Ivermectin and COVID-19: Meta Analysis of 36 studies (February 2021)

At-A-Glance:

  • 100% of the 36 studies to date report positive effects. Early treatment is more successful, with an estimated reduction of 82% in the effect measured using a random effects meta-analysis, RR 0.18 [0.10-0.34]. Prophylactic use also shows high effectiveness.
  • 100% of the 18 Randomized Controlled Trials (RCTs) report positive effects, with an estimated reduction of 71%, RR 0.29 [0.17-0.50].
  • The probability that an ineffective treatment generated results as positive as the 36 studies to date is estimated to be 1 in 69 billion (p = 0.000000000015).



Introduction
We analyze all significant studies concerning the use of ivermectin for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for mortality results only, and for Randomized Controlled Trials (RCTs) only.

We also perform a simple analysis of the distribution of study effects. If treatment was not effective, the observed effects would be randomly distributed (or more likely to be negative if treatment is harmful). We can compute the probability that the observed percentage of positive results (or higher) could occur due to chance with an ineffective treatment (the probability of >= k heads in n coin tosses, or the one-sided sign test / binomial test). Analysis of publication bias is important and adjustments may be needed if there is a bias toward publishing positive results.

Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment Stages

Results
Results by Treatment Stage


Randomized Controlled Trials (RCTs)
RCT results are similar to non-RCT results. Evidence shows that non-RCT trials can also provide reliable results. [Concato] find that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. [Anglemyer] summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. [Lee] shows that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see [DeatonNichol].

Discussion
Publishing is often biased towards positive results, which we would need to adjust for when analyzing the percentage of positive results. For ivermectin, there is currently not enough data to evaluate publication bias with high confidence. One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results. While some effects are not statistically significant when considered alone, currently all ivermectin studies report positive effects. 24 of the 36 studies are prospective studies.
Typical meta analyses involve subjective selection criteria, effect extraction rules, and study bias evaluation, which can be used to bias results towards a specific outcome. In order to avoid bias we include all studies and use a pre-specified method to extract results from all studies. Every day that the approval of ivermectin is delayed results in thousands of deaths, so it is important to consider all available data. We note that the positive results to date are very consistent and are relatively insensitive to potential selection criteria, effect extraction rules, and/or bias evaluation.
Studies vary significantly in terms of treatment delay, treatment regimen, patients characteristics, and (for the pooled effects analysis) outcomes, as reflected in the high degree of heterogeneity. However the results consistently show a positive effect of treatment, and with the exception of some late treatment studies, the effect size is large.
Additional meta analyses confirming the effectiveness of ivermectin can be found in [HillKoryLawrie][Kory] also review epidemiological data and provide suggested treatment regimens.
Conclusion
Ivermectin is an effective treatment for COVID-19. The probability that an ineffective treatment generated results as positive as the 36 studies to date is estimated to be 1 in 69 billion (p = 0.000000000015). As expected for an effective treatment, early treatment is more successful, with an estimated reduction of 82% in the effect measured using a random effects meta-analysis, RR 0.18 [0.10-0.34].

We performed ongoing searches of PubMed, medRxiv, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19ivermectin.com, which regularly receives submissions of studies upon publication. Search terms were ivermectin and COVID-19 or SARS-CoV-2, or simply ivermectin. Automated searches are performed every hour with notifications of new matches. All studies regarding the use of ivermectin for COVID-19 that report an effect compared to a control group are included in the main analysis. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in calculations for that study. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used. Clinical outcome is considered more important than PCR testing status. For PCR results reported at multiple times, where a majority of patients recover in both groups, preference is given to results mid-recovery (after most or all patients have recovered there is no room for an effective treatment to do better). When results provide an odds ratio, we computed the relative risk when possible, or converted to a relative risk according to [Zhang]. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported including propensity score matching (PSM), the PSM results are used. When needed, conversion between reported p-values and confidence intervals followed [AltmanAltman (B)], and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 [Sweeting]. Results are all expressed with RR < 1.0 suggesting effectiveness. Most results are the relative risk of something negative. If studies report relative times, results are expressed as the ratio of the time for the ivermectin group versus the time for the control group. Calculations are done in Python (3.9.1) with scipy (1.5.4), pythonmeta (1.11), numpy (1.19.4), statsmodels (0.12.1), and plotly (4.14.1).
The forest plots are computed using PythonMeta [Deng] with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case). The forest plots show simplified dosages for comparison, these are the total dose in the first two days for treatment, and the monthly dose for prophylaxis, for a 70kg person. For full dosage details see below.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment, and treatment started within 5 days after the onset of symptoms, although a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective [McLeanTreanor].
Due to the much larger size of the control group in [Bernigaud], we limit the size of the control group to be the same as the treatment group for calculation of the number of patients.
A summary of study results is below. It is easy to propose excluding certain papers for various reasons. To avoid potential bias in evaluation we currently include all studies. Analysis excluding studies with major issues can be found in Appendix 2.
Please submit updates and corrections at the bottom of this page.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in calculations, which may differ from the effect a paper focuses on.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in calculations, which may differ from the effect a paper focuses on.
Prophylaxis (Prevention)
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in calculations, which may differ from the effect a paper focuses on.
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