Another objection that has been raised to the RCT evidence supporting IVM efficacy
was that study
69 populations were too small [31]. Yet it is well known in clinical trial design
that highly effective drugs
70 will establish statistically significant results with smaller sample sizes, with
larger study populations
71 required for minimally effective drugs [32]. For example, as noted above, the
highest dose IVM treatment
72 study for COVID-19 that tracked mortality had 2 vs. 24 deaths in treatment vs.
control arms of 200
73 subjects each [22], with a z test p-value of 0.0006 [33]. But for a drug with a
more modest RR of 75%, for
74 example, the treatment and control arms would need more than 3,800 subjects each
to yield the same
75 statistical significance [33]. Although large study populations are useful to
screen for adverse effects
76 (AEs) of new drugs, IVM has been used safely in 3.7 billion doses worldwide
since 1987 [2, 3] and is
77 well tolerated even at much greater than the standard single dose of 200 μg/kg
[34, 35]. It has been used
78 in RCTs for COVID-19 treatment at cumulative doses of 1,500 μg/kg [36], 1,600
μg/kg [22] and 3,000
79 μg/kg[37] over 4 or 5 days with only small percentages of mild or transient
adverse effects.
80 Among these RCTs that established safety for high-dose IVM treatment of COVID-19
was one conducted
81 in Cali, Columbia with generally mild COVID-19 cases, median age 37, having only
one death in the
82 control group [36]. The study found no statistically significant symptom
improvements with IVM
83 treatment, yet reported a striking anomaly: AEs distinctive for its high IVM
dose, described in the study
84 protocol as “security parameters” for its IVM use, occurred at almost identical
rates in its IVM and
85 placebo arms. These included transient incidences of blurred vision (11.3%,
11.6%) and dizziness
86 (35.6%, 34.3%). These indications of IVM use in controls occurred as over-the-
counter sales of IVM
87 surged in the study region during the study period (Supplementary Table 1).
Further questions as to the
88 study’s treatment/control boundaries were raised by the mistaken substitution of
IVM for placebo for 38
89 patients, discovered by the lead pharmacist a month after the fact (study, p. 3;
study protocol supplement,
90 p. 43). In addition, blinding was breached by the use of dextrose-saline
solution as the placebo for 64
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control patients (IVM tastes distinctively bitter), while the composition of the
replacement 91 placebo
92 solution was not specified [38].
93 Supporting the findings of IVM efficacy in COVID-19 treatment as summarized
above were indications
94 of activity against SARS-CoV-2 in prevention studies. Three RCTs evaluated the
prophylactic effect of
95 IVM administered to cohorts of 100 [22], 117 [39] and 203 [40] subjects exposed
to COVID-19 patients.
96 These studies, all using IVM in doses of at least 150 μg/kg per week, reported
statistically significant
97 reductions in COVID-19 incidences, with respective RRs of 20%, 26% and 13% as
compared with
98 controls, and greater reductions in incidences of moderate and severe cases.
Another RCT for COVID-19
99 prevention administered just one dose of IVM at 12 mg (about 150 μg/kg) to 617
subjects on day one of a
100 42-day observation period, while three other preventative regimens were each
administered daily over
101 that period [41]. IVM at that single low dose yielded the best results of these
four regimens, with highly
102 statistically significant reductions of close to 50% in both symptomatic COVID-
19 and acute respiratory
103 symptoms vs. controls.
