meta|Evidence - COVID-19
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amubarvimab/romlusevimab (BRII-196 and BRII-198-Brii Biosciences) (n=418) vs. placebo (n=419)
randomized controlled trial risk of bias NA
BRII-196/BRII-198
placebo
COVID 19 outpatients
results from interim analysis; divulged in a press release dated on October and December, 2021 *Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.*
angiotensin receptor blockers (ARBs) (n=58) vs. placebo (n=59)
randomized controlled trial some concerns about risk of bias
Losartan
Losartan 25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily.
Placebo
COVID 19 outpatients
presumptive positive laboratory test for SARS-coV-2 or upper respiratory infection with recent exposure to laboratory-proven SARS-coV-2-infected personnegative influenza and respiratory virus panel
Double-blind.
3 hospitals in Minnesota, United States.
azithromycin (n=171) vs. placebo (n=92)
randomized controlled trial some concerns about risk of bias
azithromycin
oral azithromycin : a single 1.2g dose PO
placebo
COVID 19 outpatients
patients must be able to return internet-based study questionnaires
Double blind.
Across the United States.
azithromycin (n=540) vs. standard of care (n=875)
randomized controlled trial some concerns about risk of bias
azithromycin 500 mg daily for three days plus usual care
usual care alone
3 arms: usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone
COVID 19 outpatients
open-label
nationwide, UK
azithromycin (n=147) vs. standard of care (n=148)
randomized controlled trial some concerns about risk of bias
azithromycin
500 mg once daily for 14 days
standard of care
COVID 19 outpatients
open label
19 centers, UK
800 patients anticipated 298 included, primary outcome was updated after the pre-planned interim analysis and sample size was adapted
azithromycin plus hydroxychloroquine (n=152) vs. placebo (n=152)
randomized controlled trial some concerns about risk of bias
Hydroxychloroquine plus azithromycin
HCQ : 600 mg daily for one weekAZI : 500 mg day one,250 mg daily on days two through five
placebo
3 arms: Hydroxychloroquine plus azithromycin, hydroxychloroquine monotherapy, and placebo (1:1:1 ratio)
COVID 19 outpatients
Double-blind.
Multicenter: 2 centres in Doha, Qatar.
azithromycin plus hydroxychloroquine (n=42) vs. placebo (n=42)
randomized controlled trial some concerns about risk of bias
Hydroxychloroquine plus azithromycin
200 mg HCQ capsules twice a day for a total course of seven days and one 500 mg AZT capsule taken on day 1, followed by one 250 mg AZT capsule daily for the next four days (i.e. 6 capsules in total).
Placebo
The placebo capsules were formulated to have similar size, shape, color and taste as hydroxychloroquine and azithromycin capsules, and with an identical dosing regimen.
COVID 19 outpatients
Age between 18 and 65 years, Flu-like symptoms beginning 2-5 days prior, Infection by SARS-CoV-2, Not requiring hospital admittance, Consenting to study participation.
Double-blind.
Single center: Hospital Santa Paula, Sao Paulo, Brazil.
bamlanivimab monotherapy (n=101) vs. placebo (n=156)
randomized controlled trial some concerns about risk of bias
Bamlanivimab (LY-CoV555) 700 mg
placebo
5 arms: placebo, bamlanivimab 700 mg, 2800 mg, and 7000 mg and 2800 mg of bamlanivimab and 2800 mg of etesevimab
COVID 19 outpatients
double-blind
Phase 2: exploratory trial, originally designed as a safety and biomarker study. Inconclusive for the primary endpoint.
As of April 2021, regulatory authorities recommend that bamlanivumab no longer be used because of the potential risk of treatment failure due to the circulation of resistant variants of SARS-CoV-2.
bamlanivimab/etesevimab (n=-9) vs. casirivimab/imdevimab (Ronapreve) (n=-9)
randomized controlled trial high risk of bias
bamlanivimab-etesevimab
casirivimab-imdevimab
COVID 19 outpatients
open- label
Pennsylvania, USA
All pharmacies supplying all infusion sites had equal opportunity to order any available mAb from a central supply facility. All mAb were ordered by prescribers as a generic referral order
bamlanivimab/etesevimab (n=112) vs. placebo (n=156)
randomized controlled trial some concerns about risk of bias
bamlanivimab 2800 mg and etesevimab 2800 mg
placebo
5 arms: placebo, bamlanivimab 700 mg, 2800 mg, and 7000 mg and 2800 mg of bamlanivimab and 2800 mg of etesevimab
COVID 19 outpatients
double-blind
Phase 2. Exploratory trial, originally designed as a safety and biomarker study.
October, 2021 EMA ends rolling review of the antibodies bamlanivimab and etesevimab for COVID-19 following withdrawal by Lilly. Janvier, 2022: FDA limit the use of bamlanivimab and etesevimab to infection due to susceptible variants (ie not omicron).
bamlanivimab/etesevimab (n=518) vs. placebo (n=517)
randomized controlled trial some concerns about risk of bias
bamlanivimab 2,800 mg plus etesevimab 2,800 mg
single intravenous (IV) infusion within 3 days of having a positive result on a SARS-CoV-2 virologic test
placebo
COVID 19 outpatients
Participants were excluded if they had a saturation of oxygen (SpO2) ≤93% on room air, respiratory rate ≥30 breaths/min, or heart rate ≥125 bpm
double-blind
October, 2021 EMA ends rolling review of the antibodies bamlanivimab and etesevimab for COVID-19 following withdrawal by Lilly. Janvier, 2022: FDA limit the use of bamlanivimab and etesevimab to infection due to susceptible variants (ie not omicron).
bamlanivimab/etesevimab (n=158) vs. placebo (n=153)
randomized controlled trial risk of bias NA
bamlanivimab 700 mg and etesevimab 1,400 mg
placebo
3 arms : 700 mg bamlanivimab and 1,400 mg etesevimab, 2,800 mg bamlanivimab and 2,800 mg of etesevimab, and placebo
COVID 19 outpatients
double-blind
phase 2, ongoing, interim analysis (without precision about prespecification and type 1 risk control)
UNPUBLISHED preliminary data, from FDA EUA fact sheet. October, 2021 EMA ends rolling review of the antibodies bamlanivimab and etesevimab for COVID-19 following withdrawal by Lilly. Janvier, 2022: FDA limit the use of bamlanivimab and etesevimab to infection due to susceptible variants (ie not omicron).
Bebtelovimab (LY-CoV1404) (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
single-dose bebtelovimab
placebo
COVID 19 outpatients
double-blind
phase 1/2
budesonide (n=1073) vs. standard of care (n=1988)
randomized controlled trial some concerns about risk of bias
inhaled budesonide (800μg twice daily for 14 days) plus usual care
Inhaled budesonide (800μg twice daily for 14 days) plus usual care;
usual care
several arms: usual care, usual care plus budesonide or usual care plus other interventions
COVID 19 outpatients
Open-label.
United Kingdom.
budesonide (n=73) vs. standard of care (n=73)
randomized controlled trial high risk of bias
Inhaled budesonide
Budesonide dry powder inhaler (Pulmicort Turbuhaler, AstraZeneca) at a dose of 800μg twice a day (400 micrograms per inhalation, 2 inhalations twice a day).
Usual care
Usual care was supportive therapy, with the National Health Service (NHS) advising patients with COVID-19 symptoms to take anti-pyretics for symptoms of fever (products containing paracetamol, or non-steroidal anti-inflammatories such as aspirin and ibuprofen) and honey for symptoms of cough.
COVID 19 outpatients
Participant is willing and able to give informed consent for participation in the trial, Male or Female, aged 18 years or above, New onset of symptoms suggestive of COVID-19 e.g. new onset cough and/or fever, and/or loss of smell or taste within 7 or fewer days of participant being seen at visit 1, In the Investigator's opinion, is able and willing to comply with all trial requirements.
Open-label.
Single-center, Oxfordshire, United Kingdom.
Phase II. Participants were seen at their homes at randomisation (day 0), day 7 and day 14 by a trained respiratory research nurse. At day 28, all study participants were seen in the trial centre and serum SARS-CoV-2 antibody testing was performed
The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment.
casirivimab/imdevimab (Ronapreve) (n=838) vs. placebo (n=840)
randomized controlled trial some concerns about risk of bias
REGEN-CO 1200mg (casirivimab and imdevimab) IV
Placebo
3 arms: placebo, REGEN-COV 2400mg (1200mg each antibody) and REGEN-COV 1200mg (600mg each antibody). (8,000 mg data were converted to a descriptive analysis)
COVID 19 outpatients
Patients ≥18 years of age and non-hospitalized, with a confirmed local SARS-CoV-2-positive diagnostic test result ≤72 hours and onset of any Covid-19 symptom, as determined by the investigator, ≤7 days before randomization, maintain O2 saturation ≥93% breathing room air, not have prior or current use of putative COVID-19 treatments (e.g. convalescent plasma, systemic corticosteroids or remdesivir) and not have been previously or currently hospitalized for treatment of COVID-19.
Double-blind.
Analysis in modified full analysis set (subjects with positive RT-qPCR test at baseline).The primary and two key secondary endpoints were tested hierarchically. The key secondary clinical endpoints were (1) the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death from day 4 through day 29 and (2) the time to Covid-19 symptoms resolution (19 of the 23 recorded symptoms).
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.*
casirivimab/imdevimab (Ronapreve) (n=156) vs. placebo (n=158)
randomized controlled trial some concerns about risk of bias
Casirivimab 600 mg and imdevimab 600 mg
Single 1200 mg dose.
Placebo
Placebo at day 1 via subcutaneous injection.
COVID 19 outpatients
Double-blind.
112 sites in the US, Romania and Moldova.
The trial consists of a 1-day screening/baseline period, a 28-day efficacy assessment period (EAP), and a 7-month follow-up period.
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.*
ciclesonide (n=197) vs. placebo (n=203)
randomized controlled trial low risk of bias
Ciclesonide pressurised metered-dose inhaler (pMDI).
Supportive care plus ciclesonide (Alversco) 320 mcg twice daily for 30 days via pMDI.
Placebo
Supportive care plus placebo mztching Alvesco, twice daily for 30 days via pMDI.
Standard supportive care was provided at the discretion of the study nurse or physician and included recommendations for symptomatic medications and directions to seek emergency care when necessary.
COVID 19 outpatients
Double-blind.
Multicenter; 10 centers throughout the US (public and private, academic and non-academic sites).
Time to alleviation of COVID-19-related symptoms of cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell, defined as symptom-free for a continuous period of more than 24 hours (ie, later than 3 AM/PM assessments) by day 30.
Changes in primary outcome during the trial: A primary outcome based on symptom resolution was chosen rather than one based on emergency department visits or hospital admission after preliminary data demonstrated substantially lower than expected rates of emergency department visits or hospitalizations among study participants.
ciclesonide (n=108) vs. placebo (n=107)
randomized controlled trial some concerns about risk of bias
Ciclesonide
Inhaled ciclesonide (600 μg twice daily) along with the usual dose of intranasal ciclesonide (200 μg daily) for 14 days.
Placebo
Saline placebo metered dose inhaler and intranasal saline of a similar appearance to ciclesonide at the same dosing schedule.
COVID 19 outpatients
Adults aged 18 years and older who had polymerase chain reaction confirmed COVID-19 at enrolment with at least one of the symptoms of fever, cough (wet or dry), or shortness of breath (including dyspnoea, chest congestion, or chest tightness as synonyms). People were excluded if they were admitted to hospital, had only non-respiratory symptoms (eg, nasal congestion, myalgias, or gastrointestinal symptoms), had already been prescribed an inhaled steroid.
Double-blind.
Three Canadian provinces (Quebec, Ontario, and British Columbia).
Enrolment to the trial began on 15 September 2020 in Quebec, 9 February 2021 in Ontario, and 22 March 2021 in British Columbia. The last participants were recruited on 8 June 2021. Participants self-reported outcome data for the 14 days after enrolment, including improvement in covid-19 related respiratory symptoms, other covid-19 symptoms, adherence to the trial intervention, side effects, and hospital admissions.
cilgavimab and tixagevimab (Evusheld) (n=452) vs. placebo (n=451)
randomized controlled trial risk of bias NA
cilagavimab/tixagévimab
a single 600mg IM
placebo
COVID 19 outpatients
double blind
96 sites in Brazil, Czech Republic, Germany, Hungary, Italy, Japan, Mexico, Poland, Russian Federati
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.* from press AZ release https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-phiii-trial-positive-in-covid-outpatients.html
colchicine (n=2235) vs. placebo (n=2253)
randomized controlled trial low risk of bias
Colchicine
Colchicine 0.5 mg per os twice daily for the first 3 days, then once daily for the last 27 days.
Placebo
Placebo per os twice daily for the first 3 days, then once daily for the last 27 days.
COVID 19 outpatients
adults >= 40 years old diagnosed with COVID19 within the last 24h; not currently hospitalized and not under immediate consideration for hospitalization. Patients must possess at least one high-risk criteria (>70 years old, diabetes mellitus, uncontrolled hypertension, respiratory disease, heart failure, coronary disease, fever of ≥38.4°C within the last 48 hours, dyspnea at the time of presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count).
Double blind, randomized.
Brazil, Canada, Greece, South Africa, Spain, and the USA
multiple testing
premature discontinuation due to logistical issues
colchicine (n=212) vs. standard of care (n=2081)
randomized controlled trial some concerns about risk of bias
Colchicine
Usual care plus colchicine 500µg daily for 14 days.
Usual care
COVID 19 outpatients
Open-label.
Participants were followed up through an online, daily symptom diary for 28 days after randomisation, supplemented with telephone calls to non-responders on days 7, 14 and 28. The diary includes questions about illness recovery (ascertained by answering the question, “Do you feel recovered today? (i.e. symptoms associated with illness are no longer a problem) Yes/No”), overall illness severity (a rating of how well they are feeling on a scale of 1-10 [1 being the worst and 10 being the best]), individual symptom severity on a four-point scale (0 = no problem to 3 =major problem), and healthcare service utilisation.
Trial stopped for futility on May 26, 2021.
convalescent plasma treatment (n=207) vs. placebo (n=209)
randomized controlled trial low risk of bias
convalescent plasma
placebo
regular plasma
COVID 19 outpatients
double blind
netherlands
phase 3. Based on the recommendation by the DSMB (rapid uptake of vaccination and effective monoclonal antibodies available for high risk outpatients), the study was terminated on the 13th of July 2021 before the planned sample size of 690 was reached
convalescent plasma treatment (n=257) vs. placebo (n=254)
randomized controlled trial some concerns about risk of bias
COVID-19 convalescent plasma
One unit (250 mL) of ABO-compatible COVID-19 convalescent plasma.
Placebo
250 mL of normal saline (colored with a parenteral multivitamin concentrate to resemble plasma).
COVID 19 outpatients
=< 18 years with one or more symptoms of COVID-19 illness and laboratory-confirmed SARS-Cov-2 infection, at least one study defined risk factor for severe COVID-19 illness, clinical team deems stable for outpatient management without supplemental oxygen, CP available at the site at the time of enrollment, duration of symptoms =< 7 days at ED presentation, informed consent from subject.
Single-blind.
Multicenter: 48 hospital emergency departments across the United States.
Trial enrollment was halted after the second planned interim analysis of the primary outcome indicated that the a priori stopping threshold for futility had been reached on the basis of a posterior predictive probability of success of 0.042.
convalescent plasma treatment (n=188) vs. placebo (n=160)
randomized controlled trial low risk of bias
convalescent plasma
anti-SARS-CoV-2 MBT plasma plus SMT will undergo an ABO compatibility test and will receive a single infusion of 200 to 300 ml
placebo
200 to 300ml of sterile saline solution 0.9%.
COVID 19 outpatients
double blind
4 centers, Spain
The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccin
discontinuation of ACEI/ARB (n=104) vs. continuation of ACEI/ARB (n=100)
randomized controlled trial some concerns about risk of bias
discontinuation of RAS inhibition
continuation of RAS inhibition
COVID 19 outpatients
open-label
35 centres in Austria and Germany
fluvoxamine (n=334) vs. placebo (n=327)
randomized controlled trial some concerns about risk of bias
fluvoxamine at a dose of 50 mg twice daily for 14 days
placebo
COVID 19 outpatients
double-blind
US, 6 centres
2-by-3 factorial design (metformin, ivermectin, and fluvoxamine)
fluvoxamine (n=741) vs. placebo (n=756)
randomized controlled trial some concerns about risk of bias
Fluvoxamine
100mg twice daily for 10 days.
Placebo
Twice daily for 10 days.
All participants received usual standard care for COVID-19 provided by healthcare professionals workers at public health facilities. Clinicians providing usual care in public health facilities typically focus on the management of symptoms and with antipyretics, and recommend antibiotics only if they suspect bacterial pneumonia.
COVID 19 outpatients
Patients over 18 years old with the ability to provide free and informed consent with Acute Flu-Like symptoms < 07 days and at least ONE enhancement criteria (Age > 50 years; Diabetes mellitus requiring oral medication or insulin Systemic arterial hypertension requiring at least 01 oral medication for BP control; Known cardiovascular diseases (heart failure, congenital heart disease, valvar heart valve disease, coronary artery disease, cardiomyopathies) Symptomatic lung disease (emphysema, chronic bronchitis) Symptomatic asthma patients requiring chronic use of agents for control of symptoms. Fever > 38 C at baseline Obesity, defined as BMI> 30 kg / m2 body weight Transplanted patients Patient with stage IV chronic kidney disease or on dialysis. Immunosuppressed patients/ using corticosteroid therapy (equivalent to maximum 10 mg of prednisone per day) and/ or immunosuppressive therapy) Patients with a history of cancer in the last 05 years or undergoing treatment of a current cancer Chronic renal disease KDIGO IV or End-Stage Renal Disease on chronic ambulatory renal replacement therapy Patients with important limitation of daily activities due to: Dyspnea, chest pain myalgia (limited to 25% of all randomizations) ). Patient with positive rapid test for SARS-CoV2 antigen performed on occasion of the screening or patient with a positive SARS-CoV2 diagnostic test within 07 days of the onset of symptoms.
Double-blind.
10 sites in Minas Gerais, Brazil.
Bayesian analysis.
Some inconsistencies between preprint and publication in terms of population size and inclusion period.
fluvoxamine (n=80) vs. placebo (n=72)
randomized controlled trial some concerns about risk of bias
fluvoxamine
100mg 3 times daily for 15 days
placebo
COVID 19 outpatients
double-blind
St Louis metropolitan area (Missouri and Illinois), USA
fluvoxamine (n=674) vs. placebo (n=614)
randomized controlled trial low risk of bias
fluvoxamine
fluvoxamine 50 mg twice daily for 10 days
placebo
COVID 19 outpatients
non-hospitalized adults aged ≥30 years with confirmed COVID-19 experiencing ≥2 symptoms of acute infection for ≤7 days prior to randomization
double-blind
time to sustained recovery was defined as the third of 3 consecutive days without symptoms
hydroxychloroquine (n=214) vs. placebo (n=227)
randomized controlled trial some concerns about risk of bias
Hydroxychloroquine
Hydroxychloroquine loading dose of 800 mg at the time of randomization and then 400 mg in daily doses at 8:00 AM for 9 days.
Placebo
Corresponding tablets of inert material (talc). Placebo bottles were matched for the same number of tablets as active lopinavir-ritonavir.
3 arms: Hydroxychloroquine, lopinavir-ritonavir or placebo (1:1:1).
COVID 19 outpatients
Patients 18 years or older; reported less than 8 days since onset of flulike symptoms or chest computerized tomography scan consistent with COVID-19 and at least one additional criterion for high risk: aged 50 years or older; presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, or emphysema; diabetes requiring oralmedication or insulin; hypertension requiring treatment; known cardiovascular diseases (congestive heart failure of any etiology, documented coronary artery disease, clinically manifest miscellaneous heart disease); symptomatic lung disease on chronic treatment; history of transplantation; obesity (body mass index 30 [calculated as weight in kilograms divided by height in meters squared]); immunocompromised status due to disease (eg, those living with HIV with a CD4 T-cell count of <200 cells/mm3, confirmed malignant neoplasm); immunocompromised status due to medication (eg, people taking 10 mg or more of prednisone equivalents a day); and patients with cancer.
Double-blind.
10 cities in Brazil.
The trial was stopped after the interim analysis for futility with a sample size of 685 patients.
hydroxychloroquine (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
hydroxychloroquine
600mg daily for 7 days
placebo
COVID 19 outpatients
double blind
1 center, germany
found in Axfors et al meta-analysis
hydroxychloroquine (n=689) vs. placebo (n=683)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine 400 mg BID in the first day, 400 mg OD thereafter for a total of seven days
placebo
COVID 19 outpatients
double-blind
56 Brazilian sites
hydroxychloroquine (n=244) vs. placebo (n=247)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine 600mg
oral hydroxychloroquine, 800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days
placebo
COVID 19 outpatients
double-blind
United States and Canada (40 states and 3 provinces)
hydroxychloroquine (n=152) vs. placebo (n=152)
randomized controlled trial risk of bias NA
hydroxychloroquine
(600 mg daily for one week)
placebo
arms: placebo, oral HC, or oral HC plus oral AZ
COVID 19 outpatients
double-blind
2 centres, Quatar
hydroxychloroquine (n=137) vs. standard of care (n=157)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine 400mg
hydroxychloroquine (800 mg on day 1, followed by 400 mg once daily for 6 days)
standard of care
COVID 19 outpatients
moste patients were healthcare workesr (86.7%)
open-label
Catalonia, Spain
hydroxychloroquine (n=15) vs. standard of care (n=13)
randomized controlled trial some concerns about risk of bias
hydroxychloroquine
2x200mg twice a day
placebo
COVID 19 outpatients
double-blind
1 centre, USA
interim analysis. study discontinuated due to rapide decline of infection rate during the study accrual period.
ivermectin (n=602) vs. placebo (n=604)
randomized controlled trial low risk of bias
ivermectin, with a maximum targeted dose of 600 μg/kg for 6 days
placebo
COVID 19 outpatients
double-blind
93 sites in the US
ivermectin (n=250) vs. placebo (n=251)
randomized controlled trial low risk of bias
ivermectin
24 to 48 mg (depends on the weight of the patient) at day 1 and day 2
placebo
COVID 19 outpatients
double-blind
1 center, Argentina
ivermectin (n=12) vs. placebo (n=12)
randomized controlled trial low risk of bias
ivermectin
400 mcg/kg, single dose
placebo
COVID 19 outpatients
double bliind
1 center, Spain
ivermectin (n=679) vs. placebo (n=679)
randomized controlled trial low risk of bias
Ivermectin 400 mcg/kg up to 90kg weight every 24 hours for 3 days
placebo
COVID 19 outpatients
double-blind
12 public health clinics in Brazil
adaptive platform trial
ivermectin (n=817) vs. placebo (n=774)
randomized controlled trial low risk of bias
ivermectin 400 mcg/kg daily for 3 days
placebo
COVID 19 outpatients
non-hospitalized adults age >=30 years with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for <=7 days
double-blind
ivermectin (n=200) vs. placebo (n=200)
randomized controlled trial some concerns about risk of bias
Ivermectin
300 µg/kg of body weight per day of oral ivermectin in solution, for 5 days.
Placebo
300 µg/kg of body weight per day of oral placebo for 5 days.
Placebo was a solution with similar organoleptic properties to ivermectin. Bottles of ivermectinand placebo were identical throughout the study period toguarantee double-blinding.
COVID 19 outpatients
Adult subjects over 18 years of age with SARS CoV2 / COVID 19 disease confirmed by antigen detection tests authorized by INVIMA or by RT-PCR in any of the laboratories that report to the Departmental Health Secretary, approved for the diagnosis of COVID-19 by the National Institute of Health. Onset of SARS CoV2 / COVID 19 illness 7 days ago or less, subjects with mild disease, informed consent signature.
Double-blind.
Single site in Cali, Colombia.
ivermectin (n=410) vs. placebo (n=398)
randomized controlled trial some concerns about risk of bias
ivermectin at a dose of 390 to 470 μg per kilogram per day for 3 days
placebo
COVID 19 outpatients
double-blind
US, 6 centres
2-by-3 factorial design (metformin, ivermectin, and fluvoxamine)
ivermectin (n=32) vs. standard of care (n=30)
randomized controlled trial high risk of bias
ivermectin
200 micrograms/kg single dose
standard of care
included antipyretics, cough suppressants, and capsuledoxycycline (100 mg every 12 hours for seven days)
COVID 19 outpatients
open label
1 center, Bangladesh
ivermectin (n=110) vs. standard of care (n=144)
cluster randomized trial high risk of bias
ivermectin
ivermectin orally 4 tablets of 6 mg = 24 mg every 7 days for 4 weeks
standard of care
COVID 19 outpatients
open label
Argentina
ivermectin plus doxycycline (n=60) vs. hydroxychloroquine plus macrolides (n=56)
randomized controlled trial high risk of bias
Ivermectin Doxycycline
Ivermectin 200μgm/kg single dose Doxycycline 100 mg BID for 10days
hydroxychloroquine azithromycine
Hydroxychloroquine 400 mg 1st day then200mg BID for 9days Azithromycin 500 mgdaily for 5Days
COVID 19 outpatients
1 center, Bangladesh
lopinavir/ritonavir (n=244) vs. placebo (n=227)
randomized controlled trial some concerns about risk of bias
Lopinavir-ritonavir
Lopinavir-ritonavir: loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days.
Placebo
Corresponding tablets of inert material (talc). Placebo bottles were matched for the same number of tablets as active lopinavir-ritonavir.
3 arms: Hydroxychloroquine, lopinavir-ritonavir or placebo (1:1:1).
COVID 19 outpatients
Patients 18 years or older; reported less than 8 days since onset of flulike symptoms or chest computerized tomography scan consistent with COVID-19 and at least one additional criterion for high risk: aged 50 years or older; presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, or emphysema; diabetes requiring oralmedication or insulin; hypertension requiring treatment; known cardiovascular diseases (congestive heart failure of any etiology, documented coronary artery disease, clinically manifest miscellaneous heart disease); symptomatic lung disease on chronic treatment; history of transplantation; obesity (body mass index 30 [calculated as weight in kilograms divided by height in meters squared]); immunocompromised status due to disease (eg, those living with HIV with a CD4 T-cell count of <200 cells/mm3, confirmed malignant neoplasm); immunocompromised status due to medication (eg, people taking 10 mg or more of prednisone equivalents a day); and patients with cancer.
Double-blind.
10 cities in Brazil.
The trial was stopped after the interim analysis for futility with a sample size of 685 patients.
metformin (n=663) vs. placebo (n=660)
randomized controlled trial some concerns about risk of bias
immediate-release metformin administered with an increase in dose over 6 days to 1500 mg per day for 14 days,
placebo
COVID 19 outpatients
double-blind
US, 6 centres
2-by-3 factorial design (metformin, ivermectin, and fluvoxamine)
metformin (n=217) vs. placebo (n=206)
randomized controlled trial risk of bias NA
Metformin 750mg dose twice daily for 10 days
placebo
COVID 19 outpatients
double-blind
Brazil
unpublished results; metformin inclusion were interrupted in this platform trial
molnupiravir (n=716) vs. placebo (n=717)
randomized controlled trial low risk of bias
Molnupiravir (Lagevrio)
800 mg of Molnupiravir orally twice daily for 5 days.
Placebo
Placebo orally twice daily for 5 days.
COVID 19 outpatients
Patients with laboratory-confirmed mild-to-moderate COVID-19, with symptom onset within 5 days of study randomization. Eligible subjects were 18 years of age and older and had one or more pre-defined risk factors for disease progression: 60 years of age or older, diabetes, obesity (BMI >30), chronic kidney disease, serious heart conditions, chronic obstructive pulmonary disease, or active cancer. The study included symptomatic subjects not vaccinated against SARS-CoV-2 and who had laboratory confirmed SARS-CoV-2 infection and symptom onset within 5 days of enrolment.
Double-blind.
170 sites in 23 countries: Argentina, Brazil, Canada, Chile, Colombia, Egypt, France, Germany...
Planned interim analysis to assess efficacy/futility based on 50% of the planned phase 3 enrollment (775/1550) with an alpha spending function that controlled the type I error rate at alpha = 0.025 (one sided) with a criterion to declare early efficacy of p<0.0092. Missing mortality status at day 29 was imputed as hospitalization or death.
Trial stopped early for efficacy at the planned interim analysis. The formal evaluation of efficacy is considered complete at the planned interim analysis at which time the statistical criterion for success was met. The analyses of data for the full population are considered supportive analyses.
molnupiravir (n=140) vs. placebo (n=62)
randomized controlled trial some concerns about risk of bias
Molnupiravir
Molnupiravir 200mg, 400mg or 800mg administered orally twice daily for 5 days.
Placebo
Twice daily for 5 days, orally.
COVID 19 outpatients
Double-blind.
Multicenter; 10 sites in the USA.
Phase 2a.
nirmatrelvir / ritonavir (Paxlovid) (n=1120) vs. placebo (n=1126)
randomized controlled trial low risk of bias
Nirmatrelvir/ritonavir (Paxlovid)
300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days
Placebo
Patients were treated within five days of symptom onset.
COVID 19 outpatients
Patients with confirmed SARS-CoV-2 infection within 5 days prior to randomization, with at least 1 characteristic or underlying medical condition associated with an increased risk of developing illness from COVID-19.
Double-blind.
North and South America, Europe, Africa, and Asia.
nitazoxanide (n=472) vs. placebo (n=463)
randomized controlled trial risk of bias NA
Nitazoxanide
nitazoxanide 300 mgextended release tablets (600 mg per dose) orally with food twice dailyfor five days.
Placebo
matching placebo tablets orally with food twice dailyfor five days.
In addition to study medication, all subjects received a vitamin B complexsupplement twice daily
COVID 19 outpatients
Subjects at least 12 years of age presenting within 72 hours of onset of symptoms of mild or moderate COVID-19 were eligible to participate in the trial. Minimum symptom requirements were: at least two respiratory symptom domains (head, throat, nose, chest, cough) with a score of≥2 as determined by scoring the InFLUenza Patient-Reported Outcomes (FLU-PRO©) questionnaire administered at screening (only one domain score required to be ≥2 if pulse rate ≥90 beats per minute or respiratory rate ≥16 breaths per minute), with no improvement in overall symptom severity from the prior day.
Double-blind.
Multicenter, 36 centers in the U.S. and Puerto Rico.
Subjects were considered to have reachedsustained response when they experienced (i) a decrease in total FLU-PRO score from the previousdiary entry, (ii) with a corresponding patient assessment that symptoms were at least “somewhatbetter than yesterday,” (iii) no oral temperature ≥100.4°F during the past 24 hours, and (iv) nofuture increase in any of the FLU-PRO domain or subdomain scores through study day 21 exceptto the below pre-defined background levels that were considered not meaningful to patients.
peginterferon (n=916) vs. placebo (n=1020)
randomized controlled trial risk of bias NA
single injection of Peginterferon Lambda 180 mcg
placebo
COVID 19 outpatients
double-blind
Brazil, 12 sites
preliminary results
peginterferon (n=30) vs. placebo (n=30)
randomized controlled trial low risk of bias
Peginterferon lambda-1a
Single 180 µg subcutaneous injection of peginterferon lambda within 7 days ofsymptom onset or first positive swab if asymptomatic.
Placebo
Single 180 µg subcutaneous injection of saline placebo within 7 days ofsymptom onset or first positive swab if asymptomatic.
COVID 19 outpatients
Adult patients between the ages of 18 and 70 years, confirmed COVID-19 infection by PCR within 5 days of symptom onset (fever, respiratory symptoms, sore throat), and discharged to home isolation.
Double-blind.
Multicenter, 6 institutions in Toronto, Canada.
Because of non identical matching placebo, one of two study personnel administering the medication was aware of the treatmentallocation. After administering the medication, all further follow-up (phone calls and study visits) was completed by study personnel unaware of treatment allocation.
Type III Interferon.
regdanvimab (Regkirona- CT-P59-Celltrion) (n=656) vs. placebo (n=659)
randomized controlled trial risk of bias NA
regdanvimab 40 mg/kg
Single infusion (drip) into a vein within 7 days of the start of COVID-19 symptoms of regdanvimab at dose of 40 mg/kg over 60 minutes.
placebo
Single infusion of placebo over 60 minutes.
COVID 19 outpatients
Adult patients with at least one or more symptoms of COVID-19 for ≤7 days, oxygen saturation >94% on room air, not requiring supplemental oxygen therapy. 66.9% of patients were at increased risk of progressing to severe COVID-19 and/or hospitalisation (defined as having at least one of the following risk factors for severe COVID-19: age >50 years; BMI >30 kg/m2; cardiovascular disease, including hypertension; chronic lung disease, including asthma; type 1 or type 2 diabetes mellitus; chronic kidney disease, including those on dialysis; chronic liver disease; and immunosuppressed, based on investigator’s assessment). Treatment was initiated after obtaining a positive SARS-CoV-2 viral infection determination.
double-blind
60 study centres across 14 countries, Hungary, Ireland, Italy, Mexico, North Macedonia, Peru, Poland
If the primary endpoint is statistically significant, the key secondary endpoints will be tested using the fixed sequence procedure in order to preserve the Type I error
preliminary unpublished results extracted from the EMA review document. *Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.*
regdanvimab (Regkirona- CT-P59-Celltrion) (n=226) vs. placebo (n=111)
randomized controlled trial risk of bias NA
regdanvimab 40 mg/kg or 80 mg/kg
single infusion
placebo
3 arms: single infusion of regdanvimab at doses of 40 mg/kg, 80 mg/kg, or placebo
COVID 19 outpatients
double-blind
23 study centres across 4 countries, Republic of Korea, Romania, Spain and United States
The study was explorative and did not have a type-1 error controlled primary endpoint
preliminary unpublished results extracted from the EMA review document. *Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.*
remdesivir (n=292) vs. placebo (n=292)
randomized controlled trial low risk of bias
Intravenous remdesivir
Intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3).
Placebo
COVID 19 outpatients
Eligible patients were 12 years of age or older and had at least one preexisting risk factor for progression to severe Covid-19 or were 60 years of age or older, regardless of whether they had other risk factors. Risk factors included hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30), immune compromise, chronic mild or moderate kidney disease, chronic liver disease, chronic lung disease,current cancer, or sickle cell disease.
Double-blind.
64 sites in the US, Spain, Denmark, UK.
The primary efficacy end point was initially a composite of hospitalization for any cause or death from any cause by day 14 and was modified on January 14, 2021, in response to comments from the Food and Drug Administration; trial blinding was maintained. No interim statistical analyses were performed.
On April 6, 2021, an orderly closure of trial enrollment was announced by the sponsor because of administrative reasons related to a decrease in the incidence of SARS-CoV-2 infections, ethical concerns regarding assigning patients to placebo in the context of increased access to emergency-use–authorized treatments such as monoclonal antibodies, and increasing vaccination rates among high-risk persons.
SNG001 inhaled interferon beta (n=-9) vs. placebo (n=-9)
randomized controlled trial risk of bias NA
COVID 19 outpatients
sofosbuvir and daclatasvir (n=30) vs. standard of care (n=30)
randomized controlled trial some concerns about risk of bias
Sofosbuvir/Daclatasvir
Single daily oral tablet containing 400 mg sofosbuvir and 60mg daclatasvir with hydroxychloroquine 200mg twice daily, for 7 days, or until death/hospitalization.
Standard of care
Hydroxychloroquine.
Hydroxychloroquine in both groups. All patients received standard care according to the national Iranian treatment guidelines. All patients received azithromycin capsules (500mg for 6 days) with naproxen tablets (500mg, twice daily for 7 days), as well as40mg pantoprazole tablets.
COVID 19 outpatients
Patients excluded if oxygen saturation less than 93%.
Double-blind.
Single center, Miandrood Outpatient Medical Clinic in Surak, Mazandaran, Iran.
At Days 1, 3 and 5 patients were followed-up by phone call and at Day 7 by a personalvisit. At 30 days from enrolment, patients were followed-up by phone call to monitor fatigue, shortness of breath and anorexia.
sotrovimab (Xevudy; VIR-7831) (n=528) vs. placebo (n=529)
randomized controlled trial low risk of bias
Sotrovimab (VIR-7831, GSK4182136) as monotherapy
Intravenous infusion of sotrovimab 500 mg over 1 hour on day 1.
Placebo
Equal volume of saline placebo over 1 hour on day 1.
Patients were observed for approximately 2 hours after infusion.
COVID 19 outpatients
18 years of age and older with at least one of the following comorbidities: diabetes, obesity (BMI >30), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate to severe asthma, or were 55 years of age and older regardless of comorbidities. Participants must have a positive SARS-CoV-2 test result and oxygen saturation ≥94% on room air and have COVID-19 symptoms and be less than or equal to 5 days from onset of symptoms
Double-blind.
57 centers in 5 countries: US, Brazil, Spain, Canada, Peru.
*Warning! The spread of new Sars-Cov2 variants is constantly evolving, this study was performed in a different viral context than today, its results should be interpreted accordingly.* data reported in FDA emergency use authorization (EUA), results from interim analysis.
vitamin C (n=48) vs. standard of care (n=50)
randomized controlled trial some concerns about risk of bias
Ascorbic acid (high dose)
8000 mg of ascorbic acid (to be divided over 2-3 times per day with meals).
Standard of care
Usual care without any study medications.
4 arms: standard of care, ascorbic acid only, zinc only, ascorbic acid and zinc association.
COVID 19 outpatients
Outpatients ≥ 18 years presenting to Cleveland Clinic Health System in Ohio and Florida who test positive for COVID-19 having any of thefollowing symptoms: fever or chills, shortness of breath or difficulty breathing, cough, fatigue, muscle or body Aches, headache, new loss of taste, new loss of smell, congestion or runny nose, nausea, vomiting, diarrhea.
Open-label.
Cleveland Clinic Main Campus Cleveland, Ohio and Florida
Patients were asked to track their systemic illness daily based on symptoms. Patients recorded a questionnaire with only 4 symptoms (ie, fever/chills, shortness of breath, cough, and fatigue) for scores ranging from 0 to 12. For each symptom, the patients assigned a score of 0 to 3 (with 0 indicating no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms).
The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point.
zinc (n=58) vs. standard of care (n=50)
randomized controlled trial risk of bias NA
Zinc (High-dose)
50mg of zinc gluconate at bedtime.
Standard of care
Usual care without any study medications.
4 arms: standard of care, ascorbic acid only, zinc only, ascorbic acid and zinc association.
COVID 19 outpatients
Outpatients ≥ 18 years presenting to Cleveland Clinic Health System in Ohio and Florida who test positive for COVID-19 having any of thefollowing symptoms: fever or chills, shortness of breath or difficulty breathing, cough, fatigue, muscle or body Aches, headache, new loss of taste, new loss of smell, congestion or runny nose, nausea, vomiting, diarrhea.
Open-label.
Cleveland Clinic Main Campus Cleveland, Ohio and Florida
Patients were asked to track their systemic illness daily based on symptoms. Patients recorded a questionnaire with only 4 symptoms (ie, fever/chills, shortness of breath, cough, and fatigue) for scores ranging from 0 to 12. For each symptom, the patients assigned a score of 0 to 3 (with 0 indicating no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms).
The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point.
zinc plus vitamin c (n=58) vs. standard of care (n=50)
randomized controlled trial some concerns about risk of bias
Ascorbic acid (high dose) plus zinc (high dose)
8000 mg of ascorbic acid (to be divided over 2-3 times per day with meals) plus 50mg of zinc gluconate at bedtime.
Standard of care
Usual care without any study medications.
4 arms: standard of care, ascorbic acid only, zinc only, ascorbic acid and zinc association.
COVID 19 outpatients
Outpatients ≥ 18 years presenting to Cleveland Clinic Health System in Ohio and Florida who test positive for COVID-19 having any of thefollowing symptoms: fever or chills, shortness of breath or difficulty breathing, cough, fatigue, muscle or body Aches, headache, new loss of taste, new loss of smell, congestion or runny nose, nausea, vomiting, diarrhea.
Open-label.
Cleveland Clinic Main Campus Cleveland, Ohio and Florida
Patients were asked to track their systemic illness daily based on symptoms. Patients recorded a questionnaire with only 4 symptoms (ie, fever/chills, shortness of breath, cough, and fatigue) for scores ranging from 0 to 12. For each symptom, the patients assigned a score of 0 to 3 (with 0 indicating no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms).
The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point.
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