Ivermectin as a Treatment Modality in COVID-19 Patients: A Systematic Review and Meta-Analysis of Up-To-Date RCTs

Abstract

The objective of this systematic review and meta-analysis is to assess the efficacy and safety of Ivermectin compared to placebo or standard of care for the treatment and prevention of COVID-19 disease. Literature search was carried out in PubMed, Scopus, and google scholar. Clinical trial registries (clinical trail.gov) and preprint servers (Medrxiv) were also searched for registered and preprint data respectively. Mortality, Clinical recovery, Clinical worsening, duration of hospital stay, and adverse events were considered as primary outcomes while viral clearance is considered as a secondary outcome. Revised Cochrane risk of bias assessment tool was used to assess the risk of bias. Random effect meta-analysis was carried out for all the outcomes. GRADE was used to rate the certainty of evidence. A total of 19 RCTs with 1111 patients were included in the analysis. Ivermectin use did was not associated with a reduction in the incidence of mortality, duration of hospitalization, clinical worsening, and incidence of adverse events nor it was associated with an increase in clinical improvement compared to either placebo or standard of care. Ivermectin also did not show any reduction in viral clearance compared to both placebo or standard of care and this was associated with substantial inconsistency. The overall certainty of the evidence was very low to low. Based on the very low to low certainty of the evidence, we consider Ivermectin ineffective in the management of COVID-19 disease, both as treatment and prophylaxis.

INTRODUCTION

The lack of standard treatment for the management of coronavirus disease 2019 (COVID-19) fostered medical research to explore multiple treatment options and research modalities.[1] Drug repurposing, also called drug repositioning, is one area where active research is being carried out to discover effective treatment options for the management of COVID-19.[2]

As a result of it, several drugs like hydroxychloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and so on were identified as potential drugs to treat patients with COVID-19.[2,3]

Ivermectin, an anti-parasitic drug approved by Food and Drug Association, showed promising results by demonstrating in vitro antiviral effects against COVID-19 and warranted further research.[4] In the light of this finding, numerous clinical trials were registered to investigate the overall efficacy of ivermectin in the human population. Also, the limited clinical evidence existing at that point promoted the use of ivermectin in terms of reduced mortality and improved symptoms.[5] However, with the rate at which COVID-19 is spreading by evolving into different strains, there is a great need for new and updated clinical evidence to re-evaluate the current and potential therapeutic options.[6]

Researchers turned toward meta-analysis to combine all the newer evidence emerging from registered clinical trials and other interventional studies and draw conclusive evidence regarding the efficacy of ivermectin in COVID-19. The findings of the initial systematic review and meta-analysis concluded that ivermectin had a significant role in COVID-19 patients when it comes to survival, clinical recovery, and viral clearance.[7,8,9,10] Conversely, the finding of other meta-analyses suggests that ivermectin was not significant in reducing time to viral clearance, duration of hospitalization, and mortality.[11,12]

Unfortunately, the reliability of the findings in all the above analyses is undermined by clinical and methodological limitations. One important limitation is the considerable heterogeneity in the population receiving ivermectin in the studies included in the meta-analysis. Studies with different comparator groups (placebo, standard of care, and active comparators) and studies that received co-interventions (Doxycycline, Azithromycin, etc.,) along with ivermectin in the interventional group, when incorporated into a single analysis, may confound the overall assessment and make it difficult to determine the exact effect of ivermectin in COVID-19 disease.[13] Also, the potential risk of bias associated with individual studies and their implications on the overall findings of the meta-analysis[14] needs to be assessed appropriately before concluding the role of ivermectin in COVID-19.

Apart from clinical and methodological limitations, many randomized controlled trials (RCTs) included in the above-mentioned meta-analyses had a small sample size which again makes it difficult to assess the true effect of ivermectin in patients with COVID-19. Large RCTs like I TECH trail,[15] TOGETHER Trial,[16] and ACTIVE-6 Trial[17] had sufficient sample that can enhance the strength of findings of meta-analyses, but not many meta-analyses included all these trails.

This systematic review and meta-analysis aimed to determine the overall efficacy and safety of ivermectin for the prevention and treatment of COVID-19 by addressing the limitations mentioned above.

METHODS

This systematic review and meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) statement.[18]

Eligibility criteria

Randomized control trials (RCTs) that compared ivermectin to placebo or standard of care (SOC) in patients with confirmed COVID-19 were included in the analysis. RCTs that compared ivermectin to placebo or standard of care in participants who were at high risk of getting the infection were included in the assessment of the prophylactic effect of ivermectin. In both cases, if any co-interventions or active comparators are considered as the standard of care, then studies are included only if the standard of care is similar and comparable between the interventional and control groups, that is, ivermectin with SOC versus SOC alone.

The selection of studies was regardless of age, gender, severity of infection, and clinical trial setting (in-patient and out-patients). Also, trials were included irrespective of their publication’s status (peer-reviewed, in press, or preprint). All the dosing regimens of ivermectin used in RCTs were considered for the analysis. Studies that compared ivermectin to active controls like HCQ, lopinavir/ritonavir, and so on, which have no proven efficacy against COVID-19, were excluded.

Search strategy

A comprehensive literature search was carried out in electronic databases like PubMed, Scopus, and Google Scholar. Clinical trial registries (clinical trail. gov) and preprint servers (MedRxiv) were also searched for registered and preprint data, respectively. The search was limited to articles published from January 2020 to August 2022 in English language. The details of the search terms and strategy were tabulated in Supplementary e Table 1. Additionally, the reference sections of included studies and previous systematic reviews were also thoroughly searched for relevant articles.

e Table 1.

Combination of search terms and search strategy followed

Line Number	Search Phrase	Results
1	(((((((((((((((((((((((((((((((((((COVID 19) OR (COVID-19 Virus Disease)) OR (COVID 19 Virus Disease)) OR (COVID-19 Virus Diseases)) OR (Disease, COVID-19 Virus)) OR (Virus Disease, COVID-19)) OR (COVID-19 Virus Infection)) OR (COVID 19 Virus Infection)) OR (COVID-19 Virus Infections)) OR (Infection, COVID-19 Virus)) OR (Virus Infection, COVID-19)) OR (2019-nCoV Infection)) OR (2019 nCoV Infection)) OR (2019-nCoV Infections)) OR (Infection, 2019-nCoV)) OR (Coronavirus Disease-19)) OR (Coronavirus Disease 19)) OR (2019 Novel Coronavirus Disease)) OR (2019 Novel Coronavirus Infection)) OR (2019-nCoV Disease)) OR (2019 nCoV Disease)) OR (2019-nCoV Diseases)) OR (Disease, 2019-nCoV)) OR (COVID19)) OR (Coronavirus Disease 2019)) OR (Disease 2019, Coronavirus)) OR (SARS Coronavirus 2 Infection)) OR (SARS-CoV-2 Infection)) OR (Infection, SARS-CoV-2)) OR (SARS CoV 2 Infection)) OR (SARS-CoV-2 Infections)) OR (COVID-19 Pandemic)) OR (COVID 19 Pandemic)) OR (COVID-19 Pandemics)) OR (Pandemic, COVID-19))	1,85,540
2	((((((((Ivermectin) OR (Stromectol)) OR (Mectizan)) OR (MK-933)) OR (MK 933)) OR (MK933)) OR (Eqvalan)) OR (Ivomec))	9108
3	1 and 2	686

Study selection

Two authors (D. M and B. R) independently carried out the screening of abstracts and subsequent full-text articles in accordance with the above-mentioned eligibility criteria. Any discrepancies among the authors were resolved by the third author (R. K).

Data extraction

Three authors (D. M, B. R, and A. S) carried out data extraction in duplicate by using a pre-designed data extraction form, and the same was entered into an electronic spreadsheet. Details of the study (author name, year of publication, design), participants (age, gender, co-morbidities, severity of infection, hospitalization status), intervention (ivermectin dose and duration), comparator (placebo, SOC), and outcomes reported were extracted from all the individual studies.

In case of missing or incompletely reported data, we contacted the corresponding author requesting the required information. Any discrepancies during the data extraction were resolved through discussion and consensus with another author (R. K).

Outcome measures

Multiple outcomes were analyzed to assess the use of ivermectin for treatment and prophylaxis of COVID-19. All-cause mortality (up to 28 days), clinical improvement, clinical worsening, duration of hospital stay, and occurrence of adverse events were selected as primary outcomes, while viral clearance was considered as a secondary outcome.

Symptom resolution or improvement was defined by the proportion of patients discharged from the hospital (in-patients) or the proportion of patients whose symptoms were completely resolved (out-patients). Clinical worsening was considered when the patients required invasive or non-invasive mechanical ventilation. For viral clearance, the proportion of patients whose RT-PCR test was negative for COVID-19, anywhere between 7 to 14 days after confirmed infection, were taken into consideration. On the other hand, confirmed COVID-19 infections by RT-PCR test or occurrence of clinical COVID-19 symptoms and adverse events reported were the outcomes selected to assess the use of ivermectin for preventing COVID-19.

Risk of bias

We assessed the overall risk of bias individually for all the outcomes (primary and secondary) included in our analysis rather than rating the whole study and implying the same risk of bias to all the outcomes mentioned in it. Cochrane Risk of Bias 2.0 tool for randomized trials (RoB 2) was used to assess the risk of bias.[19] This tool consists of five domains that assess for the bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of outcome, and bias in the selection of reported results. Based on the algorithm given by RoB 2 tool, the risk of bias in each domain falls under one of three categories: low risk of bias, some concerns of bias, or high risk of bias. The risk of bias for every outcome was assessed in the same categories depending on the risk of bias in all the individual domains. The overall risk of bias in an outcome was considered as low risk when all the domains were rated as low risk, some concerns when one or more domains were rated as some concerns but none of the domains were rated as high risk, and high risk when one or more domains were rated as high risk of bias.

Three authors (D. M, B. R, and A. S) independently assessed the risk of bias in all the studies included in the analysis. Any disagreements were resolved by discussing with another author (R.K).

Data synthesis

Dichotomous outcomes (mortality, clinical improvement, adverse events, clinical worsening, and viral clearance) and continuous outcomes (duration of hospitalization) of treatment effect were analyzed by using Revman version 5. 4. Risk ratios (RRs) were used to express dichotomous outcomes, while continuous outcomes were expressed in terms of mean and standard deviation, both at 95% confidence intervals (CI). Statistical significance was considered when dichotomous outcomes with 95% CI do not cross 1 and when continuous outcomes with 95% CI do not cross 0. The random effects model of meta-analysis was used in all the analyses. In studies where standard deviation was not mentioned and studies in which continuous outcomes were mentioned as median with inter-quartile ranges (IQRs) instead of mean and SD, appropriate methods were used to convert them into the required parameters described in the Cochrane handbook for systematic reviews and interventions.[20]

Statistical heterogeneity among the effect sizes was determined by using I² statistic and Cochrane Q test.[20,21] Statistical heterogeneity is confirmed when the I² statistic value was greater than 40% or the Cochrane Q test P value was less than 0.1.

Sensitivity analysis

Sensitivity analysis was done to test the robustness of the treatment effects obtained in the meta-analysis. Since a lot of questions were raised about the quality of non-peer-reviewed articles that are being published and articles from preprint servers,[22] we decided to exclude those articles in the sensitivity analysis. Also, trials rated as high risk of bias were excluded.

Certainty of evidence

Grading of recommendations, assessment, development, and evaluations (GRADE) approach was used to assess the overall certainty of evidence.[23] Two authors (R. K, A. S) assessed the certainty of evidence and resolved the discrepancies by consensus. Based on the risk of bias, inconsistency, imprecision, indirectness, and publication bias, the certainty of the evidence was rated as high, moderate, low, or very low [Tables 2, 3 and 4 in S2 Index].

Summary of findings: Table 2

Ivermectin compared to Standard of Care for Covid-19
Patient or population: Covid-19 Intervention: Ivermectin Comparison: Standard of Care
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Standard of Care	Risk with Ivermectin
Mortality	36 per 1,000	20 per 1,000 (10 to 39)	RR 0.56 (0.29 to 1.08)	2698 (7 RCTs)	⨁◯◯◯ Very low	The evidence is very uncertain about the effect of ivermectin on mortality.
Clinical Improvement	700 per 1,000	736 per 1,000 (602 to 904)	RR 1.05 (0.86 to 1.29)	1230 (6 RCTs)	⨁◯◯◯ Very low	The evidence suggests that ivermectin results in little to no difference in clinical improvement.
Clinical Worsening	105 per 1,000	50 per 1,000 (21 to 121)	RR 0.48 (0.20 to 1.15)	2486 (5 RCTs)	⨁⨁◯◯ Low	The evidence is very uncertain about the effect of ivermectin on clinical worsening.
Adverse events	213 per 1,000	425 per 1,000 (160 to 1,000)	RR 1.99 (0.75 to 5.29)	2325 (8 RCTs)	⨁◯◯◯ Very low	The evidence is very uncertain about the effect of ivermectin on adverse events.
Viral Clearance	585 per 1,000	1000 per 1,000 (438 to 1,000)	RR 1.99 (0.75 to 5.29)	442 (7 RCTs)	⨁◯◯◯ Very low	The evidence is very uncertain about the effect of ivermectin on viral clearance.

*The risk in the intervention group (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

GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Summary of findings: Table 3

Ivermectin compared to Preventive measures for COVID-19 prophylaxsis
Patient or population: COVID-19 prophylaxsis Intervention: Ivermectin Comparison: Preventive measures
Outcomes	Anticipated absolute effects*(95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Preventive measures	Risk with Ivermectin
Occurence of Covid symptoms	115 per 1,000	33 per 1,000 (7 to 173)	RR 0.29 (0.06 to 1.50)	2174 (2 RCTs)	⨁◯◯◯ Very low	The evidence is very uncertain about the effect of Ivermectin on occurence of Clinical infection.
Adverse events	178 per 1,000	416 per 1,000 (48 to 1,000)	RR 2.34 (0.27 to 20.08)	2051 (2 RCTs)	⨁◯◯◯ Very low	The evidence is very uncertain about the effect of Ivermectin on adverse events.

*The risk in the intervention group (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

GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

RESULTS

Study selection

Figure 1 summarizes the sequential process in which studies were included in our analysis. A total of 845 articles were obtained during the initial search strategy, out of which 767 were excluded after reviewing the titles and abstracts. Full-text articles of the remaining 78 studies were evaluated, and a total of 28 studies[15,16,17,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] were included in the final analysis.

Figure 1.

Preferred reporting items for systematic reviews and Meta-Analysis (PRISMA) flow diagram for included studies in the meta-analysis

Study characteristics

Among the 28 RCTs[15,16,17,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] included in the analysis, 13[17,25,27,29,31,32,34,35,37,38,39,40,48] studies compared ivermectin with placebo, while15[17,25,27,29,32,33,36,37,38] studies compared ivermectin with SOC. 21[15,16,24,25,26,27,29,30,33,35,36,37,38,39,42,43,44,45,46,47,48] studies were published in peer reviewed journals, and the remaining 7[17,28,31,32,34,40,41] studies were taken from preprints. 14[15,16,24,26,28,30,33,40,41,42,43,45,46,47] studies were open-labeled, 13[17,25,27,29,31,32,34,35,36,37,39,44,48] were double-blinded studies, and one was triple-blinded study.[38]

26[15,16,17,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46] studies evaluated the effect of ivermectin in COVID-19 patients, while 2[47,48] studies assessed the role of ivermectin as a prophylactic agent in management of COVID-19. Among 26[15,16,17,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46] studies that evaluated the effect of ivermectin in RT-PCR-confirmed COVID-19 patients, 13[17,24,26,27,29,37,39,41,44,45,46,47,48] studies were conducted in out-patient setting and the remaining 9[28,32,33,34,36,38,42,43,45] studies were conducted in in-patient setting, and the remaining 6 studies were conducted in both in-patient and out-patient settings.[15,25,30,31,35,40] Ivermectin was administered as a single-dose intervention in 7[28,29,35,38,43,45,46] studies, two-doses in 4[32,37,41,47] studies, three doses over 24 hours in8[16,17,24,27,30,34,39,40] studies, four doses in 1[48] study, and five doses in 8[15,25,26,31,33,35,36,42] studies.

A detailed description of studies included in the analysis is given in Table 1.

Table 1.

Characteristics of Included studies

S. No	Name of the study	Study Design	Country	Sample size	Intervention Group	Control Group
1.	Lopez- Medina et al. [2021]	Double-blind RCT	Columbia South America	398 (200-198)	Ivermectin- 300 mcg/kg for 5 days	Placebo
2.	Mohan et al. [2021]	Triple-blinded RCT	India	125 (80-45)	Ivermectin-24 mg/12 mg For 1 day	Placebo
3.	Biber et al.[2021]	Double-blinded RCT	Israel	89 (47-42)	Ivermectin-0.2 mg/kg	Placebo
4.	Gonzalez et al.[2021]	Double-blinded RCT	Mexico	73 (36-37)	Ivermectin-12/18 mg	Placebo
5.	Ahmed et al. [2020]	Double-blinded RCT	Bangladesh	48 (24-24)	Ivermectin-12 mg for 5 days	Placebo
6.	vallejos et al. [2021]	Double-blinded RCT	Argentina	501 (250-251)	Ivermectin 80 kg-24 mg,>80 kg-36 mg+SOC	Placebo+SOC
7.	Chaccour et al. [2020]	A pilot double-blinded RCT	Spain	24 (12-12)	Ivermectin-400 mcg/kg +SOC for 5 days	Placebo
8.	Ravi kirti et al. [2021]	Double-blinded RCT	Patna, India	112 (55-57)	Ivermectin-12 mg for 2 days+SOC	Placebo+SOC
9.	Nasikarn et al. [2022]	Double-blinded RCT	Thailand	443 (229-214)	Ivermectin – 70 mcg/ml	Placebo
10.	La Rocha et al. [2022]	Double-blinded RCT	Mexico	66 (33-33)	Ivermectin 12 mg for 3 days	Placebo
11.	Miramadizadeh et al. [2022]	Double-blinded RCT	Iran	393 (262-131)	Ivermectin 12 mg for 1 day Ivermectin 12 mg for 2 days	Placebo
12.	Naggie et al. [2022]	Double-blinded RCT	India	1591 (817 – 774)	Ivermectin 400 mcg/kg for 3 days	Placebo
13.	NCT04407507 [2021]	RCT	Mexico	66 (33-33)	Ivermectin12 mg/day +paracetamol-500 mg for 14 days	Placebo+paracetamol
14.	Bukhari et al. [2020]	Open-blinded RCT	Pakistan	86 (45-41)	Ivermectin -12 mg+SOC for 1 day	SOC (oral vit C+vit D3+PCM)
15.	Okomus et al.[2021]	Open label parallel RCT	Turkey	60 (30-30)	Ivermectin-36 to 59 kg -9 mg, 51 to 65 kg-12 mg, 66 to 79 kgs-15 mg, >80 kg-200 mcg/kg+SOC	SOC (HCQ+Favipiravir +azithromycin)
16.	Abd el salam et al. [2021]	Open labeled parallel RCT	Egypt	164 (82-82)	Ivermectin-12 mg for 3 days+SOC	SOC (PCM Antibiotics+ oseltamivir+hydrocortisone)
17.	Lim et al. [2022]	Open labeled RCT	Malaysia	490 (241-249)	Ivermectin -0.4 mg/kg +SOC for 5 days	SOC (Symptomatic therapy)
18.	Chachar et al. [2020]	Open RCT	Pakistan	50 (25-25)	Ivermectin 12 mg stat and then 12 mg after 12 hrs and 12 mg after 24 hrs+SOC	SOC (conventional symptomatic treatment)
19.	Podder et al. [2020]	Open labeled RCT	Bangladesh	62 (32-30)	Ivermectin 200 mcg/kg +SOC for 7 days	SOC (symptomatic therapy)
20.	Krolewiecki et al. [2021]	Pilot Open labeled RCT	Argentina	45 (30-15)	Ivermectin-0.6 mg/kg for 5 days	SOC (symptomatic treatment)
21.	Pott junior et al. [2021]	Pilot trial open labeled RCT	Brazil	31 (27-4)	Ivermectin 100 mcg/kg, 200 mcg/kg and 400 mcg/kg (accumulated dose) for one day+SOC	SOC
22.	Saxena et al. [2021]	Open labeled RCT	India	76 (38-38)	Ivermectin 0.2 mg/kg +SOC	SOC (zinc+vit C)
23.	Reis et al. [2022]	Double-blinded RCT	Brazil	1358 (679-679)	Ivermectin 400 mcg/kg for 3 days	SOC (
24.	Manomaipiboon et al. [2022]	Double-blinded RCT	Thailand	72 (36-36)	Ivermectin 12 mg+SOC for 1 day	SOC (favipiravir+ corticosteroids+ cetirizine+PCM)
25.	Aref et al. [2021]	Open labeled RCT	Egypt	114 (57-57)	Ivermectin 12 mg for 3 days+SOC	SOC (paracetamol+HCQ- 500 mg+Azithromycin 500 mg+oseltamivir 150 mg ascorbic acid 50 mg) for 3 days
26.	NCT04673214 [2021]	Randomized parallel assignment	Mexico	111 (65-46)	Ivermectin 6 mg+SOC for 3 days	SOC (azithromycin 500 mg+rivaroxaban 10 mg+PCM 500 mg)
27.	Waheed M shoumann et al. (P) [2021]	Open labeled RCT	Egypt	304 (203-101)	Ivermectin 15 mg for 40-60 kg body weight, 18 mg for 60-80 kg, 24 mg for>80 kg for 1 day	Placebo
28.	Raymond Chee seong seet et al. (p) [2021]	Open labeled RCT	Singapore	1049 (617-432)	Ivermectin 12 mg for 42 hrs	Vit C+zinc, vit C

Intention to treat analysis was reported by almost all studies except for two studies[32,35] that reported per-protocol analysis. In one study,[35] the per-protocol analysis was because of a labeling error which resulted in the exclusion of participants in both control and interventional arms after randomization. Since the exclusion of participants was not based on treatment outcomes, we considered that the prognostic balance among both arms remains unaffected.

Risk of bias

All the studies included in the analysis were assessed for the risk of bias with respect to the outcomes of interest. The detailed assessment for all the studies per outcomes under all the domains of RoB2 was summarized in supplementary e Tables 1-9.

e Table 9.

Revised Cochrane Risk of bias assessment for the outcome: Adverse events (Ivermectin as Prophylaxis)

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from the intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Shoumann et al	High risk	Some concern	High risk	High risk	Some concern	High risk
2.	Seet RCS	Some concern	Low risk	Low risk	Low risk	Low risk	Some concern

Mortality

Eight studies[17,29,31,32,35,37,40,48] with a total of 3158 patients that compared ivermectin to placebo were included in the analysis. The findings suggest that ivermectin does not significantly reduce the risk of mortality compared to placebo (RR 0.85, 95% CI 0.39 to 1.87; low-certainty of evidence) [Figure 2]. The certainty of evidence was downgraded by one level for serious risk of bias and one level for serious imprecision due to fewer events and wide CI. Sensitivity analysis excluding preprint studies[17,31,32,40] did not alter the findings of the main analysis (RR 0.5, 95% CI 0.22 to 2. 56).

Figure 2.

Random effects meta-analysis of the effect of Ivermectin versus placebo on all cause of mortality in COVID-19 patients

Seven studies[15,16,24,36,39,41,42] with a total of 2698 patients that compared ivermectin to SOC were included in the analysis. The findings suggest that ivermectin is unlikely to reduce mortality compared to SOC (RR 0.74, 95% CI 0.48 to 1.13; low certainty of evidence) [Figure 3].

Figure 3.

Random effects meta-analysis of the effect of Ivermectin versus standard care on all cause of mortality in COVID-19 patients

The certainty of evidence was downgraded by one level for serious risk of bias and by one level for very serious imprecision due to fewer events and wide CI. Sensitivity analysis carried out by excluding studies with a high risk of bias[41,42] did not alter the findings of the main analysis (RR 0.45, 95% CI 0.17 to 1.19). Unlike all other studies that reported mortality up to 28 days, Okumus reported mortality over 3 months period. This time period can be considered ineligible to assess the effect of ivermectin on mortality. However, its effect is nullified during the sensitivity analysis which excluded the study due to high risk of bias.

We, therefore, believe that ivermectin does not reduce mortality in COVID-19 patients when compared to either placebo or SOC irrespective of the severity of the disease.

Clinical improvement: Symptom resolution or improvement

Six studies[25,31,32,34,35,37] comparing ivermectin to placebo in 1090 patients were included in the analysis; the findings indicate that ivermectin may have little to no difference in clinical improvement (RR 1.02, 95% CI 0.97 to 1.08; low certainty of evidence) (e Figure 1 ^{(676.1KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias and another one level for very serious imprecision due to fewer events and wide CI.

Sensitivity analysis excluding a preprint article[32,34] did not affect the findings of main analysis (RR 0.98, 95% CI 0.88 to 1.09).

Six studies[15,30,39,41,42,45] comparing ivermectin to SOC in 1230 patients were included in the analysis. These findings also indicate that ivermectin may have little to no difference in clinical improvement (RR 1.00, 95% CI 0.94 to 1.06; very low certainty of evidence) (e Figure 2 ^{(637.4KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias, another one level for inconsistency, and one level for very serious imprecision.

Sensitivity analysis excluding studies with high risk of bias[30,41,42] did not support the role of ivermectin clinical improvement in patients with COVID-19 (RR 0.96, 95% CI 0.81 to 1.14).

Clinical worsening

Six studies[17,31,32,35,37,48] with 2995 patients comparing ivermectin to placebo were included in the analysis. Ivermectin was not associated with a significant reduction on clinical worsening (RR 0.79, 95% CI 0.49 to 1.30; low certainty of evidence) (e Figure 3 ^{(676.1KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias and by one level for very serious imprecision due to fewer events and wide CI.

Sensitivity analysis conducted by excluding a preprint article[17,31,32] did not alter the findings of the main analysis (RR 0.8, 95% CI 0.21 to 3.39).

Five studies[15,16,24,39,44] with 2486 patients comparing ivermectin to SOC were included in the analysis. Again, ivermectin was not significant in reducing clinical worsening in COVID-19 patients (RR 0.86, 95% CI 0.68 to 1.09; low certainty of evidence) (e Figure 4 ^{(311.7KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias and by one level for very serious imprecision due to fewer events and wide CI.

These findings suggest that ivermectin does not prevent clinical worsening in COVID-19 patients when compared to placebo or SOC.

Duration of hospital stay

Duration of hospitalization was reported in one study[25] that compared ivermectin to placebo. Only one study[25] was considered for evaluation as the other study[43] reported the outcome as median with inter-quartile ranges. The median value cannot be considered similar to the mean due to asymmetric distribution of date. Findings of the analysis suggest that the effect of ivermectinon duration of hospitalization has little or no effect in patients with COVID-19. (MD-0.10 days, 95% CI -2. 57 to 2. 37; very low certainty of evidence) (RR 0.29, 95% CI 0.06 to 1.50; very low certainty of evidence) (e Figure 5 ^{(264.9KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias, another one level for inconsistency, and one level for very serious imprecision.

Two studies[15,24] comparing ivermectinto SOC in a total of 654 patients were included for the analysis. Again, ivermectin showed an insignificant response where it has little or no effect on duration of hospitalization (MD -0.78 days, 95% CI -3.27 to 1.71; very low certainty of evidence). The certainty of evidence is downgraded by one level for serious risk of bias, another level for inconsistency, and two levels for very serious imprecision.

Adverse events

Nine studies[17,27,29,34,35,37,38,40,48] with 3280 patients comparing ivermectin to placebo were included. The findings suggest that ivermectin may increase or reduce adverse events up to a period of 28 days (RR 0.94 95% CI 0.85 to 1.03; low certainty of evidence) (e Figure 6 ^{(560.1KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias and another one level for very serious imprecision.

Sensitivity analysis excluding a high risk of bias study[48] did not affect the outcome of the main analysis (RR 0.95, 95% CI 0.86 to 1.04).

Eight studies[15,16,24,30,33,41,44,45] with 2325 patients comparing ivermectin to SOC were included. The findings suggest that ivermectin may increase (or) reduce adverse events up to a period of 28 days (RR 1.26, 95% CI 0.84 to 1.90; very low certainty of evidence) (e Figure 7 ^{(525.5KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias, another one level for inconsistency, and one level for very serious imprecision.

Sensitivity analysis excluding studies with high risk of bias[30,33,44] did not affect outcome of the main analysis (RR 0.95,95% CI 0.86 to 1.04).

Viral clearance

Seven studies[25,27,29,32,34,38,48] with 914 patients comparing ivermectin to placebo were included in the main analysis. The findings suggest that ivermectin may not reduce viral clearance in patients in COVID-19 (RR 1.10, 95% CI 0.90 to 1.35; very low certainty of evidence) (e Figure 8 ^{(564.1KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias, another one level for inconsistency, and one level for very serious imprecision.

Sensitivity analysis excluding a preprint article[32] and a high-risk article[32] did not affect outcome of the main analysis (RR 1.04, 95% CI 0.83 to 1.30).

Seven studies[26,28,36,42,43,44,45] with 442 patients comparing ivermectin to SOC were included in the main analysis. The finding again suggests that ivermectin may not reduce viral clearance in patients with COVID-19 (RR 1.30, 95% CI 1.00 to 1.69; very low certainty of evidence) (e Figure 9 ^{(663.9KB, tif)} in S2 index). The certainty of evidence was downgraded by one level for serious risk of bias, another one level for inconsistency, and two levels for very serious imprecision.

The findings of the sensitivity analysis remained consistent with the main analysis in all the outcomes assessed in the analysis, indicating that studies with a high risk of bias and preprint articles did not alter the overall effect in any of the outcomes. (e Tables 1 and 2 in S2).

e Table 1.

Overall Risk estimates of Primary and secondary analysis: Ivermectin versus placebo

S.No	Outcome	Risk ratio (95%CI)
		Random effect model	Fixed effect model	Sensitivity Analysis
1.	All cause mortality	0.79(0.35-1.78)	0.68(0.31-1.74)	0.5(0.22-2.56)
2.	Clinical improvement	0.98(0.88-1.09)	1.01(0.90-1.14)	0.98(0.88-1.09)
3.	Clinical worsening	0.84-(0.21-3.39)	0.78(0.28-2.14)	0.8(0.21-3.39)
4.	Adverse effects	0.94(0.85-1.03)	0.92(0.8-1.04	0.95(0.86-1.04)
5.	Viral clearance	1.11(0.89-1.37)	1.04(0.96-1.12)	1.04(0.83-1.30)

e Table 2.

Overall Risk estimates of Primary and secondary analysis: Ivermectin versus standard of care

S.No	Outcome	Risk ratio (95%CI)
		Random effect model	Fixed effect model	Sensitivity Analysis
1.	All cause mortality	0.56(0.29-1.08)	0.53(0.27-1.02)	0.45(0.17-1.19)
2.	Clinical improvement	1.05(0.86-1.29)	1.01(0.87-1.18)	0.96(0.81-1.14)
3.	Clinical worsening	0.58(0.20-1.15)	0.50(0.29-1.18)	-
4.	Adverse effects	1.99(0.75-5.29)	2.55(1.62-4.03)	0.95(0.86-1.04)
5.	Viral clearance	1.41(0.69-2.88)	1.52(1.24-1.87)	-

Prophylaxis

Two studies[46,47] with a total of 2174 patients were included in a prophylactic analysis between ivermectin and preventive measures. Ivermectin did not show significant prophylactic benefits (RR 0.29, 95% CI 0.06 to 1.50; very low certainty of evidence) (e Figure 10 ^{(556KB, tif)} in S2 index). The certainty of evidence was downgraded by two levels for very serious risk of bias as both studies involved in the analysis had high risk of bias for the assessed outcome, that is, occurrence of COVID-19 symptoms. Certainty is again downgraded by two levels due to very serious imprecision. Similar findings were seen for adverse events also (RR 2.349, 95% CI 0.27 to 20.08; very low certainty of evidence) (e Figure 11 ^{(271KB, tif)} in S2 index).

DISCUSSION

Our systematic review and meta-analysis compiled the findings of 28 RCTs with 8001 patients in order to assess the overall efficacy and safety of ivermectin compared to placebo or SOC in patients with the COVID-19 disease. The overall findings of our review conclude that ivermectin was not superior to either placebo or SOC in all the outcomes assessed in the analysis. When compared to placebo, ivermectin was not significant in reducing the risk of mortality, clinical worsening, duration of hospital stay, and viral clearance based on very low quality of evidence nor benefited the patients in terms of clinical improvement and adverse events based on low quality of evidence. Similarly, when compared to SOC, ivermectin was not significant in reducing the risk of mortality, clinical worsening, duration of hospital stay, adverse events, and viral clearance based on very low quality of evidence nor benefited the patients in terms of clinical improvement based on low quality of evidence. Ivermectin also failed to demonstrate a prophylactic effect in patients with a risk of exposure.

Methodological limitations were identified in a few studies included in the analysis and were rated as high risk of bias. To ensure that the overall findings of the review were not affected by studies with a high risk of bias, sensitivity analysis included studies with a low risk of bias and some concerns of bias only. The results of the sensitivity analysis remained consistent with the main findings in all the measured outcomes. The certainty of evidence was downgraded by one level when most of the results of the outcomes included in the analysis were assessed as some concerns of bias. Also, the majority of the outcomes assessed in our analysis had a low number of patients and a low number of events, which was another limitation for the overall certainty of evidence. All such outcomes were downgraded by one or two levels for imprecision. Except for viral clearance and adverse events (only in ivermectin compared to SOC), heterogeneity was not a limitation in the entire study.

Unlike a few meta-analyses, we did not consider viral clearance as an effective parameter to assess the efficacy of any treatment modality because of a prolonged viral shedding time period observed in COVID-19 patients. A population-based study documented a median viral shedding duration of 12 to 28 days, and importantly, only 11.5% of the population with definitive negative results showed negative status by day 14.[49] Therefore, we felt that assessing viral clearance after a fixed duration of 7 or 14 days does not correlate with the efficacy of the treatment given and considered it as a secondary outcome.

We did not include studies in which concomitant medications like hydroxychloroquine, doxycycline, and so on were added to ivermectin in the interventional arm. Also, when these drugs were used as the SOC, we included only those studies where the SOC was comparable between both the interventional arm and control arm. This is one of the strengths of our analysis as it allowed us to determine the exact effect of ivermectin treating COVID-19 disease by eliminating the possible confounding of results due to other drugs. Earlier studies[9,10] that reported favorable outcomes with ivermectin included studies in which doxycycline was added to ivermectin the interventional arm[50,51,52] and studies that compared ivermectin with hydroxychloroquine[53,54] and lopinavir or ritonavir.[55,56] These studies when pooled together along with other studies where ivermectin was compared either with placebo or SOC, the outcomes of analysis cannot be attributed to ivermectin alone. Also, none of the interventions other than corticosteroids were proven effective in the management of COVID-19,[57] indicating that ivermectin when compared with any intervention other than corticosteroids is deemed to be inappropriate. No studies were available that compared ivermectin with corticosteroids.

All the meta-analyses which included Elgazzar Ahmed and Niaee[53,54] studies in their analysis[7,8,9,10,58] showed a clear advantage for ivermectin, especially in terms of reduction in mortality. This is because of the extreme effect size and narrow confidence intervals reported in both studies (RR 0.10, CI 0.20 to 0.42 and RR 0.18, CI 0.06 to 0.55, respectively). With Elgazzar Ahmed[53] study retracted due to potential fraudulence and Niaee[54] study including about 30% of COVID-19 negative participants, the findings of all these meta-analyses now become invalid.

A recent meta-analysis carried out by Izcovich[58] highlighted the role of bias behind the possible benefits associated with ivermectin. A substantial change in the effect size of mortality was observed when studies rated as high risk of bias were excluded from the main analysis. The effect size which clearly favored ivermectin (RR 0.50, CI 0.28 to 0.88) changed toward a null effect when studies with high risk of bias were excluded in the sensitivity analysis (RR 0.96, CI 0.58 to 1.59). Their sensitivity analysis excluding studies with high risk of bias, which was the most comparable analysis to our sensitivity analysis on mortality, differed in terms of a few included studies. Unlike them, we did not include Shahbaznejad[56] and Galan[59] owing to the use of inappropriate comparator’s ritonavir/lopinavir and hydroxychloroquine, respectively, in those studies. Also, while assessing the risk of bias, the authors assumed that lack of blinding was unlikely to introduce bias to mortality and mechanical ventilation outcomes and assessed the risk of bias for these outcomes separately. We believe that inadequate blinding can sometimes lead to the aggressiveness of care and alter supportive treatment which can influence the ultimate outcome. We, therefore, assessed the risk of bias for all the outcomes uniformly.

A very recent meta-analysis[60] also proposed similar findings of no significant effect of ivermectin in patients with COVID-19, but again, we did not include Shahbaznejad[56] and Babalola[55] owing to the use of inappropriate comparators.

Beyond all these systematic reviews and their findings, there exists a controversy of numbers regarding the use of ivermectin COVID-19 disease. Initially, Caly and associates[4] reported the in-vitro antiviral effect of ivermectin at a concentration of 5 µM which reduced the viral RNA load by 99.98% at 48 hours. But the maximum attained in-vivo concentration of ivermectin tested at a very high dose of 1700 µg/kg (FDA-approved dose being only 200 µg/kg) was found to be only 0.28 µM.[61] This questions the basic rationale for testing ivermectin at a clinical level. All the studies included in the analysis dosed ivermectin within the range of 400 µg/kg to 100 µg/kg.

Even though WHO was against the use of ivermectin patients with COVID-19 except for clinical trials,[62] ivermectin found its place in the management of COVID-19 disease all over the world. In Australia, a cross-sectional study reported a 104% increase in the dispensing of ivermectin just 1 month.[63] The United States of America saw a drastic rise from 3589 prescriptions per week to 39,102 prescriptions per week of ivermectin dispensed from outpatient retail pharmacies in a period of 10 months.[64] A few countries in Latin America officially endorsed ivermectin as a treatment for COVID-19 which even saw veterinary preparations of ivermectin administered to human population. This is because of the fact that ivermectin was dosed at 12 mg in the management of COVID-19 disease, but the commercially available formulations contain only 3 or 6 mg tablets or 6 mg/ml oral suspensions, while veterinary preparations have higher drug concentrations.[65] The poison control centers across the United States of America also received a three-fold increase in cases related to ivermectin exposure (both human and veterinary formulations) compared to the pre-pandemic baseline.[66]

COVID-19 outbreaks with different variants are expected to be normal in the near future, and neither vaccination nor previous infection can contribute to lifelong immunity.[56]

Though paxlovid (nirmatrelvir + ritonavir), the drug that was granted an emergency use authorization (EUA) by FDA, is widely available across different countries, the high cost of paxlovid may favor the use of ivermectin, which is much cheaper. In this regard, there is a strong need for clinical evidence to treat the disease better and avoid all the possible anomalies.

CONCLUSION

The outcomes of our meta-analysis go against the use of ivermectin in the management of COVID-19 disease. Ivermectin is not effective in improving clinically important outcomes of COVID-19 disease, and it comes with a very low to low certainty of evidence. There is also no evidence available that supports the prophylactic use of ivermectin for the prevention of COVID-19 infection.

Author contribution

There was equal contribution from all the authors in the overall design and implementation of the research work. R. K directed the meta-analysis, processed the experimental data, designed forest plots and wrote the manuscript. D. M. L and B. R carried out electronic search and data extraction. A. S. P carried out data extraction and assessment of bias. All the authors approved the manuscript after a thorough review.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.

Supplementary Content-1

e Table 2.

Revised Cochrane Risk of bias assessment for the outcome: Mortality

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Gonzalez	Some concern	Some concern	Low risk	Low risk	Some concern	Some concern
2.	kirti	Low risk	Some concern	Low risk	Low risk	Low risk	Some concern
3.	chaccour	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
4.	NCT	Low risk	Some concern	Low risk	Low risk	Low risk	Some concern
5.	Vallejos	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
6.	Lopez medina	Low risk	Some concern	Low risk	Low risk	Low risk	Some concern
7.	Abd Elsalam	Low risk	Some concern	Low risk	Some concern	Low risk	Some concern
8.	Lim et al	Some concern	Low risk	Low risk	Low risk	Low risk	Some concern
9.	Okumuş	High risk	High risk	Low risk	Low risk	Some concern	High risk

e Table 3.

Revised Cochrane Risk of bias assessment for the outcome: Clinical Improvement

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Ahmed	Low	Low	Low	Some concerns	Low	Some concerns
2.	Lopez	Low	Some concerns	Low	Low	Low	Some concerns
3.	Kirti	Low	Some concerns	Low	Low	Low	Some concerns
4.	Gonzalez	Some concerns	Some concerns	Low	Low	Some concerns	Some concerns
5.	Chachar	High	Some concerns	Low	Low	Low	High
6.	Lim	Some concerns	Low	Low	Low	Low	Some concerns
7.	Okumuş	High	High	Low	Low	Some concerns	High

e Table 4.

Revised Cochrane Risk of bias assessment for the outcome: Clinical Worsening

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Lopez	Low	Some concerns	Low	Low	Some concerns	Some concerns
2.	Kirti	Low	Some concerns	Low	Low	Low	Some concerns
3.	Vallejos	Low	Low	Low	Low	Low	Low
4.	Gonzalez	Some concerns	Some concerns	Low	Low	Some concerns	Some concerns
5.	Abd	Low	Some concerns	Low	Some concerns	Low	Some concerns
6.	Lim	Some concerns	Low	Low	Low	Low	Some concerns
7.	Pott junior	Low	Low	Low	Low	Some concerns	Some concerns

e Table 5.

Revised Cochrane Risk of bias assessment for the outcome: Mean Duration of hospital stay

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from the intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Ahmed et al	Some concern/low	Some concern	Low risk	Low risk	Some concern	Some concern
2.	Lim et al	Some concern	Low risk	Low risk	Some concern	Low risk	Some concern
3.	Abd et al	Low risk	Some concern	Low risk	Some concern	Low risk	Some concern

e Table 6.

Revised Cochrane Risk of bias assessment for the outcome: Adverse Events

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from the intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Biber	Low	Low	Low	Low	Some concerns	Some concerns
2.	Chaccour	Low	Low	Low	Low	Low	Low
3.	Lopez	Low	Some concerns	Low	Low	Low	Some concerns
4.	Mohan	Low	Low	Low	Low	Some concerns	Some concerns
5.	NCT	Low	Some concerns	Low	Low	Low	Some concerns
6.	Vallejos	Low	Low	Low	High	Some concerns	High
7.	Abd	Low	Some concerns	Low	Some concerns	Low	Some concerns
8.	Chachar	High	Some concerns	Low	Low	Low	High
9.	Krowlecki	Low	Low	Low	High	Low	High
10.	Lim	Some concerns	Low	Low	Low	Low	Some concerns
11.	Pott junior	Low	Low	Low	High	Some concerns	High

e Table 7.

Revised Cochrane Risk of bias assessment for the outcome: viral clearance

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from the intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Ahmed et al	Some concern	Some concern	Low risk	Low risk	Some concern	Some concern
2.	Biber et al	Low risk	Low risk	Low risk	Low risk	Some concern	Some concern
3.	Chaccour	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
4.	Mohan et al	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
5.	Ravi kirti et al	Low risk	Some concern	High risk	Low risk	Low risk	High risk
6.	Vallejos et al	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
7.	Bukhari	Some concern	Some concern	High risk	Low risk	High risk	High risk
8.	Podder	High risk	Some concern	High risk	Low risk	Some concern	High risk
9.	Pott junior	Low risk	High risk	Low risk	Low risk	Some concern	High risk
10.	Okumuş	High risk	High risk	High risk	Low risk	Some concern	High risk

e Table 8.

Revised Cochrane Risk of bias assessment for the outcome: Development of clinical COVID-19 symptoms (Ivermectin as Prophylaxis)

S.No	Name of the study	Risk of bias					Overall
		Randomization process	Deviations from the intended intervention	Missing outcome data	Measurement of outcome	Selection of the reported result
1.	Shoumann et al	High risk	Some concern	Low risk	High risk	Low risk	High risk
2.	Seet RCS	High risk	Some concern	Low risk	Some concern	Low risk	High risk

SUPPLEMENTARY CONTENT-2

e Figure 1

Random effects meta-analysis of the effect of Ivermectin versus placebo on clinical improvement in COVID-19 patients

e Figure 2

Random effects meta-analysis of the effect of Ivermectin versus standard care on clinical improvement in COVID-19 patients

e Figure 3

Random effects meta-analysis of the effect of Ivermectin versus placebo on clinical worsening in COVID-19 patients

e Figure 4

Random effects meta-analysis of the effect of Ivermectin versus standard care on clinical worsening in COVID-19 patients

e Figure 5

Random effects meta-analysis of the effect of Ivermectin versus protective measurements as prophylactic agent in occurrence of adverse events

e Figure 6

Random effects meta-analysis of Ivermectin versus placebo on the risk of adverse events in COVID-19 patients

e Figure 7

Random effects meta-analysis of Ivermectin versus standard care on the risk of adverse events in COVID-19 patients

e Figure 8

Random effects meta-analysis of the effect of Ivermectin versus placebo on viral clearance in COVID-19 patients

e Figure 9

Random effects meta-analysis of the effect of Ivermectin versus standard care on viral clearance in COVID-19 patients

e Figure 10

Random effects meta-analysis of the effect of Ivermectin versus standard care on duration of hospital stay in COVID-19 patients

e Figure 11

Random effects meta-analysis of the effect of Ivermectin versus protective measurements as prophylactic agent in onset of COVID-19 symptoms

Summary of findings: Table 1

Ivermectin compared to Placebo for Covid-19
Patient or population: Covid-19 Intervention: Ivermectin Comparison: Placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Placebo	Risk with Ivermectin
Mortality	9 per 1,000	7 per 1,000 (3 to 17)	RR 0.79 (0.35 to 1.78)	3158 (8 RCTs)	⨁⨁◯◯ Low	The evidence is very uncertain about the effect of ivermectin on mortality.
Clinical Improvement	696 per 1,000	689 per 1,000 (626 to 758)	RR 0.99 (0.90 to 1.09)	1090 (6 RCTs)	⨁⨁◯◯ Low	The evidence suggests that ivermectin results in little to no difference in clinical Improvement.
Clinical Worsening	20 per 1,000	18 per 1,000 (7 to 45)	RR 0.92 (0.37 to 2.29)	2995 (6 RCTs)	⨁⨁◯◯ Low	The evidence is very uncertain about the effect of ivermectin on clinical Worsening.
Adverse events follow-up: 28 days	174 per 1,000	163 per 1,000 (148 to 179)	RR 0.94 (0.85 to 1.03)	3280 (9 RCTs)	⨁⨁◯◯ Low	The evidence suggests that ivermectin may increase or reduce adverse events up to 28 days.
Viral Clearance	667 per 1,000	740 per 1,000 (593 to 913)	RR 1.11 (0.89 to 1.37)	914 (7 RCTs)	⨁◯◯◯ Very low	The evidence is very uncertain about the effect of ivermectin on viral Clearance.

*The risk in the intervention group (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

GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.