meta|Evidence - COVID-19
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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=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 (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 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.
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.
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
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=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.
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=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=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=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=-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=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=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=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=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.
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.
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.
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.
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.
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