Maria Popp1, Miriam Stegemann2, Maria-Inti Metzendorf3, Susan Gould4, Peter Kranke1, Patrick Meybohm1, Nicole Skoetz5, Stephanie Weibel1. 1. Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Wuerzburg, Germany. 2. Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 3. Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. 4. Royal Liverpool University Hospital, Liverpool, UK. 5. Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Abstract
BACKGROUND: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms. We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. MAIN RESULTS: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies. We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. AUTHORS' CONCLUSIONS: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.
BACKGROUND: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms. We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. MAIN RESULTS: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies. We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. AUTHORS' CONCLUSIONS: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.
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