We included randomized controlled trials (RCTs) only, as this is the best study design for evaluating the efficacy of interventions (Higgins 2020a). Therefore, it is currently unclear whether ivermectin can prevent SARSCoV2 infection in people who have had a highrisk contact. The protocol was prospectively registered and the outcome in the journal publication was reported as registered. Acute influenzalike condition presenting with 1 of the criteria below: Using serotonin reception inhibitors (donepezil, sertraline), Use of the following medications in the last 14 days, Monoamine oxide inhibitors: phenelzine, tranylcypromine, selegiline, isocarboxazide, moclobemide, Use of iodinated contrasts during start of treatment through D14, Severe psychiatric disorders or major uncontrolled depression or controlled with any of the prohibited drugs above, History of severe ventricular cardiac arrhythmia (ventricular tachycardia, people with ventricular fibrillation recovered) or long QT syndrome, History of diabetic ketoacidosis or clinical condition that maintains persistent acidosis, Surgical procedure or use of contrast designed to occur during treatment or up to 4 days after the last dose of the study medication, History of seizures in the last month or uncontrolled medical condition, Clinical history of liver cirrhosis or ChildPugh C classification, Known severe degenerative neurological diseases or serious mental disorders, Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol, Known hypersensitivity or intolerance to fluvoxamine, ivermectin or metformin, Inability to take oral or sublingual medications, Inability to follow protocolrelated procedures, Type and dose: ivermectin 6 mg, once daily for 3 days, Evaluation of emergency department visits and observation unit stay > 6 hours, Hospitalization due to COVID19 progression within 28 days, Time to > 50% clinical symptoms changes (selfreported) within 28 days, Number of days with respiratory symptoms since randomization within 28 days, Allcause and COVID19 related hospitalizations within 28 days, Cardiovascular death, respiratory death at 28 days, Health and functioning after COVID19 disease at 14 and 28 days, WHO scale for clinical improvement at 28 days, Prospective completion date: 1 March 2022, Sponsor/funding: CARDRESEARCH Cardiologia Assistencial e de Pesquisa, Trial design: doubleblind RCT with 3 parallel arms, only 2 arms relevant; the third arm investigates doxycycline, Willing and able to provide verbal/telephonic/personal or computerbased informed consent, Experiencing symptoms of COVID19 illness and tested positive for SARSCoV2 with PCR, NAAT, or antigen testing, Residents in a nursing home or longterm care facility, Immunocompromised state, including solid organ transplant, HIV infection, other immune deficiency, immunosuppressant medication including systemic corticosteroids, Chronic lung disease, including COPD, moderatetosevere asthma, cystic fibrosis, pulmonary fibrosis, Neurological disorders including dementia, Haematological disorders, including sickle cell disease and thalassaemia, Received any COVID vaccine within the last 30 days, Contraindications to ivermectin or doxycycline, History of myocardial infarction within last month, Already receiving ivermectin or doxycycline for treatment of any other disease or disorder, Allergies to ivermectin or doxycycline including angiooedema, severe asthma, exfoliative dermatitis, Steven Johnson syndrome, or psoriasis, History of angiooedema, exfoliative dermatitis, Steven Johnson syndrome, psoriasis, Currently pregnant or planning to conceive, Decreased admission rate to the hospital secondary to respiratory illness related to COVID19 within 5 weeks, Decrease in total duration of symptoms secondary to respiratory illness related to COVID19 within 5 weeks, Assessment of various blood biomarkers (e.g. We stored the full RoB 2 data (e.g. The research was part of a project supported by the Federal Ministry of Education and Research (NaFoUniMedCovid19, funding number: 01KX2021; part of the CEOsys project). Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. Ahmed 2020provided insufficient information on randomization, allocation concealment, blinding of participants and healthcare providers, and did not provide a prospectively registered protocol. One in vitro study showed thativermectin can inhibit replication ofthe humanimmunodeficiencyvirus 1 (HIV1), via inhibition of the interaction ofvirus proteinsand a human cargo protein complexcalled importin (IMP/1) (Wagstaff 2012). Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial (preprint). Need for invasive mechanical ventilation (i.e. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34249367. Liverpool School of Tropical Medicine, UK, Federal Ministry of Education and Research, Germany, Foreign, Commonwealth, and Development Office (FCDO), UK, {"type":"clinical-trial","attrs":{"text":"NCT04360356","term_id":"NCT04360356"}}, {"type":"clinical-trial","attrs":{"text":"NCT04392427","term_id":"NCT04392427"}}, {"type":"clinical-trial","attrs":{"text":"NCT04447235","term_id":"NCT04447235"}}, {"type":"clinical-trial","attrs":{"text":"NCT04482686","term_id":"NCT04482686"}}, {"type":"clinical-trial","attrs":{"text":"NCT04551755","term_id":"NCT04551755"}}, {"type":"clinical-trial","attrs":{"text":"NCT04768179","term_id":"NCT04768179"}}, {"type":"clinical-trial","attrs":{"text":"NCT04435587","term_id":"NCT04435587"}}, {"type":"clinical-trial","attrs":{"text":"NCT04345419","term_id":"NCT04345419"}}, {"type":"clinical-trial","attrs":{"text":"NCT04374279","term_id":"NCT04374279"}}, {"type":"clinical-trial","attrs":{"text":"NCT04382846","term_id":"NCT04382846"}}, 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{"type":"clinical-trial","attrs":{"text":"NCT04729140","term_id":"NCT04729140"}}, {"type":"clinical-trial","attrs":{"text":"NCT04834115","term_id":"NCT04834115"}}, {"type":"clinical-trial","attrs":{"text":"NCT04438850","term_id":"NCT04438850"}}, {"type":"clinical-trial","attrs":{"text":"NCT04472585","term_id":"NCT04472585"}}, {"type":"clinical-trial","attrs":{"text":"NCT04703205","term_id":"NCT04703205"}}, {"type":"clinical-trial","attrs":{"text":"NCT04836299","term_id":"NCT04836299"}}, {"type":"clinical-trial","attrs":{"text":"NCT04886362","term_id":"NCT04886362"}}, {"type":"clinical-trial","attrs":{"text":"NCT04727424","term_id":"NCT04727424"}}, {"type":"clinical-trial","attrs":{"text":"NCT04885530","term_id":"NCT04885530"}}, {"type":"clinical-trial","attrs":{"text":"NCT04403555","term_id":"NCT04403555"}}, {"type":"clinical-trial","attrs":{"text":"NCT04425707","term_id":"NCT04425707"}}, {"type":"clinical-trial","attrs":{"text":"NCT04602507","term_id":"NCT04602507"}}, {"type":"clinical-trial","attrs":{"text":"NCT04673214","term_id":"NCT04673214"}}, {"type":"clinical-trial","attrs":{"text":"NCT04445311","term_id":"NCT04445311"}}, {"type":"clinical-trial","attrs":{"text":"NCT04510233","term_id":"NCT04510233"}}, {"type":"clinical-trial","attrs":{"text":"NCT04894721","term_id":"NCT04894721"}}, {"type":"clinical-trial","attrs":{"text":"NCT04527211","term_id":"NCT04527211"}}, 1.1 Allcause mortality up to 28 days (primary analysis), 1.2 Worsening of clinical status need for invasive mechanical ventilation up to 28 days (primary analysis), 1.3 Worsening of clinical status need for oxygen up to 28 days (primary analysis), 1.4 Improvement of clinical status participants discharged without respiratory deterioration or death at 28 days (primary analysis), 1.5 Any adverse events within 28 days (primary analysis), 1.6 Any adverse events within 28 days (secondary analysis), 1.7 Serious adverse events within 28 days (primary analysis), 1.8 Serious adverse events within 28 days (secondary analysis), 1.9 Admission to intensive care unit (primary analysis), 1.10 Duration of hospitalization (primary analysis), 1.11 Viral clearance at 3 days (primary analysis), 1.12 Viral clearance at 3 days (secondary analysis), 1.13 Viral clearance at 7 days (primary analysis), 1.14 Viral clearance at 7 days (secondary analysis), 1.15 Viral clearance at 14 days (primary analysis), 1.16 Viral clearance at 14 days (secondary analysis), 2.1 Allcause mortality up to 28 days (primary analysis), 2.2 Worsening of clinical status need for invasive mechanical ventilation up to 14 days (primary analysis), 2.3 Worsening of clinical status need for noninvasive mechanical ventilation or high flow up to 14 days (primary analysis), 2.4 Symptom resolution number of participants with symptoms resolved up to 14 days (primary analysis), 2.5 Duration to symptom resolution (secondary analysis), 2.6 Any adverse events within 28 days (primary analysis), 2.7 Serious adverse events within 28 days (primary analysis), 2.8 Viral clearance at 7 days (primary analysis), 2.9 Viral clearance at 14 days (secondary analysis), 3.1 Development of clinical COVID19 symptoms (secondary analysis), 3.2 Any adverse events within 14 days (secondary analysis), 3.3 Allcause mortality up to 28 days (primary analysis), {"type":"clinical-trial","attrs":{"text":"NCT04390022","term_id":"NCT04390022"}}, {"type":"clinical-trial","attrs":{"text":"NCT04739410","term_id":"NCT04739410"}}, {"type":"clinical-trial","attrs":{"text":"NCT04391127","term_id":"NCT04391127"}}, {"type":"clinical-trial","attrs":{"text":"NCT04381884","term_id":"NCT04381884"}}, {"type":"clinical-trial","attrs":{"text":"NCT04405843","term_id":"NCT04405843"}}, {"type":"clinical-trial","attrs":{"text":"NCT04646109","term_id":"NCT04646109"}}, {"type":"clinical-trial","attrs":{"text":"NCT04431466","term_id":"NCT04431466"}}, {"type":"clinical-trial","attrs":{"text":"NCT04392713","term_id":"NCT04392713"}}, {"type":"clinical-trial","attrs":{"text":"NCT04422561","term_id":"NCT04422561"}}, {"type":"clinical-trial","attrs":{"text":"NCT04529525","term_id":"NCT04529525"}}. For the current review, we found no studies with active comparators. WHO scale (. The outcome was not measured as registered. One study contributed results to the primary analysis ofneed for noninvasive mechanical ventilation or high flow up to 14 daysand risk of bias was assessed as some concerns. One study investigated ivermectin for prevention of SARSCoV2 infection. A generic drug is an exact copy of the active drug in a brand-name medication. Heterogeneity was rarely a reason to downgrade the certainty of evidence. Six studies were placebocontrolled studies. Ivermectin may have little or no effect on any adverse events up to 28 days. One study comparing ivermectin to no treatmentreported the development of clinical COVID19 symptoms at 14 days in 304 asymptomatic participants with household close contacts to confirmed COVID19 index case (Shoumann 2021). Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial, Efficacy of ivermectin in adult patients with early stages of COVID-19 (EPIC Trial) (EPIC), ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=44196&EncHid=&modid=&compid=%27,%2744196det%27. The effect estimates remained robust. However, participants mostly had moderateseverity COVID19. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, International Journal of Infectious Diseases. The median duration of symptom resolution in the ivermectin group was 10 days (IQR 9 to 13 days) compared to 12 days (IQR 9 to 13 days) in the placebo group. Due to insufficient information on allocation concealment and lack of blinding of participants and health care providers, and lack of a prospectively registered protocol. There is no analysis to look at the effect of the missing data. Protocol was registered during the recruitment period. One study investigated ivermectin for the prevention of SARSCoV2 infection. Chaccour 2021was at low risk of bias in all domains. One study investigated ivermectin to prevent COVID19. Protocol violations were not described. ivermectin plus standard of care versus standard of care. One study comparing ivermectin to placebo assessed need for oxygen by mask or nasal prongs during the study period (14 days) for 45 participants without supplemental oxygen at baseline, but none of the participants in either group required supplemental oxygen during the study (Ahmed 2020). All studies administered ivermectin orally. WHO scale 5, if 4 or less at baseline). Although those types of interventions were possibly used at a certain point of time during the pandemic with the best intentions, their use was never supported by actual evidence, and they have potential adverse effects (Singh 2021). Three studies had already been published or had results posted in the trial registry (Faisal 2020;{"type":"clinical-trial","attrs":{"text":"NCT04407507","term_id":"NCT04407507"}}NCT04407507;Samaha 2021). Cochrane: London, Version February 2021, Available from: www.community.cochrane.org/mecir-manual/. Ivermectin may reduce the development of clinical COVID19 symptoms in participants in contact with confirmed COVID19 index cases compared to no treatment(RR 0.13, 95% CI 0.08 to 0.21; 1 study, 304 participants). Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. Taking ivermectin inappropriately including using the animal form in humans can be dangerous or deadly. The search processis shown inFigure 1. Details of the communication with authors are provided in theCharacteristics of included studiestable. We are uncertain whether ivermectin may increase or reduce any adverse events up to 28 days compared to placebo (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very lowcertainty evidence). The effect estimate of the secondary analysis was comparable to the primary analysis (RR 1.04, 95% CI 0.61 to 1.79; 4 studies, 314 participants). Susan Gould is partly supported by the Research, Evidence and Development Initiative (READIt). Offering lower sensitivity but greater practicality and accessibility, antigen tests are receiving increased attention, especially in pointofcare diagnostics of COVID19 (WHO 2020c). Both studies were included in the primary metaanalysis due to the overall risk of bias assessment (Analysis 1.2). We planned to use the opensource statistical software R package meta to calculate 95% PIs in review updates (Meta). The point estimate of the secondary analysis favoured ivermectin, but the 95% CI was wide including 1 and heterogeneity was high (RR 1.73, 95% CI 0.59 to 5.04; I2 = 73%; 4 studies, 288 participants). A minimal common outcome measure set for COVID-19 clinical research, Merck statement on ivermectin use during the COVID-19 pandemic, merck.com/news/merck-statement-on-ivermectin-use-during-the-covid-19-pandemic/, Coronavirus disease 2019 (COVID-19) treatment guidelines, The proportion of SARS-CoV-2 infections that are asymptomatic: a systematic review, The efficacy of topical and oral ivermectin in the treatment of human scabies, Ivermectin to be investigated in adults aged 18+ as a possible treatment for COVID-19 in the PRINCIPLE trial, principletrial.org/news/ivermectin-to-be-investigated-as-a-possible-treatment-for-covid-19-in-oxford2019s-principle-trial, Dexamethasone in hospitalized patients with Covid-19, Latin America's embrace of an unproven COVID treatment is hindering drug trials. 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