Table 1 Main characteristics of included studies
Reference | Trial registration number | Clinical trial blinding type | Setting/location and number of centers | Recruitment period | COVID-19 diagnosis method and % confirmed | Disease severity | Other inclusion criteria | Exclusion criteria |
|---|---|---|---|---|---|---|---|---|
Ivermectin vs. placebo | ||||||||
Ahmed et al. [16] | Bangladesh Medical Resource Council | Double-blinded | Hospital at Dhaka (Bangladesh) 1 center | Not clear | RT-PCR 100% | Not informed | Admitted to the hospital within the last 7 days; presence of fever (> 37,5ºC), cough and/or sore throat | Allergy to ivermectin or doxycycline, use of drug with potential for interaction with ivermectin or doxycycline, chronical illness, had received ivermectin or doxycycline in the last 7 days, pregnancy, breastfeeding, had participated in other RCT within the last month |
Babalola et al. [54] | National Agency for Food and Drug Administration and Control in Lagos | Double blinded | Lagos University Teaching Hospital (Nigeria) 1 center | May to November, 2020 | RT-PCR 100% | Asymptomatic or mild/moderate symptoms | NA | COVID-19 pneumonia or requiring MV, renal failure, thromboembolic complications or unconscious |
Biber et al. [48] | NCT04429711 | Double-blinded | Hotels in Tel-Aviv at Jerusalem and Ashkelon (Israel) 2 centers | May, 2020 to January, 2021 | RT-PCR 100% | Mild to moderate, not requiring O2 and asymptomatic cases | Not pregnant, up to 7 days of symptoms onset | Weight < 40 kg, known allergy to the drugs, unable to take oral medication, participation in other RCT, RT-PCR results in Ct value > 35 in first two consecutive tests |
Buonfrate et al. [57] | NCT04438850 | Double-blinded | Outpatients laboratory-confirmed COVID-19 during the study period (Italy) 4 centers | July, 2020 to May, 2021 | RT-PCR 100% | Mild, not requiring hospitalization or O2 supplementation | Asymptomatic or oligosymptomatic disease | Pregnancy, breastfeeding, CNS disease, participants under dialysis, severe medication conditions with prognosis < 6 months, warfarin treatment, antiviral/chloroquine phosphate/hydroxychloroquine treatment |
Chaccour et al. [59] | NCT04390022 | Double-blinded | University Clinical of Navarra (Spain) 1 center | July to September, 2020 | RT-PCR 100% | Non-severe | < 72 h of cough or fever | Positive IgG, comorbidities considered risk factors for severe disease or COVID-19 pneumonia |
Chachar et al. [80] | NCT04739410 | Open label | Fatima Memorial Hospital at Lahore (Pakistan) Number not clear | May to June, 2020 | RT-PCR 100% | Mild | NA | Known severe allergic reaction to ivermectin, pregnancy, breastfeeding, severe symptoms likely attributed to cytokine release storm, malignant disease, CKD, cirrhosis Child B or C |
Beltran-Gonzalez et al. [51] | NCT04391127 | Double-blinded | Hospital Centerio Miguel Hidalgo in the state of Aguascalientes (Mexico) 1 center | April to June, 2020 | Confirmed or suspected % not informed | COVID-19 pneumonia (CO-RADS classification) | Suspected or confirmed COVID-19 cases as well as the pneumonia ATS criteria, hospitalization | Requirement of high O2 volumes, predictors of poor response to high-flow O2 nasal therapy or MV |
Krolewiecki et al. [61] | NCT04381884 | Open label, outcome assessor blinded, | Hospitals in the metropolitan area of Buenos Aires (Argentina) 4 centers | May to September, 2020 | RT-PCR 100% | Mild to moderate | NA | Patients not requiring ICU admission, use of immunomodulators ≤ 30 days of recruitment, pregnancy, breastfeeding, poorly controlled comorbidities and known allergy to ivermectin |
López-Medina et al. [19] | NCT04405843 | Double-blinded | Colombian state’s health department electronic database (Colombia) 1 center | July to November, 2020 | RT-PCR or antigen 100% | Mild to moderate | Symptoms began within the previous 7 days | Pregnancy, breastfeeding, hospitalized patients receiving high-flow O2 or MV, asymptomatic, severe pneumonia, received ivermectin within the previous 5 days, had hepatic dysfunction or liver function test results more than 1.5 × the ULN |
Mohan et al. [62] | CTRI 2020/06/026001 | Triple-blinded | COVID-19 facility at the National Cancer Institute, All India Institute of Medical Sciences, New Delhi (India) Number not clear | July to September, 2020 | RT-PCR or antigen 79.6% | Non-severe: mild and moderate | NA | Pregnancy or lactation, known hypersensitivity to ivermectin, CKD with creatinine Cl < 30 mL/min, elevated transaminase levels, myocardial infarction or heart failure < = 90 days prior to enrolment, prolonged QTc, any other severe comorbidity or enrolment in concomitant RCT |
Ravikirti et al. [65] | CTRI 2020/08/027225 | Double-blinded | COVID-19 hospital (India) 1 center | August to October, 2020 | RT-PCR or rapid antigen test 100% | Mild or moderate disease | NA | Severe disease, known allergy or adverse drug reaction to ivermectin, unwillingness or inability to provide consent to participate in the study, prior use of ivermectin during the course of this illness, pregnancy or lactation |
Vallejos et al. [18] | NCT04529525 | Double-blinded | Province of Corrientes (Argentina) Number not clear | August 19, 2020 to February 22, 2021 | RT-PCR 100% | Not informed | ≥ 18 years, residing in the province of Corrientes. If they are women of childbearing age, they should be using a contraceptive method of proven efficacy and safety. All individuals were to weigh at the time of inclusion ≥ 48 kg | Home O2 requirement; hospitalization for COVID-19 at the time of diagnosis; had a history of hospitalization for COVID-19; pregnancy; breastfeeding; known allergy to ivermectin or the components of ivermectin or placebo tablets; presence of mal-absorptive syndrome; presence of any other concomitant acute infectious disease; known history of severe liver disease; recent or expected need for dialysis; with participation in a research study that involved the administration of a drug < = 30 days |
Reis et al. [7] | NCT04727424 | Triple-blinded | 12 public health clinics (Brazil) | June 2, 2020 to August 6, 2021 | RT-PCR or rapid antigen test 100% | Mild-to-moderate COVID-19 | ≥ 18 years, outpatients, up to 7 days after symptom onset, and at least one high-risk criterion for progression of Covid-19 (age ≥ 50 years, diabetes, hypertension leading to the use of medication, cardiovascular disease, lung disease, smoking, obesity, organ transplantation, stage IV CKD or dialysis, immunosuppressive therapy, cancer) | Patients who needed hospitalization, severe terminal illness, RR > 28/min, SaO2 < 90% or < 93% on nasal oxygen therapy at 10 L/min, PaO2/FIO2 < 300 mmHg, use of the following medications in the last 14 days: monoamine oxide Inhibitors α-1 antagonists, sotalol, clonidine, Phosphodiesterase 5 inhibitors, Methyldopa, Prazosin, terasozin, doxazosin, antiretroviral agents, serotonin reception inhibitors; pregnancy or breastfeeding; surgical procedure or use of contrast planned up to 5 days after the last dose of the study medication; inability to give informed consent or adhere to the procedures proposed in the protocol; known hypersensitivity and / or intolerance to Ips, or taking medications contraindicated by Ips; inability to follow protocol-related procedures |
Naggie S [52] | NCT04885530 | Double-blinded | 93 sites in USA | June 23, 2021 to February 4, 2022 | RT-PCR or rapid antigen test 100% | Mild-to-moderate COVID-19 | Sites verified eligibility criteria including age ≥ 30 years, confirmed SARS-CoV-2 infection within 10 days, and experiencing > 2 symptoms of acute COVID-19 for ≤ 7 days from enrollment. Symptoms included fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and loss of sense of taste or smell | Hospitalization, study drug use within 14 days, or known allergy or contraindication to study drug. Ivermectin-specific exclusion criteria were end-stage kidney disease on renal replacement therapy, liver failure, decompensated cirrhosis, pregnancy, or breastfeeding |
Ivermectin + SOC vs. SOC with no placebo | ||||||||
Abd‐Elsalam et al. [58] | NCT04403555 | Open‐label | Tanta and Assiut University Hospitals (Egypt) 2 centers | March to October, 2020 | RT-PCR 100% | Mild to moderate | NA | Allergy or contraindications to the drugs used in the study, pregnant and breastfeeding mothers, and patients with cardiac problems |
Bukhari et al. [49] | NCT04392713 | Open‐label | Combined Military Hospital Lahore (Pakistan) 1 center | March to June, 2020 | RT-PCR 100% | Either asymptomatic or mild/moderate symptoms | NA | Severe symptoms due to cytokine release syndrome, with uncontrolled comorbidities and immunocompromised states. Ivermectin allergy. Patients taking CYP3A4 inhibitors or inducers. Patients that had oxygen requirement equivalent to FiO2 ≥ 50% |
Lim et al. [63] | NCT04920942 | Open-label | 20 government hospitals and a COVID-19 quarantine center (Malaysia) | May 31 to October 25, 2021 | RT-PCR or antigen test 100% | Mild to moderate | ≥ 50 years with at least 1 comorbidity, up to 7 days from symptom onset | Asymptomatic, supplemental oxygen requirement, SpO2 < 95% at rest, severe hepatic impairment, acute medical or surgical emergency, concomitant viral infection, pregnancy or breastfeeding, warfarin therapy, history of taking any antiviral drugs with reported activity against COVID-19 (favipiravir, hydroxychloroquine, lopinavir, and remdesivir) within 7 days before enrollment |
Manomaipiboon et al. [50] | Navamindradhiraj University, Vajira Institutional Review Board no. 171/64 | Double-blindedc | Faculty of Medicine, Vajira Hospital, Navamindradhiraj University, (Thailand) 1 center | September to November, 2021 | RT-PCR 100% | Mild to moderate | 18–80 years-old, within 72 h of a positive result or onset of symptoms | Pregnancy, breastfeeding, allergy or potential for a drug-drug interaction with ivermectin; previously treatment with ivermectin in the last 7 days; received herbal medicine; severe chronic illness; concurrent bacterial infection; severe symptoms; uncontrolled co-morbidities; immunocompromised status; unwilling to participate |
Faisal et al. [55] | NA | NI | Shah Care Hospital (Pakistan) 1 center | April to May, 2020 | RT-PCR 100% | Not informed | NA | Severe comorbidities, like diabetes mellitus, cardiovascular problems, CKD and O2 dependents |
Okumuş et al. [60] | NCT04646109 | Single-blinded | Research and Education Hospital (Turkey) 4 centers | May to September, 2020 | RT-PCR 100% | Severe pneumonia | NA | < 18 years old, pregnancy, active breastfeeding, concurrent autoimmune disease, chronic liver or CKD, immunosuppression, SNP mutation in MDR-1/ABCB1 gene and/or haplotypes and mutations of the CYP3A4 gene |
Podder et al. [56] | NA | Open-label | Debidwar Upazila (sub-district) Health Complex (Bangladesh) 1 center | May to July, 2020 | RT-PCR 100% | Mild to moderate | NA | Known pre-existing hypersensitivity to ivermectin, pregnancy, breastfeeding and patients taking other antimicrobials or hydroxychloroquine, symptoms > 7 days or insufficient data |
Shahbaznejad et al. [81] | Iran Registry of Clinical Trials 20111224008507N3 | Double-blindedc | Hospitals of University of Medical Sciences (Iran) 2 centers | May to July, 2020 | RT-PCR or symptoms + contact or chest CT 64% | Moderate to severe | NA | History of chronic liver and/or kidney disease, receipt of treatment with warfarin, angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist, acquired immunodeficiency, pregnancy or breastfeeding |
La Rocha et al. [53] | NCT04407507 | Double-blind | Guadalajara and Zapopan: Hospital Hispano (Mexico) | From 2020 July 21 to 2021 January | RT-PCR 100% | asymptomatic and mild COVID-19 | > 18-year-old men and women diagnosed with SARS-CoV-2 infection by realtime polymerase chain reaction (RT–PCR) testing of nasopharyngeal swab samples. We considering viral load undetectable if the inferior limit was ≥ 40 copies/µL | Patients with moderate or severe COVID-19, 7 diagnosis of other respiratory infections, impaired liver function tests (> 5 times above the normal level of alanine aminotransferase or aspartate aminotransferase), history of recurrent urinary tract infections, pregnancy or nursing women, active participation in other clinical trials, and use of antibiotics, verapamil, cyclosporine A, trifluoperazine or antiparasitic treatment for a concomitant disease were excluded |
Ivermectin vs. active comparator | ||||||||
Galan et al. [82] | Brazilian Clinical Trial Database 8h7q82 | Double-blindedc | General Hospital of Roraima (Brazil) 1 center | May to July, 2020 | RT-PCR or IgM 100% | Severed | Hospitalized by COVID-19 | Patients < 18 years old, indigenous people, patients not fluent in Portuguese, unable to understand the objectives and methods of the study, critically ill patients who are not accompanied by legal representatives, those who reject participation in the study, patients with cardiac arrhythmia that include prolongation of the QT interval and previous use of the medication surveyed for more than 24 h |
Niaee et al. [64] | Iran Registry of Clinical Trials 20200408046987N1 | Double-blindedc | Public hospitals in Qazvin and Khuzestan(Iran) 5 centers | June to July, 2020 | RT-PCR or symptoms + contact or chest CT 71% | Mild to moderate | NA | Children, severe immunosuppression, pregnant women, known allergic reaction to the intervention drugs, 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 |
Reference | Randomized sample | Final sample | Agea | Ivermectin | Comparator | Funding |
|---|---|---|---|---|---|---|
Ivermectin vs. placebo | ||||||
Ahmed et al. [16] | 72 | 68 | 42 | A1: Ivermectin 12 mg for 5 days; A2: Ivermectin 12 mg for 4 days | Placebo | Beximco Pharmaceutical Limited, Bangladesh |
Babalola et al. [54] | 63 | 62 | 44.1 ± 14.7 | A1: Ivermectin 6 mg (given every 84 h) twice a week; A2: Ivermectin 12 mg (given every 84 h) for 2 weeks + SOCe | SOCe + placebo | NI |
Biber et al. [48] | 116 | 89 | 35 (28–47) | Ivermectin 0.2 mg/kg for 3 days | Placebo | NI |
Buonfrate et al. [57] | 93 | 93 | 47 (31.0–58.0) | Single dose 54 ivermectin 600 μg/kg plus placebo for 5 days (arm B); single dose ivermectin 1200 μg/kg for 5 days (arm C) | Placebo | Italian Ministry of Health |
Chaccour et al. [59] | 24 | 24 | NI | Ivermectin 0.4 mg/kg (single oral) | Placebo | ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra |
Chachar et al. (2020) [80] | 50 | 50 | 41.8 ± 15.7 | Ivermectin 12 mg (3 tablet in stat, 12 h and 24 h) | Placebo | NI |
Beltran-Gonzalez et al. [51] | 108 | 106 | 53.8 ± 16.9 | Ivermectin 0.2 mg/kg for 4 days | A1: Placebo A2: HCQc | NI |
Krolewiecki et al. [61] | 45 | 45 | NI | Ivermectin 0.6 mg/kg/day for 5 consecutive days with either breakfast or lunch at approximately 24 h intervals | Placebo | IP-COVID-19–625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina |
López-Medina et al. [19] | 476 | 398 | 37 (29—47.7) | Ivermectin 0.3 mg/kg for 5 days | Placebo | Centro de Estudios en Infectología Pediátrica (grant ScDi823) |
Mohan et al. [62] | 157 | 152b | 35.3 ± 10.4 | A1: Ivermectin 12 mg (single dose);A2: Ivermectin 24 mg (single dose) | Placebo | Science and Engineering Research Board, Department of Science and Technology, Government of India |
Ravikirti et al. [65] | 115 | 112 | 52.5 ± 14.7 | Ivermectin 12 mg (single dose) for 2 days | Placebo | Ivermectin tablets were procured from the learning resource allowance of the principal investigator Placebo tablets were provided by Sun Pharma Pvt. Ltd |
Vallejos et al. [18] | 501 | 501 | 42.49 ± 15.51 | Ivermectinf + SOCg | Placebo + SOCg | NI |
Reis et al. [7] | 679 | 679 | 49 (38–57) | Ivermectinh + SOCi | Placebo + SOCi | Bill and Melinda Gates Foundation (INV-019641) |
Naggie [52] | 1591 | 1591 | 48 years ± 12 | Ivermectin 400 µg/kg for 3 days | Placebo | National Center for Advancing Translational Sciences (NCATS) (3U24TR001608-05W1) |
Ivermectin + SOC vs. SOC with no placebo | ||||||
Abd‐Elsalam et al. [58] | 164 | 164 | NI | Ivermectin 12 mg (single dose) for 3 days + SOCj | SOCk | NI |
Bukhari et al. [49] | 100 | 86 | NI | Ivermectin 12 mg (single dose) + SOCk | SOCl | NI |
Faisal et al. [55] | 100 | 100 | NI | Ivermectin 12 mg once a day for 5 days + azithromycin + SOCl | Azithromycin + SOCm | NI |
Okumuş et al. [60] | 66 | 60a | NI | Ivermectin 0.2 mg/kg for 5 days + SOCm | SOCn | Afyonkarahisar Health Science University Scientific Research project |
Podder et al. [56] | 82 | 62 | 39.2 ± 12.1 | Ivermectin 0.2 mg/kg (single dose) + SOCn | SOCg | Self-financiated |
Shahbaznejad et al. [81] | 70 | 69 | 46.4 ± 22.5 | Ivermectin 0.2 mg/kg + SOCo | SOCf | NI |
Manomaipiboon et al. [50] | 72 | 72 | 48.57 ± 14.8 | Ivermectin 12 mg per day, por 5 days | SOCo | Navamindradhiraj University (grant 171/64) |
Lim et al. [63] | 500 | 490 | 62.5 ± 8.7 | 0.4 mg/kg body weight daily for 5 days + SOC | SOCp | NI |
La Rocha et al. [53] | 66 | 56 | Placebo36.4 (13) IVM 40 (15.4) | 12 mg per day ivermectin tablets or placebo for 3 days + SOCq | Placebo + SOCq | Biomédica para el Desarrollo de Fármacos S.A. de C.V |
Ivermectin vs. active comparator | ||||||
Galan et al. [82] | 167 | 167 | 53.4 ± 15.6 | A1: Ivermectin (14 mg once at day 0 + 1 placebo tablet at day 0, and once daily from day 1 to day 2, + 1 placebo tablet daily from day 3 to 4, total dose 42 mg; A2: Ivermectin (14 mg once at day 0 + 1 placebo tablet at day 0, and once daily from day 1 to day 2, + 1 placebo tablet daily from day 3 to 4, total dose 42 mg) | A1: Hydroxychloroquine A2:CQ diphosphate + HCQ sulfate | NI |
Niaee et al. [64] | 180 | 180 | 56 (45–67) | A1: Ivermectin 0,2 mg/kg (1 tablet, single dose); A2: Ivermectin 0,2 mg/kg (3 tablet in day 1, 3 and 5); A3: Ivermectin 0,4 mg/Kg (2 tablets per day, single dose); A4: Ivermectin (0.4 mg/kg, 4 tablets in day 1; 0.2 mg/kg, 4 tablets in day 3; 0.2 mg/kg, 4 tablets in day 5) | HCQ | Research deputy of Qazvin University of Medical Sciences and Science and Technology Park, Qazvin, Iran |