•100% of
36 early treatment and prophylaxis studies
report positive effects (96% of all
55 studies). 26
studies show statistically significant improvements in isolation.
•Random effects meta-analysis with
pooled effects using the most serious outcome reported shows 79% and
85% improvement for
early
treatment and prophylaxis(RR
0.21
[0.11-0.37] and
0.15
[0.09-0.25]). Results are similar after exclusion based sensitivity analysis:
81% and
87% (RR
0.19
[0.14-0.26] and
0.13
[0.07-0.25]),
and after restriction to 29 peer-reviewed studies:
82% and
88% (RR
0.18
[0.11-0.31] and
0.12
[0.05-0.30]).
•81% and
96% lower mortality is observed for early treatment and prophylaxis
(RR 0.19
[0.07-0.54] and
0.04
[0.00-0.58]). Statistically
significant improvements are seen for mortality, ventilation, hospitalization,
cases, and viral clearance.
•100% of the
17 Randomized Controlled Trials (RCTs) for early treatment and prophylaxis report positive effects,
with an estimated improvement of
73% and
83% respectively (RR 0.27
[0.18-0.41] and
0.17
[0.05-0.61]), and 93% of all
28 RCTs.
•The probability that an ineffective
treatment generated results as positive as the
55 studies to date is estimated to be 1 in
23 trillion (p = 0.000000000000043).
•Heterogeneity arises from many factors including
treatment delay, patient population, the effect measured, variants, and
treatment regimens. The consistency of positive results across a wide variety
of cases is remarkable. Heterogeneity is low in specific cases, for example
early treatment mortality.
•While many treatments have some level
of efficacy, they do not replace vaccines and other measures to avoid
infection. Only 29% of ivermectin
studies show zero events in the treatment arm. Multiple approaches are
required to protect everyone from all existing and future variants.
•Many studies do not specify
administration, or specify fasting. Administration with food may significantly
increase plasma and tissue concentration.
•All data to reproduce this paper and
the sources are in the appendix.
See [Bryant, Hill, Kory, Lawrie, Nardelli] for other meta analyses, all
with similar results confirming effectiveness.
Figure 1.A. Random effects
meta-analysis excluding late treatment. This plot shows pooled effects,
analysis for individual outcomes is below, and more details on pooled effects
can be found in the heterogeneity section. Simplified dosages are shown for
comparison, these are the total dose in the first four days for treatment, and
the monthly dose for prophylaxis, for a 70kg person. For full details see the
appendix. B. Scatter plot showing the distribution of effects reported
in early treatment studies and in all studies. C and D. Chronological
history of all reported effects, with the probability that the observed
frequency of positive results occurred due to random chance from an
ineffective treatment.
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, for COVID-19 case results,
for viral clearance results, for peer-reviewed studies, for Randomized
Controlled Trials (RCTs), and after exclusions.
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 3, 4, and 5 show results by
treatment stage. Figure 6, 7, 8, 9, 10, 11, and 12 show forest
plots for a random effects meta-analysis of all studies with pooled effects,
and for studies reporting mortality results, ICU admission, mechanical ventilation, hospitalization, COVID-19
cases, and viral clearance results only. Figure 13
shows results for peer reviewed trials only. Table 1
summarizes the results.
Treatment time
Number of studies reporting positive effects
Total number of studies
Percentage of studies reporting positive effects
Probability of an equal or greater percentage of positive results from an ineffective
treatment
Figure 4. Chronological history of early and late
treatment results, with the probability that the observed frequency of
positive results occurred due to random chance from an ineffective
treatment.
