Covid-19 living Data

Ivermectin vs Standard care/Placebo (RCT)

Hospitalized patients

Study Samaha A, Viruses 2021 has been retracted on October 26, 2021. The study was excluded from the analysis and grade assessment by December 17 the latest.

Study Pott-Junior H, 2021 (Toxicology Reports) retracted on May 11, 2022. FOREST PLOTS -2023-01-27

Studies description

Trial NCT04403555
Publication Abd-Elsalam S, J Med Virol (2021) (published paper)
Dates: 2020-03-01 to 2020-10-30
Funding: Not reported/unclear
Conflict of interest: No

Trial NCT04407130
Publication Ahmed S, Int J Infect Dis (2020) (published paper)

Funding: Private (Beximco Pharmaceutical Limited, Bangladesh)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : * / Bangladesh Follow-up duration (days): 28
Inclusion criteria	age 18-65 years admitted to hospital within the last 7 days with either fever (≥37.5C) cough or sore throat and diagnosed positive for SARS-CoV-2 by rRT-PCR
Exclusion criteria	allergic to or potential drug-drug interaction for ivermectin or doxycycline chronic illnesses (e.g., ischemic heath disease, heart failure, documented cardiomyopathy, chronic kidney disease, chronic liver disease) received ivermectin and/or doxycycline in the last 7 days were pregnant or lactating or participated in any other clinical trial within the last month
Interventions
	Treatment IVM+DX Ivermectin : 12mg once-off orally. Doxycycline : 200mg orally at day-1 followed by 100mg twice a day for next 4 days Ivermectin 12mg once a day orally for 5 days
	Control Placebo
Participants
	Randomized participants : IVM+DX=24 Ivermectin=24 Placebo=24
	Characteristics of participants N= 72 Mean age : NR 33 males Severity : Mild: n=72 / Moderate: n=0 / Severe: n=0 Critical: n=0
Primary outcome
	In the register 1.Virological clearance [ Time Frame: within 7 days after enrollment ] 2.Remission of fever [ Time Frame: within 7 days after enrollment ] 3.Remission of cough [ Time Frame: within 7 days after enrollment ]
	In the report Time required for virological clearance (a negative rRT-PCR result on nasopharyngeal swab); remission of fever (≥37.5C) and cough within 7 days
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	The published article and the regsitry were used in data extraction and assessment of risk of bias. No study protocol or statistical analysis plan were available. 4/72 participants withdrew consent because of family obligations and unwillingness to be tested further. Baseline characteristics were not reported by study group. Some efficacy outcomes were not reported in the results section of the paper although they were listed in the methods section. Mortality, reported as a study outcome in the methods, was not clearly reported. This study was updated on February 2nd, 2021 after contact with authors.

Trial NCT04391127
Publication Beltran-Gonzalez J, medRxiv (2021) (preprint)
Dates: 2020-05-04 to 2020-08-15
Funding: Public/non profit (Aguascalienes State Health Institute)
Conflict of interest: No

Methods
	RCT Blinding: Double blinded, no restrictions
	Location : Single center / Mexico Follow-up duration (days): 30
Inclusion criteria	Age 16 to 90 years hospitalized positive RT-PCR for SARS-CoV-2 by nasal and oropharyngeal swabbing pneumonia, diagnosed by X-ray or high-resolution chest CT scan, with a pattern suggesting involvement due to coronavirus recently established hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heart disease.
Exclusion criteria	Required high oxygen volumes (face mask > 10 L/ min) had predictors of a poor response to high-flow oxygen nasal prong therapy required mechanical ventilation
Interventions
	Treatment Hydroxychloroquine Initial dose: 400 mg orally twice a day for the first day. Maintenance dose: 200 mg orally twice a day for another 4 days. Ivermectin 12 mg for one day in patients weighing < 80 kg and 18 mg for one day in those >80 kg.
	Control Placebo Two calcium citrate tablets orally twice a day for one day. Subsequently one tablet twice a day for 4 more days.
Participants
	Randomized participants : Hydroxychloroquine=33 Ivermectin=36 Placebo=37
	Characteristics of participants N= 106 Mean age : NR 66 males Severity : Mild: n=0 / Moderate: n=16 / Severe: n=90 Critical: n=0
Primary outcome
	In the register Mean days of hospital stay [ Time Frame: Three months ]; Rate of Respiratory deterioration, requirement of invasive mechanical ventilation or dead [ Time Frame: Three months ]; Mean of oxygenation index delta [ Time Frame: Three months ]
	In the report Hospitalization duration until discharge due to clinical improvement, the total duration of hospitalization, and the safety outcomes were duration of hospitalization until respiratory deterioration (previously defined) or death
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. Inclusion criteria in registry and the pre-print article differ slightly in that the pre-print article also included hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heart disease. Some pre-stated primary (i.e., mean of oxygenation index delta) and secondary (i.e., mean time to negative PCR) outcomes were not reported. There were no substantive differences between the pre-print article and the trial registry in interventions. Patients considered at high risk of development of QT interval prolongation due to hydroxychloroquine were only randomized to the ivermectin or placebo arms. The trial was terminated due to a reduction in eligible participants. As a result, the target sample size was not achieved. This trial was updated on July 28th, 2021 with data gained from contact with authors.

Trial *
Publication Kishoria N, PIJR (2020) (published paper)

Funding: Not reported/unclear
Conflict of interest: *

Methods
	RCT Blinding: Unblinded
	Location : Single center / India Follow-up duration (days): 6
Inclusion criteria	Patients aged 18 years and above positive test after completion of standard care treatment for SARS-CoV-2 confirmed by reverse transcriptase–polymerase-chain-reaction (RT-PCR) assay mild/ asymptomatic no comorbidities rendering high-risk patients informed consent obtained.
Exclusion criteria	Allergy or hypersensitivity to ivermectin and/or its inactive ingredients respiratory distress or requiring intensive care used immunosuppressants (including systemic corticosteroids) in the last 30 days known HIV infection with CD4 count <300 cell/ L pregnancy or lactating patients medical conditions such as malabsorption syndromes affecting proper ivermectin absorption autoimmune disease and/or decompensated chronic diseases Uncontrolled, intercurrent diseases including renal impairment, hepatic impairment, symptomatic congestive heart failure, unstable chest angina or heart arrhythmia treated in any other study in the previous 30 days concomitant administration of enzyme inducers (such as carbamazepine) that could affect the effectiveness of the drug and those receiving CYP3A4 substrates (such as statins) due to the risk of increased toxicity.
Interventions
	Treatment Ivermectin 12 mg single dose
	Control Standard care
Participants
	Randomized participants : Ivermectin=19 Standard care=13
	Characteristics of participants N= 32 Mean age : NR 23 males Severity : Mild: n=32 / Moderate: n=0 / Severe: n=0 Critical: n=0
Primary outcome
	In the register NR
	In the report Negative throat swab report for SARS-CoV-2 conducted by RT-PCR after 48 hours of day one of research therapy. However if patient was tested positive on the then the test was repeated again after 48 hours.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	Only the published article was used in data extraction and assessment of the risk of bias. No trial registry, study protocol or statistical analysis plan was available. The sample included in this hospital-based study was small due to change in guidelines during the study in which asymptomatic patients and patients with mild symptoms were recommended to be home isolated and not hospitalized. Safety outcomes such as adverse events or death are not reported.

Trial NCT04381884
Publication Krolewiecki A, EClinicalMedicine (2021) (published paper)
Dates: 2020-05-18 to 2020-09-09
Funding: Mixed (Agencia Nacional de Promocion de la Investigacion, el Desarrollo Tecnologico y la Innovacion, Argentina and Laboratorio ELEA/Phoenix, Argentina)
Conflict of interest: Yes

Trial NCT04920942
Publication I-TECH - Lim SCL, JAMA Intern Med (2022) (published paper)
Dates: 2021-05-31 to 2021-10-09
Funding: Not reported/unclear
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Malaysia Follow-up duration (days): 28
Inclusion criteria	Patients with reverse transcriptase–polymerase chain reaction (RT-PCR) test–confirmed or antigen test–confirmed COVID-19 50 years or older with at least 1 comorbidity presented with mild to moderate illness (Malaysian COVID-19 clinical severity stage 2 or 3 WHO clinical progression scale 2-4) within 7 days from symptom onset
Exclusion criteria	Asymptomatic required supplemental oxygen pulse oximetry oxygen saturation (SpO2) level less than 95% at rest severe hepatic impairment (alanine transaminase level >10 times of upper normal limit) acute medical or surgical emergency concomitant viral infection pregnancy or breastfeeding warfarin therapy history of taking ivermectin or any antiviral drugs with reported activity against COVID-19 (favipiravir, hydroxychloroquine, lopinavir, and remdesivir) within 7 days before enrollment
Interventions
	Treatment Ivermectin 0.4 mg/kg/day orally for 5 days
	Control Standard care
Participants
	Randomized participants : Ivermectin=250 Standard care=250
	Characteristics of participants N= 500 Mean age : NR 223 males Severity : Mild: n=490 / Moderate: n=0 / Severe: n=0 Critical: n=0
Primary outcome
	In the register 1) Number of Patients who Progressed to Severe Disease (Clinical stage 4 or 5) [ Time Frame: Within 28 days since administered Ivermectin ]; 2) Time Required for Patients on Treatment Arm to Progressed to Severe Disease (Clinical stage 4 or 5) [ Time Frame: Within 28 days since administered Ivermectin ]
	In the report The proportion of patients who progressed to severe COVID-19, defined as the hypoxic stage requiring supplemental oxygen to maintain Spo2 95% or greater (Malaysian COVID-19 clinical severity stages 4 or 5; WHO clinical progression scale 5-9)
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. The primary and secondary outcomes in the article reflect those in the registry and/or protocol. The study (n = 500) achieved its target sample size (n = 500). There is no change from the trial registration in the intervention and control treatments.

Trial *
Publication Manomaipiboon A, Research square (2022) (preprint)
Dates: 2021-09-01 to 2021-11-30
Funding: Public/non profit (Navamindradhiraj University)
Conflict of interest: No

Trial CTRI/2020/06/026001
Publication RIVET-COV - Mohan A, J Infect Chemother (2021) (published paper)
Dates: 2020-07-28 to 2020-09-29
Funding: Mixed (Department of Science and Technology, Government of India; WindLas BioTech Ltd. Haryana (drug contribution))
Conflict of interest: No

Methods
	RCT Blinding: Participants, outcome assessor and health care pro
	Location : Single center / India Follow-up duration (days): 28
Inclusion criteria	- Aged 18 years or above - Diagnosed (based on a positive result on either SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) or the rapid antigen test) - Non-severe COVID-19 (i.e. room air saturation (SpO2) >90%, no hypotension or requirement of mechanical ventilation)
Exclusion criteria	- If they did not give informed consent - Pregnancy or lactation - Known hypersensitivity to ivermectin - Chronic kidney disease with creatinine clearance <30 mL/min - Elevated transaminase levels (>5 x upper limit of normal) - Myocardial infarction or heart failure within 90 days prior to enrolment - Prolonged corrected QT interval (>450 ms) on electrocardiogram - Any other severe comorbidity as per investigator’s assessment - Enrolment in a concomitant clinical trial
Interventions
	Treatment Ivermectin 12 mg 12 mg orally, single dose Ivermectin 24 mg 24 mg orally, single dose Ivermectin 12 mg orally, single dose
	Control Placebo
Participants
	Randomized participants : Ivermectin 12 mg=52 Ivermectin 24 mg=52 Placebo=53 Ivermectin=104
	Characteristics of participants N= 261 Mean age : NR 146 males Severity : Mild: n=150 / Moderate: n=15 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Frequency of RT-PCR negativity at day 5 after drug administration; Change in viral load (as determined by RTPCR cycle threshold) at day 5 as compared to baseline
	In the report Reduction of viral load and conversion to negativity of nasopharyngeal/oropharyngeal RT-PCR on day 5 after intervention
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the journal and pre-print article, the study registry and supplementary materials were used in data extraction and risk of bias assessment. It is not clear what the target sample size was and if it was achieved. Outcomes were not reported in the study registry, so it is unclear if there were reported at the correct follow-up point. There is no change from the study registration in the intervention and control treatments. This trial was updated on September 27th, 2021 with data from the peer-reviewed journal publication.

Trial IRCT20200408046987N1
Publication Niaee MS, Asian Pac J Trop Med (2021) (published paper)
Dates: 2020-06-01 to 2020-07-15
Funding: Mixed (Qazvin University of Medical Sciences and Science (publication); Chistasazan Notash Fartak Company Limited (registry))
Conflict of interest: *

Methods
	RCT Blinding:
	Location : Multicenter / Iran Follow-up duration (days): 45
Inclusion criteria	Age >18 years Signed the informed consent Clinical symptoms of suggestive of COVID-19 pneumonia: cough (with or without sputum), fever, pleuritic chest pain or dyspnea Mild to severe COVID-19 disease confirmed by chest computed tomography (CT) scan findings compatible with COVID-19 or positive real-time reverse transcription polymerase chain reaction (RT-PCR).
Exclusion criteria	Presence of severe immunosuppression (e.g., use of immune-suppressants and HIV positive) Pregnant women Allergic reaction to the intervention Chronic kidney disease Malignancy Severe COVID-19 patients and indications that the patients were unable and/or unlikely to comprehend and/or follow the protocol.
Interventions
	Treatment SC/Placebo 200 mcg/kg orally once off. Ivermectin 200 mcg/kg orally once off.
	Control Placebo/NA Standard care/NA
Participants
	Randomized participants : Placebo/NA=30 Standard care/NA=30 SC/Placebo=60 Ivermectin=120
	Characteristics of participants N= 240 Mean age : NR 54 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Chest image (CT scan) at hospital clearance; Hospitalization time; CBC and CRP
	In the report The primary endpoint of this trial was all-cause of mortality or clinical recovery. Clinical recovery was defined as normal temperature, respiratory rate, and oxygen saturation (>94%) without oxygen therapy sustained for 24 h.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. There were some differences between the registry and the published/pre-print article in terms of inclusion criteria, number of treatment arms, and outcomes (registry: chest CT scan, length of hospitalization, complete blood count, C-reactive protein; article: clinical recovery defined as normal fever, respiratory rate, and oxygen saturation >94% without oxygen therapy sustained for 24h). Mortality was not listed as an outcome in the registry. The study achieved its pre-stated sample size. The overall follow-up of the study is unclear.

Trial NCT04646109
Publication Okumus N, BMC Infectious Disea (2021) (published paper)
Dates: 2020-05-11 to 2020-09-02
Funding: Public/non profit (Afyonkarahisar Health Science University)
Conflict of interest: No

Methods
	RCT Blinding: Single blinded, no restrictions
	Location : Multicenter / Turkey Follow-up duration (days): 90
Inclusion criteria	1. Patients who were hospitalised with a pre-diagnosis of "severe COVID-19 pneumonia" and thereafter diagnosis of COVID-19 2. Confirmed microbiologically with PCR positivity in respiratory tract samples. 3. Patients with at least one of the criteria below were accepted as patients with severe COVID-19 pneumonia: a. Presence of tachypnea ≥ 30/minute SpO2 level < 90% in room air PaO2/FiO2 <300 in oxygen receiving patient b. Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities) c. Mechanical ventilation requirement d. Acute organ dysfunction findings patients with SOFA (sepsis-related organ failure assessment) score >2
Exclusion criteria	1. Children < 18 years old 2. Pregnancy 3. Active breast feeding 4. Concurrent autoimmune disease 5. Chronic liver or kidney disease 6. Immunosuppression 7. SNP mutation in MDR-1/ABCB1 gene and/or haplotypes and mutations of the CYP3A4 gene 8. Patients with known ivermectin allergy
Interventions
	Treatment Ivermectin 200 mcg/kg enterally once daily for 5 days. 9 mg between 36–50 kg, 12mg between 51–65 kg, 15mg between 66–79 kg and 200 mcg/kg in > 80 kg
	Control Standard care
Participants
	Randomized participants : Ivermectin=36 Standard care=30
	Characteristics of participants N= 66 Mean age : NR 40 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=58 Critical: n=2
Primary outcome
	In the register 1. Gender Distribution of the Patients [ Time Frame: At the first day of the study ] 2. Age Distribution of the Patients [ Time Frame: At the first day of the study] 3. Percentage of Patients With Accompanying Diseases [ Time Frame: At the first day of the study] 4. Percentage of Patients With Baseline Clinical Symptoms [ Time Frame: At the first day of the study ] 5. Body Temperature Means of the Patients [ Time Frame: At the first day of the study] 6. Heart Rate Means of the Patients [ Time Frame: At the first day of the study] 7. Respiratory Rate Means of the Patients [ Time Frame: At the first day of the study] 8. Systolic and Diastolic Pressure Means of the Patients [ Time Frame: At the first day of the study] 9. Number of Participants With Clinical Response [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day)] 10. Changes in Oxygen Saturation (Sp02) Values [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day)] 11. Changes in the Ratio of Partial Pressure of Oxygen (Pa02) to Fraction of Inspired Oxygen (Fi02) (Pa02/Fi02) [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ] 12. Changes in Serum Lymphocyte Counts [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day)] 13. Changes in the Ratio of Polymorphonuclear Leukocyte Count to Lymphocyte Count (PNUL) [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ] 14. Changes in Serum Ferritin Levels [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day)] 15. Changes in Serum D-dimer Levels [ Time Frame: From starting to the end of ivermectin therapy (0 to the end of 5th day) ] 16. Genetic Examination of Haplotypes and Mutations That Cause Function Losing for Ivermectin Metabolism [ Time Frame: At the first day of ivermectin therapy (1st day)] 17. Treatment-Related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: At the first 5 days of study]
	In the report Clinical responses and drug side effects obtained in patients on the 5th day
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the pre-print and published article, the study registry (including outcome data) and protocol were used in data extraction and risk of bias assessment. The study was registered retrospectively but the protocol was dated prospectively. The trial used a quasi-randomized design. This study was updated on April 07th, 2021, with data from the study registry. On 12th of May, 2021, this study was updated based on the published report.

Trial CTRI/2020/08/027225
Publication Ravikirti R, J Pharm Pharm Sci (2021) (published paper)
Dates: 2020-08-28 to 2020-10-31
Funding: Mixed (All India Institute of Medical Sciences; Sun Pharma Pvt. Ltd. (placebo provision); learning resource allowance of the principal investigator (ivermectin procurement))
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Single center / India Follow-up duration (days): *
Inclusion criteria	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 Definitions of Mild, moderate and severe COVID-19 - Mild: No evidence of breathlessness or Hypoxia (normal saturation) - Moderate: Breathlessness and/or hypoxia (saturation 90-94% on room air), respiratory rate of 24 or more and no features of severe disease - Severe: Any of the following – Severe respiratory distress, oxygen saturation < 90% on room air, respiratory rate > 30, shock or evidence of a life threatening organ dysfunction
Exclusion criteria	- 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
Interventions
	Treatment Ivermectin 12 mg enterally once daily on days 1 and 2
	Control Placebo
Participants
	Randomized participants : Placebo=58 Ivermectin=57
	Characteristics of participants N= 115 Mean age : NR 81 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Negative RT-PCR [Day 6]
	In the report Negative RT-PCR report on day 6
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published/pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither the protocol nor statistical analysis plan were available. There were no substantive differences between the article and the trial registry in population, procedures, or interventions. The study achieved its pre-stated sample size. Although negative conversion by RT-PCR was reported as an outcome, it is unclear what proportion of patients was positive by the same measure at baseline: inclusion criteria included diagnosis confirmed by RT-PCR or Rapid Antigen Test. Some outcomes were reported with no details of duration of follow-up (admission to ICU, invasive ventilation, in-hospital mortality). Two secondary outcomes reported (symptom free on day 6 and later discharge) and drug-related adverse events were not included in the registry

Trial NCT04392713
Publication Shah Bukhari K H, medRxiv (2021) (preprint)

Funding: Not reported/unclear ("Not applicable")
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Pakistan Follow-up duration (days): 28
Inclusion criteria	15-65 years any gender COVID-19 positive, proven by RT-PCR Mild (fever <38oC quelled without treatment with or without cough, no dyspnea, no gasping, no chronic disease, no imaging findings of pneumonia) to moderate (fever, respiratory symptoms, imaging findings of pneumonia) severity of the disease consent for trial, stated their willingness to comply with all study procedures, agreed for admission for the trial period (14 days) able to take oral medication
Exclusion criteria	Positive pregnancy test (all females were tested) severe symptoms likely due to cytokine release syndrome uncontrolled co-morbidities malignant diseases diabetes mellitus chronic kidney disease cirrhosis liver with CPT class B or C immunocompromised history of ivermectin allergy patients taking CYP 3A4 inhibitors or inducers oxygen requirements equivalent to FiO2 ≥50% in moderate severity patients
Interventions
	Treatment Ivermectin 12 mg, once-off dose on admission
	Control Standard care
Participants
	Randomized participants : Ivermectin=50 Standard care=50
	Characteristics of participants N= 100 Mean age : NR 73 males Severity : Mild: n=100 / Moderate: n=0 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Negative PCR [ Time Frame: 144 hours ] - PCR will be done at 48, 96 and 144 hours
	In the report The primary end-point of the study was viral clearance and was measured as the days to achieve RT-PCR negativity following ivermectin administration.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the pre-print article, the trial registry was used in data extraction and assessment of risk of bias. The trial was registered retrospectively while the trial was ongoing. Neither study protocol nor statistical analysis plan was available. There are some differences between the pre-print article and the trial protocol in exclusion criteria relating to comorbidities. Standard care was different between the registry (chloroquine) and the report (vitamin C, paracetamol). The primary outcome timepoints differ between the registry and the pre-print article. The secondary outcome in the registry (need for ventilation) was not reported in the pre-print article. The pre-print reported that there were no adverse drug reactions in the ivermectin arm (not listed as an outcome in the registry). The target sample size specified in the registry was achieved. The study was assessed to be at a high risk of bias due to some concerns in multiple domains.

Trial IRCT20111224008507N3
Publication Shahbaznejad L, Clin Ther (2021) (published paper)
Dates: 2020-05-23 to 2020-07-31
Funding: No specific funding (Mazandaran University of Medical Sciences)
Conflict of interest: No

Methods
	RCT Blinding: Participants and outcome assessor
	Location : Multicenter / Iran Follow-up duration (days): 7
Inclusion criteria	Hospitalized patients (age >5 years, weight >15 kg) with any of the following: a positive result of COVID-19 RT-PCR or clinical complaints of COVID-19 with a history of contact with a COVID-19 patient or abnormalities in chest computed tomography scan compatible with COVID-19 (ground-glass opacity, halo sign, reversed halo sign, and patchy infiltration).
Exclusion criteria	History of chronic liver and/or renal disease receiving treatment with warfarin, angiotensin-converting enzyme inhibitors, or angiotensin II receptor antagonists acquired immunodeficiency pregnant women and lactating mothers.
Interventions
	Treatment Ivermectin 0.2 mg/kg orally once-off (weight-based doses, i.e. 15-24 kg: 3 mg; 25-30 kg: 6 mg; 36-50 kg: 9 mg; 51-80 kg: 12 mg; >80 kg: 0.2 mg/kg).
	Control Standard care
Participants
	Randomized participants : Ivermectin=35 Standard care=38
	Characteristics of participants N= 73 Mean age : NR 36 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=3
Primary outcome
	In the register Clinical symptoms including fever, chills, sore throat, cough, shortness of breath, decreased appetite, abdominal pain, dizziness, insomnia, itching, joint pain, joint swelling, headache, nausea, vomiting, diarrhea, malaise, conjunctivitis, tachycardia, wheezing, rhonchus, retraction, hypotension, rash, other symptoms; respiratory rate and O2 saturation-The first, second, third, fourth, fifth, sixth, seventh day.
	In the report Clinical improvement after baseline defined as resolving patients’ baseline status on persistent and continuous cough (coughing a lot for more than an hour, or ≥3 coughing episodes in 24 hours that interferes with daily life and ability to work) and tachypnea in addition to increasing oxygen saturation >94%.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published report (pre-proof), the retrospective registry was used in data extraction and assessment of the risk of bias. The protocol or statistical analysis plan was not available. The study achieved the target sample size specified in the trial registry (n=60). There is no change from the trial registration in the intervention and control treatments. After selecting the samples, none of the participants was aware of randomization and allocation to groups. The evaluator nurse of data recording is from out of the study and questionnaires was provided in the form of coding to him/her. So, the present study is double-blinded (registry). Some outcomes from the report are not mentioned in the registry (e.g. adverse events, mortality).

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Egypt Follow-up duration (days): 30
Inclusion criteria	adult patients from ages 20 to 65 mildly to moderately affected COVID-19 infection confirmed by pharyngeal swab polymerase chain reaction
Exclusion criteria	allergy or contraindication to the drugs used in the study pregnant and lactating mothers patients with cardiac problems
Interventions
	Treatment Ivermectin 12 mg per day orally for 3 days
	Control Standard care
Participants
	Randomized participants : Ivermectin=82 Standard care=82
	Characteristics of participants N= 164 Mean age : NR 82 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register The number of patients with resolved viral infection [Time Frame: 6 months] (2020-05-23) The number of patients with mortality [Time Frame: 1 month] (2021-03-03)
	In the report All-cause mortality within 1 month after randomization
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry was used in data extraction and risk of bias assessment. Neither protocol not statistical analysis plan was available. The trial was first registered during the conduct of the study. There were substantial changes to methods during and after the conduct of the study from the initial trial registration to the final registration and report. The sample size was reduced. Intervention and control treatments changed from ivermectin with doxycycline compared with chloroquine to ivermectin compared with standard care. The ivermectin dosage was changed. The primary outcome changed from resolved viral infection to mortality, and additional outcomes were added after the study had been completed.

Methods
	RCT Blinding: Outcome assessor
	Location : Multicenter / Argentina Follow-up duration (days): 30
Inclusion criteria	COVID-19 patients aged 18 to 69 years-old with RT-PCR confirmed infection hospitalized not requiring intensive care COVID-19 symptoms onset ≤5 days at recruitment absence of use of drugs with potential activity against SARS-CoV-2 (hydroxychloroquine, lopinavir, remdesivir and azithromycin) those drugs were not permitted during the first week of the trial.
Exclusion criteria	The use of immunomodulators within 30 days of recruitment Pregnancy breast feeding Poorly controlled comorbidities Patients of child-bearing age (men and women) were eligible if agreed to take effective contraceptive measures during the study period and for at least 30 days after the last study drug administration
Interventions
	Treatment Ivermectin 0.6 mg/kg orally once a day for 5 days.
	Control Standard care
Participants
	Randomized participants : Ivermectin=30 Standard care=15
	Characteristics of participants N= 45 Mean age : NR 25 males Severity : Mild: n=42 / Moderate: n=3 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Reduction in SARS-CoV-2 viral load [ Time Frame: 1 - 5 days ]
	In the report Difference in SARS-CoV-2 viral load between baseline and day-5
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. There were no substantive differences between the published article and the trial registry in study procedures, population, treatments or outcomes. The study achieved its pre-stated sample size. No information is provided on what is included in standard care. There is little information on what adverse events were experienced. On July 7th, 2021, this study was updated based on the published report. On October 6th, 2021, the study was updated based on the corrigendum.

Methods
	RCT Blinding: double blinding
	Location : Single center / Thailand Follow-up duration (days): 28
Inclusion criteria	Men and women aged 18–80 years non-pregnant or breast-feeding women COVID-19 confirmed using a positive RT-PCR within 72 hours of a positive result or onset of symptoms mild-to-moderate symptoms as defined by the World Health Organization (WHO) severity score for COVID-19
Exclusion criteria	Allergic to ivermectin potential for a drug-drug interaction with ivermectin, such as tamoxifen or warfarin previously treated with ivermectin in the last 7 days received any herbal medicine severe chronic illness (severe congestive heart failure, chronic kidney disease stage 4–5, chronic liver disease, terminal cancer) concurrent bacterial infection unwilling to participate in the trial severe symptoms, likely due to cytokine release syndrome uncontrolled co-morbidities immunocompromised status
Interventions
	Treatment Ivermectin 12 mg/day orally for 5 days
	Control Placebo
Participants
	Randomized participants : Ivermectin=37 Placebo=37
	Characteristics of participants N= 74 Mean age : NR 27 males Severity : Mild: n=* / Moderate: n=* / Severe: n=0 Critical: n=0
Primary outcome
	In the register NR
	In the report Viral clearance of SARS-CoV-2 on day 7 and 14 after intervention
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	Only the pre-print article was used in data extraction and assessment of risk of bias. No registry was available and the protocol referred to as a supplementary file in the article was not available. Therefore, it is not clear whether population, intervention and outcomes were prespecified or whether there was a target sample size.