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Based on the current very low&#; to low&#;certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID&#;19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID&#;19 outside of well&#;designed randomized trials.
We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low&#;certainty evidence). The study reported results for development of COVID&#;19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS&#;CoV&#;2 infection, hospital admission, and quality of life up to 14 days.
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low&#;certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low&#;certainty evidence) or non&#;IMV or high flow oxygen requirement (0 participants required non&#;IMV or high flow; 1 study, 398 participants; very low&#;certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low&#;certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low&#;certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low&#;certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days.
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low&#;certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low&#;certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low&#;certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low&#;certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low&#;certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low&#;certainty evidence) and duration of hospitalization (mean difference (MD) &#;0.10 days, 95% CI &#;2.43 to 2.23; 1 study; 45 participants; low&#;certainty evidence). No study reported quality of life up to 28 days.
We found 14 studies with participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID&#;19 in inpatient settings and four treating mild COVID&#;19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS&#;CoV&#;2 infection. Eight studies had an open&#;label design, six were double&#;blind and placebo&#;controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.
We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate&#;to&#;severe COVID&#;19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID&#;19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS&#;CoV&#;2 infection: SARS&#;CoV&#;2 infection, development of COVID&#;19 symptoms, adverse events, mortality, admission to hospital, and quality of life.
To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID&#;19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS&#;CoV&#;2 (postexposure prophylaxis).
Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS&#;CoV&#;2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS&#;CoV&#;2 infection and COVID&#;19 treatment is conflicting.
Our confidence in the evidence is very low because we could only include 14 studies with few participants and few events, such as deaths or need for ventilation. The methods differed between studies, and they did not report everything we were interested in, such as quality of life.
We don't know whether ivermectin leads to more or fewer deaths compared with no drug (1 study, 304 people); no participant died 28 days after the drug. This study reported results for development of COVID&#;19 symptoms (but not confirmed SARS&#;CoV&#;2 infection) and unwanted events, but in a way that we could not include in our analyses. This study did not look at hospital admissions.
For treatment, there were nine studies of people with moderate COVID&#;19 in hospital and four of outpatients with mild COVID&#;19. The studies used different doses of ivermectin and different durations of treatment.
We searched for randomized controlled trials that investigated ivermectin to prevent or treat COVID&#;19 in humans. People being treated with ivermectin had to have laboratory&#;test confirmed COVID&#;19 and be receiving treatment in hospital or as outpatients.
We wanted to know if ivermectin reduces death, illness, and length of infection in people with COVID&#;19, or is useful in prevention of the disease. We included studies comparing the medicine to placebo (dummy treatment), no treatment, usual care, or treatments for COVID&#;19 that are known to work to some extent, such as remdesivir or dexamethasone. We excluded studies that compared ivermectin to other drugs that do not work, such as hydroxychloroquine, or that are not known to be effective against COVID&#;19.
Tests in the laboratory show ivermectin can slow the reproduction of the COVID&#;19 (SARS&#;CoV&#;2) virus but such effects would need major doses in humans. Medical regulators have not approved ivermectin for COVID&#;19. It should only be used as part of well&#;designed studies (called randomized controlled trials) evaluating potential effects.
Ivermectin is a medicine used to treat parasites such as intestinal parasites in animals and scabies in humans. It is cheap and is widely used in regions of the world where parasitic infestations are common. It has few unwanted effects.
As of July , the efficacy and safety of ivermectin for COVID&#;19 treatment and prophylaxis are still subject to debate. The most recent Association of the Scientific Medical Societies in Germany (AWMF) guideline recommends against the use of ivermectin as antiviral treatment ( German AWMF Guideline ), while in February , the US National Institutes of Health (NIH) revised their COVID&#;19 treatment guidelines from a recommendation 'against the use of ivermectin' to 'cannot recommend either for or against the use of ivermectin,' giving clinicians leeway in individual case decision&#;making ( NIH ). The WHO recommends that the drug only be used within clinical trials as current evidence on the use of ivermectin to treat people with COVID&#;19 is inconclusive ( WHO b ).
Several studies describe ivermectin's positive effect on resolution of mild COVID&#;19 symptoms or describe a reduction of inflammatory marker levels or shorter time to viral clearance, while other studies indicate no effect or even a negative effect on disease progression. Many studies are already summarized in existing systematic reviews, meta&#;analyses, and guidelines ( Bryant ; Hill ; NIH ). It has to be kept in mind that many available meta&#;analyses and reviews, as well as most of the underlying original studies, have not yet been published in peer&#;reviewed journals and are only available on preprint servers without any supervising authority. Given the pace of the pandemic, it is important and welcome to make new scientific findings immediately available. But non&#;peer&#;reviewed results have to be handled with care and should not be used as the sole basis for clinical decisions and recommendations. Methodological limitations in the design of original studies, data integrity, and potential conflicts of interests have to be critically appraised when judging trial results. Many reviews and meta&#;analyses of ivermectin for COVID&#;19 are not reliable due to insufficient methodological accuracy and quality.
Ivermectin is an inexpensive and widely used medicine, mainly in low&#; and middle&#;income countries with a high burden of parasitic diseases. The recently published in vitro studies, especially the results of Caly , have led to great interest in ivermectin in many countries with high numbers of SARS&#;CoV&#;2 infections, including the USA and countries of South America and Asia. In South America in particular, people started liberally self&#;medicating with ivermectin, and the drug has become part of public health policies without reliable scientific data. For example, in May , Bolivian and Peruvian health officials recommended ivermectin for the treatment of COVID&#;19 without supplying evidence. In Brazil, it was promoted as a preventive measure by municipalities ( Rodríguez&#;Mega ). Due to the rapid increase in interest in ivermectin and the risk of abuse, the US Food and Drug Administration (FDA) discouraged the use of ivermectin intended for animals ( FDA ).
The molecular hypothesis of ivermectin's antiviral mode of action, explained above, suggests an inhibitory effect on virus replication in the early stages of the disease, indicating a benefit especially for people with mild or moderate disease. This has also led to the idea of the possible preventive potency of ivermectin on infection with SARS&#;CoV&#;2 in individuals after exposure to a contagious contact, called postexposure prophylaxis. In response to the early promising in vitro studies on ivermectin, mentioned above, several COVID&#;19 clinical trials have been initiated to investigate the prophylactic and therapeutic effects of ivermectin.
Another member of the beta&#;coronavirus family, SARS&#;CoV&#;1, which also causes respiratory failure, revealed similar dependence on the IMPα/β1 interaction ( Wulan ). The pathogen causing COVID&#;19, SARS&#;CoV&#;2, is also an RNA virus closely related to SARS&#;CoV&#;1. In , ivermectin gained high interest as a promising therapeutic option against SARS&#;CoV&#;2, when Caly published their experimental study results showing that ivermectin inhibits the replication of SARS&#;CoV&#;2 in cell culture. So far, the only drugs shown to be clearly effective in COVID&#;19 treatment are targeting the immune response to a SARS&#;CoV&#;2 infection; for example, dexamethasone ( RECOVERY ). Therefore, ivermectin's potential to restrict the disease's progression, or even its outbreak, indicates that it is possibly an effective antiviral agent. However, until showing success in human clinical trials with patient&#;relevant outcomes, these findings remain suggestive.
Before the COVID&#;19 pandemic, only two clinical trials had been registered on ClinicalTrials.gov (clinicaltrials.gov/) using ivermectin as an intervention for treatment of virus diseases. Only one of these had published results ( Yamasmith ). In this small, single&#;centre study published as a conference abstract, ivermectin showed a shorter viral protein clearance time compared to placebo in people infected with dengue virus ( Yamasmith ).
One in vitro study showed that ivermectin can inhibit replication of the human&#;immunodeficiency&#;virus 1 (HIV&#;1), via inhibition of the interaction of virus proteins and a human cargo protein complex called importin (IMPα/β1) ( Wagstaff ). Importin is used by viruses for nuclear import in order to initiate their replication process ( Wagstaff ). Besides HIV&#;1, various other RNA viruses use importin as target protein, among them dengue virus, West Nile virus, and influenza. Several research groups have investigated ivermectin's efficiency on those pathogens ( Goetz ; Tay ; Yang ). Although ivermectin showed some inhibitory potential for virus replication in vitro, there is no evidence of clinical effectiveness to date.
Adhering to recommended doses, ivermectin is generally well tolerated. Adverse effects &#; which seem to arise partially from the rapid death of parasites, leading to hyperinflammation and anaphylactic reactions &#; include weakness, drowsiness, diarrhoea, nausea, and vomiting. In addition, ivermectin can cause fever and rash. Rare serious adverse effects can occur, such as vision problems, neurotoxicity, and liver damage ( González&#;Canga ).
In animals and humans, ivermectin is easily resorbed by the mucosa if taken orally or the skin if taken topically. As a lipophilic compound, it accumulates in fat and liver tissue from where it effuses and takes effect. Elimination is processed through bile and faeces. Ivermectin is widely used in veterinary medicine, but it is also approved for human parasitic diseases such as onchocerciasis, lymphatic filariasis, strongyloidiasis, and scabies in several countries (e.g. the USA, Japan, France, Germany, Australia) ( González&#;Canga ). The established dosing regimen ranges from 150 µg/kg to 200 µg/kg administered orally, with a one&#; to two&#;dose administration generally being effective. Dosing is generally low because of the agent's high potency ( Ashour ).
Ivermectin is an antiparasitic agent belonging to the group of avermectins, originally a fermentation metabolite produced by the bacterium Streptomyces avermitilis. Ivermectin was introduced for medical use in and is effective against various types of nematodes and helminths, and ectoparasites such as mites and lice. The mode of action is based on binding to specific cell membrane channels that only occur in invertebrates. Channel activation ultimately leads to blocked cell signal transmission through chloride&#;induced hyperpolarization. Consequently, parasites are paralysed and die, interrupting their reproduction cycle ( Campbell ; Dourmishev ; Panahi ). Ivermectin is on the WHO List of Essential Medicines for its high effectiveness against human ectoparasite infestations ( WHO ).
Transmission is typically inferred from population&#;level information. Inherent properties of virus variants of concern, and individual differences in infectiousness among individuals or groups make it difficult to contain its spread in the community ( WHO a ). Currently, the most effective and ubiquitously available measures to control virus spreading are non&#;pharmaceutical interventions, including physical distancing, wearing a facemask, especially when distancing cannot be maintained, keeping rooms well ventilated, avoiding crowds and close contact, regularly cleaning your hands, and coughing into a bent elbow or tissue. Research on prophylaxis of SARS&#;CoV&#;2 infection and treatment of COVID&#;19 is being carried out under great pressure worldwide. Evaluating the effectiveness of repurposed drugs represents one important strand of these research efforts. In this context, ivermectin &#; an antiparasitic intervention &#; has received substantial attention, especially in South America and parts of Asia.
Data on mortality substantially differ between locations, depending on the population structure, the case&#;mix of infected and deceased individuals, other local factors, and changes during the ongoing outbreak. With an inhospital mortality for people receiving ventilation of over 70% ( Karagiannidis ), the patients who survive often have considerable consequential damage ( Herrmann ; Prescott ). COVID&#;19 can lead to death due to a variety of causes, such as severe respiratory failure, septic shock, and multiple organ failure ( WHO a ). The case&#;fatality ratio worldwide is currently estimated at 2.2% with large statistical fluctuations (less than 0.1% in Singapore up to almost 20% in Yemen; status July ) ( Dong ). However, these varying rates should not be interpreted as markers for the quality of health care ( Karagiannidis ), or the aggressiveness of different virus variants. These statistics are influenced by the mean age of a population or of those infected, the quality and extent of local test strategies, and documentation and reporting systems ( Kobayashi ). The gold standard for confirming a SARS&#;CoV&#;2 infection is the reverse transcription polymerase chain reaction (RT&#;PCR)&#;based detection of viral ribonucleic acid (RNA) from a nasopharyngeal swab test, sputum, or tracheal secretion, with a sensitivity ranging from 70% to 98%, depending on pretest probability ( Watson ). Offering lower sensitivity but greater practicality and accessibility, antigen tests are receiving increased attention, especially in point&#;of&#;care diagnostics of COVID&#;19 ( WHO c ).
Available data suggest that one&#;third of SARS&#;CoV&#;2 infections remain asymptomatic ( Oran ), but there is still uncertainty around this estimate. About 80% of symptomatic cases show mild symptoms, including cough, fever, myalgia, headache, dyspnoea, sore throat, diarrhoea, nausea and vomiting, and loss of smell and taste. Outpatient management is appropriate for most people with a mild course of COVID&#;19. Moderate, severe, and critical cases (approximately 20%), with the need for oxygen supplementation, ventilatory support, or intensive medical care, cause a considerable burden for healthcare systems. Defined risk factors for severe disease include increasing age (over 60 years) and certain comorbidities ( Huang ; WHO a ). Comorbidities such as cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease and other lung diseases, malignancies, chronic kidney disease, solid organ or haematopoietic stem cell transplantation, and obesity are associated with severe COVID&#;19 and mortality ( Deng ; Williamson ).
COVID&#;19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS&#;CoV&#;2). On 11 March , after spreading from China to more than 144 countries, the World Health Organization (WHO) declared a COVID&#;19 pandemic. In July , over 180 million cases have been confirmed, including over 3.9 million deaths ( WHO a ; WHO b ).
To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID&#;19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS&#;CoV&#;2 (postexposure prophylaxis).
In case of emerging policy relevance because of global controversies around the intervention, we will consider republishing an updated review even though our conclusions remain unchanged. We will review the review scope and methods approximately monthly, or more frequently if appropriate, in light of potential changes in COVID&#;19 research (e.g. when additional comparisons, interventions, subgroups, or outcomes, or new review methods become available).
We will wait until the accumulating evidence changes our conclusions of the implications of research and practice before republishing the review. We will consider one or more of the following components to inform this decision.
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.
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.
We created separate summary of findings tables for the use of ivermectin with different intentions (e.g. treatment of people with COVID&#;19 in inpatient and outpatient settings, and prevention of SARS&#;CoV&#;2 infection) and for different comparisons with regard to the intervention and comparator. For the current review, we found no studies with active comparators. The summary of findings tables included the following outcomes (primary analysis).
Two review authors (SW, MP) assessed the certainty of evidence, considering risk of bias, inconsistency, imprecision, indirectness, and publication bias. We used the overall RoB 2 assessment to inform the risk of bias judgement underlying the assessment of the certainty of evidence. The primary analysis including only studies at overall low risk or some concerns of bias were used as data basis for the summary of findings tables.
We presented the main results of the review in summary of findings tables, including a rating of the certainty of evidence based on the GRADE approach. We followed current GRADE guidance as recommended in the Cochrane Handbook for Systematic Reviews of Interventions ( Schünemann ).
Since high risk of bias trials were excluded from the primary analysis, we performed a secondary analysis including the studies judged as overall high risk of bias to assess the impact of those studies on the results.
studies reporting data as median instead of mean for continuous outcomes; in the current review version there were no data reported as median that were eligible for a transformation into mean.
We investigated heterogeneity by visual inspection of the forest plot. We reported details of the intervention and age of the population for each study in the footnotes of the forest plot. We planned to investigate heterogeneity by subgroup analysis to calculate RR or MD in conjunction with the corresponding CI for each subgroup, if sufficient studies had been available (at least 10 studies per outcome). In the current review, there were not enough studies available. In review updates, we will perform subgroup analyses if statistical heterogeneity is present (P < 0.1 for the Chi 2 test of heterogeneity, I 2 of 50% or greater, or a different clinical conclusion of 95% CI versus 95% PI).
If clinical and methodological characteristics of individual studies were sufficiently homogeneous, we pooled the data in meta&#;analyses. When meta&#;analysis was feasible, we used the random&#;effects model as we assumed that the intervention effects were related but were not the same for the included studies. For dichotomous outcomes, we performed meta&#;analyses using the Mantel&#;Haenszel method under a random&#;effects model to calculate the summary (combined) intervention effect estimate as a weighted mean of the intervention effects estimated in the individual studies. For continuous outcomes, we used the inverse&#;variance method.
The primary analysis included only those studies that had low risk or some concerns of bias according to the RoB 2 assessment. We included high risk of bias studies in a secondary analysis to assess the impact on the results ( Sensitivity analysis ).
When there are 10 or more relevant studies pooled in a meta&#;analysis, we planned to investigate risk of reporting bias (publication bias) in pairwise meta&#;analyses using contour&#;enhanced funnel plots. In the current review, there were no meta&#;analyses including 10 or more studies. For review updates, if funnel plot asymmetry is suggested by a visual assessment, we plan to perform exploratory analyses (e.g. Rücker's arcsine test for dichotomous data and Egger's linear regression test for continuous data) to further investigate funnel plot asymmetry. A P value of less than 0.1 will be considered as the level of statistical significance. In review updates, we will analyse reporting bias using the open&#;source statistical software R package meta ( Meta ).
We sought to identify all research that met our predefined eligibility criteria. Missing studies can introduce bias to the analysis. We searched for completed non&#;published trials in trials registers, contacted authors to seek assurance that the results will be made available, and classified them as 'awaiting classification' until the results are reported. We reported the number of completed non&#;published trials.
We measured statistical heterogeneity using the Chi 2 test and the I 2 statistic ( Deeks ), and the 95% prediction interval (PI) for random&#;effects meta&#;analysis ( IntHout ). The prediction interval helps in the clinical interpretation of heterogeneity by estimating what true treatment effects can be expected in future settings ( IntHout ). We restricted calculation of a 95% PI to meta&#;analyses with four or more studies (200 participants or more), since the interval would be imprecise when a summary estimate was based on only a few small studies. In the current review, there are no meta&#;analyses including four or more studies. We planned to use the open&#;source statistical software R package meta to calculate 95% PIs in review updates ( Meta ). We declared statistical heterogeneity if the P value was less than 0.1 for the Chi 2 statistic, or the I 2 statistic was equal to or greater than 40% (40% to 60%: moderate heterogeneity; 50% to 90%: substantial heterogeneity; 75% to 100%: considerable heterogeneity; Deeks ), or the range of the 95% PI revealed a different clinical interpretation of the effect estimate compared to the 95% CI.
We used the descriptive statistics reported in the Characteristics of included studies table to assess whether the studies within each pairwise comparison were homogeneous enough, with respect to study and intervention details and population baseline characteristics, that the assumption of homogeneity might be plausible. In case of excessive clinical heterogeneity, we did not pool the findings of included studies.
There are many potential sources of missing data in a systematic review or meta&#;analysis, which can affect the level of studies, outcomes, summary data, individuals, or study&#;level characteristics ( Deeks ). Incomplete data can introduce bias into the meta&#;analysis, if they are not missing at random. We addressed all sources of missing data. Missing studies may be the result of reporting bias, and we addressed this as described in the Assessment of reporting biases section. Missing outcomes and summary data may be the result of selective reporting bias; missing individuals may be the result of attrition from the study or lack of intention&#;to&#;treat analysis. We addressed these sources of missing data using the RoB 2 tool ( Assessment of risk of bias in included studies ). If data were incompletely reported, we contacted the study authors to request additional information.
In studies with multiple intervention groups, we combined groups if reasonable (e.g. study arms with different doses of ivermectin). If it had not been reasonable to pool the groups, we planned to split the 'shared' comparator group to avoid double&#;counting of participants. There was no need to split shared groups for the current review.
We considered effect estimates of dichotomous outcomes with the range of the 95% CIs not crossing 1 and continuous outcomes with the range of the 95% CIs not crossing 0 as statistically significant effect estimates. A statistically significant effect does not necessarily mean that the estimated effect is clinically relevant. We assessed the clinical relevance of the effect size separately and reported it transparently.
For continuous outcomes, we recorded the mean, the standard deviation (SD), and the number of analyzed participants in the intervention and control groups. If the standard deviation was not reported, we used standard errors, CIs, or P values to calculate the SD with the formulas described in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins d ). If studies reported data as median with interquartile range (IQR), we assumed that the median was similar to the mean when sample sizes were large and the distribution of the outcome was similar to the normal distribution. In these cases, the width of the IQR is approximately 1.35 SDs ( Higgins d ). We used the MD with 95% CI as effect measure.
The primary analysis included only those studies that had low risk or some concerns of bias. We included studies at high risk of bias in a secondary analysis to assess the impact on the results.
Similarly, we reached an overall risk of bias judgement for a specific outcome by considering all domains resulting in one of the three judgement options described above. Overall low risk of bias of the trial result was assumed when all domains were at low risk; some concerns of bias was assumed when the trial result was judged to raise some concerns in at least one domain for this result, but not at high risk of bias for any domain; overall high risk of bias of the trial result was assumed when the trial was at high risk of bias in at least one domain for this result or when it was judged to have some concerns for multiple domains in a way that substantially lowered confidence in the result ( Higgins c ).
We assessed the risk of bias in the included studies using the Cochrane risk of bias tool 2 (RoB 2) ( Higgins c ; Sterne ). The effect of interest was the effect of assignment at baseline, regardless of whether the interventions were received as intended (the 'intention&#;to&#;treat effect'). We assessed the risk of bias for all results (outcomes) reported in the included studies that we specified as outcomes for the current review and that contributed to the review's summary of findings table.
Two review authors (SW, MP) independently extracted data using a standardized data extraction form, including details of the study, participants, intervention, comparator, and outcomes. If necessary, we tried to obtain missing data by contacting the authors of relevant articles. At each step of data extraction, we resolved any discrepancies through discussion between the review authors.
We documented the study selection process in a PRISMA flow diagram with the total number of studies included, excluded, awaiting classification, and ongoing. We listed the reasons for exclusion and awaiting classification in the Characteristics of excluded studies and Characteristics of studies awaiting classification tables.
We performed study selection in accordance with the Cochrane Handbook for Systematic Reviews of Interventions ( Lefebvre ). Two review authors (SW, MP) independently screened titles and abstracts of identified records. We retrieved full&#;text articles and independently assessed eligibility of the remaining records against the predefined eligibility criteria. We resolved discrepancies through discussion between the review authors. We included studies irrespective of whether measured outcome data were reported in a 'usable' way. We collated multiple reports of the same study, so that the study, rather than the report, was the unit of interest in the review.
We searched for grey literature, which we defined as searching trials registries such as ClinicalTrials.gov and WHO ICTRP contained in the CCSR, as well as searching preprint servers. In addition, we screened the 'All RCTs' section on the website ivmmeta.com , which lists studies related to ivermectin and COVID&#;19, and the regarding section on COVID&#;NMA Working Group for eligible trials.
We did not conduct separate searches of the databases required by the Methodological Expectations of Cochrane Intervention Reviews (MECIR) standards ( Higgins ), since these databases are already regularly searched for the production of the CCSR. For greater precision, we searched the Web of Science database from 1 January onwards. We searched all other resources without date limits.
We expected that included studies measured several outcomes &#; including serious adverse events, quality of life, and viral clearance &#; at different time points. We analyzed different time points for viral clearance separately due to the dynamic course of the viral load. For other inpatient setting outcomes, the main time point of interest was 28 days after randomization. For other outpatient setting trials outcomes, the main time point of interest was 14 days after randomization, except for mortality (28 days)and (serious) adverse events (28 days). For prevention trials, the main time point of interest was 14 days, except for mortality only (28 days). If only a few studies contributed data to an outcome, we pooled different time points, as long as the studies had produced valid data and pooling was clinically reasonable. We reported time points of outcome measurement in the footnotes of the forest plots. If sufficient data are available for review updates, we will group the measurement time points of eligible outcomes into those measured directly after treatment (up to seven days), medium&#;term outcomes (up to 14 days), and longer&#;term outcomes (28 days or more).
We expected that included studies measured several outcomes &#; including clinical status, SARS&#;CoV&#;2 infection, and adverse events &#; at different time points. For inpatient setting outcomes, the main time point of interest was 28 days after randomization. For outpatient setting outcomes, the main time point of interest was 14 days after randomization, except for mortality and (serious) adverse events (28 days). For prevention trials, the main time point was 14 days, except for mortality only (28 days). If only a few studies had contributed data to an outcome, we pooled different time points, provided the studies had produced valid data and pooling was clinically reasonable. We reported time points of outcome measurement in the footnotes of the forest plots. If sufficient data are available for review updates, we will group the measurement time points of eligible outcomes into those measured directly after treatment (up to seven days), medium&#;term outcomes (up to 14 days), and longer&#;term outcomes (28 days or more).
Development of clinical COVID&#;19 symptoms up to 14 days; assessed in accordance with individual items of the WHO scale ( Marshall ). If the study did not use a standardized scale to assess the status of the participants, we categorized their status according to the WHO scale with the information provided by the study.
Clinical status, assessed by need for respiratory support with standardized scales (e.g. WHO scale ( Marshall )) up to 14 days. If the study did not use a standardized scale to assess the status of the participants, we categorized their status according to the WHO scale with the information provided by the study. Clinical status is a complex outcome with substantial heterogeneity. We pooled data only if clinically reasonable (see the list of specific outcomes below). When there were only a few studies available that reported different outcomes in terms of clinical status, we described the results narratively.
Clinical status, assessed by need for respiratory support with standardized scales (e.g. WHO Clinical Progression Scale ( Marshall ), hereafter referred to as the WHO scale) up to 28 days. If the study did not use a standardized scale to assess the status of the participants, we categorized their status according to the WHO scale with the information provided by the study. Clinical status is a complex outcome with substantial heterogeneity. We pooled data only if clinically reasonable (see the list of specific outcomes below). When there were only a few studies available that reported different outcomes in terms of clinical status, we describe them in the results narratively.
We analyzed different outcomes for the use of ivermectin for treatment of people with COVID&#;19 in inpatient and outpatient settings, and for the prevention of SARS&#;CoV&#;2 infection. If studies were eligible for inclusion regarding design, population, intervention, and comparator, but did not report outcomes of interest, they were not included for meta&#;analysis. However, we summarized reported outcomes for all included studies in the Characteristics of included studies table.
Studies investigating various concomitant medications (e.g. doxycycline, hydroxychloroquine, azithromycin, zinc) in addition to ivermectin or as comparator drug were not eligible for this review. Due to unproven efficacy, possible adverse effects, and drug interactions, these comparisons may confound the assessment of the efficacy or safety of ivermectin.
We planned to compare ivermectin to any other active pharmacological comparator with proven efficacy for prevention or treatment of COVID&#;19. For dexamethasone, it has been shown that mortality from COVID&#;19 was lower among people who were randomized to receive dexamethasone than among those who received the usual standard of care ( RECOVERY ; Siemieniuk ). Remdesivir showed some benefit for people hospitalized with COVID&#;19, though to a lesser extent ( Beigel ). Therefore, dexamethasone and remdesivir will be considered eligible active comparators for review updates. For patients that qualify for (for example) dexamethasone therapy or for another intervention that proves to be beneficial in the future, it would be unethical to further conduct trials that use placebo only. In contrast, studies using comparators (e.g. hydroxychloroquine) without proven efficacy may confound the assessment of the efficacy or safety of ivermectin and were excluded. Although those types of interventions were possibly used at a certain point of time during the pandemic with the best intentions, their use was never supported by actual evidence, and they have potential adverse effects ( Singh ). From those comparisons, no reliable evidence can be obtained.
All doses and regimens of ivermectin were eligible and pooled for the primary analysis. Dosing schemes were considered and categorized into low (up to 0.2 mg/kg orally, single dose) and high doses (greater than 0.2 mg/kg orally, single dose or with higher frequency). We planned to analyse different doses in subgroup analyses, if sufficient studies are available for review updates.
We included studies investigating participants who were not infected with SARS&#;CoV&#;2 at enrolment, but were at high risk of developing the infection (e.g. after high&#;risk exposure), regardless of age, gender, ethnicity, disease severity, and setting (inpatient and outpatients). Participants may have been hospitalized for reasons other than COVID&#;19. Eligible trials must have reported the history of previous SARS&#;CoV&#;2 infections or serological evidence in included participants. A history of SARS&#;CoV&#;2 infection was not an exclusion criterion.
We included studies investigating participants with confirmed SARS&#;CoV&#;2 infection (RT&#;PCR or antigen testing), regardless of age, gender, ethnicity, disease severity, and setting (inpatients and outpatients). If studies included participants with a confirmed or suspected COVID&#;19 diagnosis, we used only the data for the patient population with confirmed COVID&#;19 diagnosis. In cases, where data were not reported separately for people with confirmed or suspected COVID&#;19 diagnosis, we excluded the study.
We included full&#;text journal articles published in PubMed&#;indexed and non&#;indexed journals, preprint articles, results published in trial registers, and abstract publications. All studies, especially preprint articles that have not been peer&#;reviewed, must have reported robust and valid data on study design, participants' characteristics, interventions, and outcomes, to be eligible for inclusion. We categorized studies in question as 'awaiting classification' until the authors publish further information or clarify certain questions.
We included randomized controlled trials (RCTs) only, as this is the best study design for evaluating the efficacy of interventions ( Higgins a ). Non&#;standard RCT designs, such as cluster&#;randomized and cross&#;over trials, were not eligible for the review ( Higgins b ). These designs are not appropriate in this context, since the underlying cause of COVID&#;19 is an infection with the SARS&#;CoV&#;2 virus and the medical condition evolves over time.
One study comparing ivermectin to no treatment reported mortality within 14 days in 304 asymptomatic participants with household close contacts to confirmed COVID&#;19 index case ( Shoumann ). The study result was included in the primary meta&#;analysis due to the overall risk of bias assessment ( ). We are uncertain whether ivermectin reduces or increases mortality up to 28 days compared to no treatment as none of the participants in either group died (RR not estimable; 1 study, 304 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to zero events and few participants. The study was published as a journal article.
One study comparing ivermectin to no treatment reported any adverse events within 14 days in 304 asymptomatic participants with household close contacts to confirmed COVID&#;19 index case n ( Shoumann ). The study result was not eligible for the primary analysis due to the overall risk of bias assessment. The data of Shoumann with high risk of bias were included in a secondary analysis ( ). We are uncertain whether ivermectin increases or reduces any adverse events in participants in contact with confirmed COVID&#;19 index cases compared to no treatment (RR 11.50, 95% CI 0.68 to 193.21; 1 study, 304 participants). The study was published as a journal article.
One study comparing ivermectin to no treatment reported the development of clinical COVID&#;19 symptoms at 14 days in 304 asymptomatic participants with household close contacts to confirmed COVID&#;19 index case ( Shoumann ). The study result was not eligible for the primary analysis due to the overall risk of bias assessment. The data of Shoumann with high risk of bias were included in a secondary analysis ( ). Ivermectin may reduce the development of clinical COVID&#;19 symptoms in participants in contact with confirmed COVID&#;19 index cases compared to no treatment (RR 0.13, 95% CI 0.08 to 0.21; 1 study, 304 participants). The study was published as a journal article.
One study comparing ivermectin to standard of care reported viral clearance at 14 days in 40 participants with mild disease ( Podder ). The study was not eligible for the primary analysis due the overall risk of bias assessment. The data of Podder with high risk of bias were included in a secondary analysis ( ). Ivermectin may have no effect on viral clearance at 14 days compared to standard of care (RR 0.95, 95% CI 0.79 to 1.13; 1 study, 40 participants). The study was published as a journal article.
One study comparing ivermectin to placebo reported viral clearance at seven days in 24 participants with mild disease ( Chaccour ). The study was eligible for the primary analysis due the overall risk of bias assessment ( ). We are uncertain whether ivermectin increases or reduces viral clearance at seven days compared to placebo (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low&#;certainty evidence). We downgraded the certainty of evidence two levels for very serious imprecision due to few participants, few events, and wide CIs. The study was published as a journal article.
Two studies comparing ivermectin to placebo reported serious adverse events within 21 days ( López&#;Medina ) and 28 days ( Chaccour ) in 422 participants with mild disease. Both studies were included in the primary analysis due the overall risk of bias assessment ( ). Chaccour reported zero events in both groups. We are uncertain whether ivermectin increases or reduce serious adverse events within 28 days compared to placebo (RR 0.99, 95% CI 0.14 to 6.96; 2 studies, 422 participants). Both studies were published as journal articles.
Two studies comparing ivermectin to placebo reported any adverse events within 21 days ( López&#;Medina ) and 28 days ( Chaccour ) in 422 participants with mild disease. Both studies were included in the primary analysis due the overall risk of bias assessment ( ). Ivermectin may have little or no effect on any adverse events compared to placebo (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and one level for serious imprecision due to few participants. Both studies were published as journal articles.
Two studies reported data on duration of symptom resolution ( López&#;Medina ; Podder ). One studies comparing ivermectin to placebo reported data as median with IQR on duration of symptom resolution in 398 participants with mild disease ( López&#;Medina ). The median duration of symptom resolution in the ivermectin group was 10 days (IQR 9 to 13 days) compared to 12 days (IQR 9 to 13 days) in the placebo group. The study was not eligible for meta&#;analysis due to an asymmetric distribution of the data. The other study comparing ivermectin to standard of care reported data as means with SDs on duration to symptom resolution in 62 participants with mild disease ( Podder ). The study was not eligible for a primary analysis due to the overall risk of bias assessment. This study with high risk of bias was analyzed in a secondary analysis ( ). The effect estimate of the secondary analysis showed no clinically relevant difference in the duration to symptom resolution (MD &#;1.02 days, 95% CI &#;2.76 to 0.72; 1 study, 62 participants). Both studies were published as journal articles.
One study comparing ivermectin to placebo reported data on symptom resolution at 15 days in 398 participants with mild disease ( López&#;Medina ). The study was eligible for the primary meta&#;analysis due to the overall risk of bias assessment ( ). Ivermectin may have little or no effect on clinical improvement assessed by the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and one level for serious imprecision due to few participants. The study was published as a journal article.
López&#;Medina reported hospitalization with or without supplemental oxygen. The data were not eligible for meta&#;analysis as less than 1% of the participants already had a WHO status of 4 and 5 at baseline. Therefore, these data were not useful to judge clinical worsening.
One study comparing ivermectin to placebo reported the need for non&#;invasive mechanical ventilation or high flow at 15 days in 398 participants with mild disease ( López&#;Medina ). None of the participants in either group required non&#;invasive mechanical ventilation or high flow at 15 days. The study was eligible for the primary analysis due to the overall risk of bias assessment ( ). We are uncertain whether ivermectin reduces or increases clinical worsening assessed by the need for non&#;invasive mechanical ventilation or high flow at 15 days compared to placebo (RR not estimable; 1 study, 398 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to zero events and few participants. López&#;Medina was published as a journal article.
One study comparing ivermectin to placebo reported data on clinical worsening assessed by need for invasive mechanical ventilation at 15 days in 398 participants with mild disease ( López&#;Medina ). The study was eligible for the primary meta&#;analysis due to the overall risk of bias assessment ( ). One participant in the ivermectin group and no participants in the placebo group showed clinical worsening. We are uncertain whether ivermectin reduces or increases clinical worsening assessed by the need for invasive mechanical ventilation compared to placebo up to 14 days (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to few participants, few events, and wide CIs. The study was published as a journal article.
Two studies comparing ivermectin to placebo reported data on mortality at 21 days ( López&#;Medina ) and at 28 days ( Chaccour ) for 422 participants with mild disease. Both studies were included in the primary meta&#;analysis due to the overall risk of bias assessment ( ). In the meta&#;analysis, none of the participants died in the ivermectin group and one participant died in the placebo group. We are uncertain whether ivermectin reduces or increases all&#;cause mortality up to 28 days compared to placebo (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to few participants, few events, and wide CIs. Both studies were published as journal articles.
Two studies comparing ivermectin to placebo or standard of care reported viral clearance at 14 days in 69 participants with moderate&#;to&#;severe disease ( Ahmed ; Okumuş ). One of the studies with 45 participants was included in the primary analysis due the overall risk of bias assessment ( ) ( Ahmed ). Ivermectin may increase viral clearance at 14 days compared to placebo (RR 1.97, 95% CI 1.13 to 3.45; 1 study, 45 participants). The other study with high risk of bias was included in a secondary analysis ( ) ( Okumuş ). The effect estimate of the secondary analysis was comparable to the primary analysis (RR 2.07, 95% CI 1.28 to 3.33; 2 studies, 69 participants). The study included in the primary analysis was published as a journal article ( Ahmed ).
Four studies comparing ivermectin to placebo or standard of care reported viral clearance at seven days in 265 participants with moderate disease ( Ahmed ; Kirti ; Mohan ; Pott&#;Junior ). Two of the studies with 159 participants were included in the primary analysis due the overall risk of bias assessment ( ) ( Ahmed ; Mohan ). We are uncertain whether ivermectin increases or reduces viral clearance at seven days compared to placebo (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias, one level for serious heterogeneity (I 2 = 77%), and two levels for very serious imprecision due to few participants and wide CIs. The other two studies with high risk of bias were included in a secondary analysis ( ) ( Kirti ; Pott&#;Junior ). The point estimate of the secondary analysis lay closer to 1 and the 95% CI was wide and included 1 (RR 1.19, 95% CI 0.76 to 1.86; 4 studies, 265 participants). One study included in the primary analysis was published as a preprint article ( Mohan ), the other study was published as a journal article ( Ahmed ). The sensitivity analysis including only the study published in a journal favoured ivermectin compared to placebo (RR 3.83, 95% CI 1.23 to 11.93; 1 study, 45 participants).
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Four studies comparing ivermectin to placebo or standard of care reported viral clearance at three days in 288 participants with moderate disease ( Ahmed ; Kishoria ; Mohan ; Shah Bukhari ). Two of the studies with 170 participants were included in the primary analysis due to the overall risk of bias assessment ( ) ( Ahmed ; Mohan ). We are uncertain whether ivermectin increases or reduces viral clearance at three days compared to placebo (RR 1.02, 95% CI 0.45 to 2.32; 2 studies, 170 participants). The other two studies with high risk of bias were included in a secondary analysis ( ) ( Kishoria ; Shah Bukhari ). The point estimate of the secondary analysis favoured ivermectin, but the 95% CI was wide including 1 and heterogeneity was high (RR 1.73, 95% CI 0.59 to 5.04; I 2 = 73%; 4 studies, 288 participants). One study included in the primary analysis was published as a preprint article ( Mohan ), the other study was published as a journal article ( Ahmed ). The sensitivity analysis including only the study published in a journal estimated the intervention effect at RR 2.09 (95% CI 0.42 to 10.29; 1 study, 45 participants).
Two studies comparing ivermectin to placebo reported duration of hospitalization ( Ahmed ; Gonzalez ). One of these studies reported data as median with IQR on duration of hospitalization in 73 participants with moderate disease ( Gonzalez ). The median duration of hospitalization in the ivermectin group was six days (IQR 4 to 11 days) compared to five days (IQR 4 to 7 days) in the placebo group. Ahmed , investigating 45 participants with moderate disease, was included in the primary meta&#;analysis due to the overall risk of bias assessment and reporting data as means with SDs ( ). Ivermectin may have little or no effect on duration of hospitalization compared to placebo (MD &#;0.10 days, 95% CI &#;2.43 to 2.23; 1 study, 45 participants; low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and one level for serious imprecision due to few participants. Ahmed was published as a journal article and Gonzalez was published as a preprint article.
Two studies comparing ivermectin to placebo or standard of care reported the number of participants who were admitted to ICU at 28 days for participants with moderate disease ( Kirti ; Pott&#;Junior ). Both studies with 143 participants were included in the primary analysis due the overall risk of bias assessment ( ). We are uncertain whether ivermectin increases or reduces the number of participants who were admitted to the ICU at 28 days compared to placebo or standard of care (RR 0.53, 95% CI 0.11 to 2.51; 2 studies, 143 participants). One study was published as a preprint article ( Kirti ), the other was published as journal publication ( Pott&#;Junior ). The sensitivity analysis including only the study published in a journal estimated the intervention effect at RR 0.15 (95% CI 0.01 to 1.93; 1 study, 31 participants).
Three studies comparing ivermectin to placebo or standard of care reported serious adverse events within 14 days ( Ahmed ; Mohan ) and 30 days ( Krolewiecki ) in 242 participants with moderate disease. Two of these studies with 197 participants were included in the primary analysis due the overall risk of bias assessment ( ) ( Krolewiecki ; Mohan ). We are uncertain whether ivermectin increases or reduces serious adverse events up to 28 days compared to placebo or standard of care (RR 1.55, 95% CI 0.07 to 35.89; 2 studies, 197 participants). The other study with high risk of bias was included in a secondary analysis ( ) ( Ahmed ). The effect estimate of the secondary analysis is identical to the primary analysis as the study contributed no events (RR 1.55, 95% CI 0.07 to 35.89; 3 studies, 242 participants). The two studies included in the primary analysis were published as preprint articles ( Krolewiecki ; Mohan ).
Four studies comparing ivermectin to placebo or standard of care reported any adverse events within 14 days ( Mohan ), 28 days ( Pott&#;Junior ; Shah Bukhari ), and one month ( Krolewiecki ) in 314 participants with moderate disease. One of these studies was included in the primary analysis due the overall risk of bias assessment ( ) ( Mohan ). We are uncertain whether ivermectin may increase or reduce any adverse events up to 28 days compared to placebo (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to few participants and wide CIs. The other three studies with high risk of bias were included in a secondary analysis ( ) ( Krolewiecki ; Pott&#;Junior ; Shah Bukhari ). The effect estimate of the secondary analysis was comparable to the primary analysis (RR 1.04, 95% CI 0.61 to 1.79; 4 studies, 314 participants). Only the study included in the primary analysis was published as a preprint article ( Mohan ).
One study comparing ivermectin to placebo in 73 participants with moderate disease reported patients discharged without respiratory deterioration or death at 28 days ( Gonzalez ). The study was included in the primary meta&#;analysis due to the overall risk of bias assessment ( ). In both groups, 27 participants were discharged without respiratory deterioration or death at 28 days. Ivermectin may have little or no effect on clinical improvement assessed by the number of participants discharged without respiratory deterioration or death up to 28 days compared to placebo (RR 1.03, 95% CI 0.78 to 1.35; 1 study, 73 participants; low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and one level for serious imprecision due to few participants. Gonzalez was published as a preprint article.
One study comparing ivermectin to placebo assessed need for oxygen by mask or nasal prongs during the study period (14 days) for 45 participants without supplemental oxygen at baseline, but none of the participants in either group required supplemental oxygen during the study ( Ahmed ). We accepted the shorter time point of 14 days for the outcome as there are no other data available that would cause clinical incompatibility. The study was included in the primary meta&#;analysis due to the overall risk of bias assessment ( ). We are uncertain whether ivermectin reduces or increases clinical worsening assessed by the need for oxygen support up to 28 days compared to placebo (RR not estimable; 1 study, 45 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to zero events and few participants. Ahmed was published as a journal article.
Two studies in an inpatient setting reported worsening of clinical status at seven days ( Krolewiecki ) and 14 days ( Mohan ), which was clinically not comparable with studies reporting our predefined time point of 28 days. Therefore, those studies were not eligible for meta&#;analysis.
Two studies comparing ivermectin to placebo reported data on clinical worsening assessed by need for invasive mechanical ventilation at 28 days for 185 participants with moderate disease ( Gonzalez ; Kirti ). Both studies were included in the primary meta&#;analysis due to the overall risk of bias assessment ( ). In the meta&#;analysis, four participants in the ivermectin group and eight participants in the placebo group showed clinical worsening. We are uncertain whether ivermectin reduces or increases clinical worsening assessed by the need for invasive mechanical ventilation compared to placebo up to 28 days (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to few participants, few events, and wide CIs. Both studies were published as preprint articles.
Two studies in an inpatient setting reported mortality at time points not eligible for meta&#;analysis. Mohan reported mortality at 14 days, which is too short, and Okumuş reported an unclear time frame of follow&#;up. In both cases, data were not comparable with studies reporting our predefined time point of 28 days.
Two studies comparing ivermectin to placebo reported data on mortality at 28 days for 185 participants with moderate disease ( Gonzalez ; Kirti ). Both studies were included in the primary meta&#;analysis due to the overall risk of bias assessment ( ). In the meta&#;analysis, five participants died in the ivermectin group and nine participants in the placebo group. We are uncertain whether ivermectin reduces or increases all&#;cause mortality up to 28 days compared to placebo (RR 0.60, 95% CI 0.14 to 2.51; 2 RCTs, 185 participants; very low&#;certainty evidence). We downgraded the certainty of evidence one level for serious risk of bias and two levels for very serious imprecision due to few participants, few events, and wide CIs. Both studies were published as preprint articles.
One study contributed results to the primary analysis of mortality up to 28 days and risk of bias was assessed as some concerns. Shoumann provided insufficient information on randomization, allocation concealment, and missing outcome data, and did not prospectively register the outcome.
One study reported results that were not eligible for the primary analysis because of an overall high risk of bias assessment due to lack of information on measurement of the outcome and lack of blinding of outcome assessors ( Shoumann ).
One study reported results that were not eligible for the primary analysis because of an overall high risk of bias assessment due to lack of information on measurement of the outcome and lack of blinding of outcome assessors ( Shoumann ).
Two studies contributed results to the primary analysis of any adverse events within 28 days and risk of bias was assessed as some concerns. Chaccour was at overall low risk of bias. In López&#;Medina , the primary analysis was per&#;protocol due to a labelling error that resulted in 16% of participants receiving the wrong intervention. Both participants and those delivering the intervention were unaware of intervention received and reported an as&#;treated sensitivity analysis where results did not differ.
One study reported data as median with interquartile range, which were not eligible for meta&#;analysis ( López&#;Medina ). The other study was not eligible for a primary analysis because of an overall high risk of bias assessment due to inadequate randomization and lack of blinding of participants, healthcare providers, and outcome assessors, and due to missing outcome data and lack of a registered protocol ( Podder ).
One study contributed results to the primary analysis of number of participants with symptoms resolved up to 14 days and risk of bias was assessed as some concerns. In López&#;Medina , the primary analysis was per&#;protocol due to a labelling error that resulted in 16% of participants receiving the wrong intervention. Both participants and those delivering the intervention were unaware of intervention received and reported an as&#;treated sensitivity analysis where results did not differ.
One study contributed results to the primary analysis of need for non&#;invasive mechanical ventilation or high flow up to 14 days and risk of bias was assessed as some concerns. In López&#;Medina , the primary analysis was per&#;protocol due to a labelling error that resulted in 16% of participants receiving the wrong intervention. Both participants and those delivering the intervention were unaware of intervention received and reported an as&#;treated sensitivity analysis where results did not differ.
One study contributed results to the primary analysis of need for invasive mechanical ventilation at 14 days and risk of bias was assessed as some concerns. In López&#;Medina , the primary analysis was per&#;protocol due to a labelling error that resulted in 16% of participants receiving the wrong intervention. Both participants and those delivering the intervention were unaware of intervention received and reported an as&#;treated sensitivity analysis where results did not differ.
Two studies contributed results to the primary analysis of mortality up to 28 days and risk of bias was assessed as some concerns. Chaccour was at overall low risk of bias. In López&#;Medina , the primary analysis was per&#;protocol due to a labelling error that resulted in 16% of participants receiving the wrong intervention. Both participants and those delivering the intervention were unaware of intervention received and reported an as&#;treated sensitivity analysis where results did not differ.
Two studies with high risk of bias were not eligible for the primary analysis ( Kirti ; Pott&#;Junior ). Kirti had more than 30% of missing data due to discharge or inconclusive results. In Pott&#;Junior , participants and those delivering the intervention were aware of the intervention received and 25% of participants (one of four) in the control group were excluded due to protocol violations (per&#;protocol analysis). Protocol violations were not described.
Two studies contributed results to the primary analysis of viral clearance at seven days and risk of bias was assessed as some concerns. Mohan was at overall low risk of bias. Ahmed provided insufficient information on randomization, allocation concealment, blinding of participants and healthcare providers, and did not provide a prospectively registered protocol.
One study contributed results to the primary analysis of duration of hospitalization and risk of bias was assessed as some concerns. Ahmed provided insufficient information on randomization, allocation concealment, and blinding of participants and healthcare providers, and did not provide a prospectively registered protocol.
Three studies with high risk of bias were not eligible for the primary analysis ( Krolewiecki ; Pott&#;Junior ; Shah Bukhari ). All three studies provided insufficient information on definition, and measurement of the outcome and outcome assessors were not blinded. One study had missing outcome data of more than 14% ( Shah Bukhari ). Participants withdrew against medical advice before completion of the study.
One study contributed results to the primary analysis of any adverse events within 28 days and risk of bias was assessed as some concerns. Mohan provided insufficient information on definition and measurement of the outcome, and did not prespecify the outcome in the prospectively registered protocol.
One study contributed results to the primary analysis of patients discharged without respiratory deterioration or death at 28 days and risk of bias was assessed as some concerns. Gonzalez provided insufficient information on allocation concealment and blinding of healthcare providers and did not register the outcome in the protocol.
One study contributed results to the primary analysis of need for oxygen by mask or nasal prongs up to 28 days and risk of bias was assessed as some concerns. Ahmed provided insufficient information on randomization, allocation concealment, and blinding of participants and healthcare providers, and did not provide a prospectively registered protocol.
Two studies contributed results to the primary analysis of need for invasive mechanical ventilation up to 28 days and risk of bias was assessed as some concerns. Gonzalez provided insufficient information on allocation concealment and blinding of healthcare providers, and did not define the time point of outcome measurement in the protocol. Kirti performed an inappropriate analysis (per&#;protocol analysis).
Two studies contributed results to the primary analysis of mortality up to 28 days and risk of bias was assessed as some concerns. Gonzalez provided insufficient information on allocation concealment and blinding of healthcare providers, and did not define the time point of outcome measurement in the protocol. Kirti performed an inappropriate analysis (per&#;protocol analysis).
Most of the 41 study results (56.1%) had some concerns for the overall risk of bias. Thirteen (31.7%) of the 41 study results were at overall high risk of bias. We excluded studies with overall high risk of bias from the primary meta&#;analyses of the review. The main reasons a study result was assessed at high risk of bias were missing outcome data and measurement of the outcome. Studies with high risk of bias were included in secondary meta&#;analyses. Two studies contributing five study results (12.2%) to four outcomes, including all&#;cause mortality, adverse events, and viral clearance at three and seven days, were at overall low risk of bias ( Chaccour ; Mohan ).
Five studies are comparing ivermectin to placebo or no treatment with the intention to prevent SARS&#;CoV&#;2 infection in close contacts of COVID&#;19 index cases. Two of those are planned as substudies on close contacts that also investigate treatment in 266 ( &#;&#;66/ES ) and 240 ( PACTR ) participants. Three larger trials, all of which are using placebo as control, are solely focusing on the period after high&#;risk exposure to COVID&#;19. One trial with 750 close contacts is still recruiting, but expected to be completed during the time of review publication ( {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ), another one including close contacts will be completed in October ( PACTR ). Finally, one study is evaluating postexposure prophylaxis in 550 healthcare workers ( {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). This study was supposed to be completed in December , but according to the trial registry has not started recruiting yet.
Ten of 31 ongoing studies are comparing ivermectin plus standard of care to standard of care alone, and plan to evaluate between 50 and 240 participants. Six of 10 studies include participants in inpatients settings ( CTRI//05/ ; CTRI//05/ ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; PACTR ), one study includes outpatients ( {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ), and three studies are unclear about this issue in their protocol ( IRCTN2 ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). Most of those studies were expected to be completed by May , but according to the trial registry, five are still recruiting ( {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ), one has not started recruitment yet ( {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ), and one does not report the recruitment status ( IRCTN2 ). One trial that is currently recruiting is expected to be completed in ( PACTR ). The two studies without an indicated completion date have not started recruiting yet ( CTRI//05/ ; CTRI//05/ ).
We identified five completed and potentially eligible RCTs from trial register entries, but there were no results available or published ( &#;&#;12/BG ; Hosseini ; IRCTN3 ; IRCTN2 ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). Three studies investigated ivermectin with standard of care versus standard of care alone in 220 participants in an inpatient setting ( Hosseini ; IRCTN3 ; IRCTN2 ), another two completed studies used placebo as comparator in 192 participants ( &#;&#;12/BG ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). Ten studies were not explicit enough in their protocol to make a final decision on eligibility. First, none of the following eight studies reported a clear description of the type of control intervention used as comparator ( &#;&#;33/ES ; CTRI//04/ ; CTRI//06/ ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). Additionally, for two of those trials, it was unclear if an RT&#;PCR&#;confirmed COVID&#;19 diagnosis was required for inclusion ( {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). Similarly, two studies investigating prevention were not well&#;defined regarding the inclusion criteria of high&#;risk exposure to an index patient ( ISRCTN ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ). Finally, for another trial, we could not evaluate the actual rationale or the considered patient population due to inconclusive PICO details ( IRCTN3 ).
Three studies had already been published or had results posted in the trial registry ( Faisal ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT ; Samaha ). However, despite using the term 'randomized controlled trial,' there were contradictory details throughout the published text or protocol that led us to believe those studies were not fulfilling criteria of genuine RCTs. We contacted study authors for clarification but received no response at the time of review publication.
The only included study with intention to prevent SARS&#;CoV&#;2 infection reported two of the primary outcomes defined by the review, including development of clinical COVID&#;19 symptoms at 14 days and adverse events within 14 days ( Shoumann ). The number of participants with confirmed SARS&#;CoV&#;2 infection was not investigated.
Participants included in three of the four outpatient studies had mostly mild COVID&#;19 according to a patient state of 2 to 3 on the WHO scale ( Chaccour ; Chachar ; Podder ). Participants in López&#;Medina had mostly mild COVID&#;19 defined as WHO scale 2 to 3, but less than 1% of participants were hospitalized with or without supplemental oxygen.
The literature search resulted in 326 records. A handsearch of reference lists identified a further 22 records, resulting in an overall 348 records. After removing duplicates, 318 records remained. During title and abstract screening, 175 records were judged as irrelevant as they did not meet the prespecified inclusion criteria. We proceeded to full&#;text screening with 143 records, considering published full texts or, if these were unavailable, trial register entries. We excluded 57 records related to 38 studies after full&#;text assessment. Twelve studies investigated combined treatments including ivermectin, eight studies used an active comparator without proven efficacy, and five studies analyzed inappropriate study populations including RT&#;PCR&#;negative participants. Furthermore, nine studies were not RCTs and four studies focused on an intervention other than ivermectin. We identified 31 ongoing studies with 37 records and 18 studies with 20 records awaiting assessment. Fourteen studies with 29 records met our eligibility criteria and were used for qualitative synthesis. One study did not report on outcome time points relevant to this review, hence, 13 studies contributed data to our meta&#;analyses (quantitative syntheses). The search process is shown in .
This review included 14 studies with participants investigating ivermectin compared to placebo or standard of care. With intention to treat COVID&#;19, nine studies were conducted in inpatient settings with mainly moderate COVID&#;19 (WHO 4 to 5) and four studies in outpatient settings with mild COVID&#;19 (WHO 2 to 3). One study investigated ivermectin for the prevention of SARS&#;CoV&#;2 infection. The included studies contributed 41 study results to the review of which about one third were assessed at overall high risk of bias. The main findings of this review are summarized in (treatment; inpatients), (treatment; outpatients), and (prevention). The number of studies per outcome was low. Only one or two studies per outcome provided useful data for our prioritized outcomes included in the summary of findings tables.
Ivermectin showed no evidence of an effect on increasing or decreasing mortality at 28 days, the most important outcome during this pandemic, neither in inpatients (two studies), outpatients (two studies), or the preventive setting (one study). The certainty for this finding was very low. The same accounts for clinical worsening up to 28 days in an inpatient setting and up to 14 days in an outpatient setting.
With regard to clinical improvement, ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days and duration of hospitalizations in an inpatient setting. For outpatients, ivermectin may have little or no effect on the number of participants with symptoms resolved up to 14 days. Based on very low certainty evidence, there was no significant increase in viral clearance at seven days in participants treated with ivermectin in inpatient settings and based on low&#;certainty evidence for outpatient settings. For adverse events, ivermectin may have little or no difference on occurrence of adverse events within 14 days in an outpatient setting, while we are uncertain about the effect of ivermectin on adverse events within 28 days in an inpatient setting.
The most significant outcome for participants not infected but at high risk of developing the infection following high&#;risk exposure was development of confirmed SARS&#;CoV&#;2 infection, which no studies reported. One study reported development of clinical COVID&#;19 symptoms, which we could not include in the primary analysis due to high risk of bias. The same accounted for adverse events within 14 days.
Nine of 14 included studies were conducted in inpatient settings. However, participants mostly had moderate&#;severity COVID&#;19. Only one study included participants with severe COVID&#;19 requiring mechanical ventilation at baseline (Okumuş ). Therefore, the findings of this review are transferable to inpatients with moderate COVID&#;19 only. Four of 14 included studies were conducted in an outpatient setting with mild COVID&#;19 symptoms, though only two studies reported relevant outcomes and also had overall low risk or some concerns of bias (Chaccour ; López&#;Medina ). Based on the eligible study pool, there is currently no evidence available for the use of ivermectin in severely ill people with COVID&#;19 or those at high risk of disease progression. Most studies reported a mean age far below 60 years (overall mean age was 43 years with a mean range from 28 to 62 years) and included people with very few or no comorbidities (e.g. obesity). This major risk factor for severe COVID&#;19, was only reported in three studies (Chachar ; Krolewiecki ; López&#;Medina ). Considering age and pre&#;existing conditions as the most important risk factors for developing severe COVID&#;19, the current evidence is not applicable to patients who are at most risk of death from COVID&#;19.
Hence, for outpatients as well as for inpatients we are still in need of good&#;quality trials in relevant populations to obtain evidence that would justify the use of ivermectin in regular patient care. In June , the PRINCIPLE trialists announced inclusion of ivermectin in their platform trial, which might provide us with applicable data that helps to complete evidence for outpatient treatment (PRINCIPLE trial).
Only 1 of 14 included studies investigated the potential of ivermectin for prevention of SARS&#;CoV&#;2 infection in people after high&#;risk exposure. The study did not report results free of high risk of bias for one of the primary outcomes of interest for this review. Therefore, it is currently unclear whether ivermectin can prevent SARS&#;CoV&#;2 infection in people who have had a high&#;risk contact.
Seven studies were conducted in Asia, four studies in South America, two in Europe, and one in Africa. In some countries where studies were conducted, uncontrolled ivermectin use is making it difficult to test the effectiveness of the antiparasite drug against SARS&#;CoV&#;2 (Rodríguez&#;Mega ). With Chaccour , only one study was conducted in a country with high healthcare expenditure.
All studies administered ivermectin per mouth, but the doses and durations of administration varied. We set 200 µg/kg orally per day as the low dose based on the dosing recommendation for strongyloidiasis (WHO ). Four of the 14 studies used low doses in at least one study arm. All other studies utilized higher doses either in a single dose or over two to five days. Due to the small number of studies per outcome, we did not perform any subgroup analyses with low versus high doses and no evidence or clinical implication can be obtained regarding a certain dosing regimen.
We found no studies that compared ivermectin to an active comparator with confirmed efficacy such as dexamethasone. Eight of the 14 studies had an open&#;label design and used no treatment or standard of care as comparators. Six studies were placebo&#;controlled studies. Standard of care must be comparable between the studies' arms. There are several studies circulating that investigate various concomitant medications (e.g. doxycycline, hydroxychloroquine, azithromycin, zinc) in addition to ivermectin. Due to unproven efficacy and possible adverse effects, these comparisons may confound the assessment of the efficacy or safety of ivermectin, and we considered the inclusion of such combination therapies inappropriate. The same accounts for the comparison of ivermectin with an active comparator that has no proven efficacy in COVID&#;19. Although those types of interventions (e.g. hydroxychloroquine) were possibly used at a certain point of the pandemic with the best intentions, their use was never supported by actual evidence, and they have potential adverse effects (Singh ). As we do not know the effect of many of those experimental comparators in people with COVID&#;19, consequently no reliable evidence for ivermectin can be obtained from those comparisons either.
Although 14 studies were eligible for the review questions, primary outcomes for studies with intention to treat COVID&#;19, as defined by the review, were only reported by a minority of studies. For some outcomes, different time points of outcome assessment or different outcome definitions prevented clinically useful pooling of the study results. Clinical worsening and improvement were heterogeneously reported, including outcomes that represent competing risks. Few studies followed the WHO Clinical Progression Scale (Marshall ). One study reported improvement and worsening of clinical status in an inpatient setting as the number of 'patients discharged without respiratory deterioration or death at 28 days' and as 'patients with respiratory deterioration or death at 28 days' (Gonzalez ). If reported at the same day, both outcomes give useful information on the clinical status of the study population in both directions &#; improvement and worsening &#; without containing competing risks. The outcome 'patients discharged without respiratory deterioration or death at 28 days' was deemed to be clinically useful and was added as a new primary outcome during preparation of this review. With further studies reporting these two very precise and unambiguous endpoints, evidence on ivermectin becomes more complete and patient&#;relevant.
Finally, 31 studies are ongoing and 18 studies are awaiting classification due to an unpublished status or requiring clarification due to inconsistencies. When the studies are published or inconsistencies are clarified by study authors via personal communication, we will include them in a review update and conclusions of this review may change. Especially the most recently registered trials are proposing much larger numbers of participants than those of published trials so far. With group sizes ranging within the thousands, those trials may help to increase the certainty of evidence on the efficacy and safety of ivermectin. So far, we included only one study with intention to prevent SARS&#;CoV&#;2 infection. We identified several ongoing and unpublished studies focusing on this rationale. We are awaiting publication of those results to close the current gaps in the evidence on ivermectin used in postexposure prophylaxis.
The certainty of evidence for prioritized outcomes presented in the summary of findings tables ranged from very low to low ( ; ; ).
For the summary of findings and assessment of the certainty of the evidence according to Schünemann , we used the results from the primary meta&#;analyses. Primary meta&#;analyses included only studies with low risk or some concerns of bias. We excluded studies at high risk of bias for their respective outcome and only analyzed them in secondary analyses to test the robustness of the results. One third of the study results were at overall high risk of bias. Most study results had some concerns for risk of bias. Two studies contributing five study results to four outcomes, including all&#;cause mortality, adverse events, and viral clearance at three and seven days, were at overall low risk of bias (Chaccour ; Mohan ). For the summary of findings, the certainty of evidence was downgraded one level due to serious risk of bias because most of the results were assessed as 'some concerns' of bias. Details of the risk of bias assessments per outcome are reported in Risk of bias in included studies. We could only include one study with overall low risk of bias on viral clearance at day seven in an outpatient setting in the primary analysis (Chaccour ). The certainty of evidence was not downgraded for study limitations. Nevertheless, this effect estimate was associated with high uncertainty based on the low number of participants and few events.
Another limitation for the certainty of evidence was the low number of participants, or events, or both, leading to wide CIs and high uncertainty of the estimated effects. All outcomes included in the summary of findings tables were downgraded one or two levels for imprecision.
Heterogeneity was rarely a reason to downgrade the certainty of evidence. This is mainly due to the small number of studies per meta&#;analysis. The only outcome with high heterogeneity (I2 = 77%) included in the summary of findings tables was viral clearance at day seven in an inpatient setting. Two studies with conflicting results, one favouring ivermectin (Ahmed ), and one showing no important difference between ivermectin and placebo (Mohan ), caused the high statistical heterogeneity.
We did not downgrade any of the outcomes included in the summary of findings tables for indirectness. In all cases, the effect estimates were based on comparisons of interest, on the population of interest, and on outcomes of interest.
In the current phase of the pandemic, it is impossible to reliably assess the risk of publication bias. Most of the registered studies are still ongoing or, in the case of a completed study status, their results have not yet been published. We will follow the publication and trial history of each ongoing study and study awaiting classification. Currently, we did not suspect publication bias for any outcome included in this review. However, this may change in updates of this review.
This review aimed to provide a complete evidence profile for ivermectin with regard to efficacy and safety for postexposure prophylaxis and treatment of COVID&#;19 based on current Cochrane standards (Higgins a).
The review team is part of the German research project 'CEOsys' (COVID&#;19 Evidence&#;Ecosystem). CEOsys is a consortium of clinical and methodological experts supported by the German Federal Ministry of Education and Research to synthesize clinical evidence during this global pandemic. The involved medical information specialists of this consortium carried out a rigorous search of electronic databases including preprint servers and clinical trial registries to identify the complete extent of published and ongoing trials on this topic. Additionally, we compared our search results with those from 'living' meta&#;analysis and reviews (COVID&#;NMA Working Group; ivmmeta.com). Therefore, we are confident that we identified all relevant studies and are monitoring ongoing studies as well as full publication of preprints closely after the publication of this review.
Five studies were preprint articles. We are aware that articles may change following peer&#;review. Nevertheless, we are convinced that including all eligible data in a highly dynamic situation such as the COVID&#;19 pandemic is crucial to be up&#;to&#;date and to provide timely information on potentially promising treatment options. Journal publications and corresponding preprint articles were compared in terms of consistency and all study results were assessed for their risk of bias.
The immense amount of ongoing RCTs reflects the persistent lack of clarity on this intervention and the need for an update of this review. It should be considered that conclusions of the updated version differ from those of the present review. Review updates may allow for a more concise judgement of the effectiveness and the safety of ivermectin for treatment and prevention of COVID&#;19.
To minimise errors in screening, data extraction, and risk of bias assessment, two review authors independently conducted all processes. Analyses were conducted by one review author and checked by a second review author. We provided reasons for the exclusion of studies from this systematic review and described each included study in full detail and made explicit judgements on individual risk of bias.
We contacted study authors if the publication included unclear or inconclusive information or in case of missing information. Unfortunately, not all attempts of gathering data were successful. Details of the communication with authors are provided in the Characteristics of included studies table.
For three studies that had already published results, we could not finally judge eligibility due to inconsistencies in their study design description (Faisal ; {"type":"clinical-trial","attrs":{"text":"NCT","term_id":"NCT"}}NCT; Samaha ). We contacted the corresponding authors to clarify those questions, though we have not received any satisfying response at the time of review publication. Another 15 trials classified as awaiting classification have not yet published results appropriately. We will monitor trials that have completed recruitment according to the trial registry closely for publication in the near future.
None of the members of the review author team has any affiliation with any stakeholder group who favours or disapproves of ivermectin or the comparators used in relevant studies.
Ahead of full US authorisation of the Pfizer coronavirus vaccine, the federal Food and Drug Administration (FDA) had a simple message for Americans contemplating using ivermectin, a medicine used to deworm livestock, instead of getting a Covid shot.
&#;You are not a horse,&#; it said. &#;You are not a cow. Seriously, y&#;all. Stop it.&#;
As with other purported alternative treatments for Covid-19, misinformation about ivermectin has spread on social media and through rightwing media and politicians.
In July, Bret Weinstein, an evolutionary biologist, told Fox News host Tucker Carlson: &#;[If] ivermectin is what those of us who have looked at the evidence think it is &#; the debate about the vaccines would be over by definition.&#;
In a Senate hearing last December, doctors touted ivermectin alongside hydroxychloroquine, once championed by Donald Trump, and other alternatives.
In comments shared widely on social media, Dr Pierre Kory, then a pulmonary and critical care specialist at Aurora St Luke&#;s medical center in Milwaukee, called ivermectin a &#;wonder drug&#;. Kory subsequently left Aurora St Luke&#;s.
Experts said then that test results suggesting ivermectin could inhibit replication of the SARS-CoV-2 virus did not amount to official authorisation for use.
&#;It is a far cry from an in-vitro lab replication to helping humans,&#; Dr Nasia Safdar, medical director of infection prevention at the University of Wisconsin-Madison Hospital, told the Associated Press.
Eight months later, many US states are struggling to boost vaccination rates and contain the contagious Delta variant, some running out of intensive care capacity.
The vast majority of hospitalisations and deaths in the US involve unvaccinated people. On Saturday night in Alabama, the state with the lowest vaccination rate, Trump told a crowd to get the shot. He was booed and jeered.
On Sunday the US surgeon general, Dr Vivek Murthy, told CNN: &#;The best protection we have against Covid-19 is the vaccine, and if you get Covid-19, we actually do have treatments that work.
&#;Ivermectin is not one of them.&#;
The Pfizer shot was formally approved on Monday.
The FDA accompanied its Saturday tweet with a fact sheet. In answer to the question &#;Should I take ivermectin to treat Covid-19&#;, it said: &#;No. While there are approved uses for ivermectin in people and animals, it is not approved for the prevention or treatment of Covid-19.
&#;You should not take any medication to treat or prevent Covid-19 unless it has been prescribed to you by your healthcare provider and acquired from a legitimate source.&#;
Additional studies, it said, were needed to determine whether ivermectin &#;might be appropriate to prevent or treat coronavirus or Covid-19&#;.
The FDA said it approved ivermectin for use &#;for treatment of certain internal and external parasites in various animal species&#; and &#;people should never take animal drugs [as] using these products in humans could cause serious harm&#;.
Side-effects that could be associated with ivermectin, it said, included &#;skin rash, nausea, vomiting, diarrhoea, stomach pain, facial or limb swelling, neurologic adverse events (dizziness, seizures, confusion), sudden drop in blood pressure, severe skin rash potentially requiring hospitalisation, and liver injury (hepatitis).
&#;Laboratory test abnormalities include decrease in white cell count and elevated liver tests. Any use of ivermectin for the prevention or treatment of Covid-19 should be avoided.&#;
In Mississippi last week, the state health department said at least one person had been hospitalised after ingesting ivermectin.
Dr Thomas Dobbs, Mississippi&#;s state health officer, said using the drug as a preventative &#;is really kind of crazy. So please don&#;t do that.&#;
The FDA also said some animal owners may be having difficulties finding ivermectin because of humans seeking Covid cures.
Ivermectin tablets are approved for use in humans, the FDA said, for &#;the treatment of some parasitic worms&#;. Formulations can be used by prescription only for the treatment of &#;skin conditions such as rosacea&#; and &#;external parasites such as headlice&#; &#; or nits.
This article was amended on 24 August to clarify that Dr Pierre Kory is no longer employed by Aurora St Luke&#;s medical center.
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