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

doi:10.21203/rs.3.rs-317485/v1

Download PDF

Research

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

https://doi.org/10.21203/rs.3.rs-317485/v1

This work is licensed under a CC BY 4.0 License

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

Background

Re-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.

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; I²=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

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.

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 EC₅₀ 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 studies¹⁹. 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 mechanism²⁰ 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 globally⁶. 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 days²² (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

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 guidance²⁴ 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

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 I² statistic (I² ≥ 60% was considered substantial heterogeneity),²⁷ by a formal statistical test to indicate statistically significant heterogeneity²⁸ 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 R³¹ through an interface³² 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 trials³⁴ 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.

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 2020¹⁰⁰	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 2020¹⁰¹	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 2020²³	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 2020¹²⁷	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 2020¹²⁸	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 2020⁵⁰	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 2021¹⁰²	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 2020¹²⁹	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 2020¹⁰³	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 2020¹⁰⁴	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 2021¹⁰⁷	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 2020¹⁰⁵	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 2021¹¹¹	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 2021¹³⁰	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 2020¹³¹	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 2021¹⁰⁹	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 2021¹⁰⁶	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 2020¹⁰⁸	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 2021¹¹⁰	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 2021¹³²	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 2020⁵⁰	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 2020¹³³	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; I² = 57%; risk of death 2.5% versus 9.1% among hospitalised patients in this analysis, respectively (Summary of Findings (SoF) Table 2a and Fig. 3). Heterogeneity was explained by the exclusion of one trial¹⁰² in a sensitivity analysis (average RR 0.25, 95% CI 0.13 to 0.48, n = 1725, I² = 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, I² = 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, I² = 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 2a 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)	Low¹
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 2a). 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; I² = 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 trial¹⁰⁴ had oesophagitis (this is a known side effect of doxycycline, which was co-administered with ivermectin in this trial); one patient in Krolewiecki et al¹⁰³ had hyponatraemia (this trial used high-dose ivermectin for 5 days); and two patients in a study from Turkey¹¹¹ 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 2a).

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 2b; Fig. 11).

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 source⁵ 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.

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

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. We also thank Isabella Rushforth for her voluntary assistance with the preparation of the reference lists.

We 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.

Horby P, Lim WS, Emberson J, et al. Dexamethasone in hospitalised patients with Covid-19 - preliminary report. medRxiv 2020.
Barrows NJ, Campos RK, Powell ST, et al. A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. Cell Host & Microbe 2016; 20(2): 259-70.
Conterno LO, Turchi MD, Corrêa I, Monteiro de Barros Almeida RA. Anthelmintic drugs for treating ascariasis. Cochrane Database of Systematic Reviews 2020; 1(4).
World Health Organization. 21st Model List of Essential Medicines. Geneva, Switzerland, 2019.
Nicolas P, Maia MF, Bassat Q, et al. Safety of oral ivermectin during pregnancy: a systematic review and meta-analysis. Lancet Global Health 2020; 8(1): e92-e100.
Banerjee K, Nandy M, Dalai CK, Ahmed SN. The Battle against covid 19 Pandemic: What we Need to Know Before we "Test Fire" Ivermectin. Drug Res (Stuttg) 2020; 70(8): 337-40.
Navarro M, Camprubí D, Requena-Méndez A, et al. Safety of high-dose ivermectin: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy 2020; 75(4): 827-34.
Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. 2016.
Kory P, Meduri GU, Iglesias J, et al. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of covid-19. OSF, 2020; Preprint (wx3zn).
Hill A, Abdulamir A, Ahmed S, et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection, 19 Research Square 2021; PREPRINT (Version 1).
National Institute of Health. The covid-19 treatment guidelines panel's statement on the use of ivermectin for the treatment of covid-19. USA; 2021.
Heidary H, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiotics 2020; 73: 593-602.
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178: 104787.
Jans DA, Wagstaff KM. Ivermectin as a broad-spectrum host-directed anti-viral: The real deal? Cells 2020; 9(2100).
Schmith VD, Zhou J, Lohmer LRL. The approved dose of ivermectin alone is not the ideal dose for the treatment of Covid-19. Clin Pharmacol and Therapeutics 2020.
Anand K, Ziebuhr J, Wadhwani P, Mesters J R, Hilgenfeld R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 2003; 300: 1763-7.
Mody V, Ho J, Wills S, et al. Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents. Nature: Communications Biology 2021; 4(1): 93.
DiNicolantonio JJ, Barroso J, McCarty. Ivermectin may be a clinically useful anti-inflammatory agent for late-stage covid-19. Open Heart 2020; 7: e001350-e.
Lehrer A, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 Spike Receptor Binding Domain attached to ACE2. In vivo 2020; 34(5): 3023-26.
Scheim D. From cold to killer: How SARS-CoV-2 evolved without hemagglutinin esterase to agglutinate, then clot blood Cells in pulmonary and systemic microvasculature. SSRN 2020.
WHO Expert Committee on the Selection and Use of Essential Medicines. Application for inclusion of ivermectin on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) for the indication of Scabies, 2018.
Vora A, Arora VK, Behera D, Tripathy S. White paper on Ivermectin as a potential therapy for covid-19. Indian journal of tuberculosis 2020; 67(3): 448-51.
Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect of early treatment with ivermectin on viralload, symptoms and humoral response in patientswith mild covid-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. Research Square 2020; PREPRINT Version 1.
Aluko P, Graybill E, Craig D, et al. Chapter 20: Economic evidence. In: Higgins J, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions (version 61): Cochrane; 2020.
Bryant A, Lawrie T, Dowsell T, et al. Ivermectin for prevention and treatment of covid-19 (Protocol). The Evidence-Based Medical Consultancy Ltd; 2021. https://tinyurl.com/cx7pnaxa
Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions Version 6.0 Cochrane; 2019.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414): 557-60.
Deeks JJ, Altman DG, Bradburn MJ. Chapter 15: Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. Systematic Reviews in Health Care: Meta-Analysis in Context. London: BMJ Publication Group; 2001.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7: 177-88.
RevMan. Review Manager 5. The Cochrane Collaboration; 2020.
R: A language and environment for statistical computing. R Foundation for Statistical Computing V, Austria. R Foundation for Statistical Computing. Vienna, Austria.; 2021.
Owen RK, Bradbury N, Xin Y, Cooper N, Sutton A. MetaInsight: An interactive web-based tool for analyzing, interrogating, and visualizing network meta-analyses using R-shiny and netmeta. Res Syn Meth 2019; 10: 569-81.
Rücker G, Schwarzer G, Krahn U, König J. Network Meta-Analysis using Frequentist Methods. 2017.
Efthimiou O. Practical guide to the meta-analysis of rare events. Evid Based Mental Health 2018; 21(2): 72-6.
Stijnen T, Hamza TH, Ozdemir P. Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. Stat Med 2010; 29: 3046–67.
Chen Y, Chu H, Luo S, Nie LC, S. Bayesian analysis on meta-analysis of casecontrol studies accounting for within-study correlation. Stat Methods Med Res 2015; 24: 836–55.
Rücker G, Schwarzer G, Carpenter J, Olkin I. Why add anything to nothing? The arcsine difference as a measure of treatment effect in meta-analysis with zero cells. Stat Med 2009; 28: 721–38.
Tian L, Cai T, Pfeffer MA, Piankov NC, PY. Wei, LJ. . Exact and efficient inference procedure for meta-analysis and its application to the analysis of independent 2 x 2 tables with all available data but without artificial continuity correction. Biostatistics 2009; 10: 275–81.
Cai T, Parast L, Ryan L. Meta-analysis for rare events. Stat Med 2010; 29: 2078–89.
Schünemann H, Vist G, Higgins J, et al. Chapter 15: Interpreting results and drawing conclusions. In: Higgins J, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions version 61 (updated September 2020): Cochrane; 2020.
Cochrane Effective Practice and Organisation of Care (EPOC). EPOC resources for review authors 2017. www.epoc.cochrane.org/epoc-specific-resources-review-authors (accessed February 1 2021).
Alam MT, Murshe R, Bhiuyan E, Saber S, Alam RF, Robin RC. A Case Series of 100 covid-19 Positive Patients Treatedwith Combination of Ivermectin and Doxycycline. Journal of Bangladesh College of Physicians and Surgeons 2020; 38: 10-5.
Behera P, Patro BK, Singh AK, et al. Role of ivermectin in the prevention of covid-19 infection among healthcare workers in India: A matched case-control study. medRxiv 2020.
Bernigaud C, Guillemot D, Ahmed-Belkacem A, et al. Ivermectin benefit: from scabies to covid-19, an example of serendipity. Annales de Dermatologie et de Vénéréologie 2020; 147(12): A194-A.
Budhiraja S, Soni A, Jha V, et al. Clinical Profile of First 1000 covid-19 Cases Admitted at Tertiary Care Hospitals and the Correlates of their Mortality: An Indian Experience. medRxiv 2020.
Cadegiani FA, Goren A, Wambier CG, McCoy J. Early covid-19 Therapy with Azithromycin Plus Nitazoxanide, Ivermectin or Hydroxychloroquine in Outpatient Settings Significantly Reduced SymptomsCompared to Known Outcomes in Untreated Patients. medRxiv 2020.
Camprubí D, Almuedo-Riera A, Martí-Soler H, et al. Lack of efficacy of standard doses of ivermectin in severe covid-19 patients. PloS one 2020; 15(11): e0242184.
Carvallo H, Hirsch R, Farinella M. Safety and efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against covid 19. medRxiv 2020.
Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter J-J. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019. CHEST 2021; 159(1): 85-92.
Elgazzar A, Eltaweel A, Youssef SA, Hany B, Hafez M, Moussa H. Efficacy and Safety of ivermectin for Treatment and prophylaxis of covid-19 Pandemic. Res Square 2020.
Espitia-Hernandez G, Munguia L, Diaz-Chiguer D, Lopez-Elizalde R, Jimenez-Ponce F. Effects of Ivermectin-azithromycin-cholecalciferol combined therapy on COVID-19 infected patients: A proof of concept study. Biomedical Research 2020; 31(5).
Gorial FI, Mashhadani S, Sayaly HM, et al. Effectiveness of Ivermectin as add-on Therapy in covid-19 Management (Pilot Trial). medRxiv 2020.
Hellwig MD, Maia A. A covid-19 Prophylaxis? Lower incidence associated withprophylactic administration of Ivermectin. International Journal of Antimicrobial Agent 2021; 57(1).
Khan M, Khan M, Debnath C, et al. Ivermectin Treatment May Improve the Prognosis of Patients With covid-19. Archivos de Bronconeumología 2020; 56(12): 832-.
Morgenstern J, Redondo JN, De León A, et al. The use of compassionate ivermectin in the management of symptomatic outpatients and hospitalized patients with clinical diagnosis of covid-19 at the medical center bournigal and the medical center punta cana, rescue group, dominican republic. medRxiv 2020.
Portmann-Baracco A, Bryce-Alberti M, Accinelli RA. Antiviral and anti-inflammatory properties ofivermectin and its potential use in Covid-19. Arch Bronconeumol 2020; 56: 831.
Shokati Z. A randomized clinical trial study, comparison of the therapeutic effects of Ivermectin, Kaletra and Chloroquine with Kaletra and Chloroquine in the treatment of patients with coronavirus [Protocol]. 2019. https://en.irct.ir/trial/48444 (accessed January 2021).
Spoorthi V, Sasank S. Utility of Ivermectin and Doxycycline combination for the treatment of SARS- CoV-2. International Archives of Integrated Medicine 2020; 7(10): 177-82.
Abd-Elsalam S. The Efficacy of Ivermectin and Nitazoxanide in covid-19 Treatment. 2020. https://clinicaltrials.gov/ct2/show/NCT04351347 (accessed January 2021).
Abd-Elsalam S. Ivermectin as a Novel Therapy in covid-19 Treatment. 2020. https://clinicaltrials.gov/ct2/show/NCT04403555 (accessed January 2021).
Alam MT. Safety and Efficacy of Ivermectin and Doxycycline in Treatment of Covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04551755 (accessed January 2021).
Arnold S. Novel Agents for Treatment of High-risk covid-19 Positive Patients. 2020. https://clinicaltrials.gov/ct2/show/NCT04374019 (accessed January 2021).
Centenario Hospital Miguel Hidalgo. Hydroxychloroquine and Ivermectin for the Treatment of covid-19 Infection. 2020. https://clinicaltrials.gov/ct2/show/NCT04391127 (accessed January 2021).
Ashraf S. Efficacy of Subcutaneous Ivermectin With or Without Zinc and Nigella Sativa in covid-19 Patients (SINZ-covid-PK). 2020. https://clinicaltrials.gov/ct2/show/NCT04472585 (accessed January 2021).
Ataee Z. Evaluation of the effect of Ivermectin in hospitalized patients with covid-19 in Imam Reza Hospital in Mashhad. 2020. https://en.irct.ir/trial/49180 (accessed January 2021).
Bisoffi Z. COVidIVERmectin: Ivermectin for Treatment of Covid-19 (COVER). 2020. https://clinicaltrials.gov/ct2/show/NCT04438850 (accessed January 2021).
ProgenaBiom. Trial of Combination Therapy to Treat covid-19 Infection. 2020. https://clinicaltrials.gov/ct2/show/NCT04482686 (accessed January 2021).
Perez A. Efficacy, Safety and Tolerability of Ivermectin in Subjects Infected With SARS-CoV-2 With or Without Symptoms (SILVERBULLET). 2020. https://clinicaltrials.gov/ct2/show/NCT04407507 (accessed January 2021).
Echeverri E. Effectiveness and Safety of Ivermectin for the Prevention of Covid-19 Infection in Colombian Health Personnel (IveprofCovid19). 2020. https://clinicaltrials.gov/ct2/show/NCT04527211 (accessed January 2021).
Elalfy H. New Antiviral Drugs for Treatment of covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04392427 (accessed January 2021).
Exman P. Early Treatment With Ivermectin and LosarTAN for Cancer Patients With covid-19 Infection (TITAN). 2020. https://clinicaltrials.gov/ct2/show/NCT04447235 (accessed January 2021).
Fathalipour M. The efficacy and safety of Ivermectin in patients with covid-19: a randomized clinical trial. 2020. https://www.irct.ir/trial/49501 (accessed January 2021).
George B. A Phase IIB open label randomized controlled trial to evaluate the efficacy and safety of Ivermectin in reducing viral loads in patients with hematological disorders who are admitted with covid 19 infection. 2020. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43449 (accessed January 2021).
Gheibi N. Dose-Finding study of Ivermectin treatment on patients infected with Covid-19:A clinical trial. 2020. https://en.irct.ir/trial/47012 (accessed January 2021).
Gheibi N. Determination the therapeutic effect of Ivermectin and Sovodak on patients infected with covid-19: A clinical trial. 2020. https://en.irct.ir/trial/51007 (accessed January 2021).
Temple University. Outpatient Use of Ivermectin in covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04530474 (accessed January 2021).
Pott Junior H. A Study to Compare the Efficacy and Safety of Different Doses of Ivermectin for covid-19 (IFORS). 2020. https://clinicaltrials.gov/ct2/show/NCT04431466 (accessed January 2021).
Kamal E. Ivermectin In Treatment of covid 19 Patients. 2020. https://clinicaltrials.gov/ct2/show/NCT04425707 (accessed January 2021).
Saibannavar 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. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46392 (accessed January 2021).
López-Medina E. Efficacy of Ivermectin in Adult Patients With Early Stages of covid-19 (EPIC Trial). 2020. https://clinicaltrials.gov/ct2/show/NCT04405843 (accessed January 2021).
García 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. https://clinicaltrials.gov/ct2/show/NCT04635943 (accessed January 2021).
Okasha K. Ivermectin and Nitazoxanide Combination Therapy for covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04360356 (accessed January 2021).
Okasha K. Ivermectin Nasal Spray for covid19 Patients. 2020. https://clinicaltrials.gov/ct2/show/NCT04510233 (accessed January 2021).
Rathi S. Study to efficacy of Ivermectin in patients of covid-19. 2020. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43728 (accessed January 2021).
Pathak 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. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46676 (accessed January 2021).
Prakash A. A clinical Trial to Study the Effects of Hydroxychloroquine, Ciclesonide and Ivermectin in treatment of moderate covid-19 illness. 2020. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43364 (accessed January 2021).
Ochoa-Jaramillo F. Ivermectin in Adults With Severe covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04602507 (accessed January 2021).
Saxena R. Assessment of response of ivermectin on virological clearance in covid 19 patients. 2020. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=46873 (accessed January 2021).
Hidalgo C. Pragmatic study "CORIVER": Ivermectin as antiviral treatment for patients infected by SARS-COV2 (covid-19). 2020. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001971-33/ES (accessed January 2021).
Shahbazi F. Evaluation effects of the standard regimen along with ivermectin on treatment of corona virus type 2 pneumonia. 2020. https://www.irct.ir/trial/49280 (accessed January 2021).
Stein M. A randomized double-blind placebo-controlled trial of oral ivermectin for outpatient treatment of those at high risk for hospitalization due to covid-19. 2020. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380506&isReview=true (accessed January 2021).
Suputtamongkol Y. Ivermectin vs Combined Hydroxychloroquine and Antiretroviral Drugs (ART) Among Asymptomatic covid-19 Infection (IDRA-covid19). 2020. https://clinicaltrials.gov/ct2/show/NCT04435587 (accessed January 2021).
Fundació Assistencial Mútua Terrassa. Randomised clinical trial of ivermectin for treatment and prophylaxis of covid-19. 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-001994-66 (accessed January 2021).
Ghandali M. Evaluating the efficacy and safety of Ivermectin in the treatment of covid-19 patients: A double-blind randomized controlled trial, phase II. 2020. https://en.irct.ir/trial/49935 (accessed January 2021).
Yamaoka K. Placebo-controlled randomized, double-blind (evaluator, patient) multicenter, parallel-group comparative study investigating the efficacy and safety of ivermectin in patients with covid-19. 2020. https://jrct.niph.go.jp/en-latest-detail/jRCT2031200120 (accessed January 2021).
Zendehdel A. Evaluation of the effect of oral Ivermectin on the outcome of patients with covid-19 and compare it with the effect of conucntional therapics in patients admitted to Ziaeian, Baharloo, Imam Khomeini in the spring and summer 2020. 2020. https://en.irct.ir/trial/50305 (accessed January 2021).
Instituto de Cardiología de Corrientes. Ivermectin to Prevent Hospitalizations in covid-19 (IVERCORcovid19). 2020. https://clinicaltrials.gov/ct2/show/NCT04529525 (accessed January 2021).
Asghar A. Efficacy of Ivermectin in COVID-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04392713 (accessed January 2021).
National University Hospital Singapore. A Preventive Treatment for Migrant Workers at High-risk of Covid-19. 2020. https://clinicaltrials.gov/ct2/show/NCT04446104 (accessed January 2021).
Ahmed S, Karim MM, Ross AG, et al. A five day course of ivermectin for the treatment of covid-19 may reduce the duration of illness. Int J Infect Diseases 2020.
Babaola OE, Bode CO, Ajayi AA, et al. Ivermectin shows clinical benefits in mild to moderate covid19: A randomised controlled double blind dose response study in Lagos. medRxiv 2021.
Fonseca. The effect of chloroquine, hydroxychloroquine OR ivermectin in patients with severe manifestations of coronavirus. 2021. https://ensaiosclinicos.gov.br/rg/RBR-8h7q82/
Krolewiecki A, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso D. Antiviral effect of high-dose ivermectin in adults with covid-19: a pilot randomised,controlled, open label, multicentre trial. ResearchGate 2020.
Mahmud R. Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. 2020. https://clinicaltrials.gov/ct2/show/NCT04523831 (accessed January 2021).
Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult covid-19 patients: A randomized multi-centre clinical trial. Res Square 2020.
Ravikirti, Ranjini R, Chandrima P, et al. Ivermectin as a potential treatment for mild to moderate covid-19 – A double blind randomized placebo-controlled trial. medRxiv 2021.
Mohan A. Randomised Controlled Trial of Ivermectin in hospitalised patients with covid19. 2020. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=44196 (accessed January 2021).
Rezai M. Effectiveness of Ivermectin in the Treatment of Coronavirus Infection in Patients admitted to Educational Hospitals of Mazandaran in 2020. 2020. https://en.irct.ir/trial/49174 (accessed January 2021).
Raad H. 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.

Due to technical limitations, table 4 docx is only available as a download in the Supplemental Files section.

Download PDF

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

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

Status:

Journal Publication

Version 1

Abstract

Figures

Research In Context

Introduction

Methods

Search strategy and selection criteria

Data analysis

Role of funding source

Results

Discussion

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1