meta|Evidence - COVID-19
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chloroquine (n=18) vs. standard of care (n=12)
randomized controlled trial high risk of bias
chloroquine
chloroquine phosphate group: First dose of chloroquine phosphate 1 g first day, then 0.5g × 9 days
standard of care
according to the Chinese Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th Edition)
3 arms chloroquine, hydroxychloroquine and SoC
COVID 19 all comers
open-label
China, single center
Study planned to recruit 100 subjects with confirmed mild/moderate types ofCOVID-19. Study discontinuated after enrolling only 67 subjects with mild/moderate COVID-19Publication report only data on 48 patients with moderate type of COVID-19
darunavir cobicistat (n=15) vs. standard of care (n=15)
randomized controlled trial high risk of bias
Darunavir and cobicistat
1 pill of darunavir/cobicistat (a single-tablet regimen containing 800 mg of darunavir and 150 mg of cobicistat) per day for 5 days.
Conventional treatments
Patients did not receive oral antiviral drugs.
All the participants received interferon alpha 2b and standard of care as per guideline recommendation in China.
COVID 19 all comers
Diagnosed as pneumonia caused by 2019-ncoV, according to the notice on printing and distributing the diagnosis and treatment plan of pneumonia with new coronavirus infection made by national health commission of the people's republic of China.
Open-label.
Single-center, Shanghai Public Health Clinical Center, China.
After randomization, respiratory samples were collected every 1–2 days until viral clearance. Viral clearance was defined as reverse transcriptase polymerase chain reaction (RT-PCR) negative on at least 2 consecutive oropharyngeal swabs collected at least 1–2 days apart.
Pilot study.
favipiravir (n=44) vs. favipiravir (n=45)
randomized controlled trial high risk of bias
immediate favipiravir
favipiravir administered orally between day 1 and day 10, 1800 mg twice a day on day 1 followed by 800 mg twice a day from day 2
delayed favipiravir
favipiravir administered orally between day 6 and day 15, 1800 mg twice a day on day 6 followed by 800 mg twice a day from day 7
COVID 19 all comers
asymptomatic and minimally symptomatic patientsRT-PCR test positive
open label
25 centres, japan
favipiravir (n=10) vs. standard of care (n=10)
randomized controlled trial some concerns about risk of bias
favipiravir
The first dose was 1600 mg or 2200mg orally, followed by 600 mg each time, three times a day, and the duration of administration was not more than 14 days
standard treatment
antiviral treatment included lopinavir/ritonavir (400 mg/100 mg, bid, po.) or darunavir/cobicistat (800 mg/150 mg, qd, po.) and arbidol (200 mg, tid, po.
3 arms: favipiravir (n=10), baloxavir marboxil (n=10), current antiviral treatment (n=10)
COVID 19 all comers
exclusion of considered as severe disease: has an ongoing respiratory deficiency and subjected to invasive mechanical ventilation; or presence of shock; or admitted to the ICU due to complications;
open-label, randomized
1 center, China
Time to clinical improvement was defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven category ordinal scale or live discharge from the hospital, whichever came first.
favipiravir (n=-9) vs. tocilizumab (n=-9)
randomized controlled trial some concerns about risk of bias
favipavir
Favipiravir: On the 1st day, 1600mg each time, twice a day; from the 2nd to the 7th day, 600mg each time, twice a day
tocilizumab
1 dose 4-8 mg/kg (max 400mg). 2nd dose within 24h if persistent fever
COVID 19 all comers
open label
10 centres, China
3 arms : Favipiravir Combined With Tocilizumab ; Favipiravir; Tocilizumab
favipiravir (n=120) vs. umifenovir (arbidol) (n=120)
randomized controlled trial some concerns about risk of bias
favipiravir
favipiravir tablets (1600 mg/time on the first day, twice a day; 600 mg/time from the second day to the end of the experiment, twice a day)
umifenovir
umifenovir (200 mg each time, 3 times a day, from the first day to the end of the trial)
COVID 19 all comers
double-blind
China, 3 hospitals
Clinical recovery was defined as continuous (>72 hours) recovery of body temperature, respiratory rate, oxygen saturation and cough relief after treatment
Some incorrectness in the paper (for example in the result table (table 2), it is not the rate ratio that is reported but the risk difference). Arise some concern about a selective reporting.
hydroxychloroquine (n=18) vs. standard of care (n=12)
randomized controlled trial high risk of bias
hydroxychloroquine
Hydroxychloroquine sulfate group 0.2 g BID × 10 days
standard of care
according to the Chinese Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (5th Edition)
COVID 19 all comers
open-label
China, single center
Study planned to recruit 100 subjects with confirmed mild/moderate types ofCOVID-19. Study discontinuated after enrolling only 67 subjects with mild/moderate COVID-19Publication report only data on 48 patients with moderate type of COVID-19
nirmatrelvir / ritonavir (Paxlovid) (n=1140) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
paxlovid
placebo
COVID 19 all comers
double blind
interim results from pfizer press release https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results
remdesivir (n=43) vs. standard of care (n=58)
randomized controlled trial some concerns about risk of bias
Remdesivir
Standard of care plus 200 mg of intravenous remdesivir on day 1, then 100 mg daily up to 9 days. All study treatments were discontinued at discharge.
Standard care
Local SoC.
3 arms: hydroxychloroquine, remdesivir and standard of care. During the study, local SoC changed as the RECOVERY trial and updated WHO guidelines recommending systemic steroids for severe and critical COVID-19.
COVID 19 all comers
Adult patients (≥18 years) with SARS-CoV-2 infection confirmed by PCR who were admitted to the hospital ward or intensive care unit (ICU) with no anticipated transfer to a nonstudy hospital within 72 hours of inclusion. Informed consent by the study participant or legally authorized representative was provided before inclusion.
Open-label.
23 hospitals in Norway.
From 8 June 2020 on, NOR-Solidarity allocated patients only to SoC and remdesivir (hydroxychloroquine removed because of lack of evidence of its effectiveness).
Add-on Solidarity trial.
remdesivir (n=43) vs. standard of care (n=58)
randomized controlled trial low risk of bias
Remdesivir
Standard of care plus intravenous remdesivir 400 mg on day 1, then 200 mg daily up to 9 days.
Standard of care
Local SoC.
3 arms: remdesivir, hydroxychloroquine, standard of care. All study treatments were stopped at discharge. During the course of the study, local SoC changed as a result of the RECOVERY trial and updated WHO guidelines recommending systemic steroids for severe and critical COVID-19 (September 4th 2020).
COVID 19 all comers
adult patients (≥18 years), with confirmed SARS-2-CoV-2 infection by PCR, admitted to the hospital ward or the intensive care unit (ICU), with no anticipated transfer to a non-study hospital within 72 hours of inclusion. Informed consent by the study subject or legally authorized representative was provided prior to inclusion.
Open-label.
23 hospitals in Norway.
umifenovir (arbidol) (n=16) vs. standard of care (n=7)
randomized controlled trial some concerns about risk of bias
arbidol
arbidol (100mg) (oral, 200mg TID for 7-14 days)
standard care
3 arms : lopinavir/ritonavir; arbidol and standard care
COVID 19 all comers
open-label
China, single center
azithromycin (n=56) vs. standard of care (n=55)
randomized controlled trial some concerns about risk of bias
azithromycine plus lopinavir/ritonavir plus hydroxychloroquine
oral AZM 500 mg daily, oral LPV/r 400/100 mg twice daily and oral HCQ 400 mg daily for 5 days
lopinavir/ritonavir plus hydroxychloroquine
oral LPV/r 400/100 mg twice daily and oral HCQ 400 mg daily for 5 days
COVID 19 hospitalized
open label
1 center, Iran
azithromycin (n=2582) vs. standard of care (n=5181)
randomized controlled trial some concerns about risk of bias
azithromycin
azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge. 16% received another macrolide
standard of care
COVID 19 hospitalized
open label
176 centres, UK
azithromycin plus hydroxychloroquine (n=61) vs. placebo (n=56)
randomized controlled trial low risk of bias
Hydroxychloroquine plus azithromycin
500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice daily hydroxychloroquine for all 15 days.
Placebo/Placebo
Matching placebo capsules
All patients in both groups received standard assessment and treatment is based on organ supportive therapy such as oxygen therapy (central), fluid therapy, antibiotic therapy for secondary infections. If the disease progress to severe acute respiratory failure, the patients will often require referral to an intensive care unit for mechanical ventilation.
COVID 19 hospitalized
Patients ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive SARS-CoV-2 RT-PCR test. Patients receiving more than 5 L oxygen supply were excluded.
Double-blind.
Multicenter; 6 hospitals in Denmark.
Phase 2.
After randomisation of 117 patients (50%), at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria.
baloxavir marboxil (n=10) vs. standard of care (n=10)
randomized controlled trial some concerns about risk of bias
Baloxavir marboxil
80 mg once a day orally on Day 1 and Day 4; for patients who are still positive in virological test, they can be given again on Day 7, no more than three additional doses.
Standard antiviral treatment
The existing antiviral treatment included lopinavir/ritonavir (400mg/100mg, bid, po.) or darunavir/cobicistat (800mg/150mg, qd, po.) and arbidol (200mg, tid, po.). All of them were used in combination with interferon-α inhalation (100,000 iu, tid or qid).
3 arms: favipiravir (n = 10), baloxavir marboxil (n=10), current antiviral treatment (n=10). Standard of care in both groups.
COVID 19 hospitalized
Adults 18-85 years of age, either man or woman, who have signed the informed consent voluntarily, with confirmed as COVID-19: positive results of throat swab or blood samples by real-time RT-PCR assay for 2019-nCoV; no difficulty in swallowing oral drugs; ability to follow the protocol according to the judgment of researchers. Subjects excluded if they had critical illness meeting one of the following conditions: respiratory failure and mechanical ventilation; shock; other organ failure requiring ICU monitoring and treatment;
Open-label
Single center, in The First Affiliated Hospital, Zhejiang University School of Medicine, China.
Time from randomization to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first.
No statistical plan available.
bromhexine (n=39) vs. standard of care (n=39)
randomized controlled trial high risk of bias
Bromhexine hydrochloride.
Oral bromhexine hydrochloride 8 mg three times a day for two weeks in addition to standard therapy.
Standard of care.
Iranian national COVID-19 treatment protocol and hydroxychloroquine 200 mg/d for two weeks, in addition to supportive and symptomatic therapy.
COVID 19 hospitalized
18 years old or older patients with chest imaging and clinical symptoms consistent with COVID-19 pneumonia. The diagnosis of COVID-19 pneumonia was made by a board-certified pulmonologist based on clinical symptomsand signs, as well as chest CT findings compatible with the COVID-19 pneumonia pattern.
Open-label.
Single center, University Hospital, Tabriz, Iran.
Several inaccuracies and incorrectness in the text, the p value reported are one sided without it was specified,
bromhexine (n=59) vs. standard of care (n=52)
- high risk of bias
Bromhexine
Oral bromhexine hydrochloride 8mg four times a day for 2 weeks in addition of standard therapy.
Standard of care
Lopinavir/ritonavir 400/100 two times per day for 7 days or discharge from hospital and interferon beta-1a 44 μg subcutaneous every other day for five doses in addition to supportive and symptomatic therapy.
All patients received standard of care based on the hospital COVID-19 treatment protocol and best practice guidelines in place at that time.
COVID 19 hospitalized
hospital admission,18 years old or greater at the time of signing the informedconsent, chest imaging and clinical symptoms consistentwith COVID-19 pneumonia, laboratory (reverse transcription polymerase chain reaction (RT-PCR)) confirmed infection with 2019-nCoV, willingness to participate in the study,and no concurrent participation in other clinical trials.
Open-label
Single center, Masih Daneshvari Hospital, Iran.
The primary outcome was clinical improvement within 28 days. Clinical improvement was defined as the time (in days) from initiation of the study treatment (active or placebo) until a decline of two categories on a clinical status scale occurred. The six-category ordinal scale of clinical status which ranged from hospital discharge to death and is itemized as follows:(1) hospital discharge or meeting discharge criteria (discharge criteria are defined as clinical recovery, ie, fever, respiratory rate, oxygen saturation returning to normal, and coughrelief); (2) non-intensive care unit (ICU) hospitalization, notrequiring supplemental oxygen; (3) non-ICU hospitalization, requiring supplemental oxygen (but not noninvasive ventilation/high-flow nasal cannula); (4) ICU/non-ICU hospitalization, requiring noninvasive ventilation/high-flow nasal cannula therapy; (5) ICU hospitalization, requiring invasive mechanical ventilation; and (6) death.
chloroquine (n=10) vs. lopinavir/ritonavir (n=12)
randomized controlled trial some concerns about risk of bias
chloroquine 500 mg orally twice daily for 10 days
Lopinavir/Ritonavir 400/100 mg orally twice daily for 10 days
COVID 19 hospitalized
open label
China, Zhuhai
Fifth Affiliated Hospital of Sun Yat-sen University in Zhuhai
Emtricitabine/tenofovir plus colchicine plus rosuvastatin (n=163) vs. standard of care (n=162)
randomized controlled trial some concerns about risk of bias
Colchicine plus rosuvastatin
Emtricitabine (200 mg) plus tenofovir disoproxil (300 mg), once a day for 10 days PO, plus colchicine, 0.5 mg twice a day, plus rosuvastatin, 40 mg once a day for 14 days PO.
Standard of care
The standard of care follows the recommendations of the Colombian Consensus forCovid-19 Treatment in Hospitalized Patients,21 consisting of the use of dexamethasone,antiparasitic treatment (ivermectin or albendazole), enoxaparin, acetaminophen, oxygen asneeded, and supportive treatment for organ failure (i.e., use mechanical ventilation, ordialysis).
COVID 19 hospitalized
Adults aged 18 years or more, with a positive real-time polymerase chain reaction (RT-PCR) or with high suspicion of SARS CoV-2 by clinical criteria and a diagnosis of mild, severe, or critical pneumonia, requiring hospital management in six high complexity referral hospitals located in Bogota.
Open-label.
6 hospitals in Bogota, Colombia.
Relative Risks adjusted for age, sex, and severity of pneumonia using g Log-binomial General Estimating Equation models, assuming exchangeable correlation structure with each center as a cluster.
favipiravir (n=75) vs. standard of care (n=75)
randomized controlled trial some concerns about risk of bias
favipiravir
3,600 mg (1,800 mg BID) (Day 1) 1,600 mg (800 mg BID) (Day 2 or later) for up to maximum of 14 days
sandard of care
Drugs thought to have antiviral activity against SARS CoV2 (including hydroxychloroquine) were prohibited
COVID 19 hospitalized
open label
12 centres, India
Clinical cure was based on clinician assessment and defined as recovery of fever (axillary temperature ≤97.8°F), respiratory rate of ≤20 breaths/minute, oxygen saturation ≥98% without oxygen supplementation (which was later revised to align with the discharge criterion of ≥95% oxygen saturation issued by the Indian Ministry of Health prior to the start of the study), and cough relief (mild or no cough) maintained for ≥72 hours.
favipiravir (n=20) vs. standard of care (n=20)
randomized controlled trial some concerns about risk of bias
favipiravir
Favipiravir 1600 mg twice a day (BID) on Day 1 followed by 600 mg BID on Days 2-14 (1600/600 mg), or Favipiravir 1800 mg BID on Day 1 followed by 800 mg BID on Days 2-14 (1800/800 mg)
standard of care
COVID 19 hospitalized
open label
6 centres, Russia
adaptative phase II/III3 arms : favipiravir low dose, or favipiravir high dose or SOC
hydroxychloroquine (n=42) vs. azithromycin (n=43)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
hydroxychloroquine 400 mg by mouth twice daily for 1 day, then 200 mg by mouth twice daily for 4 days (dose reductions for weight < 45 kg or GFR (glomerular filtration rate)<50ml/min)
azithromycin
azithromycin 500 mg on day 1 plus 250 mg daily on days 2-5 (may be administered intravenously per clinician preference). if the patient has already received azithromycin prior to randomization, the prior doses will count toward the 5-day total
COVID 19 hospitalized
enrolled within 48 hours of hospital admissioncurrent known Qtc>500 msec
open label
united states, 13 centres
300 participants. Trial was stopped early afterenrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded
hydroxychloroquine (n=242) vs. placebo (n=237)
randomized controlled trial low risk of bias
hydroxychloroquine
hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses)
placebo
COVID 19 hospitalized
hospitalized for less than 48 hours with laboratory-confirmed SARS-CoV-2 infection andsymptoms of respiratory illness for less than 10 days were enrolled
double-blind, randomized
US, 34 centers
trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. The scale consisted of 7 mutually exclusivecategories: 1, death; 2, hospitalized, receiving extracorporealmembrane oxygenation (ECMO) or invasive mechanicalventilation; 3, hospitalized, receiving noninvasive mechanicalventilation or nasal high-flow oxygen therapy; 4, hospitalized,receiving supplemental oxygen without positivepressure or high flow; 5, hospitalized, not receiving supplementaloxygen; 6, not hospitalized and unable to performnormal activities; and 7, not hospitalized and able to performnormal activities.
hydroxychloroquine (n=67) vs. placebo (n=61)
randomized controlled trial some concerns about risk of bias
hydroxyxhloroquine
2x400 mg on day 1, then 2x200mg/day for 4 days
placebo
COVID 19 hospitalized
626 patients would need to be enrolled to provide 80% power
double blind
2 centres, USA
Randomization was stratified by age (>60 years old) and study site
hydroxychloroquine (n=124) vs. placebo (n=123)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
2x400 mg Day 1 , then 2x200mg/d for 8 days
placebo
COVID 19 hospitalized
double blind
34 centres, France
The trial was stopped after 250 patients were included due to a slowdown of the pandemic in France
hydroxychloroquine (n=33) vs. placebo (n=37)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
400 mg every 12 hours on the first day, followed by 200 mg every 12 hours for another 4 days
Placebo
COVID 19 hospitalized
Patients with 1) positive RT-PCR for SARS-CoV-2 by nasal and oropharyngeal swabbing, 2) Pneumonia, diagnosed by X-ray or high-resolution chest CTscan, with a pattern suggesting involvement due to coronavirus, 3) Recently established hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heartdisease. Patients were excluded if they required high oxygen volumes (face mask > 10 L/ min), if they had predictors of a poor response to high-flow oxygen nasal prong therapy or if they required mechanical ventilation.
Double-blind.
Single center, Mexico.
3 arms : hydroxychloroquine, ivermectin, or placebo.study interrupted early only 108 patients included out of 200 patients anticipated
hydroxychloroquine (n=75) vs. standard of care (n=75)
randomized controlled trial high risk of bias
hydroxychloroquine 800mg
hydroxychloroquine loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days for 2 or 3 weeks
standard of care
COVID 19 hospitalized
open label
16 centers in China
prematurely discontinuated for efficacy on secondary post hoc criteria, no adjustment for multiplicity
lesser included patients than the 200 initialy planned. Several criteria were uninterpretable because not all patients included were appropriate for measuring these criteria
hydroxychloroquine (n=2) vs. standard of care (n=3)
randomized controlled trial risk of bias NA
hydroxychloroquine azi
drug: hydroxychloroquinehydroxychloroquine will be administered orally or via feeding tube at a dosage of 800 mg on day 1, followed by 600 mg daily on days 2-5
standard of care azithromycin
factorial design with azithromycin
COVID 19 hospitalized
hospitalized patients with confirmed SARS-coV-2 infection
open label
united states
pragmatic factorial randomized trial
Found in Afors et al
hydroxychloroquine (n=1561) vs. standard of care (n=3155)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
400mg after loading dose
no additional treatment.
Factorial design, 5 arms for the first randomisation and convalescent plasma for the second randomisation
COVID 19 hospitalized
open-label
175 NHS hospitals in the UK
hydroxychloroquine (n=947) vs. standard of care (n=906)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
Day 1 H0 800 mg, H6 800 mg then since H12 400 mg twice daily for 10 days
standard of care
COVID 19 hospitalized
open label
405 hospitals in 30 countries
7 June 2020 : WHO announced that the hydroxychloroquine (HCQ) arm of the Solidarity Trial to find an effective COVID-19 treatment was being stopped,18 June 2020 : Hydroxychloroquine arm was discontinued for futility
hydroxychloroquine (n=21) vs. standard of care (n=12)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
HCQ 400 mg twice for 1 d and HCQ 200 mg twice daily for 6 days
standard of care
supportive treatment for subjects with mild clinical COVID-19 symptoms and antimicrobial therapy for subjects presenting with moderate clinical COVID-19 symptoms
AZI co-administration allowed. only 1 patient 1 HCQ group and 2 in control group
COVID 19 hospitalized
Patient stratified into three groups : mild illness, moderate illness and severe illness. Patient with severe illness were excluded from this study
open-label
11 designated public hospitals in Taiwan
Publication present results of RCT and a retrospective study (medical records). In the retrospective study, 12 (42.9%) in the HCQ group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 (p = 0.70).
hydroxychloroquine (n=27) vs. standard of care (n=26)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
400 mg twice daily for seven days
standard of care
COVID 19 hospitalized
open label
1 center, Norway
hydroxychloroquine (n=97) vs. standard of care (n=97)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
hydroxychloroquine added to standard care400 mg twice daily (in day 1) followed by 200 mg tablets twice daily for 15 days
standard of care
Standard of care : standard of care : paracetamol, oxygen, fluids (according to assessment), empiric antibiotic (cephalosporins), oseltamivir if needed (75 mg/ 12 hours for 5 days), and invasive mechanical ventilation with hydrocortisone for severe cases
COVID 19 hospitalized
patients with cardiac problem (chronic heart failure or prolonged QT interval on electrocardiogram [ECG]) were excluded from the study.
open-label
three major university hospitals in Egypt
randomization by strate
hydroxychloroquine (n=-9) vs. standard of care (n=-9)
randomized controlled trial risk of bias NA
COVID 19 hospitalized
double blinded
hydroxychloroquine (n=4) vs. standard of care (n=2)
randomized controlled trial risk of bias NA
hydroxychloroquine
800 mg on day 1, followed by 600 mg daily on days 2-5
standard of care
4 arms : standard of care, HCQ, AZI HCQ, AZI
COVID 19 hospitalized
open- label
4 centers, USA
hydroxychloroquine (n=9) vs. standard of care (n=6)
randomized controlled trial risk of bias NA
hydroxychloroquine
loading dose 400mg bid followed by 200mg twice a day; total treatment duration 5 days
standard of care
no antiviral
COVID 19 hospitalized
open label
Netherlans
found in Axfors et al. meta-analysis
hydroxychloroquine (n=-9) vs. standard of care (n=-9)
randomized controlled trial risk of bias NA
hydroxychloroquine azithromycine
600 mg/d for 5 days
azithromycine
COVID 19 hospitalized
open label
11 centers, Pakistan
found in Axfors et al meta analysis
hydroxychloroquine (n=10) vs. standard of care (n=6)
randomized controlled trial risk of bias NA
hydroxychloroquine
400 mg 2x day on day 1, followed by 200 mg 2x day days 2-5
standard of care
COVID 19 hospitalized
open-label
1 center, Hawaii
found in Axfors et al. meta-analysis
hydroxychloroquine (n=62) vs. standard of care (n=63)
randomized controlled trial risk of bias NA
hydroxychloroquine oseltamivir
600 mg/d for 5 days
oseltamivir
COVID 19 hospitalized
open label
11 centers, Pakistan
found in Axfors et al meta analysis
hydroxychloroquine plus macrolides (n=-9) vs. standard of care (n=2)
randomized controlled trial risk of bias NA
hydroxychloroquine
800 mg on day 1, followed by 600 mg daily on days 2-5
standard of care
4 arms : standard of care, HCQ, AZI HCQ, AZI
COVID 19 hospitalized
open- label
4 centers, USA
ivermectin (n=36) vs. placebo (n=37)
randomized controlled trial some concerns about risk of bias
ivermectine
Single dose :12 mg in patients weighing less than 80 kg and 18 mg in those above 80 kg
Placebo
COVID 19 hospitalized
Patients with 1) positive RT-PCR for SARS-CoV-2 by nasal and oropharyngeal swabbing, 2) Pneumonia, diagnosed by X-ray or high-resolution chest CTscan, with a pattern suggesting involvement due to coronavirus, 3) Recently established hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heartdisease. Patients were excluded if they required high oxygen volumes (face mask > 10 L/ min), if they had predictors of a poor response to high-flow oxygen nasal prong therapy or if they required mechanical ventilation.
Double-blind.
Single center, Mexico.
3 arms : hydroxychloroquine, ivermectin, or placebo.study interrupted early only 108 patients included out of 200 patients anticipated
ivermectin plus doxycycline (n=70) vs. standard of care (n=70)
randomized controlled trial some concerns about risk of bias
ivermectin doxycycline
200ug/kg PO of Ivermectin per day for 2-3 days along with 100mg PO doxycycline twice per day for 5-10 days
standard of care
COVID 19 hospitalized
single blind
2 centres, Iraq
recovery of COVID-19 patients was based on the disappearance of symptoms, clearance of radiological chest x-ray or Ct-scans, and getting negative PCR results.
lopinavir/ritonavir (n=1616) vs. standard of care (n=3424)
randomized controlled trial some concerns about risk of bias
lopinavir-ritonavir
400 mg and 100 mg, respectively, by mouth for 10 days or until discharge, plus standard of care.
Standard of care
Standard of care alone.
Standard care in both groups.
COVID 19 hospitalized
Open-label
175 NHS hospitals in UK
lopinavir/ritonavir (n=1399) vs. standard of care (n=1372)
randomized controlled trial some concerns about risk of bias
Lopinavir-ritonavir
Two tablets twice daily for 14 days. Each tablet contained 200mg Lopinavir (plus 50mg Ritonavir, to slow hepatic clearance of Lopinavir). Other formulations were not provided, so ventilated patients received no study Lopinavir while unable to swallow.
Standard of care.
Local standard of care alone.
COVID 19 hospitalized
age ≥18 years, hospitalized with a diagnosis of COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours, and, in the physician’s view, with no contra-indication to any study drug
Open-label
405 hospitals in 30 countries
Mortality during the original episode of hospitalization (follow-up ceased at discharge) not only in all patients but also in those with moderate COVID and in those with severe COVID (subsequently defined as ventilated when randomized).
lopinavir/ritonavir (n=-9) vs. standard of care (n=-9)
randomized controlled trial some concerns about risk of bias
Lopinavir-ritonavir
SoC plus lopinavir-ritonavir (400 mg lopinavir and 100 mg ritonavir orally twice a day for 14 days).
Standard of care
4 arms (1:1:1:1 ratio): SoC, lopinavir-ritonavir, lopinavir-ritonavir plus interferon, hydroxychloroquine. Supportive treatments: corticosteroids, anticoagulants or immunomodulatory agents were allowed, but not antivirals.
COVID 19 hospitalized
Open-label.
30 sites in France and 2 sites in Luxembourg.
Clinical status was measured on a 7-point ordinal scale: (1) not hospitalized, no limitation 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; (7) death.
lopinavir/ritonavir (n=50) vs. umifenovir (arbidol) (n=50)
randomized controlled trial some concerns about risk of bias
Lopinavir-ritonavir
Hydroxychloroquine (400 mg just on first day) followed by 400 mg Kaletra (Lopinavir-ritonavir) BD
Arbidol (umifenovir)
Hydroxychloroquine (400 mg BD on first day followed by 200 mg BD) followed by ARB (200 mg TDS) 7 to 14 days based on the severity of disease.
HCQ in both groups.
COVID 19 hospitalized
Open-label
single center, teaching hospital of Iran University of medical Sciences (IUMS), Tehran, Iran.
The criteria of improvement were relief of cough, dyspnea and fever.
lopinavir/ritonavir plus interferon ß-1a (n=145) vs. standard of care (n=148)
randomized controlled trial some concerns about risk of bias
Lopinavir/ritonavir plus interferon beta-1a
Standard of care plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir orally twice on day for 14 days) plus IFN-ß-1a (44 µg of subcutaneous IFN-ß-1a on days 1, 3, and 6).
Standard of care
Supportive treatments corticosteroids, anticoagulants or immunomodulatory agents were allowed except antivirals.
COVID 19 hospitalized
Open-label.
30 sites in France and 2 in Luxembourg.
The 7-point ordinal scale was defined as: 1. Not hospitalized, no limitation 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; 7. Death.
Add-on trial to Solidarity.
niclosamide (n=75) vs. standard of care (n=75)
randomized controlled trial some concerns about risk of bias
Niclosamide (NCS)
Standard of care plus NCS: NCS 2 grams orally loading dose chewable then 1g every 12 hours were admisntered in the first day, then on the 2nd day; 1g x3 for 7 days. (Only in the first day 4 gm/d then on the second day 3g/d in 3 divided doses for 7 days).
Standard of care
SoC only.
Standard of care inluded all or some of thr following, according to the clinical condition of each patient: Acetaminophen, vitamin C, zinc, ivermectin, doxycyclin, favipiravir, vitamin D3, azithromycin, oxygen therapy, dexamethasone or methylprednisolone, mechanical ventilation.
COVID 19 hospitalized
Patients with age above 18 years and of any gender with a definite diagnosis of COVID-19 according to the WHO classification criteria. Patients symptomatic for no more than three days for mild-moderate cases, no more than two days after being severe cases, and no more than one day after being critical cases.
Open-label.
2 hospitals in Baghdad city, Iraq.
The physician will check for the following: Fever: axillary temperature ≤36.6 ◦C or oral temperature ≤37.2 ◦C; Respiratory rate: ≤24/minute on room air; Oxygen saturation: >94% on room air; Cough: mild or absent on a patient reported scale of severe, moderate, mild, absent.) and elevated D-dimer, C reactive pro-tein, ferritin, thrombocyte, PT, aPTT, and fibrinogen were associated with a poor outcome in COVID19. These parameters will be checked on day 1 and day 3
remdesivir (n=541) vs. placebo (n=521)
randomized controlled trial some concerns about risk of bias
Remdesivir
200 mg of remdesivir administered intravenously on day 1, followed by a 100 mg once-daily maintenance dose of remdesivir for the duration of the hospitalization up to a 10 days total course
Placebo
COVID 19 hospitalized
At least one of the following criteria : radiographic infiltrates by imaging OR clinical assessment (evidence of rales/crackles on exam) AND spO2 < / = 94% on room air, OR requiring supplemental oxygen, OR requiring mechanical ventilation
Double-blind.
68 sites in US, Europe and Asia
Adaptative trial : there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. Primary endpoint change (initially it was percentage of subjects reporting each severity rating on an 8-point ordinal scale at D15). The categories of the clinical scale are as follows: 1, not hospitalized and no limitations of activities; 2,not hospitalized, with limitation of activities,home oxygen requirement, or both; 3, hospitalized,not requiring supplemental oxygen and nolonger requiring ongoing medical care (used if hospitalization was extended for infection-controlor other nonmedical reasons); 4, hospitalized,not requiring supplemental oxygen but requiringongoing medical care (related to Covid-19or to other medical conditions); 5, hospitalized,requiring any supplemental oxygen; 6, hospitalized,requiring noninvasive ventilation or use ofhigh-flow oxygen devices; 7, hospitalized, receivinginvasive mechanical ventilation or extracorporealmembrane oxygenation (ECMO); and 8,death.
Preliminary results from unplanned interim analysis (with no adjustement for multiplicity).
remdesivir (n=429) vs. standard of care (n=428)
randomized controlled trial some concerns about risk of bias
Remdesivir
Usual standard care in combination with intravenous remdesivir: 200mg on day 1 followed by a 100 mg 1-hour infusion once-daily for a total duration of 10 days. Its cessation was allowed after 5 days if the participant was discharged from the hospital.
Standard of care
Standard of care alone.
Corticosteroids and anticoagulants were added to the SoC on October 1st, 2020. Other supportive treatments, such as immunomodulatory agents, were allowed in all arms and left to the investigator’s discretion.
COVID 19 hospitalized
Laboratory-confirmed SARS-coV-2 infection as determined by PCR, or other commercial or public health assay in any specimen < 72 hours prior to randomization hospitalized patients with illness of any duration, and at least one of the following:clinical assessment (evidence of rales/crackles on exam) AND spO2 ≤ 94% on room air, OR acute respiratory failure requiring mechanical ventilation and/or supplemental oxygen.
Open-label.
48 sites in 5 European countries (France, Belgium, Portugal, Austria, Luxembourg).
7-point ordinal scale: 1. Not hospitalized, no limitation 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 extracorporeal membrane oxygenation (ECMO); 7. Dead.
updated with final results
remdesivir (n=2750) vs. standard of care (n=2725)
randomized controlled trial some concerns about risk of bias
Remdesivir
Intravenous remdesivir; 200mg at day 1, then 100 mg once daily for 9 days.
Standard care only
COVID 19 hospitalized
age ≥18 years, hospitalized with a diagnosis of COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours, and, in the physician’s view, with no contra-indication to any study drug
Open-label.
405 hospitals in 30 countries.
remdesivir (n=41) vs. standard of care (n=41)
randomized controlled trial some concerns about risk of bias
Remdesivir
Intravenous (IV) remdesivir for five days plus the standard care (SC). IV 200 mg remdesivir on day 1, followed by 100 mg of remdesivir once daily for the subsequent four days.
Standard of care
Both treatment groups continued supportive therapy throughout the duration of the study. Drugslike corticosteroids and heparin were given as per SC protocol. 1 cross-over: from remdesivir group to control group (after four days of admission).
COVID 19 hospitalized
Hospitalised patients who were between 18 and 60 years age group and had SARS-CoV-2infection confirmed by polymerase-chain-reaction assay within the last 4 days. All participating patients in the study had radiographic evidence of pneumonia,respiratory rate >24/min and oxygen saturation of 94% or less. Patients receiving mechanical ventilation or patients with multi organ failure were not included
Open-label.
1 medical college hospital, India.
Patient’s clinical status was assessed by laboratory investigations and physical examination (from day 1 to day 12 on a 4‑point ordinal scale and from day 12 to 24 on a 6‑point ordinal scale).
sofosbuvir (n=27) vs. Interferon plus lopinavir/ritonavir (n=30)
randomized controlled trial some concerns about risk of bias
Sofosbuvir
Sofosbuvir 400 mg single dose daily, orally, plus standard of care.
Interferon beta-1a and Lopinavir/Ritonavir
Interferon-beta-1a 12 Mu (44 microgram) on day 1 and then every other day subcutaneously plus Lopinavir/ritonavir (200/50 mg, orally; two tablets twice a day) plus standard of care.
All patients received standard of care: supplemental oxygen, noninvasive or invasive ventilation, use of anticoagulants or antibiotic agents, vasopressor support, renal-replacement therapy, use of Immunomodulatory agents and performing extracorporeal membrane oxygenation (ECMO). The duration of antiviral treatment was determined by the time to clinical recovery in the study population sustained,at least for 72 hours.
COVID 19 hospitalized
Patients between 18-75 with chest computerized tomography (CT) findings suggestive of pulmonary infection by COVID-19 with fever (temperature: ≥36.6 °C armpit or ≥ 37.2 °C oral or ≥37.8 °C rectal), physical finding concluding of respiratory infection (rales/crackles or decreased respiratory sounds plus ego phony or increased tactile fremitus or vocal fremitus) and oxygen Saturation of 93% or lower (at room air) and positive report of RT PCR-COVID-19 RNA by a distinguished national diagnostic laboratory. Patients who required mechanical ventilation were excluded.
Open-label.
Single center, Imam 87 Hossein Medical Center, Tehran, Iran.
Clinical recovery as defined by normal body temperature and normal oxygen saturation, sustained for at least 72 hours within 14 days since the initiation of antiviral therapy.
Preliminary results of the phase II.
sofosbuvir (n=22) vs. lopinavir/ritonavir (n=32)
randomized controlled trial high risk of bias
Sofosbuvir plus hydroxychloroquine
Hydroxychloroquine (200 mg q 12 h) plus Sofosbuvir (400 mg daily).
Lopinavir/Ritonavir plus hydroxychloroquine
Hydroxychloroquine (400 mg stat) and Kaletra (400/100 mg q 12 h)
Hydroxychloroquine in both groups.
COVID 19 hospitalized
Age above 18, hospitalized patients with fever (Oral temperature ≥ 38 °C) and at least one of the following: a respiratory rate more than 24/min or an O2 Saturation level less than 93% or the PaO2/ FiO2 ratio lower than 300. Patients had to have a confirmed PCR for the nuclide acid of SARS-COV-2 in a nasopharyngeal swab specimen or a chest lung CT scan compatible with COVID-19 patterns.
Open-label.
Single center, referral hospital for COVID-19 patients in Tehran, Iran.
sofosbuvir and daclatasvir (n=541) vs. placebo (n=542)
randomized controlled trial some concerns about risk of bias
Sofosbuvir/Daclatasvir
Sofosbuvir/Daclatasvir 400/60mg (Sovodak, RojanPharma, Tehran) once daily for 10 days with standard care.
Placebo
Standard care plus an identically-looking placebo tablet once daily for 10 days.
All participants received standard care following national treatment guidelines.
COVID 19 hospitalized
Patients with clinically diagnosed COVID-19 by either PCR positivity or COVID-19 compatible lung chest CT scan findings were considered for inclusion if they were >18 years old and provided written informed consent. In addition, patients were required to have any one of fever (oral temperature ≥ 37.8 °C), dry cough, severe fatigue, dyspnea, and oxygen saturation<95%.
Double-blind.
Multicenter, 19 hospitals in 12 cities in Iran.
Subjects were discharged based on the managing physician’s decision and when clinical recovery was evident defined as 24 hours of no fever or dyspnoea, no or improved cough and fatigue, and tolerance of oral feeding.
sofosbuvir and daclatasvir (n=541) vs. placebo (n=542)
randomized controlled trial risk of bias NA
Sofosbuvir/Daclatasvir
Sofosbuvir/Daclatasvir 400/60 mg administered orally once-daily for 10 days in addition to standard of care.
Placebo
Placebo for 10 days in addition to standard of care.
Standard of care was administered following national treatment guidelines, which varied throughout the study and included concomitant use of interferon-b, dexamethasone (or other corticosteroids), lopinavir/ritonavir and other therapeutic agents.
COVID 19 hospitalized
Individuals were required to have an oxygen saturation <95% and at least one symptom of fever (oral temperature 37.8C), dry cough, severe fatigue or dyspnoea. Patients were excluded if they had multi-organ failure or required intubation on admission.
Double-blind.
19 hospitals across 12 cities in Iran.
Patients were discharged on the managing physician’s decision based on the absence of fever or dyspnoea, no or improved cough and fatigue, and tolerance of oral feeding, with a stable O2 saturation of 95%. During the first 2 weeks of the study, the 95% O2 saturation criterion for clinical recovery and subsequent discharge was not possible to enforce due to shortages of hospital beds. As such, at the beginning of the third week of the study this final criterion was removed.
sofosbuvir and daclatasvir (n=35) vs. standard of care (n=35)
randomized controlled trial some concerns about risk of bias
Sofosbuvir/Daclatasvir
Single daily oral tablet containing 400mg sofosbuvir and 60mg daclatasvir (Sovodak, RojanPharma, Tehran, Iran) in addition to standard care for 14 days. Treatment started 24-48h after admission.
Standard of care
Standard of care alone.
All patients received standard care according to the national Iranian COVID-19 treatment guidelines which at the time of the study was hydroxychloroquine 200mg twice daily with or without lopinavir/ritonavir 200mg/50mg twice daily.
COVID 19 hospitalized
All adult patients aged at least 18 years admitted with suspected COVID-19 with positive qualitative RT–PCR on nasopharyngeal swab AND chest CT scan compatible withmoderate or severe COVID-19 infection. In addition, participants were required to have signs of severity of disease defined as fever (oral temperature>=37.8°C at any one time prior to enrolment) and at least one of respiratory rate >24/min, O2 saturation <94% or PaO2/FiO2 ratio <300 mgHg.
Open-label.
Four university hospitals in Iran.
Clinical recovery was defined as normalization of fever (<=37.2°C),respiratory rate (<=24/min) and oxygen saturation (>=94%) without supplementary oxygen therapy sustained for at least 24h.If patients maintained these criteria for over 24 h they were safely discharged from hospital.
sofosbuvir and daclatasvir (n=44) vs. standard of care (n=45)
randomized controlled trial some concerns about risk of bias
Sofosbuvir/Daclatasvir
One 400 mg tablet sofosbuvir and one 60 mg daclatasvir daily for 10 days in addition to standard of care.
Standard of care
Standard of care alone.
Standard of care, according to the Egyptian MOH Protocol, was given to all patients: Plaquenil (Hydroxychloroquine) which was given in a dose of 4 tablets of 200 mg, on Day 1 followed by 2 tablets daily from day 2 through day 5. Azithromycin was given in a daily dose of 500 mg for 5 days. Full nutritional support with balanced diet and multivitamin and zinc supplements with vitamin C and D were offered to all patients.
COVID 19 hospitalized
Males or females between 18 and 75 years of age and presenting with laboratory-confirmed COVID19 (SARS-CoV-2 infection) as determined by polymerase chain reaction (PCR) assay in any specimen collected within 72 hours prior to randomization; in addition to being symptomatic at screening, presenting with clinical manifestations under one of three severity categories: Mild, Moderate or Severe disease. Patients with critically severe COVID19 requiring invasive mechanical ventilation at screening were excluded.
Open-label.
Single center in Cairo, Egypt.
sofosbuvir and ledipasvir (n=125) vs. standard of care (n=125)
randomized controlled trial some concerns about risk of bias
Sofosbuvir/Ledipasvir
Sofosbuvir plus Ledipasvir once daily for 15 days.
Oseltamivir, Hydroxychloroquine, and Azithromycin.
Oseltamivir 150 mg q 12 hours for 10 days,HCQ 400 q 12 hours for one day followed by 200mg q 12 hours for nine days, and Azithromycin 500mg one time, followed by 250mg once daily for 6 days.
Additional medications were given, including third-generation cephalosporin Ceftriaxone 2 gm/24 hours for seven days, methylprednisolone 1 mg/kg/day for seven days, and prophylactic lowmolecular weight heparin (enoxaparin) 40 mg/24 hours was given throughout the hospitalizationperiod.
COVID 19 hospitalized
Moderate cases criteria: fever (measured temperature of at least 38 °C), respiratory symptoms (cough, shortness of breath), and imaging-confirmed pneumonia. Inclusion criteria also included age more than 18 and less than 75 years old.
Single-blind.
Single center, Egypt.
tenofovir/emtricitabine (n=163) vs. standard of care (n=162)
randomized controlled trial some concerns about risk of bias
Emtricitabine/tenofovir
emtricitabine(200 mg) tenofovir disoproxil (300 mg), once a day for 10 days PO,
Standard of care
The standard of care follows the recommendations of the Colombian Consensus forCovid-19 Treatment in Hospitalized Patients,21 consisting of the use of dexamethasone,antiparasitic treatment (ivermectin or albendazole), enoxaparin, acetaminophen, oxygen asneeded, and supportive treatment for organ failure (i.e., use mechanical ventilation, ordialysis).
COVID 19 hospitalized
Adults aged 18 years or more, with a positive real-time polymerase chain reaction (RT-PCR) or with high suspicion of SARS CoV-2 by clinical criteria and a diagnosis of mild, severe, or critical pneumonia, requiring hospital management in six high complexity referral hospitals located in Bogota.
Open-label.
6 hospitals in Bogota, Colombia.
Relative Risks adjusted for age, sex, and severity of pneumonia using g Log-binomial General Estimating Equation models, assuming exchangeable correlation structure with each center as a cluster.
umifenovir (arbidol) (n=50) vs. lopinavir/ritonavir (n=50)
randomized controlled trial some concerns about risk of bias
Arbidol (umifenovir)
Hydroxychloroquine (400 mg BD on first day followed by 200 mg BD) followed by ARB (200 mg TDS) 7 to 14 days based on the severity of disease.
Lopinavir-ritonavir (Kaletra)
Hydroxychloroquine (400 mg just on first day) followed by 400 mg Kaletra (Lopinavir-ritonavir) BD
HCQ in both groups. Arbidol 100mg caps.
COVID 19 hospitalized
Open-label
single center, teaching hospital of Iran University of medical Sciences (IUMS), Tehran, Iran.
The criteria of improvement were relief of cough, dyspnea and fever.
zinc (n=15) vs. placebo (n=18)
- high risk of bias
High-dose Zinc HDIVZn
Zinc Chloride (ZnCl2) diluted in 250 mL of normal saline and infused via peripheral intravenous access over 3 hrs at a dose of 0.5 mg/kg/d (elemental zinc concentration 0.24 mg/kg/d), once daily, for a maximum of 7 days, or until hospital discharge or death.
Placebo
Saline placebo.
COVID 19 hospitalized
Consenting adult patients adult male or female, age ≥18years old, laboratory-confirmedSARS-CoV-2 infection as determined by PCR, hospitalised with an illness of any duration with evidence of pneumonia and severe disease, critical disease or multisystem organ dysfunction at baseline, ability to provide informed consent signed by study patient or legally acceptable representative, willingness and ability to comply with study-related procedures/assessments, have an oxygen saturation (SaO2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen(FiO2) (PaO2: FiO2) at or below 300 mg Hg, no chronic kidney disease (CKD) defined by stage II or higher using the Kidney Disease Improving Global Outcomes classification.
Double-blind.
Phase IIa. The investigators, study coordinators, treating physicians, bedside nurses and patients/family remained blinded to the allocated studysolution.
The study did not reach its target enrolment. Consequently, the primary outcome of whether HDIVZn reduced thelevel of oxygenation in non-ventilated or improved the PaO2/FiO2 ratio in the four ventilated patients and other clinical efficacy outcomes could not be assessed.
azithromycin (n=172) vs. standard of care (n=159)
randomized controlled trial some concerns about risk of bias
azithromycin plus hydroxychloroquine
standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days
hydroxychloroquine
standard care plus hydroxychloroquine at a dose of 400 mg twice dailyThe use of glucocorticoids, other immunomodulators, antibiotic agents others than macrolides , and antiviral agents was allowed
3 arms: hydroxychloroquine plus azythromycin, hydroxychloroquine monotherapy and standard of care
COVID-19 mild to moderate
open-label
Brazil, 55 sites
Randomization was performed in blocks of six and was stratified according to the use or nonuse of supplemental oxygen at the time of randomization
azithromycin (n=107) vs. standard of care (n=99)
randomized controlled trial some concerns about risk of bias
azithromycin
azithromycin 500 mg/24 h for 7 days
standard of care
3 arms azithromycin, clarithromycin or standard of care
COVID-19 mild to moderate
open-label
1 centre, Egypt
azithromycin plus hydroxychloroquine (n=217) vs. standard of care (n=227)
randomized controlled trial some concerns about risk of bias
Hydroxychloroquine plus azithromycin
Standard of care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days.
Standard of care
The use of glucocorticoids, other immunomodulators, antibiotic agents, and antiviral agents was allowed.
3 arms: hydroxychloroquine plus azythromycin, hydroxychloroquine monotherapy and standard of care (1:1:1 ratio). All patients received standard of care.
COVID-19 mild to moderate
Adult patients (18 years and older) with suspected or confirmed COVID-19 admitted to inpatients units and intensive care units. Patients using non-invasive ventilation or invasive mechanical ventilation were excluded. Patients with previous use of chloroquine, hydroxychloroquine, azithromycin or any other macrolide for more than 24h before enrollment were excluded.
Open-label.
Multicenter; 55 sites in Brazil.
Scores on the scale were defined as follows: a score of 1 indicated not hospitalized with no limitations on activities; 2, not hospitalized but with limitations on activities; 3, hospitalized and not receiving supplemental oxygen; 4,hospitalized and receiving supplemental oxygen;5, hospitalized and receiving oxygen supplementation administered by a high-flow nasal cannula or noninvasive ventilation; 6, hospitalized and receiving mechanical ventilation; and 7, death.
3 interim analyses planned, only the first one was conducted.
azvudine (n=10) vs. antiviral and associated therapy (n=10)
randomized controlled trial some concerns about risk of bias
Azvudine
Oral azvudine tablets 5 mg/day (five tablets once a night) and symptomatic treatment.
Standard antiviral
interferon alpha, kaletra and ribavirin, chloroquine phosphate, and hydroxychloroquine sulfate
When patients developed clinical symptoms and signs, such as fever and cough, patients in both groups were treated with febrifuge or cough mixture, which was called symptomatic treatment.
COVID-19 mild to moderate
Confirmed COVID-19 by RT-PCR. The definition of mild COVID-19 was patients with mild clinical symptoms and without signs of pneumonia in imaging; the definition of commonCOVID-19 was patients with fever, respiratory, or other related symptoms, and with signs of pneumonia in imaging. Patients with one of the following conditions: respiratory failure and the need for mechanical ventilation; shock; intensive care unit (ICU) monitoring and treatment for other organ failures were excluded.
Open-label
Single center, Guangshan County People’s Hospital, China.
bromhexine (n=12) vs. standard of care (n=6)
randomized controlled trial some concerns about risk of bias
Bromhexine hydrochloride
Patients in the treatment group received BRH tablets (32 mg t.i.d.) three times per day after meals for 14 consecutive days. Treatment was discontinued once the patient met the discharge criteria.
Standard of care
Antiviral drugs, including arbidol hydrochloride granules (0.1 g–0.2 g t.i.d.) and recombinant human interferon α 2b spray (0.083 mL t.i.d.)
All patients were divided into the treatment group (BRH group) or the control group (control group) at a 2:1 ratio. All participants were treated with antiviral drugs, including arbidol hydrochloride granules (0.1 g–0.2 g t.i.d.) and recombinant human interferon α 2b spray (0.083 mL t.i.d.), on the doctors’ discretion according to China’s Novel Coronavirus Pneumonia Diagnosis and Treatment Plan.
COVID-19 mild to moderate
Hospitalized patients with COVID-19 (≥ 18 years but ≤ 80 years) with confirmed or clinically suspected mild or moderatecoronavirus pneumonia (COVID-19), based on China’s Novel Coronavirus Pneumonia Diagnosis and Treatment Plan.
Open-label.
Single center, The Second Affiliated Hospital of Wenzhou Medical University, Zhejiang, China.
Clinical recovery was defined as clinical symptoms (fever and respiratory symptoms) returning to normal over 48 hours. Disease deterioration was defined as the presence of respiratory distress, respiratory rate ≥ 30 times/minute, oxygen saturation ≤ 93% in the resting state, and oxygenation index ≤ 300 mmHg.
chloroquine (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
chloroquine
450 mg x2 day 1, then 450 mg/d for 4 days
placebo
COVID-19 mild to moderate
double-blind
1 center, Brazil
found in Axfors et al meta-analysis
Ensitrelvir (XOCOVA) (n=-9) vs. placebo (n=-9)
randomized controlled trial some concerns about risk of bias
ensitrelvir 125 mg or 250 mg
loading dose of ensitrelvir on day1 (375 mg for the 125 mg group and 750 mg for the 250 mg group), followed by the maintenance dose (125 mg for the 125 mg group and 250 mg for the 250 mg group) on days 2 through 5 without dose modification
placebo
COVID-19 mild to moderate
A majority of the patients in the ITT population had been vaccinated (ensitrelvir 125 mg, 14 [87.5%]; ensitrelvir 250 mg, 12 [85.7%]; and placebo, 123 12 [70.6%])
double blind
japan, 56 centers
favipiravir (n=193) vs. lopinavir/ritonavir (n=187)
randomized controlled trial some concerns about risk of bias
favipiravir
Favipiravir 1600 mg stat and then 600 mg every 8 h plus hydroxychloroquine 200 mg twice a day for 1 week.
lopinavir/ritonavir
single dose of hydroxychloroquine 400 mg followed by 100 400 Lopinavir/Ritonavir twice a day for 1 week
Later on, during the trial (31 May 2020), in light of emerging evidence, daily hydroxychloroquine in the Favipiravir group was reduced to a single dose of 400 mg as in control group
COVID-19 mild to moderate
open-label
20 centres, Iran
favipiravir (n=75) vs. placebo (n=74)
randomized controlled trial risk of bias NA
Favipiravir
Favipiravir administered orally, 1800 mg on the first dose (day 1) followed by 800 mg twice daily for the next 9 days (days 2-10).
placebo
COVID-19 mild to moderate
double blind
USA
favipiravir (n=175) vs. placebo (n=178)
randomized controlled trial high risk of bias
favipiravir
1,800 mg BID on Day 1 800 mg BID for next 9 days (maximum)
placebo
COVID-19 mild to moderate
double blind
20 centres, Kuwait
favipiravir (n=107) vs. placebo (n=49)
randomized controlled trial some concerns about risk of bias
Favipiravir
1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days.
placebo
1:2 ratio. Seven patients in the placebo group were switched to treatment with favipiravir during Days 2–8 due to a lack of efficacy.
COVID-19 mild to moderate
Single blind.
Japan
Improvement was defined as follows:(1) improvement in temperature was defined as axillary temperature falling to =< 37.4 C and remaining at =< 37.4 C for at least 24 h (temperature recordings taken within 4 h after use ofan antipyretic were excluded); (2) improvement in SpO2 was defined as SpO2 remaining >= 96%for at least 24 h without the use of oxygen therapy; (3) improvement on chest imaging was defined as improvement in chest imaging findings taken at least 24 h after the previous image judged to be the worst; and (4) recovery to SARS-CoV-2-negative was defined as two consecutive negative results on qualitative tests by nucleic acid amplification separated by at least 24 h.
favipiravir (n=50) vs. standard of care (n=50)
randomized controlled trial some concerns about risk of bias
favipiravir
3200 mg (1600 mg 12 hourly) loading dose on day-1 followed by 1200 mg maintenance dose (600 mg 12 hourly daily) on day-2 to day-10
standard of care
oseltamivir 75 mg 12 hourly for 5-10 days and hydroxychloroquine 400mg 12 hourly day -1 followed by 200mg 12 hourly daily on day- 2 to day-5-10
COVID-19 mild to moderate
open label, randomized
2 centres, Egypt
favipiravir (n=125) vs. standard of care (n=129)
randomized controlled trial some concerns about risk of bias
Favipiravir and Hydroxychloroquine
Favipiravir: 1800 mg twice daily for one day, followed by 800mg (total days of therapy is 10 days or till hospital discharge)Hydroxychloroquine (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily.
standard of care
COVID-19 mild to moderate
open label
9 centers, Saudi Arabia
Moderate or Severe confirmed COVID-19
Trial stopped for futility after the first interim analysis
favipiravir (n=100) vs. standard of care (n=100)
randomized controlled trial some concerns about risk of bias
favipiravir
1600 mg 2 times a day; on days 2-14 of treatment - 600 mg 2 times a day
standard of care
COVID-19 mild to moderate
open label
5 centres, Russia
Rate of clinical status improvement by categorical ordinal scale of clinical status improvement by 2 or more categories by Day 10 WHO Ordinal Scale for Clinical Improvement (WHO-OSCI), 0 - uninfected (There are no clinical and virological signs of infection), 8 - dead, higher scores mean a worse outcome
Article published in Russian. Results extracted from clinicaltrials.gov.
favipiravir (n=112) vs. standard of care (n=56)
randomized controlled trial some concerns about risk of bias
favipiravir
1800 mg BID on day 1, followed by 800 mg BID for up to9 days)
standard of care
umifenovir intranasal interferon alpha-2b, orhydroxychloroquine) for up to 10 days
COVID-19 mild to moderate
open label
10 centres, Russia
favipiravir plus interferon (n=44) vs. standard of care (n=45)
randomized controlled trial some concerns about risk of bias
favipiravir with interferon beta-1b by inhalation aerosol
favipiravir : 1600 mg (Day 1) followed by 600mg twice a day for a maximum of 10 daysinterferon beta-1 : 8million IU (0.25µg) twice a day for 5 days (through nebulization)
standard of care
HCQ 400 mg twice per day on the day 1, then 200 mg twice per day for 7 days
COVID-19 mild to moderate
open label
1 center, Oman
200 patients needed; due to logistical and financial constraints, only a total of 89 COVID-19 patients were enrolled into the study
hydroxychloroquine (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
hydroxychloroquine
placebo
COVID-19 mild to moderate
double blind
international
found in Axfors et al meta-analysisTerminated (Rate of enrollment too slow to allow completion in a reasonable timeframe
hydroxychloroquine (n=15) vs. standard of care (n=15)
randomized controlled trial high risk of bias
hydroxychloroquine 400mg
hydroxychloroquine 400mg per day for 5 days
standard of care
COVID-19 mild to moderate
open-label
China
paper in chinese
hydroxychloroquine (n=31) vs. standard of care (n=31)
randomized controlled trial high risk of bias
hydroxychloroquine 400mg
additional oral HCQ (hydroxychloroquine sulfate tablets, Shanghai Pharma) 400 mg/d (200 mg/bid) between days 1 and 5
standard of care
COVID-19 mild to moderate
(RT-PCR) positive of SARS-coV-2; chest CT with pneumonia; saO2/SPO2 ratio > 93% or paO2/FIO2 ratio > 300 mmhg under room air
open-label
China, single center
there is some changes in the publication compared to the registry record (open control in place of placebo, sample size and the primary endpoint changed that does rule out the possibility of a selective publication bias)
hydroxychloroquine (n=221) vs. standard of care (n=227)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine at a dose of 400 mg twice daily
hydroxychloroquine [400mg 2x/day, 12/12h] for 7 days
standard of care
The use of glucocorticoids, other immunomodulators, antibiotic agents, and antiviral agents was allowed
3 arms: hydroxychloroquine plus azythromycin, hydroxychloroquine monotherapy and standard of care
COVID-19 mild to moderate
open-label
Brazil, 55 sites
Randomization was performed in blocks of six and was stratified according to the use or nonuse of supplemental oxygen at the time of randomization
hydroxychloroquine (n=360) vs. standard of care (n=180)
randomized controlled trial high risk of bias
Hydroxychloroquine
Standard of care plus hydroxychloroquine 400mg twice daily on day 1, then 200mg twice daily for the next 5 days.
Standard of care
SOC treatment comprised daily oral vitamin C (2 g), oral zinc (50 mg), oral vitamin D(alfacalcidol 1 µg), and oral acetaminophen (for body aches and fever).
2:1 ratio. All patients received standard of care.
COVID-19 mild to moderate
Adult patients (18-80) with mild COVID-19 (PCR confirmed infection) and hospitalized.
Open-label.
Single-center; Pak Emirates Military Hospital, Rawalpindi, Pakistan.
Progression of disease was defined by the development of fever >101°F for >72 hours, shortness of breath with minimal exertion, derangement of basic laboratory parameters (ALC < 1000 or raised CRP), or appearance of infiltrates on X-ray chest.
ivermectin (n=82) vs. control (n=82)
randomized controlled trial high risk of bias
ivermectin12mg once daily for 3 days
standard protocol of treatment alone for 14 days
COVID-19 mild to moderate
patients from ages 20 to 65 with mildly to moderately affected COVID-19 infection confirmed by pharyngeal swab PCR
open-label
two tertiary hospitals in Egypt
ivermectin (n=21) vs. lopinavir/ritonavir (n=20)
randomized controlled trial high risk of bias
Ivermectin 6mg (given every 84 hours) twice a week, or Ivermectin 12mg (given every 84 hours) for 2 weeks,
lopinavir / ritonavir daily for 2 weeks
COVID-19 mild to moderate
double-bind
proof of concept study
ivermectin (n=48) vs. placebo (n=24)
randomized controlled trial high risk of bias
ivermectin alone or in combination with doxycycline
oral ivermectin alone (12 mg once daily for 5 days) or in combination with doxycycline (12 mg ivermectin single dose and 200 mg stat doxycycline day-1 followed by 100 mg 12hrly for next 4 days)
placebo
COVID-19 mild to moderate
says as double blind
Dhaka, Bangladesh
ivermectin (n=12) vs. placebo (n=12)
randomized controlled trial low risk of bias
ivermectin
400 mcg/kg, single dose
placebo
COVID-19 mild to moderate
double bliind
1 center, Spain
ivermectin (n=57) vs. placebo (n=58)
randomized controlled trial some concerns about risk of bias
Ivermectin
ivermectin 12 mg on day 1 and day 2
Placebo
COVID-19 mild to moderate
All patients above the age of 18 admitted with a diagnosis of COVID -19 (on the basis of a positive RT PCR or Rapid Antigen Test report) at AIIMS, Patna, India with mild or moderate disease as defined by the ministry of health and family welfare guidelines and not meeting any of the exclusion criteria were considered eligible for the study. The exclusion criteria were: known allergy to or adverse drug reaction with Ivermectin; unwillingness or inability to provide consent to participate in the study; prior use of ivermectin during the course of this illness; pregnancy and lactation.
Double-blind.
Single center, tertiary care dedicated COVID-19 hospital in Bihar, India.
ivermectin (n=104) vs. placebo (n=52)
randomized controlled trial high risk of bias
Ivermectin 24mg and 12mg
Single oral administration of Ivermectin 12 mg (equivalent to 200 µg/kg) elixir or Ivermectin 24 mg (equivalent to 400 µg/kg) elixir. A 20 mL dose of final formulation consisted of ivermectin (12 or 24mg) in ethanol (40% v/v) sweetened with syrup base.
Placebo
3 arms: Ivermectin 24 mg (single dose), Ivermectin 12 mg (single dose), or placebo.
COVID-19 mild to moderate
Aged 18 years or above and diagnosed with non-severe COVID-19, i.e. room air saturation (SpO2) >90%, and with no hypotension or requirement of mechanical ventilation. Diagnosis of COVID-19 was based on a positive result on either SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) or the rapid antigen test.
Double-blind.
Single center, India.
ivermectin (n=35) vs. standard of care (n=38)
randomized controlled trial some concerns about risk of bias
Ivermectin
Single dose of 0.2 mg/kg
Standard of care
Standard drugs of the national protocol are used.
All patients in both groups received supportive medical treatment for COVID-19 according to the national protocols of Iran at the time of this study (hydroxychloroquine and/or lopinavir/ritonavir).
COVID-19 mild to moderate
The diagnostic criteria for COVID-19 included any of the following: (1) positive result on COVID-19 reverse-transcription polymerase chain reaction; (2) clinical symptoms of COVID-19, with a history of contact with a patient with COVID-19; and/or (3) abnormalities on chest computed tomography (CT) compatible with COVID19 (ground-glass opacity, halo sign, reversed halo sign, and patchy infiltration).
Double-blind.
2 centers in Mazandaran, Iran.
Clinical improvement after baseline was defined as resolving a patient’s baseline status on persistent and continuous cough (persistent cough for >1 hour, or ≥3 coughing episodes in 24 hours, that interferes with activities of daily living and the ability to work) and tachypnea in addition to increasing oxygen saturation to >94%.
ivermectin (n=25) vs. standard of care (n=25)
randomized controlled trial high risk of bias
ivermectin
12mg stat and then 12 mg after 12 hours and 12mg after 24 hours
standard of care
COVID-19 mild to moderate
open label
1 center, Pakistan
ivermectin (n=50) vs. standard of care (n=50)
randomized controlled trial high risk of bias
ivermectin (single dose of 12 milligrams)
standard of care
COVID-19 mild to moderate
open-label
one hospital in Lahore, Pakistan
ivermectin (n=30) vs. standard of care (n=15)
randomized controlled trial some concerns about risk of bias
Ivermectin
Standard of care plus oral ivermectin at 0.6 mg/kg/day for 5 days.
Standard of care
All patients in both groups received standard of care.
COVID-19 mild to moderate
Eligibility criteria included COVID-19 symptoms onset ≤ 5 days at recruitment, absence of use of drugs with potentialactivity against SARS-CoV-2 and available in Argentina during the trial (hydroxychloroquine, chloroquine, lopinavir and azithromycin); and those drugs were not permitted during the first week of the trial.
Open-label.
4 hospitals in the metropolitan area of Buenos Aires, Argentina.
ivermectin (n=241) vs. standard of care (n=249)
randomized controlled trial some concerns about risk of bias
oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care
standard of care alone
symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.
COVID-19 mild to moderate
open-label
Malaysia
ivermectin plus doxycycline (n=200) vs. standard of care (n=200)
randomized controlled trial some concerns about risk of bias
Ivermectin and Doxycycline
Ivermectin 6 mg, 2 tab stat and Doxycycline 100 mg twice daily for 5 days
standard of care
COVID-19 mild to moderate
double blind
1 center, Bangladesh
lopinavir/ritonavir (n=21) vs. standard of care (n=7)
randomized controlled trial some concerns about risk of bias
Lopinavir-ritonavir
Lopinavir (200mg) boosted by ritonavir (50mg) (oral, q12h, 500 mg each time for 7-14 days) monotherapy
Standard of care.
No antiviral medication. Supportive care and effective oxygen therapy if in need.
3 arms: lopinavir/ritonavir (n=21), arbidol=umifénovir (n=16) and standard of care (n=7).Standard of care in both groups.
COVID-19 mild to moderate
Open-label
China, single center
lopinavir/ritonavir, ribavirin and interferon beta-1b (n=86) vs. lopinavir/ritonavir (n=41)
randomized controlled trial some concerns about risk of bias
Interferon beta-1b, lopinavir–ritonavir, and ribavirin
14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days
lopinavir–ritonavir
14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h
COVID-19 mild to moderate
age at least 18 years, a national early warning score 2 (NEWS2) of at least 1, and symptom duration of 14 days or less upon recruitment
Open-label.
Hong Kong, 6 centers
phase 2, intention-to-treat population
there is a discrepancy between the main objective of the study mentioned in clinicaltrials.gov which refers to mortality and the main endpoint presented in the publication. The sample size calculation also refers to mortality. However, at the date of initial registration (Feb. 19), the primary endpoint was already PCR-negative conversion, which allows to rule out result-driven change.
nitazoxanide (n=238) vs. placebo (n=237)
randomized controlled trial high risk of bias
Nitazoxanide
500 mg oral solution, 20 mg/mL (25 mL), three times daily ( 8/8hours) for 5 days.
Placebo
Placebo 8/8 hours for 5 days in the early clinical phase of COVID-19.
Placebo and nitazoxanide were color-matched.
COVID-19 mild to moderate
Consecutive adult patients (aged 18 years or older) who presented with clinical symptoms of Covid-19 (defined for the purposes of this trial as dry cough, fever, and/or fatigue) of no longer than 3 days’ duration were enrolled. Patients with negative reverse-transcriptase quantitative real-time polymerase chain reaction (RT-PCR) test for SARS-CoV-2 were excluded.
Double-blind.
2 hospitals in Brazil.
All patients took home a symptom journal designed to gather information on daily symptoms, new symptoms, and the date of resolution of each symptom
Nitazoxanide in the early clinical phase of COVID-19.
nitazoxanide (n=33) vs. placebo (n=13)
randomized controlled trial high risk of bias
Nitazoxanide
The protocol began with 1 g every 8 hours (3 g/day), but soon afterwards, it was changed to 500 mg (1 film-coated tablet) every 6 hours (2 g/day) plus standard of care.
Placebo
Placebo plus standard of care.
Patients were randomized 2:1 to receive nitazoxanide or placebo.
COVID-19 mild to moderate
people of both sexes aged = 18 years, with COVID-19, with a positive quantitative real-time polymerase reaction (rtq-PCR), no more than 4 days after the onset of symptoms. Patients with a chest Rx or lung ultrasound consistent with COVID-19 pneumonia were included if they had mild symptoms, defined as SpO2 = 95% when breathing room air and a RF < 24 per minute, or moderate symptoms, defined as SpO2 = 92% when breathing FiO2 through a low flow O2 cannula (< 5 l per minute).
Single-blind.
2 centers in Buenos Aires, Argentina.
Erradication will be considered a reduction of the viral load on day 7 greater than 35% with respect to placebo.
nitazoxanide (n=25) vs. placebo (n=25)
randomized controlled trial risk of bias NA
Nitazoxanide
NTZ 600 mg BID administered with food for 7 days
Placebo
Placebo BID administered with food for 7 days.
COVID-19 mild to moderate
Doubleblind.
6 hospitals in Sao Paulo, Brazil.
Phase II.
remdesivir (n=200) vs. remdesivir (n=197)
randomized controlled trial some concerns about risk of bias
Remdesivir (5 days)
Intravenous remdesivir 200 mg on day 1, followed by 100 mg of remdesivir once daily for the subsequent 4 days.
Remdesivir (10 days)
Intravenous remdesivir 200 mg on day 1, followed by 100 mg of remdesivir once daily for the subsequent 9 days.
Both treatment groups continued supportive therapy at the discretion of the investigator throughout the duration of the trial.
COVID-19 mild to moderate
Patients who were receiving mechanical ventilation and extracorporeal membrane oxygenation (ECMO) at screening were excluded, as were patients with signs of multiorgan failure.
Open-label.
55 hospitals in the United States, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, Taiwan.
7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplementaloxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and 7, not hospitalized.
remdesivir (n=197) vs. standard of care (n=200)
randomized controlled trial some concerns about risk of bias
Remdesivir (10 days)
200 mg of remdesivir intravenously on day 1, followed by 100 mg of remdesivir once daily for the 9 subsequent days, infused over 30 to 60 minutes.
Standard of care
Treatment with SOC according to local practice.
3 arms study : RDV 5 days, RDV 10 days, standard of care. All participants will continue to receive SOC therapy according to local guidelines. Participants randomized to receive RDV will receive thisin addition to their other care. Remdesivir treatment was to be discontinued in any patient experiencing severe elevations in liver enzymes or decreases in estimated creatinine clearance to less than 30 mL/min.
COVID-19 mild to moderate
Participants with COVID-19 confirmed by polymerase chain reaction (PCR) who meet the following criteria: Willing and able to provide written informed consent (age ≥18) or assent (age ≥12 to <18, where locally and nationally approved) prior to performing study procedures, Hospitalized and requiring medical care for COVID-19, SpO2 > 94% on room air at screening, Radiographic evidence of pulmonary infiltrates.
Open-label.
Multicenter: 105 hospitals in the United States, Europe, and Asia.
7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; 3, hospitalized, requiringnoninvasive ventilation or use of high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related or not to COVID-19); 6, hospitalized, not requiring supplemental oxygen orongoing medical care; and 7, not hospitalized. Differences between remdesivir treatment groups and standard care were calculated usingproportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicatesdifference in clinical status distribution toward category 7 for the remdesivir group vs thestandard care group.
remdesivir (n=199) vs. standard of care (n=200)
randomized controlled trial some concerns about risk of bias
5-day course of remdesivir
200 mg of remdesivir intravenously on day 1, followed by 100 mg of remdesivir once daily for the subsequent days, infused over 30 to 60 minutes.
Standard care
Treatment with SOC according to local practice.
3 arms study : RDV 5 days, RDV 10 days, standard of care. All participants will continue to receive SOC therapy according to local guidelines. Participants randomized to receive RDV will receive thisin addition to their other care. Remdesivir treatment was to be discontinued in any patient experiencing severe elevations in liver enzymes or decreases in estimated creatinine clearance to less than 30 mL/min.
COVID-19 mild to moderate
Participants with COVID-19 confirmed by polymerase chain reaction (PCR) who meet the following criteria: Willing and able to provide written informed consent (age ≥18) or assent (age ≥12 to <18, where locally and nationally approved) prior to performing study procedures, Hospitalized and requiring medical care for COVID-19, SpO2 > 94% on room air at screening, Radiographic evidence of pulmonary infiltrates.
Open-label.
Multicenter: 105 hospitals in the United States, Europe, and Asia.
7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; 3, hospitalized, requiringnoninvasive ventilation or use of high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related or not to COVID-19); 6, hospitalized, not requiring supplemental oxygen orongoing medical care; and 7, not hospitalized. Differences between remdesivir treatment groups and standard care were calculated usingproportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicatesdifference in clinical status distribution toward category 7 for the remdesivir group vs thestandard care group.
sofosbuvir and ledipasvir (n=45) vs. standard of care (n=45)
randomized controlled trial some concerns about risk of bias
Sofosbuvir/ledipasvir
SOF/LDP 400/90 mg daily for 10 days plus standard of care.
Standard of care
Standard of care alone.
In addition to the supportive care modalities, the standard of care according to the hospital protocol included hydroxychloroquine (HCQ 400 mg BD at first day then 200 mg BD for 7 days) plus atazanavir/ritonavir 300/100 mg daily for 7 days. Standard of care in both groups.
COVID-19 mild to moderate
Adult patients (≥18 years old) with highly suspected (according to the clinical signs/symptoms andimaging findings) or confirmed (a positive PCR of pharyngeal or nasopharyngeal samples) COVID-19 who were admitted to medical wards of the hospital, were included.
Open-label.
Single-center, Imam Khomeini Hospital Complex, Tehran, Iran.
Clinical response was defined as one order decline in disease category in the five category ordinal scale. The categories are: death (5), mechanical ventilation (4), non-invasive ventilation (3), oxygen mask or nasal cannula (2), discharge(1).
umifenovir (arbidol) (n=35) vs. lopinavir/ritonavir (n=34)
randomized controlled trial some concerns about risk of bias
Umifenovir
Arbidol (100mg) (oral, 200mg TID for 7-14 days)
Lopinavir/ritonavir
Lopinavir (200mg) boosted by ritonavir (50mg) (orally administed, twice daily, 500 mg, each time for 7-14 days).
3 arms : lopinavir/ritonavir; arbidol and standard care
COVID-19 mild to moderate
Open-label
China, single center
No deaths occurred.
umifenovir (arbidol) (n=15) vs. standard of care (n=15)
randomized controlled trial high risk of bias
Umifenovir
600mg/d: orally administered, 200 mg three times per day for 1–5 days
Standard of care
Antivirals, antibiotics, immunoglobulin, and corticosteroids.
Standard of care in both groups.
COVID-19 mild to moderate
Age: 18-60
Not specified.
Single center, City Clinical Hospital in Bishkek, Kyrgyzstan.
Blindness unclear.
azithromycin (n=214) vs. standard of care (n=183)
randomized controlled trial some concerns about risk of bias
azithromycin plus SoC
azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care including HCQ 400 mg x2 for 10 days
standard of care without macrolide
Soc include HCQ 400 mg x2 for 10 days for all patients
All patients received hydroxychloroquine (400 mg twice daily for 10 days)
COVID-19 severe or critically
patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation
open-label
57 centres in Brazil
Several sites enrolling patients in this trial were also participating in the COALITION I trial, another randomised study from our group that tested hydroxychloroquine, with or without azithromycin, in patients with mild to moderate COVID-19.14 Investigators were not allowed totransfer patients between trials, and co-enrolment was also not possible because the trials’ inclusion criteria were mutually exclusive.
hydroxychloroquine (n=106) vs. placebo (n=108)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
200x2 for 10 days
placebo
COVID-19 severe or critically
double-blind
3 centres, Mexico
pr-specified sample size : 300 vs 300. In mid-July, 2020, the rhythm of recruitment was reduced drastically, due to severalreasons including patient refusal, that of their relatives, or that of their treating physicians,coinciding with the worldwide suspension of several large trials testing HCQ in which no benefitsof the drug were found
hydroxychloroquine (n=61) vs. standard of care (n=81)
randomized controlled trial risk of bias NA
hydroxychloroquine
Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge
standar of care
COVID-19 severe or critically
open label
90 centers, international
found in Axfors et al. meta-analysis
ivermectin (n=53) vs. chloroquine (n=115)
randomized controlled trial some concerns about risk of bias
Ivermectin
14 mg once at day 0 1 placebo tablet at day 0, and once daily from day 1 to day 2, 1 placebo tablet daily from day 3 to 4, total dose 42 mg
Hydroxychloroquine or Chloroquine
HCQ : 400 mg twice on day 0, and once daily from day 1 to day 4, total dose 2.4 gCQ : 450 mg, twice on day 0, and once daily from day 1 to day 4, total dose 2.7 g
3 arms: chloroquine, hydroxychloroquine, ivermectin.
COVID-19 severe or critically
Double-blind.
Single center, Brasil.
Phase II.
ivermectin (n=30) vs. standard of care (n=30)
randomized controlled trial high risk of bias
ivermectin soc
Ivermectin (Enteral solution at 200 microgr/kg/day (9mg between 36-50 kg, 12mg between 51-65 kg, 15mg between 66-79 kg and 200 microgram/kg in > 80 kg) for 5 days
Soc
Favipiravir (2x1600mg loading dose followed by 2x600mg maintenance dose, po, total 5 days); Hydroxychloroquine (2x400mg loading dose followed by 2x200mg, po, 5 days);Azithromycin (500mg first day loading dose, followed by 250mg/day, po, total 5 days)
COVID-19 severe or critically
single blind
4 centres, Turkey
described as crossover assignment and several inconsistencies in the description of endpoints in clinicalTrials.gov
results up-dated with pre-print
lopinavir/ritonavir (n=99) vs. standard of care (n=100)
randomized controlled trial some concerns about risk of bias
Lopinavir–ritonavir
Lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care.
Standard care
Standard care alone.
Both groups received standard care: supplemental oxygen,noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation (ECMO).
COVID-19 severe or critically
Male and nonpregnant female patients 18 years of age or older were eligible if they had a diagnostic specimen that was positive on RT-PCR, had pneumonia confirmed by chest imaging, and had an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2)(Pao2:Fio2) at or below 300 mg Hg.
Open-label.
Single center, Jin Yin-Tan Hospital, Wuhan, Hubei Province, China.
The seven-category ordinal scale consisted of the following categories: 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 nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7, death.
Wuhan Infectious Diseases Hospital
lopinavir/ritonavir (n=268) vs. standard of care (n=377)
randomized controlled trial some concerns about risk of bias
Lopinavir/ritonavir
400 mg of lopinavir and 100 mg of ritonavir every 12h for 5 days minimum, up to a maximum of 14 days or until ICU discharge whichever occurred first. Patients with a gastric tube who were unable to swallow tablets, lopinavir-ritonavir (at the same dose) was administered as a 5-ml suspension every 12h or alternatively as two dissolved tablets or four crushed tablets (double dose).
Standard of care
No antiviral treatment.
COVID-19 severe or critically
≥18 years old, admitted with suspected or confrmed COVID-19, and were receiving respiratory or cardiovascular organ failure support in an intensive care unit (ICU). Organ support included the provision of invasive mechanical ventilation, noninvasive mechanical ventilation, high-fow nasal cannulae with a fow rate of at least 30 L per minute and a fractionalinspired oxygen concentration of 0.4 or higher, or the infusion of vasopressor or inotropes for shock.
Open-label.
99 sites across 8 countries.
In the register PE was: all-cause mortality (day 90); days alive and not receiving organ support in ICU (day 21).
Enrollment into the lopinavir-ritonavir arm was halted on November 19, 2020, after reaching the prespecifed futility threshold.
Lopinavir/ritonavir plus hydroxychloroquine (n=29) vs. standard of care (n=377)
randomized controlled trial some concerns about risk of bias
Lopinavir/ritonavir plus hydroxychloroquine.
400 mg of lopinavir and 100 mg of ritonavir every 12h for 5 days minimum, up to a maximum of 14 days or until ICU discharge whichever occurred first. Hydroxychloroquine was administered as two loading doses of 800 mg, 6-h apart, followed 6 h later by 400 mg 12 hourly for 12 doses.
Standard of care
No antiviral treatment.
COVID-19 severe or critically
≥18 years old, admitted with suspected or confrmed COVID-19, and were receiving respiratory or cardiovascular organ failure support in an intensive care unit (ICU). Organ support included the provision of invasive mechanical ventilation, noninvasive mechanical ventilation, high-fow nasal cannulae with a fow rate of at least 30 L per minute and a fractionalinspired oxygen concentration of 0.4 or higher, or the infusion of vasopressor or inotropes for shock.
Open-label.
99 sites across 8 countries.
In the register PE was: all-cause mortality (day 90); days alive and not receiving organ support in ICU (day 21).
remdesivir (n=158) vs. placebo (n=79)
randomized controlled trial low risk of bias
Remdesivir
Intravenous remdesivir 200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions.
Placebo
Placebo matched remdesivir, loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.
2:1 ratio. Concomitant use of lopinavir–ritonavir, interferons, and corticosteroids permitted.
COVID-19 severe or critically
Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection, within 12 days of symptoms onset , oxygen saturation of 94% or less on ambient air or a ratio SaO2/FiO2 of 300 mm Hg or less, and radiologically confirmed pneumonia.
Double-blind.
10 hospitals in Hubei, China.
The six-point scale was as follows: death=6; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5; hospital admission for noninvasive ventilation or high-flow oxygen therapy=4; hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3; hospital admission but not requiring oxygen therapy=2; and discharged or having reached discharge criteria (defined as clinical recovery—ie, normalisation of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen >94% on room air, and relief of cough, all maintained for at least 72 h)=1.
Study prematurely discontinued because of the control of the outbreak in Wuhan after March 12.One patient in the placebo group who withdrew after randomisation was not included in the ITT population.
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