined as: level 1—not admitted to hospital and with no limitation in activities, level 2—not admitted to hospital but with limitation in activities, level 3—admitted to hospital and not receiving supplemental oxygen, level 4—admitted to hospital and receiving supplemental oxygen, level 5—admitted to hospital and receiving non-invasive positive pressure ventilation or high flow oxygen through a nasal cannula, level 6—admitted to hospital and receiving mechanical ventilation, and level 7—death.
data monitoring committee recommended stopping the trial early because of an increase of deaths at 15 days in the tocilizumab group
tocilizumab (n=49) vs. standard of care (n=43)
randomized controlled trial
Tocilizumab
Single intravenous infusion of Tocilizumab (at a dose of 8 mg per kilogram of body weight), plus usual care, on day 1 and on day 3 if clinically indicated.
usual care alone
usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants
COVID-19 severe or critically
Adults (18 and older) with respiratory failure AND (requiring mechanical ventilation OR NIV OR High flow), WHO progression scale >=6, No do-not-resuscitate order (DNR order).
Open-label.
9 university hospitals in France.
Unpublished study. Results and risk of bias assessment were extracted from the WHO REACT working group meta-analysis: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330.
tocilizumab (n=20) vs. standard of care (n=20)
randomized controlled trial
Tocilizumab
Usual care plus tocilizumab 8mg/kg, 1 or 2 dosages (if the patient’s conditions were not stable, 2 doses by 12 hours were administrated, maximum dose: 800 mg).
Usual care
Usual care alone.
All patients received usual care for the disease based on the Iranian protocol for diagnosis and treatment of COVID-19
COVID-19 severe or critically
COVID-19 patients confirmed by positive PCR test for SARS-CoV-19 or confirmed by abnormal CT scan finding (bilateral, sub pleural, peripheral ground glass opacities), With blood oxygen saturation <93%, or respiratory rate> 24 high CRP rate, lymphopenia < 1100 not responding to standard COVID-19 treatment and not connecting to the mechanical ventilator.
Double-blind.
2 centers; Imam Khomeini and Shariati Hospital, Tehran University of Medical Sciences, Iran.
Phase II
tocilizumab (n=64) vs. standard of care (n=67)
randomized controlled trial
Tocilizumab
Single intravenous infusion of Tocilizumab (at a dose of 8 mg per kilogram of body weight), plus usual care, on day 1 and on day 3 if clinically indicated.
usual care alone
usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants
COVID-19 severe or critically
patients withCOVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen butwithout ventilation or admission to the intensive care unit
Open-label.
9 university hospitals in France
tocilizumab (n=353) vs. standard of care (n=402)
randomized controlled trial
tocilizumab (8mg/kg)
standard care
3 arms : tocilizumab (8mg/kg) or sarilumab (400mg) and control (standard care)
COVID-19 severe or critically
open-label
bayesian trial with a neurol prior (not necessary uninformative) and borrowing between the two tested treatment
tocilizumab (n=48) vs. tocilizumab (n=49)
randomized controlled trial
1 dose tocilizumab 4 mg/kg SOC
1 dose tocilizumab 8 mg/kg SOC
standard of car : antiviral treatment, low-dose corticosteroids, and supportive care
An additional infusion (same as initial dose) could be administered 8 to 24 hours after the first if a patient had a sustained fever or clinically significantworsening of signs or symptoms, such as an increased supplemental oxygen requirement
COVID-19 severe or critically
Patients who were on invasive ventilation >24 hours, on ECMO, in shock, or with multiorgan failure requiring treatment in an intensive care unit were excluded.
open-label
24 centers, USA
phase 2 study. Randomization was stratified by pneumonia severity (moderate or severe). Efficacy outcomes were exploratory
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