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Therefore, assuming it does not widely deviate from other published systematic reviews, a pragmatic decision was therefore made to power on the pooled meta-analysis effect estimate for all-cause mortality a priori. This is more reflective of a true meaningful difference. We used a model variance-based estimate to correct for heterogeneity. A continuity correction of 0.

The required IS is the sample size required for a reliable and conclusive meta-analysis and is at least as large as that needed in a single powered RCT. The heterogeneity corrected required IS was used to construct sequential monitoring boundaries based on the O'Brien—Fleming type alpha-spending function for the cumulative z-scores corresponding to the cumulative meta-analysis , 43 analogous to interim monitoring in an RCT, to determine when sufficient evidence had been accrued.

These monitoring boundaries are relatively insensitive to the number of repeated significance tests. They can be used to further contextualize the original meta-analysis and enhance our certainty around its conclusions. We used a two-sided test, so also considered futility boundaries to test for no statistically significant difference and the possibility that ivermectin could harm. Sensitivity analyses were performed excluding the trial of Fonseca, 44 which was a cause of substantial heterogeneity but retained in the core analysis because it was at low risk of bias.

Its removal dramatically reduced I 2 and D 2 diversity estimates, thus reducing the model variance-based estimate to correct for heterogeneity. Two further sensitivity analyses were performed using 2 alternative random effect models, namely the Biggerstaff—Tweedie BT and Sidik—Jonkman SJ methods.

All outcomes have been assessed independently by 2 review authors T. The results of the TSAs will also form part of the judgment for the primary all-cause mortality outcome. The results are presented in a summary of findings table. Any differences in judgments were resolved by discussion with the wider group. We also identified 11 records from other sources reference lists, etc. The supplementary search for the BEC identified 17 studies, of which 4 were retrieved in full.

No full trial- or model-based economic evaluations cost—utility analyses, cost—effectiveness analyses, or cost—benefit analyses were identified. In effect, there were 22 trials in treatment and 3 in prophylaxis. All of these contributed data to at least one review outcome and meta-analysis. Fifteen trials contributed data for the primary outcome for ivermectin treatment death ; 3 studies reported the primary outcome for prophylaxis COVID infection.

Seventeen studies 47 — 63 were excluded as they were not RCTs and we identified 39 ongoing studies 64 — and 2 studies , are awaiting classification. Eleven studies 23 , 24 , 44 , 47 , , — used satisfactory random sequence generation and allocation concealment. Two trials described satisfactory sequence generation, but it was unclear whether allocation was concealed.

Risk-of-bias summary: review authors' judgments about each risk of bias item for each included study. We considered blinding to be a less important criterion for evaluation of evidence related to the review's primary outcomes, namely death and laboratory-confirmed COVID infection, which are objective outcomes. We did not consider publication on preprint web sites to constitute a risk of bias because all studies were scrutinized and peer reviewed by us during the review process and, where additional information was needed, we contacted the authors for clarification.

Twenty-four RCTs including 3 quasi-RCTs involving participants were included, with sample sizes ranging from 24 to participants. Twenty-two trials in treatment and 3 trials in prophylaxis met review inclusion, including the trial of Elgazzar et al, which reported both components.

Three RCTs involving participants were included in the prophylaxis trials. Most trials were registered, self-funded, and undertaken by clinicians working in the field. There were no obvious conflicts of interest noted, with the exception of two trials.

Twenty-two trials participants contributed data to the comparison ivermectin treatment versus no ivermectin treatment for COVID treatment. Much of the heterogeneity was explained by the exclusion of one trial 44 in a sensitivity analysis average RR 0. The source of heterogeneity may be due to the use of active comparators in the trial design. The results were also robust to sensitivity analyses excluding 2 other studies with an active treatment comparator average RR 0.

The results were also not sensitive to the exclusion of studies that were potentially at higher risk of bias average RR 0. The effect on reducing deaths was consistent across mild to moderate and severe disease subgroups. Subgrouping data according to inpatient and outpatient trials was not informative because few outpatient studies reported this serious outcome.

The conclusions of the primary outcome were also robust to a series of alternative post hoc analyses that explored the impact of numerous trials that reported no deaths in either arm. Extreme sensitivity analyses using a treatment arm continuity correction of between 0. Sensitivity analyses for death from any cause considering methods for dealing with zero events in trials. TSA, using the DL random-effects method, showed that there may have been sufficient evidence accrued before the end of to show significant benefit of ivermectin over control for all-cause mortality.

This estimate is similar to effect estimates reported in other reviews. We used a model variance-based estimate of The solid blue line is the cumulative z-curve and represents the observed trials in the cumulative meta-analysis.

The adjusted significance boundaries for the cumulative z-curve were constructed under the assumption that significance testing may have been performed each time a new trial was added to the meta-analysis.

Sensitivity analysis excluding the trial of Fonseca 44 significantly reduced heterogeneity in the meta-analysis and thus the diversity estimate in the TSA using the DL model. Because the DL estimator could potentially underestimate the between-trials variance, 43 we performed further sensitivity analyses using 2 alternative random-effects model approaches. The TSA comprehensively confirms the result of the conventional meta-analysis.

The required IS was The SJ estimator may overestimate the between-trials variance in meta-analyses with mild heterogeneity, thus producing artificially wide confidence intervals. There was no evidence of futility using the SJ method in any scenario. Furthermore, the ease with which trial reports can be uploaded as preprints should reduce this risk. Funnel plot of ivermectin versus control for COVID treatment for all-cause death subgrouped by severity.

All other secondary outcome findings were assessed as very low certainty. Meta-analysis of 11 trials, assessing participants, found that there was no significant difference between ivermectin and control in the risk of severe adverse events aRR 1. Seven severe adverse events were reported in the ivermectin group and 2 in controls. GRADE working group grades of evidence; High quality: Further research is very unlikely to change our confidence in the estimate of effect; Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality: We are very uncertain about the estimate.

The findings indicate with moderate certainty that ivermectin treatment in COVID provides a significant survival benefit. Our certainty of evidence judgment was consolidated by the results of trial sequential analyses, which show that the required IS has probably already been met.

Low-certainty evidence on improvement and deterioration also support a likely clinical benefit of ivermectin. Low-certainty evidence suggests a significant effect in prophylaxis. Overall, the evidence also suggests that early use of ivermectin may reduce morbidity and mortality from COVID This is based on 1 reductions in COVID infections when ivermectin was used as prophylaxis, 2 the more favorable effect estimates for mild to moderate disease compared with severe disease for death due to any cause, and 3 on the evidence demonstrating reductions in deterioration.

The evidence on severe adverse events in this review was graded as low certainty, partly because there were too few events to reach statistical significance. Evidence from a recent systematic review of ivermectin use among people with parasitic infections suggests that ivermectin administered at the usual doses 0. We restricted the included studies to the highest level of evidence, that is, RCTs, as a policy.

This was despite there being numerous observational but nonrandomized trials of ivermectin, which one could argue could also be considered in an emergency.

We included preprint and unpublished data from completed but not yet published trials due to the urgency related to evidence synthesis in the context of a global pandemic. There are a number of limitations with this review. Several of the studies contributing data did not provide full descriptions of methods, so assessing risk of bias was challenging.

Where descriptions of study methods were sparse or unclear, we attempted to contact authors to clarify methods, but lack of information led us to downgrade findings in several instances. Overall interpretation of findings was hampered due to variability in the participants recruited, treatment regimen, and the care offered to those in control groups. We have tried to take this variation into account through subgroup and sensitivity analyses. We did not include laboratory outcome measures, such as viral clearance.

The latter and other biochemical outcomes have been reported in several studies and reviews and tend to favor ivermectin. Because we did not undertake in our protocol to perform narrative evidence synthesis, and because these data tended to favor ivermectin, the certainty of the effects of ivermectin on these continuous outcomes may be underestimated. However, there was also a suggestion that ivermectin reduced the risk of death in treatment of COVID in these reviews. The recently updated WHO therapeutics guidelines 12 included 7 trials and people in the analysis of mortality.

In addition to the evidence from systematic reviews, the findings of several controlled observational studies are consistent with existing evidence and suggest improved outcomes with ivermectin treatment. Clarifying ivermectin safety in pregnancy is a key question in patient acceptability for pregnant women contracting COVID A recent meta-analysis 5 found little evidence of increased risk of abnormal pregnancies but similarly weak evidence of absence of risk.

For pre-exposure prophylaxis in pregnancy, where vaccines may be contraindicated, the alternative of hydroxychloroquine has been advocated.

RCTs in this review did not specifically examine use of ivermectin in the elderly, although this is a known high-risk group for severe COVID In the setting of care homes, it is also notorious for rapid contagion. A standard indication for ivermectin in the elderly is scabies. We identified 2 recent reports suggesting that ivermectin may be efficacious as prevention and treatment of COVID in this age group.

There is also evidence emerging from countries where ivermectin has been implemented. Other considerations related to the use of ivermectin treatment in the COVID pandemic include people's values and preferences, equity implications, acceptability, and feasibility. However, in health care decision making, evidence on effectiveness is seldom taken in isolation without considering these factors. Despite ivermectin being a low-cost medication in many countries globally, the apparent shortage of economic evaluations indicates that economic evidence on ivermectin for treatment and prophylaxis of SARS-CoV-2 is currently lacking.

Given the evidence of efficacy, safety, low cost, and current death rates, ivermectin is likely to have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with an unknown safety profile. Ivermectin is likely to be an equitable, acceptable, and feasible global intervention against COVID Health professionals should strongly consider its use, in both treatment and prophylaxis.

The authors also thank Isabella Rushforth for her voluntary assistance with the preparation of the reference lists. The authors thank Gill Gyte for detailed comments, feedback, and involvement in this review, and Michael Grayling and David Tovey for useful peer review comments before submission. The authors also thank the external peer reviewers for their helpful comments and Peter Manu for the opportunity to publish our findings.

The preprint of this review received no funding. The authors have no conflicts of interest to declare. Lawrie and A. Bryant cowrote the review; they also sifted the search and classified studies for inclusion and entered and checked the data in RevMan and performed analyses.

Data extraction was divided among T. Lawrie, A. Bryant, and T. Dowswell and A. Bryant graded the evidence. Fordham prepared the text on ivermectin mechanisms, use in pregnancy, and among the elderly. Hill prepared the brief economic commentary. Clinicians S. Mitchell and T. Tham contributed to the interpretation of the evidence in the discussion and conclusions. All authors reviewed and approved the final version of the manuscript. National Center for Biotechnology Information , U.

American Journal of Therapeutics. Am J Ther. Published online Jun Hill , PhD, 1 and Tony C. Theresa A. Edmund J. Sarah R. Tony C. Find articles by Tony C. Author information Copyright and License information Disclaimer. Lawrie: ku. Fordham: ten. Hill: ku. Tham: moc. E-mail: ku. Published by Wolters Kluwer Health, Inc.

The work cannot be changed in any way or used commercially without permission from the journal. This article has been cited by other articles in PMC. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID infection. Data sources: We searched bibliographic databases up to April 25, Therapeutic Advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin average risk ratio 0.

Conclusions: Moderate-certainty evidence finds that large reductions in COVID deaths are possible using ivermectin. METHODS The conduct of this review was guided by a protocol that was initially written using Cochrane's rapid review template and subsequently expanded to a full protocol for a comprehensive review. Open in a separate window. Table 1. Summary of study characteristics. SOC, standard of care; PR, peer review.

Main findings Twenty-four RCTs including 3 quasi-RCTs involving participants were included, with sample sizes ranging from 24 to participants. Ivermectin treatment versus no ivermectin treatment Twenty-two trials participants contributed data to the comparison ivermectin treatment versus no ivermectin treatment for COVID treatment. Table 2. Table 3. Trial sequential analysis TSA, using the DL random-effects method, showed that there may have been sufficient evidence accrued before the end of to show significant benefit of ivermectin over control for all-cause mortality.

Sensitivity analyses Sensitivity analysis excluding the trial of Fonseca 44 significantly reduced heterogeneity in the meta-analysis and thus the diversity estimate in the TSA using the DL model. Death due to any cause, excluding an outlier study responsible for the heterogeneity. Could this lead to R. Kelly exposing many members of the Epstein ring and high level members of the cabal?

The more important question at this point is whether or not he will actually go through it, as Willie D explains in his video below:. CrookedIntriago Watson Thoughts.

Epstein was ready to give up names, and then was found dead in his cell…….. Kelly no doubt knows this, I wonder which choice he will make:. RIP R. KELLY in advance. So R Kelly plans to snitch on pedophiles and all of a sudden all social media sites are down???

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