Ivermectin for Prevention and Treatment of COVID-19 Infection: a Systematic Review and Meta-analysis

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The antiparasitic medicine ivermectin, which has anti-viral and anti-inflammatory properties, has been tested in numerous clinical trials with promising results. Methods We assessed the efficacy of ivermectin treatment and/or prophylaxis among people with, or at high risk of covid-19 infection. We searched bibliographic databases up to February 2021 and two review authors sifted for studies, extracted data and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using GRADE approach. Findings Twenty-one RCTs involving 2741 participants met review inclusion. Meta-analysis of 13 trials found ivermectin reduced risk of death compared with no ivermectin (average Risk Ratio 0.32, 95% confidence interval (CI) 0.14 to 0.72; n=1892; I 2 =57%; low to moderate-certainty evidence. Low-certainty evidence found ivermectin prophylaxis reduced covid-19 infection by an average 86% (95% CI 79% to 91%). Secondary outcomes provided very-low or low certainty evidence. Low certainty evidence suggests that that there may be no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ favoured ivermectin use. Severe adverse events were rare and evidence of no difference was assessed as low to very low-certainty. Evidence on other secondary outcomes was very low certainty. Interpretation Low to moderate-certainty evidence suggests reductions in covid-19 deaths and infections may be possible by using ivermectin. Employing ivermectin early on may reduce the number of people progressing to severe disease. The apparent safety and low cost suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally. Health Economics & Outcomes Research Infectious Diseases ivermectin prophylaxis prevention treatment covid-19 SARS-CoV-2 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Research In Context Evidence before this study In countries across the world, hospitalisations and deaths from covid-19 have increased rapidly over recent months, with estimated total deaths now exceeding 2 million people. The population of developed countries will eventually be given the choice of having a vaccine, but this choice may not be afforded to low- and middle-income countries (LMICs) for a long time. The antiparasitic medicine ivermectin, which is widely available in LMICs, has been tested in numerous clinical trials of prevention and treatment of covid-19 with promising results. To date, three reviews of ivermectin use for covid-19 have been published but only one has been peer-reviewed and limited meta-analyses have been performed on the available data. Added value of this study To our knowledge, this is the first systematic review and meta-analysis done using rigorous Cochrane methods. Evidence was assessed using the GRADE approach which judges the certainty of the evidence. We found low- to moderate certainty evidence that ivermectin treatment may reduce the risk of death among people hospitalised with covid-19. Low-certainty evidence also shows that prophylaxis with ivermectin may reduce the risk of getting infected with covid-19 among those with high exposure. Implications of all the available evidence The apparent safety and low cost suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally. Ivermectin is not a new and experimental drug with safety concerns; it is a WHO ‘essential medicine’ usually used in different indications. It may be useful for more health professionals to get access to this medicine for use against covid-19 during the ongoing pandemic. Further results from trials are expected soon. Introduction To date, very few treatments have been demonstrated to reduce the burden of morbidity and mortality from covid-19. While corticosteroids have been proven to reduce mortality in severe disease, 1 there has been little convincing evidence on interventions that may prevent disease, reduce hospitalisations and reduce the numbers of people progressing to critical disease and death. Ivermectin is a well-known medicine that is approved by the World Health Organization and the US Food and Drug Administration (FDA) for use as an anti-parasitic medication. It is widely used in low- and middle-income countries (LMICs) to treat worm infections. 2 , 3 Also used for the treatment of scabies and lice, it is one of the World Health Organisation’s Essential Medicines. 4 With total doses of ivermectin distributed apparently equalling one-third of the present world population, 5 ivermectin at the usual doses (0.2 mg/kg to 0.4 mg/kg) is considered extremely safe for use in humans. 6 , 7 In addition to its anti-parasitic activity, it has been noted to have antiviral and anti-inflammatory properties, leading to an increasing list of therapeutic indications. 8 Since the start of the SARS-CoV-2 pandemic, both observational and randomised studies have evaluated ivermectin as a treatment for, and as prophylaxis against, covid-19 infection. A review by the Front Line Covid-19 Critical Care Alliance (FLCCC) summarised findings from 27 studies on the effects of ivermectin for the prevention and treatment of covid-19 infection, concluding that ivermectin “demonstrates a strong signal of therapeutic efficacy” against Covid-19. 9 Another recent review found that ivermectin reduced deaths by 75%. 10 Despite these findings, the National Institute of Health in the US recently stated that "there are insufficient data to recommend either for or against the use of ivermectin for the treatment of covid-19". 11 Ivermectin has antiviral activity against a wide range of RNA and some DNA viruses, e.g. Zika, Dengue, Yellow Fever, and others. 12 Caly et al 13 , 14 demonstrated specific action against SARS-CoV-2 in vitro with a suggested host-directed mechanism of action being the blocking of the nuclear import of viral proteins 13 , 14 which suppress normal immune responses. However, the cell culture EC 50 may not be achievable in vivo. 15 Other conjectured mechanisms include: inhibition of SARS-CoV-2 3CLPro activity 16 , 17 (a protease essential for viral replication), a variety of anti-inflammatory effects, 18 and competitive binding of ivermectin with the viral S protein as shown in multiple in silico studies 19 . Analogously to neutralizing antibodies, the latter would inhibit viral binding to ACE-2 receptors suppressing infection. Haemagglutination via viral binding to sialic acid (SA) receptors on erythrocytes is a recently-proposed pathologic mechanism 20 that would be similarly disrupted. Both host-directed and virus-directed mechanisms have thus been proposed, the clinical mechanism may be multi-modal, and a comprehensive review of mechanisms of action is warranted. Developing new medications can take years; therefore, identifying existing drugs that can be re-purposed against covid-19 and that already have a strong safety profile through decades of use could play a critical role in suppressing or even ending the SARS-CoV-2 pandemic. Using re-purposed medications may be especially important because it could take months, possibly years, for much of the world's population to get vaccinated, particularly among low- and middle-income country (LMIC) populations. Ivermectin has now been shown to have anti-viral and anti-inflammatory properties, suggesting that its effect against SARS-CoV-2 requires systematic review. Currently, ivermectin is commercially available and affordable in many countries globally 6 . A 2018 application for ivermectin use for scabies gives a direct cost of $2.90 for 100 12 mg tablets. 21 A therapeutic course of ivermectin for cases of covid-19 infection in India, for example, has been reported to cost less than PPP$ 53.93 for a dose of 12mg twice daily for 7 days 22 (PPP = purchasing power parity in 2021). This price for ivermectin represents that of a dosage at the upper-end of what has be used to treat covid-19 cases. 22 For these reasons, the exploration of ivermectin’s potential effectiveness against SARS-CoV-2 may be of particular importance for settings with limited resources. 23 If demonstrated to be effective as a treatment for covid-19, the cost-effectiveness of ivermectin should be considered against existing treatments and prophylaxes. The aim of this review was to assess the efficacy of ivermectin treatment among people with covid-19 infection and as a prophylaxis among people at higher risk of covid-19 infection. Additionally, we aimed to prepare a brief economic commentary (BEC) of ivermectin as treatment and as prophylaxis for covid-19. 24 Methods The conduct of this review was guided by a protocol that was initially written using Cochrane’s rapid review template and subsequently expanded to a full protocol for a comprehensive review. 25 Search strategy and selection criteria Two reviewers independently searched the electronic databases of Medline, Embase, CENTRAL, Cochrane covid-19 Study Register and Chinese databases for randomised controlled trials (RCTs) up to February 01 2021 (Appendix 1–3); current guidance 24 for the BEC was followed for a supplementary search of economic evaluations. There were no language restrictions and translations were planned to be carried out when necessary. We searched the reference list of included studies, and of two other 2021 literature reviews on ivermectin. 9 We contacted experts in the field (Drs. Andrew Hill, Pierre Kory and Paul Marik) for information on new and emerging trial data. Additionally, all trials registered on clinical trial registries were checked and trialists of 39 ongoing trials or unclassified studies were contacted to request information on trial status and data where available. Many pre-print publications and unpublished articles were identified from the pre-print sever Medrxiv and the International Clinical Trials Registry Platform. This is a rapidly expanding evidence base so the number of trials are increasing quickly. Reasons for exclusion were recorded for all studies excluded after full text review. Data analysis We extracted information or data on study design (including methods, location, sites, funding, study author declaration of interests, inclusion/exclusion criteria), setting, participant characteristics (disease severity, age, gender, co-morbidities, smoking, occupational risk), and intervention and comparator characteristics (dose and frequency of ivermectin/comparator). The primary outcome for the intervention component of the review included death from any cause and presence of covid-19 infection (as defined by investigators) for ivermectin prophylaxis. Secondary outcomes included PCR negativity, clinical recovery, length of hospital stay, admission to hospital (for outpatient treatment), admission to ICU or requiring mechanical ventilation, duration of mechanical ventilation, and severe or serious adverse events, as well as post hoc assessments of improvement and deterioration. All of these data were extracted as measured and reported by investigators. Numerical data for outcomes of interest were extracted according to intention to treat. If there was a conflict between data reported across multiple sources for a single study (e.g. between a published article and a trial registry record), we contacted the authors for clarification. Assessments were conducted by two reviewers (TL, TD, AB or GG) using the Cochrane RCT risk of bias tool. 26 Discrepancies were resolved by discussion. Continuous outcomes were measured as the mean difference (MD) and 95% confidence intervals (CI); dichotomous outcomes as risk ratio (RR) and 95% CI. We did not impute missing data for any of the outcomes. Authors were contacted for missing outcome data and for clarification on study methods, where possible, and for trial status for ongoing trials. We assessed heterogeneity between studies by visual inspection of forest plots, by estimation of the I 2 statistic (I 2 ≥ 60% was considered substantial heterogeneity), 27 by a formal statistical test to indicate statistically significant heterogeneity 28 and, where possible, by subgroup analyses (see below). If there was evidence of substantial heterogeneity, the possible reasons for this were investigated and reported. We assessed reporting biases using funnel plots if more than 10 studies contributed to a meta-analysis. We meta-analysed data using the random effects model (DerSimonian and Laird method) 29 using RevMan 5.4 software. 26 , 30 Results used the inverse variance method for weighting. 26 Some sensitivity analyses used other methods that are outlined below and some calculations were performed in R 31 through an interface 32 to the netmeta package. 33 Where possible, we performed subgroup analyses grouping trials by disease severity, inpatients versus outpatients and single dose versus multiple doses. We performed sensitivity analyses by excluding studies at high risk of bias. We conducted further post hoc sensitivity analyses using alternative methods to test the robustness of results in the presence of zero events in both arms in a number of trials 34 and estimated odds ratios (and additionally risk ratio for the MH (Mantel-Haenszel) method) using a fixed effects model. The models incorporate evidence from single-zero studies without having to resort to continuity corrections. However double-zero studies are excluded from the analysis so the risk difference (RD) was also assessed using the MH method as this approach can adequately incorporate trials with double zero events. This method can also use a random effects component. A ‘treatment-arm’ continuity correction was used, where the values 0.01, 0.1 and 0.25 were added where trials reported zero events in both arms. It has been shown that a non-fixed continuity correction is preferable to the usual 0.5. 34 Other methods are available but were not considered due to difficulty in interpretation, sensitivity of assumptions or the fact they are rarely used in practice. 35 – 39 All outcomes have been assessed independently by two review authors (TD and AB) using the GRADE approach, 40 which ranks the quality of the evidence. Results are presented in a summary of findings table. Any differences were resolved by discussion with the wider group. We used Cochrane Effective Practice and Organisation of Care guidance to interpret the evidence. 41 Role of funding source There was no funding source for this study. Results Search results and risk of bias assessment The combined and preliminary de-duplicated total was n = 523. We also identified 11 records from other sources (reference lists, etc). See PRISMA flow diagram for inclusion and exclusion details of these references (Fig. 1 ). The supplementary search for the BEC identified seventeen studies, of which four were retrieved in full. No full trial- or model-based economic evaluations (cost-utility analyses, cost-effectiveness analyses or cost-benefit analyses) were identified. Twenty-one trials met inclusion and all of these contributed data to at least one review outcome and meta-analysis. Thirteen trials contributed data for the primary outcome for ivermectin treatment (death); three studies reported the primary outcome for prophylaxis (covid-19 infection). Characteristics of included studies are given in Table 1 . Seventeen studies 42 – 58 were excluded as they were not RCTs and we identified 39 ongoing studies 59 – 97 and two studies 98 , 99 are awaiting classification. Table 1 Summary of study characteristics Study ID Country Design Funding Participants Sample size Ivermectin dose and frequency* Comparator Origin of data Main outcomes reported covid-19 treatment studies Ahmed 2020 100 Bangladesh Double-blind BPL(Pharma); Bangladesh, Canada, Sweden, and UK govt Mild to moderate covid (inpatients) 72 12mg x 1 day or x 5 days (3 study arms)* Placebo Published in PR journal; emailed/responded with data Time to viral clearance (PCR -ve), remission of fever and cough within 7 days, duration of hospitalisation, mortality, failing to maintain sats > 93%, adverse events, PCR -ve at 7 and 14 days Babalola 2020 101 Nigeria Double blind Self-funded Asymptomatic, mild or moderate covid (45 inpatients and 17 outpatients) 62 6 mg every 84 hrs x 2 wks (arm 1) or 12 mg every 84 hrs x 2 wks (arm 2) Ritonavir/lopinavir MedRxiv pre-print: emailed/responded with data. Paper accepted for publication Time to PCR -ve, laboratory parameters (platelets, lymphocytes, clotting time), clinical symptom parameters Chaccour 2020 23 Spain Double blind Idapharma, ISGlobal and the University of Navarra Mild covid (outpatients) 24 0.4mg/kg x 1 dose Placebo Published in PR journal PCR + ve at day 7, proportion symptomatic at day 4,7,14,21, progression, death, adverse events Chachar 2020 127 Pakistan Open label Self-funded Mild covid (outpatients) 50 12mg at 0, 12, and 24 hours (3 doses) SOC Published in PR journal Symptomatic at day 7 Chowdhury 2020 128 Bangladesh Quasi-RCT None reported Outpatients with a + ve PCR (approx. 78% symptomatic) 116 0.2mg/kg x1 dose* HCQ 400 mg 1st day then 200mg BID x 9 days + AZM 500 mg daily x 5 days Research Square pre-print Time to -ve PCR test; period to symptomatic recovery; adverse events Elgazzar 2020 50 Egypt RCT None reported Mild to severe covid (inpatients) 200 0.4mg/kg daily x 4 days HCQ 400 mg BID x 1 day then 200 mg BID x 9 days Research Square pre-print: emailed/responded with data Improved, progressed, died. Also measured CRP, D-dimers, HB, lymphocyte, serum ferritin after one week of treatment Fonseca 2021 102 Brazil Double blind Institution-funded Moderate to severe (inpatients) 167 14mg daily x 3 days (plus placebos x 2 additional days) HCQ − 400mg BID on day 0 then daily x 4 days ; CQ -450mg BID day 0 then daily x 4 days Pre-publication data/ manuscript in progress obtained via email Death, invasive ventilation Hashim 2020 129 Iran Quasi-RCT None reported Mild to critical (inpatients) 140 0.2mg/kg x 2 days* Some had a 3rd dose a week later SOC MedRxiv pre-print Death, mean time to recovery, disease progression (deterioration) Krolewiecki 2020 103 Argentina Open label None reported Mild to moderate (inpatients) 45 0.6mg/kg/day x 5 days Placebo Published in PR journal Viral load reduction in respiratory secretions day 5, IVM concentrations in plasma, severe adverse events Mahmud 2020 104 Bangladesh Double blind None reported Mild to moderate covid (inpatients) 363 12mg x 1 dose* Placebo + SOC Data published on clinical trial registry and clarification obtained via email Improvement, deterioration, late clinical recovery, persistent PCR test + ve Mohan 2021 107 India Double blind Institution funded Mild to moderate 152 12 mg or 24 mg elixir x 1 dose Placebo MedRxiv pre-print Research Conversion of RT-PCR to negative result, decline of viral load at day 5 from enrolment Niaee 2020 105 Iran Double blind Institution-funded Mild to severe covid 180 0.2mg/kg x 1 and 3 other dosing options) ~ 14 mg tablet** HCQ 200mg/kg BID or placebo Research Square pre-print Deaths, length of stay, biochemical parameters Okumus 2021 111 Turkey Quasi-RCT None reported Severe covid 66 0.2mg/kg x 5 days SOC Pre-publication data/manuscript in progress obtained via email Clinical improvement, deterioration, death, SOFA scores Petkov 2021 130 Bulgaria Double blind Pharma funded Mild to moderate covid 100 0.4mg/kg x 3 days Placebo Pre-publication data obtained from another source Rate of conversion to PCR negative Podder 2020 131 Bangladesh Open label Self-funded Mild to moderate (outpatients) 62 0.2mg/kg x 1 dose SOC Published in PR journal Duration of symptoms, recovery time to symptom free from enrolment, recovery time to symptom free from symptom onset, repeat PCR result on day 10 Raad 2021 109 Lebanon Double blind Self-funded Asymptomatic outpatients 100 9 mg PO if 45kg to 64kg, 12mg PO if 65kg to 84kg and 0.15mg/kg if body weight ≥ 85 Kg Placebo Pre-publication data/manuscript in progress obtained via email Viral load reduction, hospitalisation, adverse effects Ravikirti 2021 106 India Double blind Self-funded Mild to moderate covid (inpatients) 112 12mg x 2 days + SOC Placebo + SOC Published in PR journal A negative RT-PCR report on day 6, symptomatic on day 6, discharge by day 10, admission to ICU, need for invasive mechanical ventilation, mortality Rezai 2020 108 Iran Double blind None reported Mild to moderate (inpatient) 60 0.2 mg/kg x 1 dose SOC Pre-publication data obtained from another source Clinical symptoms, respiratory rate and O2 saturation Schwartz 2021 110 Israel Double blind None reported Mild to moderate (outpatients) 94 0.15 to 0.3 mg/ kg x 3 days Placebo Pre-publication data obtained from another source Viral clearance at day 4, 6, 8 and 10 ), hospitalisation covid-19 prophylaxis studies Chala 2021 132 Argentina Open label None reported Health care workers 234 12 mg (in drops) weekly + lota-carrageenan 6 sprays daily x 4 wks SOC Pre-publication data/manuscript in progress obtained via email Covid-19 infection (not clear if measured by PCR or symptoms) Elgazzar 2020 50 Egypt Open label Self-funded Health care and family contacts 200 0.4mg/kg, weekly x 2 weeks SOC Research Square pre-print: emailed/responded with data Positive PCR test Shouman 2020 133 Egypt Open label Self-funded Family contacts 303 2 doses (15mg – 24 mg depending on weight) on day 1 and day 3 SOC Published in PR journal Symptoms and/or positive covid-19 PCR test within 14 days; adverse events Footnotes * Also administered doxycycline ** multi-arm trial SOC: Standard of care; RCT: Randomised controlled trial; PR: peer review; mg: milligram; kg: kilogram; PCR: polymerase chain reaction; hrs: hours A risk of bias summary graph is given in Fig. 2 . Eleven studies 23,50,100−108 used satisfactory random sequence generation and allocation concealment. One study described satisfactory sequence generation, but it was unclear whether allocation was concealed. 109 Ten trials reported blinding of the participants/personnel and/or the outcome assessors. 23 , 100 – 102 , 104 , 106 – 110 The others were either unclear or high risk for blinding. We considered blinding to be a less important criterion for evaluation of evidence related to the review's primary outcomes, namely death and laboratory-confirmed covid-19 infection, which are objective outcomes. We did not consider publication on pre-print websites to constitute a risk of bias, as all studies were scrutinised and peer reviewed by us during the review process and, where additional information was needed, we contacted the authors for clarification. Most trials were self-funded or did not report funding and we did not note any apparent conflicts of interest among the trialists. Main findings Twenty-one RCTs (including 2 quasi-RCTs) involving 2741 participants were included, with sample sizes ranging from 24 to 363 participants. For trials of covid-19 treatment, 14 evaluated ivermectin among participants with mild to moderate covid-19 only; four trials included patients with severe covid-19. Most compared ivermectin with placebo or no ivermectin; four trials included an active comparator (Table 1 ). Three RCTs involving 738 participants were included in the prophylaxis studies. Most studies were registered, self-funded and undertaken by clinicians working in the field. There were no obvious conflicts of interest noted. Ivermectin treatment vs no ivermectin treatment Nineteen studies (2003 participants) contributed data to the comparison ivermectin treatment vs no ivermectin treatment for covid-19 treatment. Meta-analysis of 13 trials, assessing 1892 participants, found that ivermectin reduced the risk of death by an average of 68% (95% CI, 28–86%) compared with no ivermectin treatment (average risk ratio (aRR) 0.32, 95% CI 0.14 to 0.72; I 2 = 57%; risk of death 2.5% versus 9.1% among hospitalised patients in this analysis, respectively (Summary of Findings (SoF) Table 2 a and Fig. 3 ). Heterogeneity was explained by the exclusion of one trial 102 in a sensitivity analysis (average RR 0.25, 95% CI 0.13 to 0.48, n = 1725, I 2 = 12%), but since this trial was at low risk of bias it was retained in the main analysis. The source of heterogeneity may be due to the use of active comparators in the trial design. The results were also robust to sensitivity analyses excluding three other studies with an active treatment comparator (average RR 0.45, 95% CI 0.21 to 0.98, n = 1083, I 2 = 0%). The results were also not sensitive to the exclusion of studies that were potentially at higher risk of bias (average RR 0.28, 95% CI 0.09 to 0.85, 11 studies, n = 1697, I 2 = 67%), but in subgroup analysis it was unclear as to whether a single dose would be sufficient. The effect on reducing deaths was consistent across mild to moderate and severe disease subgroups. Subgrouping data according to inpatient and outpatient trials was not informative because few outpatient studies reported this serious outcome. The conclusions of the primary outcome were also robust to a series of alternative post hoc analyses that explored the impact of numerous trials that reported no deaths in either arm. Extreme sensitivity analyses using a treatment arm continuity correction of between 0.01 and 0.5 did not change the certainty of the evidence judgements (Table 3 ). Overall, death from any cause, taking into account all composite analyses, was judged to provide low to moderate-certainty evidence (SoF Table 2 a and Fig. 4 – 6 ). A funnel plot corresponding to the primary outcome of death from any cause did not appear to suggest any evidence of publication bias (Fig. 7 ). Furthermore, the ease with which trial reports can be uploaded as preprints should reduce this risk. Table 2a Summary of findings table of ivermectin versus no ivermectin for covid-19 treatment in any setting Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Assumed risk Corresponding risk No ivermectin Ivermectin Death from any cause 91 per 1000 (all disease severity) 62 fewer deaths per 1000 (25 to 78) RR = 0.32 (0.14 to 0.72) 1892 (13) Low to moderate 1 , 2 Recovery time to negative PCR test, in days Absolute risks were not computed due to certainty of evidence being low and in some cases number of events being sparse MD = -3.20 (-5.99 to -0.40) 375 (6) Very Low 1 , 3 , 4 Time to clinical recovery, in days (outpatients) (MD = -1.06 (-1.63 to -0.49) 176 (2) Very low 1 , 3 , 4 Time to clinical recovery, in days (mild to moderate covid-19 inpatients) MD = -7.32 (-9.25 to -5.39) 96 (1) Very low 1 , 5 Time to clinical recovery, in days (severe covid-19 inpatients) MD = -3.98 (-10.06 to 2.10) 33 (1) Very low 1 , 5 Admission to ICU RR = 1.22 (0.75 to 2.00) 379 (2) Very low 5 , 6 Need for mechanical ventilation RR = 0.66 (0.14 to 3.00) 431 (3) Low 4 , 6 Length of hospital stay, in days MD = 0.13 (-2.04 to 2.30) 68 (2) Very low 1 , 5 Admission to hospital RR 0.16 (0.02 to 1.32) 194 (2) Very low 1 , 5 Duration of mechanical ventilation Not reported Improvement (mild to moderate covid-19)* 543 improved per 1000 185 more per 1000 (from 119 more to 260 more) RR 1.34 (1.22 to 1.48) 681 (4) Low 1 , 3 Deterioration (any disease severity) 189 per 1000 140 fewer per 1000 (from 77 fewer to 166 fewer) RR 0.26 (0.12 to 0.59) 1041 (5) Low 1 , 3 Serious adverse events 5/542 (1%) had an SAE in ivermectin group and 0/370 (0%) in control RR = 3.23 (0.55 to 18.87) 728 (8) Low 1 , 3 *Only one study contributed to the ‘severe’ covid-19 subgroup and subgroup data were not pooled due to subgroup differences 1 Downgraded − 1 for study design limitations 2 Downgraded − 1 each for discrepancies in composite sensitivity analyses 3 Downgraded − 1 for inconsistency 4 Downgraded − 1 for imprecision 5 Downgraded − 2 for imprecision/sparse data 6 Downgraded − 1 for indirectness Table 2b Summary of findings table of ivermectin versus no ivermectin for covid-19 prophylaxis in healthy population (people without covid-19 infection) Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Assumed risk Corresponding risk No ivermectin Ivermectin covid-19 infection 296 per 1000 245 fewer infections per 1000 (234 to 269) RR = 0.14 (0.09 to 0.21) 738 (3) Low 1 Admission to hospital Not reported Death from any cause Not reported Serious adverse events No events occurred in 538 participants (2 studies), therefore the effect could not be estimated. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI : Confidence interval; RR : Risk Ratio; RCT: Randomised controlled trial; NNT: number needed to treat. GRADE Working Group grades of evidence High quality : Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality : Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality : Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality : We are very uncertain about the estimate. 1 Downgraded − 2 for study design limitations Table 3 Sensitivity analyses for death from any cause considering methods for dealing with zero events in trials Method Measure Model Effect size (95% CI) Details Peto OR FE 0.33 (0.21 to 0.50) Handles single zero trials M-H OR FE 0.33 (0.21 to 0.50) Handles single zero trials M-H OR RE 0.28 (0.11 to 0.66) Handles single zero trials M-H RR FE 0.39 (0.27 to 0.58) Handles single zero trials M-H RR RE 0.32 (0.14 to 0.73) Handles single zero trials M-H RD FE -0.05 (-0.07 to -0.03) Handles double zero trials M-H RD RE -0.04 (-0.07 to -0.00) Handles double zero trials IV RD FE -0.02 (-0.03 to -0.01) Handles double zero trials IV RD RE -0.03 (-0.05 to -0.01) Handles double zero trials Treatment arm continuity correction methods using IV Accounting for double zeros Accounting for all zeros 0.01 RR FE 0.51 (0.34 to 0.77) 0.55 (0.36 to 0.85) 0.01 RR RE 0.36 (0.19 to 0.68) 0.47 (0.27 to 0.81) 0.1 RR FE 0.51 (0.34 to 0.77) 0.53 (0.35 to 0.82) 0.1 RR RE 0.37 (0.20 to 0.69) 0.38 (0.19 to 0.76) 0.25 RR FE 0.51 (0.34 to 0.77) 0.52 (0.34 to 0.79) 0.25 RR RE 0.38 (0.20 to 0.70) 0.38 (0.20 to 0.72) 0.5 RR FE 0.52 (0.35 to 0.77) 0.52 (0.35 to 0.78) 0.5 RR RE 0.39 (0.22 to 0.71) 0.41 (0.23 to 0.71) M-H: Mantel-Haenszel; IV: Inverse variance; TACC: Treatment arm continuity correction; OR: odds ratio; RR: Risk ratio; RD: Risk difference; FE: fixed effects; RE: Random effects; CI: Confidence interval Secondary outcomes provided low to very low certainty evidence (SoF Table 2 a). Low certainty findings suggested that that there may be no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ favoured ivermectin but were graded as low certainty due to study design limitations and inconsistency (Fig. 8 to 10 ). All other secondary outcome findings were assessed as very low certainty. Meta-analysis of eight trials, assessing 728 participants, found that there was no significant difference between ivermectin and control in the risk of severe adverse events (aRR 3.23, 95% CI 0.55 to 18.87; I 2 = 0%; low certainty evidence , downgraded for imprecision and study design limitations). Five severe adverse events were reported in the ivermectin group and none in controls. The SAEs were as follows: two patients in the Mahmud 2020 trial 104 had oesophagitis (this is a known side effect of doxycycline, which was co-administered with ivermectin in this trial); one patient in Krolewiecki et al 103 had hyponatraemia (this trial used high-dose ivermectin for 5 days); and two patients in a study from Turkey 111 had serious "delirium-like behaviour, agitation, aggressive attitude and altered state of consciousness", which the authors attributed to metabolic insufficiencies in MDR-1/ABCB1 or CYP3A4 genes, screening for which was a study feature (see SoF Table 2 a). Ivermectin prophylaxis versus no ivermectin prophylaxis Three studies involving 738 participants evaluated ivermectin for covid-19 prophylaxis among health care workers and covid-19 contacts. Meta-analysis of these 3 trials, assessing 738 participants, found that ivermectin prophylaxis among health care workers and covid-19 contacts probably reduces the risk of covid-19 infection by an average of 86% (79–91%) (3 trials, 738 participants; aRR 0.14, 95% CI 0.09 to 0.21; 5.0% vs 29.6% contracted covid-19, respectively; low-certainty evidence ; downgraded due to study design limitations and few included trials). In two trials involving 538 participants, no severe adverse events were recorded (SoF Table 2 b; Fig. 11 ). Discussion These findings suggest low to moderate-certainty evidence showing a survival benefit without harm of ivermectin for treatment against covid-19. Low certainty evidence on improvement and deterioration support the possibility of clinical benefit with ivermectin. Low certainty evidence also suggest it could be a useful prophylaxis. Overall, therefore, the evidence suggests that early use of ivermectin may reduce morbidity and mortality from covid-19, based on reductions in covid-19 infections when ivermectin was used as post-exposure prophylaxis, more favourable point estimates for mild to moderate disease compared with severe disease for death due to any cause, and on the evidence demonstrating reductions in the number of patients deteriorating. The evidence on severe adverse events in this review was graded as low certainty, partly because there were too few events to reach statistical significance. However, evidence from a recent systematic review of ivermectin use among people with parasitic infections suggests that ivermectin administered at the usual doses (0.2mg/kg or 0.4mg/kg) is safe and could be safe at higher doses. 7 , 112 A recent World Health Organization document on ivermectin use for scabies found that adverse events with ivermectin were primarily minor and transient. 21 We decided to restrict the included studies to the highest level of evidence, i.e. RCTs, despite the use of observational evidence being potentially used in times of emergency, 113 and the numerous observational studies on ivermectin for covid-19. We included pre-print and unpublished data from completed but not yet published trials due to the urgency related to evidence synthesis in the context of a global pandemic. 114 Whilst there is the potential for selective reporting of outcomes and publication bias, we have factored in these considerations in interpreting results and forming conclusions. We adhered to PRISMA guidelines and the WHO statement on developing global norms for sharing data and results during public health emergencies. 114 There are a number of limitations with this review. Several of the studies contributing data did not provide full descriptions of methods, so assessing risk of bias was challenging. Where descriptions of study methods were sparse or unclear, we attempted to contact authors to clarify methods, but lack of information led us to downgrade findings in several instances. Overall interpretation of findings was hampered due to variability in the participants recruited, treatment regimen and in the care offered to those in control groups. We have tried to take this variation into account through subgroup and sensitivity analyses, nevertheless dosing and treatment regimens and the use of ivermectin with other components of “standard care” require further research. We did not include laboratory outcome measures, such as viral clearance. The latter, as well as other biochemical outcomes have been reported in several studies and reviews and tend to favour ivermectin. 10 , 50 , 101 , 105 Several trials reported continuous data, such as length of hospital stay, as medians and interquartile ranges, therefore, we were unable to include these data in meta-analysis. As we did not undertake in our protocol to perform narrative evidence synthesis, and as these data tended to favour ivermectin, the certainty of the effects of ivermectin on these continuous outcomes may be underestimated. To date, three other reviews of ivermectin use for covid-19 have been published 9 , 10 , 115 but only one has been peer-reviewed. 9 We applied AMSTAR 2, 116 a critical appraisal tool for systematic reviews of healthcare interventions, to the two non-peered systematic reviews 10 , 115 and both were judged to be of low quality (Table 4 ). However, there was also a suggestion that ivermectin may reduce risk of death in treatment of covid-19 in these reviews. In addition to these reviews, the findings of several controlled observational studies are consistent with existing evidence and suggest improved outcomes with ivermectin treatment. 49 , 52 , 54 Similarly, with respect to ivermectin prophylaxis of frontline workers and those at risk, controlled observational studies from Bangladesh and Argentina (the latter which involved 1195 health care workers) have shown apparent reductions in covid-19 transmission with ivermectin prophylaxis. 42 , 48 Clarifying ivermectin safety in pregnancy is a key question in patient acceptability for pregnant women contracting covid-19. One source 5 found little evidence of increased risk of abnormal pregnancies but similarly weak evidence of absence of risk. For (pre-exposure) prophylaxis in pregnancy, where vaccines may be contraindicated, the alternative of hydroxychloroquine has been advocated. 117 , 118 In addition to safety and relative efficacy, different risk-benefit judgments may be presented for prophylaxis (pre- and post-exposure), and for treatment, with pregnancy a high-risk status for covid-19. RCTs in this review did not specifically examine use of ivermectin in the elderly, though this is a known high-risk group for severe covid-19. In the setting of care homes, it is also notorious for rapid contagion. A standard indication for ivermectin in the elderly is scabies. We identified two recent reports suggesting that ivermectin may be efficacious as prevention and treatment of covid-19 in this age group. 44 , 119 There is also evidence emerging from countries where ivermectin has been implemented. For example, Peru had a very high death toll from covid-19 early on in the pandemic. 120 Based on observational evidence, the Peruvian government approved ivermectin for use against covid-19 in May 2020. 120 After implementation, death rates in eight states reduced by 64–91% over a two-month period. 120 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30 + days and of 75% at 45 + days. 121 However, factors such as change in behaviour, social distancing, and face-mask use could have played a role in this reduction. Other considerations related to the use of ivermectin treatment in the covid-19 pandemic include people's values and preferences, equity implications, acceptability and feasibility. 122 None of the identified reviews specifically discussed these criteria in relation to ivermectin. However, in health care decision-making, evidence on effectiveness is seldom taken in isolation without considering these factors. Ultimately, if ivermectin is to be more widespread in its implementation, then some considerations are needed related to these decision-making criteria specified in the GRADE-DECIDE framework. 122 Ivermectin may be equitable, acceptable and feasible global intervention against covid-19. There are numerous emerging ongoing clinical trials assessing ivermectin for covid-19. The trade-off with policy and potential implementation based on evidence synthesis reviews and/or RCTs will vary considerably from country to country. Certain South American countries, Indian states, and more recently Slovakia and other countries in Europe, have implemented its use for covid-19. 121,123−126 Despite ivermectin being a low-cost medication in many countries globally, the apparent shortage of economic evaluations indicates that economic evidence on ivermectin for treatment and prophylaxis of SARS-CoV-2 is currently lacking. This may impact more on LMICs that are potentially waiting for guidance from organizations like the WHO. Given the evidence of efficacy, safety, low cost and current death rates, ivermectin may potentially have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with safety concerns. It is a WHO ‘Essential Medicine’ used in several different indications. Health professionals should consider its use against Covid-19 in both treatment and prophylaxis. Declarations Contributors Tess Lawrie and Andrew Bryant co-wrote the review; they also sifted the search and classified studies for inclusion and entered and checked the data in RevMan and performed analyses. Data extraction was divided amongst Tess Lawrie, Andrew Bryant and Therese Dowswell. Therese Dowswell and Andrew Bryant graded the evidence. Edmund Fordham prepared the text on ivermectin mechanisms, use in pregnancy and among the elderly. Sarah Hill prepared the brief economic commentary. Clinicians Scott Mitchell and Tony Tham contributed to the interpretation of the evidence in the discussion and conclusions. All authors reviewed and approved the final version of the manuscript. Ethical Approval and Consent to participate Not applicable Consent for publication Not applicable Availability of supporting data All data are presented in this review and references to included and ongoing trials are provided. Competing interests None declared Funding None Authors' contributions Tess Lawrie and Andrew Bryant co-wrote the review; they also sifted the search and classified studies for inclusion and entered and checked the data in RevMan and performed analyses. Data extraction was divided amongst Tess Lawrie, Andrew Bryant and Therese Dowswell. Therese Dowswell and Andrew Bryant graded the evidence. Edmund Fordham prepared the text on ivermectin mechanisms, use in pregnancy and among the elderly. Sarah Hill prepared the brief economic commentary. Clinicians Scott Mitchell and Tony Tham contributed to the interpretation of the evidence in the discussion and conclusions. All authors reviewed and approved the final version of the manuscript. Acknowledgements We thank Information Specialist, Jo Platt, of the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer (CGNOC) group for designing the search strategy and running the search, as well as Anna Noel Storr for reviewing the strategy. 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In vivo use of ivermectin (IVR) for treatment for corona virus infected patients (covid-19): a randomized controlled trial. 2021. http://www.chictr.org.cn/showproj.aspx?proj=54707 (accessed January 2021). Schwartz E. Ivermectin vs. Placebo for the Treatment of Patients With Mild to Moderate covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04429711 (accessed January 2021). Okumus N. Ivermectin for Severe covid-19 Management. 2020. https://clinicaltrials.gov/ct2/show/NCT04646109 (accessed January 2021). Guzzo C, Furtek C, Porras AC, C. Tipping, R. Clineschmidt, C. Sciberras, D. Hsieh, J., Lasseter K. Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects. Journal of Clinical Pharmacology 2002; 42 (10): 1122-33. Clancy R. covid-19: A realistic approach to community management. 2021. https://quadrant.org.au/opinion/qed/2021/01/covid-19-a-realistic-approach-to-community-management/ (accessed January 2021). World Health Organization. Developing global norms for sharing data and results during public health emergencies. 2015. https://www.who.int/medicines/ebola-treatment/blueprint_phe_data-share-results/en/ (accessed January 2021). Castañeda-Sabogal A, Chambergo-Michilot D, Toro-Huamanchumo CJ, Silva-Rengifo C, Gonzales Z, Barboza JJ. Outcomes of Ivermectin in the treatment of covid-19: a systematic review and meta-analysis. medRxiv 2021. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358 (j4008). Fesler ML, Stricker RB. Pre-exposure prophylaxis for covid-19 in pregnant women. Int J Gen Med 2021; 14 : 279-84. Stricker RB, Fesler ML. Flattening the Risk: Pre-Exposure Prophylaxis for COVID-19. Infection & Drug Resistance 2020; 13 : 3689-94. Chesler DL. Letter to Dr Bray at the National Institutes of Health. Personal communication; 2021. Chamie J. Real-World Evidence: The Case of Peru. Causality between Ivermectin and COVID-19 Infection Fatality Rate. ResearchGate; 2020. https://www.researchgate.net/publication/344469305 Chamie-Quintero J, Hibberd J, Scheim DE. Covid-19 case fatalities and total deaths with and without ivermectin treatment in different states in Peru. Open Science Foundation 2021. GRADE-DECIDE. The DECIDE Project. 2016. http://www.decide-collaboration.eu/ . (accessed January 2021). Roguski J. Ivermectin. unknown date. https://www.thecompleteguidetohealth.com/Ivermectin.html# (accessed January 2021). Ministerio de Salud y Deportes. Ministry of Health authorizes the use of ivermectin against COVID-19 under protocol. 2020. https://www.minsalud.gob.bo/4157-ministerio-de-salud-autoriza-uso-de-ivermectina-contra-el-covid-19-bajo-protocolo (accessed January 2021). Despacho de Comunicaciones y Estrategia Presidencial. Coronavirus COVID-19 In Honduras. 2021. https://covid19honduras.org/ (accessed January 2021). TrialSiteNews. Slovakia Becomes the First EU Nation to Formally Approve Ivermectin for Both Prophylaxis and Treatment for COVID-19 Patients. 2021. https://trialsitenews.com/slovakia-becomes-the-first-eu-nation-to-formally-approve-ivermectin-for-both-prophylaxis-and-treatment-for-covid-19-patients/ (accessed February 2021). Chaccour C, Casellas A, Matteo A, et al. Effectiveness of Ivermectin in SARS-CoV-2/covid-19 Patients. International Journal of Sciences 2020. Chowdhury ATMM, Shahbaz M, Karim R, et a. Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on covid19 patients. Res Square 2020. Hashim HA, Maulood MF, Rasheed AM, et al. Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating covid-19 patients in Baghdad, Iraq. medRxiv 2020. Petkov S. Multicenter, randomized, double-blind, placebo-controlled study investigating efficacy, safety and tolerability of ivermectin HUVE-19 in patients with proven SARS-CoV-2 infection (covid-19) and manifested clinical symptoms. 2021. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002091-12/BG (accessed January 2021). Podder CS, Chowdhury N, Mohim IS, Haque W. Outcome of ivermectin treated mild to moderate covid-19 cases: a single-centre, open-label, randomised controlled study. IMC Journal of Medical Science 2020; 14 (2): 002. Chala RE. Prophylaxis Covid-19 in Healthcare Agents by Intensive Treatment With Ivermectin and Iota-carrageenan (Ivercar-Tuc). 2021. https://clinicaltrials.gov/ct2/show/NCT04701710 (accessed January 2021). Shouman W. Use of Ivermectin as a Prophylactic Option in Asymptomatic Family Close Contact for Patient with Covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04422561 (accessed January 2021). Campbell M, McKenzie JE, Sowden A, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ 2020; 16 (368): l6890. Tables Due to technical limitations, table 4 docx is only available as a download in the Supplemental Files section. Supplementary Files Appendices.docx Table4.docx Cite Share Download PDF Status: Published Journal Publication published 17 Jun, 2021 Read the published version in American Journal of Therapeutics → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-317485","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":16572115,"identity":"af77a14d-52ab-48d3-bcd6-2eac2d21ae98","order_by":0,"name":"Andrew Bryant","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYHACAwbGBjCD8QEDgwWE1UCcFmZmAwYGCdK0sEkQpYV/dvM2CcYd9xL7Z/cfqy6okWDgbz/AJjkDjxaJO8fKJBjPFCfOuHOY7faMYxIMEmcS2CQ34HPWjRwzCca2hMSGG8lst3kbgA67wcAm+QCPDnmYlvlALcUgLfKEtBjAtGwAamEGaTEAacHnMMMbacUWiWcSjDfeSDaW5jkmwWN4JrHZEp/35W4kb7zxcUeC7LwbiQ8/89TYyMkdP3zwZg8+7zMwsEgkMDA4NkB5PIQjEhiFH4CEPSFVo2AUjIJRMIIBALK0Sy0KafoUAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4351-8865","institution":"Newcastle University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Bryant","suffix":""},{"id":16572116,"identity":"e6f59e5e-95bb-4fb3-8a31-4ebf2cceb05f","order_by":1,"name":"Theresa A Lawrie","email":"","orcid":"","institution":"Evidence-based Medicine Consultancy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"A","lastName":"Lawrie","suffix":""},{"id":16572117,"identity":"c0d2636e-0653-4266-b323-4e90d8c04461","order_by":2,"name":"Therese Dowswell","email":"","orcid":"","institution":"Evidence-Based Medicine Consultancy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Therese","middleName":"","lastName":"Dowswell","suffix":""},{"id":16572118,"identity":"2914f698-aad3-42af-9658-9af6a11cf1eb","order_by":3,"name":"Edmund Fordham","email":"","orcid":"","institution":"Evidence-Based Medicine Consultancy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Edmund","middleName":"","lastName":"Fordham","suffix":""},{"id":16572119,"identity":"6a67bd60-b431-4f38-b798-e1916a1e9c4b","order_by":4,"name":"Scott Mitchell","email":"","orcid":"","institution":"Emergency Department, Princess Elizabeth Hospital, Guernsey","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Scott","middleName":"","lastName":"Mitchell","suffix":""},{"id":16572120,"identity":"70581f60-a233-46db-992a-7a28ebcfb3b1","order_by":5,"name":"Sarah Hill","email":"","orcid":"","institution":"Newcastle University Institute for Health and Society","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Hill","suffix":""},{"id":16572121,"identity":"edba6c7c-6b2c-4ff8-9be7-76c59b4af2ae","order_by":6,"name":"Tony Tham","email":"","orcid":"","institution":"Dundonald Hospital: Ulster Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tony","middleName":"","lastName":"Tham","suffix":""}],"badges":[],"createdAt":"2021-03-10 22:53:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-317485/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-317485/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1097/MJT.0000000000001402","type":"published","date":"2021-06-17T13:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":7130710,"identity":"4b2783cd-87f5-42ff-8cd0-1aa49f5cad4b","added_by":"auto","created_at":"2021-03-18 22:59:15","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85352,"visible":true,"origin":"","legend":"Study flow diagram from search conducted on 01 February 2021","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/1a104e1ff39c15d959c1dc10.jpg"},{"id":7130708,"identity":"23b2e548-5f6a-4d22-9664-3e3f8661d809","added_by":"auto","created_at":"2021-03-18 22:59:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":162667,"visible":true,"origin":"","legend":"Risk of bias summary: review authors' judgements about each risk of bias item for each included study. ","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/ea854b74a711b7ab12d068c6.jpg"},{"id":7130711,"identity":"6682f2aa-6c12-4234-827b-584465922f93","added_by":"auto","created_at":"2021-03-18 22:59:15","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":180828,"visible":true,"origin":"","legend":"Death due to any cause","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/b1dc932a044c12e0899c2d95.jpg"},{"id":7130314,"identity":"5916a477-8c51-4144-9cf5-c3ee26d7c6a1","added_by":"auto","created_at":"2021-03-18 22:56:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":173276,"visible":true,"origin":"","legend":"Death due to any cause, excluding an outlier study responsible for the heterogeneity","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/64a1529fcedbfc4e52c33d6d.jpg"},{"id":7130308,"identity":"16f39c19-b21a-4bf7-8d1c-1341e9e5aa47","added_by":"auto","created_at":"2021-03-18 22:56:15","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":157400,"visible":true,"origin":"","legend":"Death due to any cause, excluding high risk of bias studies","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/2496cca50e3f684d318db17a.jpg"},{"id":7130715,"identity":"3e52d289-375a-4c3c-953b-e3ab1af549c1","added_by":"auto","created_at":"2021-03-18 22:59:16","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":141905,"visible":true,"origin":"","legend":"Death due to any cause, excluding studies with active controls","description":"","filename":"Fig6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/fff4dd2d70c0865b1308f0d8.jpg"},{"id":7130712,"identity":"32be373a-6f4f-4bf4-80d5-63b3d8dbba95","added_by":"auto","created_at":"2021-03-18 22:59:15","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":30321,"visible":true,"origin":"","legend":"Funnel plot of Ivermectin vs control for covid-19 treatment for all cause death (subgrouped by severity)","description":"","filename":"Fig7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/8ddaf5b70d022b8ad0881e88.jpg"},{"id":7131042,"identity":"71a2e4f4-9254-4ee0-8acf-ec6fcc269f26","added_by":"auto","created_at":"2021-03-18 23:02:15","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":51318,"visible":true,"origin":"","legend":"Need for mechanical ventilation","description":"","filename":"Fig8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/a2a5f8e6e73371c1fce0effd.jpg"},{"id":7130714,"identity":"a1dda88b-e2ef-42bc-8fc9-450981d6574c","added_by":"auto","created_at":"2021-03-18 22:59:16","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":91853,"visible":true,"origin":"","legend":"Improvement","description":"","filename":"Fig9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/2c020465ba3d92461bd7323f.jpg"},{"id":7130307,"identity":"25160047-32c6-464e-8517-830429fc62e5","added_by":"auto","created_at":"2021-03-18 22:56:15","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":106589,"visible":true,"origin":"","legend":"Deterioration","description":"","filename":"Fig10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/8f2eb3500dfe29a2b2e75647.jpg"},{"id":7131043,"identity":"5b7d6d36-d4c9-4693-9fd4-bf19581083a9","added_by":"auto","created_at":"2021-03-18 23:02:15","extension":"jpg","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":54949,"visible":true,"origin":"","legend":"Covid-19 infection (prophylaxis studies)","description":"","filename":"Fig11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/26eceba4255fc3624c16ca0a.jpg"},{"id":13681401,"identity":"d96a97b0-862d-4f11-b149-65e554f6c4c5","added_by":"auto","created_at":"2021-09-17 11:51:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1495748,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/67e8bc7d-e2c0-4025-b8fa-89839ffb1a73.pdf"},{"id":7130303,"identity":"4e45b4b3-05cd-42ce-b496-78afece19c56","added_by":"auto","created_at":"2021-03-18 22:56:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16545,"visible":true,"origin":"","legend":"","description":"","filename":"Appendices.docx","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/d7c4e05aa247806c43f76cf7.docx"},{"id":7130311,"identity":"7129216b-4636-451b-b790-b06516af804a","added_by":"auto","created_at":"2021-03-18 22:56:15","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":34375,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-317485/v1/6d1b9f71e7e99ec8f65c0894.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eIvermectin for Prevention and Treatment of COVID-19\u0026nbsp;Infection: a Systematic Review and Meta-analysis\u003c/p\u003e","fulltext":[{"header":"Research In Context ","content":"\u003cp\u003e\u003cstrong\u003eEvidence before this study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn countries across the world, hospitalisations and deaths from covid-19 have increased rapidly over recent months, with estimated total deaths now exceeding 2 million people. The population of developed countries will eventually be given the choice of having a vaccine, but this choice may not be afforded to low- and middle-income countries (LMICs) for a long time. The antiparasitic medicine ivermectin, which is widely available in LMICs, has been tested in numerous clinical trials of prevention and treatment of covid-19 with promising results. To date, three reviews of ivermectin use for covid-19 have been published but only one has been peer-reviewed and limited meta-analyses have been performed on the available data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdded value of this study \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first systematic review and meta-analysis done using rigorous Cochrane methods. Evidence was assessed using the GRADE approach which judges the certainty of the evidence. We found low- to moderate certainty evidence that ivermectin treatment may reduce the risk of death among people hospitalised with covid-19. Low-certainty evidence also shows that prophylaxis with ivermectin may reduce the risk of getting infected with covid-19 among those with high exposure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplications of all the available evidence \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe apparent safety and low cost suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally. Ivermectin is not a new and experimental drug with safety concerns; it is a WHO \u0026lsquo;essential medicine\u0026rsquo; usually used in different indications. It may be useful for more health professionals to get access to this medicine for use against covid-19 during the ongoing pandemic. Further results from trials are expected soon.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eTo date, very few treatments have been demonstrated to reduce the burden of morbidity and mortality from covid-19. While corticosteroids have been proven to reduce mortality in severe disease,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e there has been little convincing evidence on interventions that may prevent disease, reduce hospitalisations and reduce the numbers of people progressing to critical disease and death.\u003c/p\u003e\n\u003cp\u003eIvermectin is a well-known medicine that is approved by the World Health Organization and the US Food and Drug Administration (FDA) for use as an anti-parasitic medication. It is widely used in low- and middle-income countries (LMICs) to treat worm infections.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Also used for the treatment of scabies and lice, it is one of the World Health Organisation\u0026rsquo;s Essential Medicines.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e With total doses of ivermectin distributed apparently equalling one-third of the present world population,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e ivermectin at the usual doses (0.2 mg/kg to 0.4 mg/kg) is considered extremely safe for use in humans.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e In addition to its anti-parasitic activity, it has been noted to have antiviral and anti-inflammatory properties, leading to an increasing list of therapeutic indications.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eSince the start of the SARS-CoV-2 pandemic, both observational and randomised studies have evaluated ivermectin as a treatment for, and as prophylaxis against, covid-19 infection. A review by the Front Line Covid-19 Critical Care Alliance (FLCCC) summarised findings from 27 studies on the effects of ivermectin for the prevention and treatment of covid-19 infection, concluding that ivermectin \u0026ldquo;demonstrates a strong signal of therapeutic efficacy\u0026rdquo; against Covid-19.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Another recent review found that ivermectin reduced deaths by 75%.\u003csup\u003e10\u003c/sup\u003e Despite these findings, the National Institute of Health in the US recently stated that \"there are insufficient data to recommend either for or against the use of ivermectin for the treatment of covid-19\".\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIvermectin has antiviral activity against a wide range of RNA and some DNA viruses, e.g. Zika, Dengue, Yellow Fever, and others.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Caly et al\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e demonstrated specific action against SARS-CoV-2 \u003cem\u003ein vitro\u003c/em\u003e with a suggested host-directed mechanism of action being the blocking of the nuclear import of viral proteins\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e which suppress normal immune responses. However, the cell culture EC\u003csub\u003e50\u003c/sub\u003e may not be achievable \u003cem\u003ein vivo.\u003c/em\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Other conjectured mechanisms include: inhibition of SARS-CoV-2 3CLPro activity \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e (a protease essential for viral replication), a variety of anti-inflammatory effects,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e and competitive binding of ivermectin with the viral S protein as shown in multiple \u003cem\u003ein silico\u003c/em\u003e studies\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Analogously to neutralizing antibodies, the latter would inhibit viral binding to ACE-2 receptors suppressing infection. Haemagglutination via viral binding to sialic acid (SA) receptors on erythrocytes is a recently-proposed pathologic mechanism\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e that would be similarly disrupted. Both host-directed and virus-directed mechanisms have thus been proposed, the clinical mechanism may be multi-modal, and a comprehensive review of mechanisms of action is warranted.\u003c/p\u003e\n\u003cp\u003eDeveloping new medications can take years; therefore, identifying existing drugs that can be re-purposed against covid-19 and that already have a strong safety profile through decades of use could play a critical role in suppressing or even ending the SARS-CoV-2 pandemic. Using re-purposed medications may be especially important because it could take months, possibly years, for much of the world's population to get vaccinated, particularly among low- and middle-income country (LMIC) populations.\u003c/p\u003e\n\u003cp\u003eIvermectin has now been shown to have anti-viral and anti-inflammatory properties, suggesting that its effect against SARS-CoV-2 requires systematic review. Currently, ivermectin is commercially available and affordable in many countries globally\u003csup\u003e \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e \u003c/sup\u003e. A 2018 application for ivermectin use for scabies gives a direct cost of $2.90 for 100 12 mg tablets.\u003csup\u003e \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e \u003c/sup\u003e A therapeutic course of ivermectin for cases of covid-19 infection in India, for example, has been reported to cost less than PPP$ 53.93 for a dose of 12mg twice daily for 7 days\u003csup\u003e \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e \u003c/sup\u003e (PPP\u0026thinsp;=\u0026thinsp;purchasing power parity in 2021). This price for ivermectin represents that of a dosage at the upper-end of what has be used to treat covid-19 cases.\u003csup\u003e \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e \u003c/sup\u003e For these reasons, the exploration of ivermectin\u0026rsquo;s potential effectiveness against SARS-CoV-2 may be of particular importance for settings with limited resources.\u003csup\u003e \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e \u003c/sup\u003e If demonstrated to be effective as a treatment for covid-19, the cost-effectiveness of ivermectin should be considered against existing treatments and prophylaxes.\u003c/p\u003e\n\u003cp\u003eThe aim of this review was to assess the efficacy of ivermectin treatment among people with covid-19 infection and as a prophylaxis among people at higher risk of covid-19 infection. Additionally, we aimed to prepare a brief economic commentary (BEC) of ivermectin as treatment and as prophylaxis for covid-19.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003eThe conduct of this review was guided by a protocol that was initially written using Cochrane\u0026rsquo;s rapid review template and subsequently expanded to a full protocol for a comprehensive review.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section3\"\u003e\n\u003ch2\u003eSearch strategy and selection criteria\u003c/h2\u003e\n\u003cp\u003eTwo reviewers independently searched the electronic databases of Medline, Embase, CENTRAL, Cochrane covid-19 Study Register and Chinese databases for randomised controlled trials (RCTs) up to February 01 2021 (Appendix 1\u0026ndash;3); current guidance\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e for the BEC was followed for a supplementary search of economic evaluations. There were no language restrictions and translations were planned to be carried out when necessary.\u003c/p\u003e\n\u003cp\u003eWe searched the reference list of included studies, and of two other 2021 literature reviews on ivermectin.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e We contacted experts in the field (Drs. Andrew Hill, Pierre Kory and Paul Marik) for information on new and emerging trial data. Additionally, all trials registered on clinical trial registries were checked and trialists of 39 ongoing trials or unclassified studies were contacted to request information on trial status and data where available. Many pre-print publications and unpublished articles were identified from the pre-print sever Medrxiv and the International Clinical Trials Registry Platform. This is a rapidly expanding evidence base so the number of trials are increasing quickly. Reasons for exclusion were recorded for all studies excluded after full text review.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eData analysis\u003c/h2\u003e\n\u003cdiv class=\"Ethics-ToolTip\"\u003eWe extracted information or data on study design (including methods, location, sites, funding, study author declaration of interests, inclusion/exclusion criteria), setting, participant characteristics (disease severity, age, gender, co-morbidities, smoking, occupational risk), and intervention and comparator characteristics (dose and frequency of ivermectin/comparator).\u003c/div\u003e\n\u003cp\u003eThe primary outcome for the intervention component of the review included death from any cause and presence of covid-19 infection (as defined by investigators) for ivermectin prophylaxis. Secondary outcomes included PCR negativity, clinical recovery, length of hospital stay, admission to hospital (for outpatient treatment), admission to ICU or requiring mechanical ventilation, duration of mechanical ventilation, and severe or serious adverse events, as well as post hoc assessments of improvement and deterioration. All of these data were extracted as measured and reported by investigators. Numerical data for outcomes of interest were extracted according to intention to treat.\u003c/p\u003e\n\u003cp\u003eIf there was a conflict between data reported across multiple sources for a single study (e.g. between a published article and a trial registry record), we contacted the authors for clarification. Assessments were conducted by two reviewers (TL, TD, AB or GG) using the Cochrane RCT risk of bias tool.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Discrepancies were resolved by discussion.\u003c/p\u003e\n\u003cp\u003eContinuous outcomes were measured as the mean difference (MD) and 95% confidence intervals (CI); dichotomous outcomes as risk ratio (RR) and 95% CI.\u003c/p\u003e\n\u003cp\u003eWe did not impute missing data for any of the outcomes. Authors were contacted for missing outcome data and for clarification on study methods, where possible, and for trial status for ongoing trials.\u003c/p\u003e\n\u003cp\u003eWe assessed heterogeneity between studies by visual inspection of forest plots, by estimation of the I\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e statistic (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;60% was considered substantial heterogeneity),\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e by a formal statistical test to indicate statistically significant heterogeneity\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e and, where possible, by subgroup analyses (see below). If there was evidence of substantial heterogeneity, the possible reasons for this were investigated and reported. We assessed reporting biases using funnel plots if more than 10 studies contributed to a meta-analysis.\u003c/p\u003e\n\u003cp\u003eWe meta-analysed data using the random effects model (DerSimonian and Laird method)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e using RevMan 5.4 software.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Results used the inverse variance method for weighting.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Some sensitivity analyses used other methods that are outlined below and some calculations were performed in R\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e through an interface\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e to the netmeta package.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Where possible, we performed subgroup analyses grouping trials by disease severity, inpatients versus outpatients and single dose versus multiple doses. We performed sensitivity analyses by excluding studies at high risk of bias. We conducted further post hoc sensitivity analyses using alternative methods to test the robustness of results in the presence of zero events in both arms in a number of trials\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and estimated odds ratios (and additionally risk ratio for the MH (Mantel-Haenszel) method) using a fixed effects model. The models incorporate evidence from single-zero studies without having to resort to continuity corrections. However double-zero studies are excluded from the analysis so the risk difference (RD) was also assessed using the MH method as this approach can adequately incorporate trials with double zero events. This method can also use a random effects component. A \u0026lsquo;treatment-arm\u0026rsquo; continuity correction was used, where the values 0.01, 0.1 and 0.25 were added where trials reported zero events in both arms. It has been shown that a non-fixed continuity correction is preferable to the usual 0.5.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Other methods are available but were not considered due to difficulty in interpretation, sensitivity of assumptions or the fact they are rarely used in practice.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAll outcomes have been assessed independently by two review authors (TD and AB) using the GRADE approach,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e which ranks the quality of the evidence. Results are presented in a summary of findings table. Any differences were resolved by discussion with the wider group. We used Cochrane Effective Practice and Organisation of Care guidance to interpret the evidence.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n\u003ch2\u003eRole of funding source\u003c/h2\u003e\n\u003cp\u003eThere was no funding source for this study.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSearch results and risk of bias assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe combined and preliminary de-duplicated total was n\u0026thinsp;=\u0026thinsp;523. We also identified 11 records from other sources (reference lists, etc). See PRISMA flow diagram for inclusion and exclusion details of these references (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe supplementary search for the BEC identified seventeen studies, of which four were retrieved in full. No full trial- or model-based economic evaluations (cost-utility analyses, cost-effectiveness analyses or cost-benefit analyses) were identified.\u003c/p\u003e\n\u003cp\u003eTwenty-one trials met inclusion and all of these contributed data to at least one review outcome and meta-analysis. Thirteen trials contributed data for the primary outcome for ivermectin treatment (death); three studies reported the primary outcome for prophylaxis (covid-19 infection). Characteristics of included studies are given in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Seventeen studies\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e were excluded as they were not RCTs and we identified 39 ongoing studies\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e97\u003c/span\u003e\u003c/sup\u003e and two studies\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e98\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e99\u003c/span\u003e\u003c/sup\u003e are awaiting classification.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSummary of study characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy ID\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCountry\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDesign\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParticipants\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSample size\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIvermectin dose and frequency*\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eComparator\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOrigin of data\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMain outcomes reported\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"9\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ecovid-19 treatment studies\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAhmed 2020\u003csup\u003e100\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBangladesh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble-blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPL(Pharma); Bangladesh, Canada, Sweden, and UK govt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate covid (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12mg x 1 day or x 5 days (3 study arms)*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal; emailed/responded with data\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTime to viral clearance (PCR -ve), remission of fever and cough within 7 days, duration of hospitalisation, mortality, failing to maintain sats\u0026thinsp;\u0026gt;\u0026thinsp;93%, adverse events, PCR -ve at 7 and 14 days\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBabalola 2020\u003csup\u003e101\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNigeria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsymptomatic, mild or moderate covid (45 inpatients and 17 outpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 mg every 84 hrs x 2 wks (arm 1) or 12 mg every 84 hrs x 2 wks (arm 2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRitonavir/lopinavir\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedRxiv pre-print: emailed/responded with data. Paper accepted for publication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTime to PCR -ve, laboratory parameters (platelets, lymphocytes, clotting time), clinical symptom parameters\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChaccour 2020\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSpain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdapharma, ISGlobal and the University of Navarra\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild covid (outpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4mg/kg x 1 dose\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCR\u0026thinsp;+\u0026thinsp;ve at day 7, proportion symptomatic at day 4,7,14,21, progression, death, adverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChachar 2020\u003csup\u003e127\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePakistan\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOpen label\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild covid (outpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12mg at 0, 12, and 24 hours (3 doses)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSymptomatic at day 7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChowdhury 2020\u003csup\u003e128\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBangladesh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQuasi-RCT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOutpatients with a\u0026thinsp;+\u0026thinsp;ve PCR (approx. 78% symptomatic)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e116\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2mg/kg x1 dose*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHCQ 400 mg 1st day then 200mg BID x 9 days\u0026thinsp;+\u0026thinsp;AZM 500 mg\u003c/p\u003e\n\u003cp\u003edaily x 5 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResearch Square pre-print\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTime to -ve PCR test; period to symptomatic recovery; adverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eElgazzar 2020\u003csup\u003e50\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRCT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to severe covid (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e200\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4mg/kg daily x 4 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHCQ 400 mg BID x 1 day then 200 mg BID x 9 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResearch Square pre-print: emailed/responded with data\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eImproved, progressed, died. Also measured CRP, D-dimers, HB, lymphocyte, serum ferritin after one week of treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFonseca 2021\u003csup\u003e102\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrazil\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInstitution-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate to severe (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e167\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14mg daily x 3 days (plus placebos x 2 additional days)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHCQ \u0026minus;\u0026thinsp;400mg BID on day 0 then daily x 4 days ; CQ -450mg BID day 0 then daily x 4 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data/ manuscript in progress obtained via email\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeath, invasive ventilation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHashim 2020\u003csup\u003e129\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQuasi-RCT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to critical (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e140\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2mg/kg x 2 days*\u003c/p\u003e\n\u003cp\u003eSome had a 3rd dose a week later\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedRxiv pre-print\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeath, mean time to recovery, disease progression (deterioration)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKrolewiecki 2020\u003csup\u003e103\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArgentina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOpen label\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6mg/kg/day x 5 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eViral load reduction in respiratory secretions day 5, IVM concentrations in plasma, severe adverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMahmud 2020\u003csup\u003e104\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBangladesh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate covid (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e363\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12mg x 1 dose*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;SOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eData published on clinical trial registry and clarification obtained via email\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eImprovement, deterioration, late clinical recovery, persistent PCR test\u0026thinsp;+\u0026thinsp;ve\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMohan\u003c/p\u003e\n\u003cp\u003e2021\u003csup\u003e107\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInstitution funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e152\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 mg or 24 mg elixir x 1 dose\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedRxiv pre-print Research\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConversion of RT-PCR to negative result, decline of viral load at day 5 from enrolment\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNiaee 2020\u003csup\u003e105\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInstitution-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to severe covid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e180\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2mg/kg x 1 and 3 other dosing options)\u0026thinsp;~\u0026thinsp;14 mg tablet**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHCQ 200mg/kg BID or placebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResearch Square pre-print\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeaths, length of stay, biochemical parameters\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOkumus 2021\u003csup\u003e111\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTurkey\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQuasi-RCT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere covid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2mg/kg x 5 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data/manuscript in progress obtained via email\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinical improvement, deterioration, death, SOFA scores\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePetkov 2021\u003csup\u003e130\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBulgaria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePharma funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate covid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4mg/kg x 3 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data obtained from another source\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRate of conversion to PCR negative\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePodder 2020\u003csup\u003e131\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBangladesh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOpen label\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate (outpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2mg/kg x 1 dose\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuration of symptoms, recovery time to symptom free from enrolment, recovery time to symptom free from symptom onset, repeat PCR result on day 10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRaad 2021\u003csup\u003e109\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLebanon\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsymptomatic outpatients\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 mg PO if 45kg to 64kg, 12mg PO if 65kg to 84kg and 0.15mg/kg if body weight\u0026thinsp;\u0026ge;\u0026thinsp;85 Kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data/manuscript in progress obtained via email\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eViral load reduction, hospitalisation, adverse effects\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRavikirti 2021\u003csup\u003e106\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate covid (inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12mg x 2 days\u0026thinsp;+\u0026thinsp;SOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u0026thinsp;+\u0026thinsp;SOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eA negative RT-PCR report on day 6, symptomatic on day 6, discharge by day 10, admission to ICU, need for invasive mechanical ventilation, mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRezai\u003c/p\u003e\n\u003cp\u003e2020\u003csup\u003e108\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate (inpatient)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2 mg/kg x 1 dose\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data obtained from another source\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinical symptoms, respiratory rate and O2 saturation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSchwartz\u003c/p\u003e\n\u003cp\u003e2021\u003csup\u003e110\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIsrael\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDouble blind\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild to moderate (outpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e94\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.15 to 0.3 mg/ kg x 3 days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlacebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data obtained from another source\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eViral clearance at day 4, 6, 8 and 10 ), hospitalisation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"9\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ecovid-19 prophylaxis studies\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChala 2021\u003csup\u003e132\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArgentina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOpen label\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHealth care workers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e234\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 mg (in drops) weekly\u0026thinsp;+\u0026thinsp;lota-carrageenan 6 sprays daily x 4 wks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-publication data/manuscript in progress obtained via email\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCovid-19 infection (not clear if measured by PCR or symptoms)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eElgazzar 2020\u003csup\u003e50\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOpen label\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHealth care and family contacts\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e200\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4mg/kg, weekly x 2 weeks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eResearch Square pre-print: emailed/responded with data\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePositive PCR test\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eShouman 2020\u003csup\u003e133\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOpen label\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSelf-funded\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFamily contacts\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e303\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 doses (15mg \u0026ndash; 24 mg depending on weight) on day 1 and day 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePublished in PR journal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSymptoms and/or positive covid-19 PCR test within 14 days; adverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\"\u003e\u003cem\u003eFootnotes\u003c/em\u003e\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\"\u003e* Also administered doxycycline\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\"\u003e** multi-arm trial\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\"\u003eSOC: Standard of care; RCT: Randomised controlled trial; PR: peer review; mg: milligram; kg: kilogram; PCR: polymerase chain reaction; hrs: hours\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA risk of bias summary graph is given in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Eleven studies\u003csup\u003e23,50,100\u0026minus;108\u003c/sup\u003e used satisfactory random sequence generation and allocation concealment. One study described satisfactory sequence generation, but it was unclear whether allocation was concealed.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e109\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eTen trials reported blinding of the participants/personnel and/or the outcome assessors.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e100\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e102\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e106\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e110\u003c/span\u003e\u003c/sup\u003e The others were either unclear or high risk for blinding. We considered blinding to be a less important criterion for evaluation of evidence related to the review's primary outcomes, namely death and laboratory-confirmed covid-19 infection, which are objective outcomes.\u003c/p\u003e\n\u003cp\u003eWe did not consider publication on pre-print websites to constitute a risk of bias, as all studies were scrutinised and peer reviewed by us during the review process and, where additional information was needed, we contacted the authors for clarification. Most trials were self-funded or did not report funding and we did not note any apparent conflicts of interest among the trialists.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-one RCTs (including 2 quasi-RCTs) involving 2741 participants were included, with sample sizes ranging from 24 to 363 participants. For trials of covid-19 treatment, 14 evaluated ivermectin among participants with mild to moderate covid-19 only; four trials included patients with severe covid-19. Most compared ivermectin with placebo or no ivermectin; four trials included an active comparator (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Three RCTs involving 738 participants were included in the prophylaxis studies. Most studies were registered, self-funded and undertaken by clinicians working in the field. There were no obvious conflicts of interest noted.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIvermectin treatment vs no ivermectin treatment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNineteen studies (2003 participants) contributed data to the comparison ivermectin treatment vs no ivermectin treatment for covid-19 treatment.\u003c/p\u003e\n\u003cp\u003eMeta-analysis of 13 trials, assessing 1892 participants, found that ivermectin reduced the risk of death by an average of 68% (95% CI, 28\u0026ndash;86%) compared with no ivermectin treatment (average risk ratio (aRR) 0.32, 95% CI 0.14 to 0.72; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;57%; risk of death 2.5% versus 9.1% among hospitalised patients in this analysis, respectively (Summary of Findings (SoF) Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Heterogeneity was explained by the exclusion of one trial\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e102\u003c/span\u003e\u003c/sup\u003e in a sensitivity analysis (average RR 0.25, 95% CI 0.13 to 0.48, n\u0026thinsp;=\u0026thinsp;1725, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;12%), but since this trial was at low risk of bias it was retained in the main analysis. The source of heterogeneity may be due to the use of active comparators in the trial design. The results were also robust to sensitivity analyses excluding three other studies with an active treatment comparator (average RR 0.45, 95% CI 0.21 to 0.98, n\u0026thinsp;=\u0026thinsp;1083, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%). The results were also not sensitive to the exclusion of studies that were potentially at higher risk of bias (average RR 0.28, 95% CI 0.09 to 0.85, 11 studies, n\u0026thinsp;=\u0026thinsp;1697, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;67%), but in subgroup analysis it was unclear as to whether a single dose would be sufficient. The effect on reducing deaths was consistent across mild to moderate and severe disease subgroups. Subgrouping data according to inpatient and outpatient trials was not informative because few outpatient studies reported this serious outcome. The conclusions of the primary outcome were also robust to a series of alternative post hoc analyses that explored the impact of numerous trials that reported no deaths in either arm. Extreme sensitivity analyses using a treatment arm continuity correction of between 0.01 and 0.5 did not change the certainty of the evidence judgements (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Overall, death from any cause, taking into account all composite analyses, was judged to provide low to moderate-certainty evidence (SoF Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). A funnel plot corresponding to the primary outcome of death from any cause did not appear to suggest any evidence of publication bias (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e). Furthermore, the ease with which trial reports can be uploaded as preprints should reduce this risk.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2a\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSummary of findings table of ivermectin versus no ivermectin for covid-19 treatment in any setting\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eOutcomes\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eIllustrative comparative risks* (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eRelative effect\u003c/p\u003e\n\u003cp\u003e(95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eNo of Participants\u003c/p\u003e\n\u003cp\u003e(studies)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eQuality of the evidence\u003c/p\u003e\n\u003cp\u003e(GRADE)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAssumed risk\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding risk\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo ivermectin\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eIvermectin\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeath from any cause\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91 per 1000 (all disease severity)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e62 fewer deaths per 1000 (25 to 78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u0026thinsp;=\u0026thinsp;0.32 (0.14 to 0.72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1892 (13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow to moderate\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRecovery time to negative PCR test, in days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" rowspan=\"8\" align=\"left\"\u003e\n\u003cp\u003eAbsolute risks were not computed due to certainty of evidence being low and in some cases number of events being sparse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMD = -3.20 (-5.99 to -0.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e375 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery Low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTime to clinical recovery, in days (outpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(MD = -1.06 (-1.63 to -0.49)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e176 (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTime to clinical recovery, in days (mild to moderate covid-19 inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMD = -7.32 (-9.25 to -5.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTime to clinical recovery, in days (severe covid-19 inpatients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMD = -3.98 (-10.06 to 2.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdmission to ICU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.22 (0.75 to 2.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e379 (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeed for mechanical ventilation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u0026thinsp;=\u0026thinsp;0.66 (0.14 to 3.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e431 (3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLength of hospital stay, in days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMD\u0026thinsp;=\u0026thinsp;0.13 (-2.04 to 2.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68 (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdmission to hospital\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR 0.16 (0.02 to 1.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e194 (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVery low\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuration of mechanical ventilation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eImprovement (mild to moderate covid-19)*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e543 improved per 1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e185 more per 1000 (from 119 more to 260 more)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR 1.34 (1.22 to 1.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e681 (4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeterioration (any disease severity)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e189 per 1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e140 fewer per 1000 (from 77 fewer to 166 fewer)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR 0.26 (0.12 to 0.59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1041 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSerious adverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e5/542 (1%) had an SAE in ivermectin group and 0/370 (0%) in control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.23 (0.55 to 18.87)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e728 (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e*Only one study contributed to the \u0026lsquo;severe\u0026rsquo; covid-19 subgroup and subgroup data were not pooled due to subgroup differences\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;1 for study design limitations\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;1 each for discrepancies in composite sensitivity analyses\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;1 for inconsistency\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;1 for imprecision\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;2 for imprecision/sparse data\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;1 for indirectness\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2b\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSummary of findings table of ivermectin versus no ivermectin for covid-19 prophylaxis in healthy population (people without covid-19 infection)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eOutcomes\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eIllustrative comparative risks* (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eRelative effect\u003c/p\u003e\n\u003cp\u003e(95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eNo of Participants\u003c/p\u003e\n\u003cp\u003e(studies)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eQuality of the evidence\u003c/p\u003e\n\u003cp\u003e(GRADE)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAssumed risk\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding risk\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo ivermectin\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eIvermectin\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecovid-19 infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e296 per 1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e245 fewer infections per 1000\u003c/p\u003e\n\u003cp\u003e(234 to 269)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u0026thinsp;=\u0026thinsp;0.14 (0.09 to 0.21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e738 (3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdmission to hospital\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeath from any cause\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eNot reported\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSerious adverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eNo events occurred in 538 participants (2 studies), therefore the effect could not be estimated.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\" align=\"left\"\u003e\n\u003cp\u003e*The basis for the \u003cstrong\u003eassumed risk\u003c/strong\u003e (e.g. the median control group risk across studies) is provided in footnotes. The \u003cstrong\u003ecorresponding risk\u003c/strong\u003e (and its 95% confidence interval) is based on the assumed risk in the comparison group and the \u003cstrong\u003erelative effect\u003c/strong\u003e of the intervention (and its 95% CI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e: Confidence interval; \u003cstrong\u003eRR\u003c/strong\u003e: Risk Ratio; RCT: Randomised controlled trial; NNT: number needed to treat.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\" align=\"left\"\u003e\n\u003cp\u003eGRADE Working Group grades of evidence\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHigh quality\u003c/strong\u003e: Further research is very unlikely to change our confidence in the estimate of effect.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eModerate quality\u003c/strong\u003e: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLow quality\u003c/strong\u003e: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVery low quality\u003c/strong\u003e: We are very uncertain about the estimate.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Downgraded \u0026minus;\u0026thinsp;2 for study design limitations\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSensitivity analyses for death from any cause considering methods for dealing with zero events in trials\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMethod\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMeasure\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eModel\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEffect size (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDetails\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeto\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33 (0.21 to 0.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles single zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eM-H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33 (0.21 to 0.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles single zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eM-H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.28 (0.11 to 0.66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles single zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eM-H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39 (0.27 to 0.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles single zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eM-H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32 (0.14 to 0.73)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles single zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eM-H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.05 (-0.07 to -0.03)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles double zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eM-H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.04 (-0.07 to -0.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles double zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.02 (-0.03 to -0.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles double zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.03 (-0.05 to -0.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHandles double zero trials\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTreatment arm continuity correction methods using IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAccounting for double zeros\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAccounting for all zeros\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51 (0.34 to 0.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.55 (0.36 to 0.85)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.36 (0.19 to 0.68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47 (0.27 to 0.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51 (0.34 to 0.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.53 (0.35 to 0.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.37 (0.20 to 0.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.38 (0.19 to 0.76)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51 (0.34 to 0.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.52 (0.34 to 0.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.38 (0.20 to 0.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.38 (0.20 to 0.72)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.52 (0.35 to 0.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.52 (0.35 to 0.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39 (0.22 to 0.71)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41 (0.23 to 0.71)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eM-H: Mantel-Haenszel; IV: Inverse variance; TACC: Treatment arm continuity correction; OR: odds ratio; RR: Risk ratio; RD: Risk difference; FE: fixed effects; RE: Random effects; CI: Confidence interval\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecondary outcomes provided low to very low certainty evidence (SoF Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). Low certainty findings suggested that that there may be no benefit with ivermectin for \u0026lsquo;need for mechanical ventilation\u0026rsquo;, whereas effect estimates for \u0026lsquo;improvement\u0026rsquo; and \u0026lsquo;deterioration\u0026rsquo; favoured ivermectin but were graded as low certainty due to study design limitations and inconsistency (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003e to \u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003e). All other secondary outcome findings were assessed as very low certainty.\u003c/p\u003e\n\u003cp\u003eMeta-analysis of eight trials, assessing 728 participants, found that there was no significant difference between ivermectin and control in the risk of severe adverse events (aRR 3.23, 95% CI 0.55 to 18.87; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; \u003cem\u003elow certainty evidence\u003c/em\u003e, downgraded for imprecision and study design limitations). Five severe adverse events were reported in the ivermectin group and none in controls. The SAEs were as follows: two patients in the Mahmud 2020 trial\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e104\u003c/span\u003e\u003c/sup\u003e had oesophagitis (this is a known side effect of doxycycline, which was co-administered with ivermectin in this trial); one patient in Krolewiecki et al\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e103\u003c/span\u003e\u003c/sup\u003e had hyponatraemia (this trial used high-dose ivermectin for 5 days); and two patients in a study from Turkey\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e111\u003c/span\u003e\u003c/sup\u003e had serious \"delirium-like behaviour, agitation, aggressive attitude and altered state of consciousness\", which the authors attributed to metabolic insufficiencies in MDR-1/ABCB1 or CYP3A4 genes, screening for which was a study feature (see SoF Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIvermectin prophylaxis versus no ivermectin prophylaxis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThree studies involving 738 participants evaluated ivermectin for covid-19 prophylaxis among health care workers and covid-19 contacts. Meta-analysis of these 3 trials, assessing 738 participants, found that ivermectin prophylaxis among health care workers and covid-19 contacts probably reduces the risk of covid-19 infection by an average of 86% (79\u0026ndash;91%) (3 trials, 738 participants; aRR 0.14, 95% CI 0.09 to 0.21; 5.0% vs 29.6% contracted covid-19, respectively; \u003cem\u003elow-certainty evidence\u003c/em\u003e; downgraded due to study design limitations and few included trials). In two trials involving 538 participants, no severe adverse events were recorded (SoF Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThese findings suggest low to moderate-certainty evidence showing a survival benefit without harm of ivermectin for treatment against covid-19. Low certainty evidence on improvement and deterioration support the possibility of clinical benefit with ivermectin. Low certainty evidence also suggest it could be a useful prophylaxis. Overall, therefore, the evidence suggests that early use of ivermectin may reduce morbidity and mortality from covid-19, based on reductions in covid-19 infections when ivermectin was used as post-exposure prophylaxis, more favourable point estimates for mild to moderate disease compared with severe disease for death due to any cause, and on the evidence demonstrating reductions in the number of patients deteriorating.\u003c/p\u003e\n\u003cp\u003eThe evidence on severe adverse events in this review was graded as low certainty, partly because there were too few events to reach statistical significance. However, evidence from a recent systematic review of ivermectin use among people with parasitic infections suggests that ivermectin administered at the usual doses (0.2mg/kg or 0.4mg/kg) is safe and could be safe at higher doses.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e112\u003c/span\u003e\u003c/sup\u003e A recent World Health Organization document on ivermectin use for scabies found that adverse events with ivermectin were primarily minor and transient.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eWe decided to restrict the included studies to the highest level of evidence, i.e. RCTs, despite the use of observational evidence being potentially used in times of emergency,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e113\u003c/span\u003e\u003c/sup\u003e and the numerous observational studies on ivermectin for covid-19. We included pre-print and unpublished data from completed but not yet published trials due to the urgency related to evidence synthesis in the context of a global pandemic.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e114\u003c/span\u003e\u003c/sup\u003e Whilst there is the potential for selective reporting of outcomes and publication bias, we have factored in these considerations in interpreting results and forming conclusions. We adhered to PRISMA guidelines and the WHO statement on developing global norms for sharing data and results during public health emergencies.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e114\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThere are a number of limitations with this review. Several of the studies contributing data did not provide full descriptions of methods, so assessing risk of bias was challenging. Where descriptions of study methods were sparse or unclear, we attempted to contact authors to clarify methods, but lack of information led us to downgrade findings in several instances. Overall interpretation of findings was hampered due to variability in the participants recruited, treatment regimen and in the care offered to those in control groups. We have tried to take this variation into account through subgroup and sensitivity analyses, nevertheless dosing and treatment regimens and the use of ivermectin with other components of \u0026ldquo;standard care\u0026rdquo; require further research. We did not include laboratory outcome measures, such as viral clearance. The latter, as well as other biochemical outcomes have been reported in several studies and reviews and tend to favour ivermectin.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e101\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e105\u003c/span\u003e\u003c/sup\u003e Several trials reported continuous data, such as length of hospital stay, as medians and interquartile ranges, therefore, we were unable to include these data in meta-analysis. As we did not undertake in our protocol to perform narrative evidence synthesis, and as these data tended to favour ivermectin, the certainty of the effects of ivermectin on these continuous outcomes may be underestimated.\u003c/p\u003e\n\u003cp\u003eTo date, three other reviews of ivermectin use for covid-19 have been published\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e115\u003c/span\u003e\u003c/sup\u003e but only one has been peer-reviewed.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e We applied AMSTAR 2,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e116\u003c/span\u003e\u003c/sup\u003e a critical appraisal tool for systematic reviews of healthcare interventions, to the two non-peered systematic reviews\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e115\u003c/span\u003e\u003c/sup\u003e and both were judged to be of low quality (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). However, there was also a suggestion that ivermectin may reduce risk of death in treatment of covid-19 in these reviews.\u003c/p\u003e\n\u003cp\u003eIn addition to these reviews, the findings of several controlled observational studies are consistent with existing evidence and suggest improved outcomes with ivermectin treatment.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e Similarly, with respect to ivermectin prophylaxis of frontline workers and those at risk, controlled observational studies from Bangladesh and Argentina (the latter which involved 1195 health care workers) have shown apparent reductions in covid-19 transmission with ivermectin prophylaxis.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eClarifying ivermectin safety in pregnancy is a key question in patient acceptability for pregnant women contracting covid-19. One source\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e found little evidence of increased risk of abnormal pregnancies but similarly weak evidence of absence of risk. For (pre-exposure) prophylaxis in pregnancy, where vaccines may be contraindicated, the alternative of hydroxychloroquine has been advocated.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e117\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e118\u003c/span\u003e\u003c/sup\u003e In addition to safety and relative efficacy, different risk-benefit judgments may be presented for prophylaxis (pre- and post-exposure), and for treatment, with pregnancy a high-risk status for covid-19.\u003c/p\u003e\n\u003cp\u003eRCTs in this review did not specifically examine use of ivermectin in the elderly, though this is a known high-risk group for severe covid-19. In the setting of care homes, it is also notorious for rapid contagion. A standard indication for ivermectin in the elderly is scabies. We identified two recent reports suggesting that ivermectin may be efficacious as prevention and treatment of covid-19 in this age group.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e119\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThere is also evidence emerging from countries where ivermectin has been implemented. For example, Peru had a very high death toll from covid-19 early on in the pandemic.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e120\u003c/span\u003e\u003c/sup\u003e Based on observational evidence, the Peruvian government approved ivermectin for use against covid-19 in May 2020.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e120\u003c/span\u003e\u003c/sup\u003e After implementation, death rates in eight states reduced by 64\u0026ndash;91% over a two-month period.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e120\u003c/span\u003e\u003c/sup\u003e Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30\u0026thinsp;+\u0026thinsp;days and of 75% at 45\u0026thinsp;+\u0026thinsp;days.\u003csup\u003e121\u003c/sup\u003e However, factors such as change in behaviour, social distancing, and face-mask use could have played a role in this reduction.\u003c/p\u003e\n\u003cp\u003eOther considerations related to the use of ivermectin treatment in the covid-19 pandemic include people's values and preferences, equity implications, acceptability and feasibility.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e122\u003c/span\u003e\u003c/sup\u003e None of the identified reviews specifically discussed these criteria in relation to ivermectin. However, in health care decision-making, evidence on effectiveness is seldom taken in isolation without considering these factors. Ultimately, if ivermectin is to be more widespread in its implementation, then some considerations are needed related to these decision-making criteria specified in the GRADE-DECIDE framework.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e122\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIvermectin may be equitable, acceptable and feasible global intervention against covid-19. There are numerous emerging ongoing clinical trials assessing ivermectin for covid-19. The trade-off with policy and potential implementation based on evidence synthesis reviews and/or RCTs will vary considerably from country to country. Certain South American countries, Indian states, and more recently Slovakia and other countries in Europe, have implemented its use for covid-19.\u003csup\u003e121,123\u0026minus;126\u003c/sup\u003e Despite ivermectin being a low-cost medication in many countries globally, the apparent shortage of economic evaluations indicates that economic evidence on ivermectin for treatment and prophylaxis of SARS-CoV-2 is currently lacking. This may impact more on LMICs that are potentially waiting for guidance from organizations like the WHO.\u003c/p\u003e\n\u003cp\u003eGiven the evidence of efficacy, safety, low cost and current death rates, ivermectin may potentially have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with safety concerns. It is a WHO \u0026lsquo;Essential Medicine\u0026rsquo; used in several different indications. Health professionals should consider its use against Covid-19 in both treatment and prophylaxis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTess Lawrie and Andrew Bryant co-wrote the review; they also sifted the search and classified studies for inclusion and entered and checked the data in RevMan and performed analyses. Data extraction was divided amongst Tess Lawrie, Andrew Bryant and Therese Dowswell. Therese Dowswell and Andrew Bryant graded the evidence. Edmund Fordham prepared the text on ivermectin mechanisms, use in pregnancy and among the elderly. Sarah Hill prepared the brief economic commentary. Clinicians Scott Mitchell and Tony Tham contributed to the interpretation of the evidence in the discussion and conclusions. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are presented in this review and references to included and ongoing trials are provided.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTess Lawrie and Andrew Bryant co-wrote the review; they also sifted the search and classified studies for inclusion and entered and checked the data in RevMan and performed analyses. Data extraction was divided amongst Tess Lawrie, Andrew Bryant and Therese Dowswell. Therese Dowswell and Andrew Bryant graded the evidence. Edmund Fordham prepared the text on ivermectin mechanisms, use in pregnancy and among the elderly. Sarah Hill prepared the brief economic commentary. Clinicians Scott Mitchell and Tony Tham contributed to the interpretation of the evidence in the discussion and conclusions. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Information Specialist, Jo Platt, of the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer (CGNOC) group for designing the search strategy and running the search, as well as Anna Noel Storr for reviewing the strategy. We also thank Isabella Rushforth for her voluntary assistance with the preparation of the reference lists.\u003c/p\u003e\n\u003cp\u003eWe thank Gill Gyte for detailed comments, feedback and involvement in this review, Michael Grayling, and David Tovey for useful peer review comments prior to submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHorby P, Lim WS, Emberson J, et al. Dexamethasone in hospitalised patients with Covid-19 - preliminary report. \u003cem\u003emedRxiv\u003c/em\u003e 2020.\u003c/li\u003e\n\u003cli\u003eBarrows NJ, Campos RK, Powell ST, et al. A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. \u003cem\u003eCell Host \u0026amp; Microbe\u003c/em\u003e 2016; \u003cstrong\u003e20\u003c/strong\u003e(2): 259-70.\u003c/li\u003e\n\u003cli\u003eConterno LO, Turchi MD, Corr\u0026ecirc;a I, Monteiro de Barros Almeida RA. 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Ivermectin In Treatment of covid 19 Patients. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04425707\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04425707\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eSaibannavar A. An open label, prospective comparative study to evaluate the proposed therapy in adults with mild symptomatic covid-19 patients receiving the standard treatment of covid infection. 2020. \u003ca href=\"http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46392\"\u003ehttp://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46392\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez-Medina E. Efficacy of Ivermectin in Adult Patients With Early Stages of covid-19 (EPIC Trial). 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04405843\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04405843\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a Funegra P. Randomized Phase IIA Clinical Trial to Evaluate the Efficacy of Ivermectin to Obtain Negative PCR Results in Patients With Early Phase covid-19 (SAINT-PERU). 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04635943\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04635943\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eOkasha K. Ivermectin and Nitazoxanide Combination Therapy for covid-19. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04360356\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04360356\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eOkasha K. Ivermectin Nasal Spray for covid19 Patients. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04510233\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04510233\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eRathi S. Study to efficacy of Ivermectin in patients of covid-19. 2020. \u003ca href=\"http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43728\"\u003ehttp://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43728\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003ePathak R. Effectiveness of Ivermectin in preventing development of symptomatic Covid-19 among primary contacts of newly diagnosed Covid-19 positive patients at a tertiary care hospital in North India - an interventional study. 2020. \u003ca href=\"http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46676\"\u003ehttp://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46676\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003ePrakash A. 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Antiviral effect of high-dose ivermectin in adults with covid-19: a pilot randomised,controlled, open label, multicentre trial. \u003cem\u003eResearchGate\u003c/em\u003e 2020.\u003c/li\u003e\n\u003cli\u003eMahmud R. Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04523831\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04523831\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eNiaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult covid-19 patients: A randomized multi-centre clinical trial. \u003cem\u003eRes Square\u003c/em\u003e 2020.\u003c/li\u003e\n\u003cli\u003eRavikirti, Ranjini R, Chandrima P, et al. Ivermectin as a potential treatment for mild to moderate covid-19 \u0026ndash; A double blind randomized placebo-controlled trial. \u003cem\u003emedRxiv\u003c/em\u003e 2021.\u003c/li\u003e\n\u003cli\u003eMohan A. Randomised Controlled Trial of Ivermectin in hospitalised patients with covid19. 2020. \u003ca href=\"http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=44196\"\u003ehttp://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=44196\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eRezai M. Effectiveness of Ivermectin in the Treatment of Coronavirus Infection in Patients admitted to Educational Hospitals of Mazandaran in 2020. 2020. \u003ca href=\"https://en.irct.ir/trial/49174\"\u003ehttps://en.irct.ir/trial/49174\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eRaad H. In vivo use of ivermectin (IVR) for treatment for corona virus infected patients (covid-19): a randomized controlled trial. 2021. \u003ca href=\"http://www.chictr.org.cn/showproj.aspx?proj=54707\"\u003ehttp://www.chictr.org.cn/showproj.aspx?proj=54707\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eSchwartz E. Ivermectin vs. Placebo for the Treatment of Patients With Mild to Moderate covid-19. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04429711\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04429711\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eOkumus N. Ivermectin for Severe covid-19 Management. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04646109\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04646109\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eGuzzo C, Furtek C, Porras AC, C. Tipping, R. Clineschmidt, C. Sciberras, D. Hsieh, J., Lasseter K. Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects. \u003cem\u003eJournal of Clinical Pharmacology\u003c/em\u003e 2002; \u003cstrong\u003e42\u003c/strong\u003e(10): 1122-33.\u003c/li\u003e\n\u003cli\u003eClancy R. covid-19: A realistic approach to community management. 2021. \u003ca href=\"https://quadrant.org.au/opinion/qed/2021/01/covid-19-a-realistic-approach-to-community-management/\"\u003ehttps://quadrant.org.au/opinion/qed/2021/01/covid-19-a-realistic-approach-to-community-management/\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Developing global norms for sharing data and results during public health emergencies. 2015. \u003ca href=\"https://www.who.int/medicines/ebola-treatment/blueprint_phe_data-share-results/en/\"\u003ehttps://www.who.int/medicines/ebola-treatment/blueprint_phe_data-share-results/en/\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eCastañeda-Sabogal A, Chambergo-Michilot D, Toro-Huamanchumo CJ, Silva-Rengifo C, Gonzales Z, Barboza JJ. Outcomes of Ivermectin in the treatment of covid-19: a systematic review and meta-analysis. \u003cem\u003emedRxiv\u003c/em\u003e 2021.\u003c/li\u003e\n\u003cli\u003eShea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. \u003cem\u003eBMJ\u003c/em\u003e 2017; \u003cstrong\u003e358\u003c/strong\u003e(j4008).\u003c/li\u003e\n\u003cli\u003eFesler ML, Stricker RB. Pre-exposure prophylaxis for covid-19 in pregnant women. \u003cem\u003eInt J Gen Med\u003c/em\u003e 2021; \u003cstrong\u003e14\u003c/strong\u003e: 279-84.\u003c/li\u003e\n\u003cli\u003eStricker RB, Fesler ML. Flattening the Risk: Pre-Exposure Prophylaxis for COVID-19. \u003cem\u003eInfection \u0026amp; Drug Resistance\u003c/em\u003e 2020; \u003cstrong\u003e13\u003c/strong\u003e: 3689-94.\u003c/li\u003e\n\u003cli\u003eChesler DL. Letter to Dr Bray at the National Institutes of Health. Personal communication; 2021.\u003c/li\u003e\n\u003cli\u003eChamie J. Real-World Evidence: The Case of Peru. Causality between Ivermectin and COVID-19 Infection Fatality Rate. ResearchGate; 2020. \u003ca href=\"https://www.researchgate.net/publication/344469305\"\u003ehttps://www.researchgate.net/publication/344469305\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eChamie-Quintero J, Hibberd J, Scheim DE. Covid-19 case fatalities and total deaths with and without ivermectin treatment in different states in Peru. \u003cem\u003eOpen Science Foundation\u003c/em\u003e 2021.\u003c/li\u003e\n\u003cli\u003eGRADE-DECIDE. The DECIDE Project. 2016. \u003ca href=\"http://www.decide-collaboration.eu/\"\u003ehttp://www.decide-collaboration.eu/\u003c/a\u003e. (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eRoguski J. Ivermectin. unknown date. \u003ca href=\"https://www.thecompleteguidetohealth.com/Ivermectin.html\"\u003ehttps://www.thecompleteguidetohealth.com/Ivermectin.html#\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eMinisterio de Salud y Deportes. Ministry of Health authorizes the use of ivermectin against COVID-19 under protocol. 2020. \u003ca href=\"https://www.minsalud.gob.bo/4157-ministerio-de-salud-autoriza-uso-de-ivermectina-contra-el-covid-19-bajo-protocolo\"\u003ehttps://www.minsalud.gob.bo/4157-ministerio-de-salud-autoriza-uso-de-ivermectina-contra-el-covid-19-bajo-protocolo\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eDespacho de Comunicaciones y Estrategia Presidencial. Coronavirus COVID-19 In Honduras. 2021. \u003ca href=\"https://covid19honduras.org/\"\u003ehttps://covid19honduras.org/\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eTrialSiteNews. Slovakia Becomes the First EU Nation to Formally Approve Ivermectin for Both Prophylaxis and Treatment for COVID-19 Patients. 2021. \u003ca href=\"https://trialsitenews.com/slovakia-becomes-the-first-eu-nation-to-formally-approve-ivermectin-for-both-prophylaxis-and-treatment-for-covid-19-patients/\"\u003ehttps://trialsitenews.com/slovakia-becomes-the-first-eu-nation-to-formally-approve-ivermectin-for-both-prophylaxis-and-treatment-for-covid-19-patients/\u003c/a\u003e (accessed February 2021).\u003c/li\u003e\n\u003cli\u003eChaccour C, Casellas A, Matteo A, et al. Effectiveness of Ivermectin in SARS-CoV-2/covid-19 Patients. \u003cem\u003eInternational Journal of Sciences\u003c/em\u003e 2020.\u003c/li\u003e\n\u003cli\u003eChowdhury ATMM, Shahbaz M, Karim R, et a. Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on covid19 patients. \u003cem\u003eRes Square\u003c/em\u003e 2020.\u003c/li\u003e\n\u003cli\u003eHashim HA, Maulood MF, Rasheed AM, et al. Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating covid-19 patients in Baghdad, Iraq. \u003cem\u003emedRxiv\u003c/em\u003e 2020.\u003c/li\u003e\n\u003cli\u003ePetkov S. Multicenter, randomized, double-blind, placebo-controlled study investigating efficacy, safety and tolerability of ivermectin HUVE-19 in patients with proven SARS-CoV-2 infection (covid-19) and manifested clinical symptoms. 2021. \u003ca href=\"https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002091-12/BG\"\u003ehttps://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002091-12/BG\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003ePodder CS, Chowdhury N, Mohim IS, Haque W. Outcome of ivermectin treated mild to moderate covid-19 cases: a single-centre, open-label, randomised controlled study. \u003cem\u003eIMC Journal of Medical Science\u003c/em\u003e 2020; \u003cstrong\u003e14\u003c/strong\u003e(2): 002.\u003c/li\u003e\n\u003cli\u003eChala RE. Prophylaxis Covid-19 in Healthcare Agents by Intensive Treatment With Ivermectin and Iota-carrageenan (Ivercar-Tuc). 2021. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04701710\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04701710\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eShouman W. Use of Ivermectin as a Prophylactic Option in Asymptomatic Family Close Contact for Patient with Covid-19. 2020. \u003ca href=\"https://clinicaltrials.gov/ct2/show/NCT04422561\"\u003ehttps://clinicaltrials.gov/ct2/show/NCT04422561\u003c/a\u003e (accessed January 2021).\u003c/li\u003e\n\u003cli\u003eCampbell M, McKenzie JE, Sowden A, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. \u003cem\u003eBMJ\u003c/em\u003e 2020; \u003cstrong\u003e16\u003c/strong\u003e(368): l6890.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, table 4 docx is only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ivermectin, prophylaxis, prevention treatment, covid-19, SARS-CoV-2","lastPublishedDoi":"10.21203/rs.3.rs-317485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-317485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eRe-purposed medicines may have role in combating the SARS-CoV-2 virus. The antiparasitic medicine ivermectin, which has anti-viral and anti-inflammatory properties, has been tested in numerous clinical trials with promising results.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eWe assessed the efficacy of ivermectin treatment and/or prophylaxis among people with, or at high risk of covid-19 infection. We searched bibliographic databases up to February 2021 and two review authors sifted for studies, extracted data and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using GRADE approach.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFindings \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTwenty-one RCTs involving 2741 participants met review inclusion. Meta-analysis of 13 trials found ivermectin reduced risk of death compared with no ivermectin (average Risk Ratio 0.32, 95% confidence interval (CI) 0.14 to 0.72; n=1892; I\u003csup\u003e2\u003c/sup\u003e=57%; low to moderate-certainty evidence. Low-certainty evidence found ivermectin prophylaxis reduced covid-19 infection by an average 86% (95% CI 79% to 91%). Secondary outcomes provided very-low or low certainty evidence. Low certainty evidence suggests that that there may be no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ favoured ivermectin use. Severe adverse events were rare and evidence of no difference was assessed as low to very low-certainty. Evidence on other secondary outcomes was very low certainty.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInterpretation \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eLow to moderate-certainty evidence suggests reductions in covid-19 deaths and infections may be possible by using ivermectin. Employing ivermectin early on may reduce the number of people progressing to severe disease. The apparent safety and low cost suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally.\u003c/p\u003e","manuscriptTitle":"Ivermectin for Prevention and Treatment of COVID-19\u0026nbsp;Infection: a Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-18 22:56:13","doi":"10.21203/rs.3.rs-317485/v1","editorialEvents":[{"type":"communityComments","content":5}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"aa8d81e0-efb0-4aef-acbb-da51d97e1e07","owner":[],"postedDate":"March 18th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":3050176,"name":"Health Economics \u0026 Outcomes Research"},{"id":3050177,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2021-06-21T12:56:31+00:00","versionOfRecord":{"articleIdentity":"rs-317485","link":"https://doi.org/10.1097/MJT.0000000000001402","journal":{"identity":"american-journal-of-therapeutics","isVorOnly":true,"title":"American Journal of Therapeutics"},"publishedOn":"2021-06-17 13:00:00","publishedOnDateReadable":"June 17th, 2021"},"versionCreatedAt":"2021-03-18 22:56:13","video":"","vorDoi":"10.1097/MJT.0000000000001402","vorDoiUrl":"https://doi.org/10.1097/MJT.0000000000001402","workflowStages":[]},"version":"v1","identity":"rs-317485","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-317485","identity":"rs-317485","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}