RCT low-risk outpatients with very late treatment (median 6
days, 25% ≥8 days) in the USA, showing 98% probability of efficacy for
clinical progression at day 14, a treatment delay-response relationship, and
significant efficacy for patients with severe symptoms at baseline. Efficacy
was higher over calendar time, which may reflect higher efficacy with more
recent variants. Efficacy was higher for vaccinated patients.
Design, presentation, and analysis shows a strong negative
bias. While authors recommend and are performing further study, notably they
are continuing with most flaws including a design focusing on very late
monotherapy, while extensive research shows that early treatment is critical
for antivirals, and a growing body of research shows greater and synergistic
benefits from polytherapy protocols commonly used by physicians that treat
COVID-19. Submit Updates or
There are many major issues as below.
Superiority found, not reported.
Both day 7 and day 14 clinical progression results show superiority of
ivermectin. The protocol states: "The Study Drug is found to have benefit
(efficacy): A posterior probability of meaningful benefit (e.g. OR < 0.9) for
a study drug in comparison to the placebo control of > 0.95 will result in a
declaration of overall superiority"
Primary outcome not reported, closest
reported outcome shows superiority of ivermectin.
The protocol shows
the primary outcome using a longitudinal statistical model with an ordinal
variable based on symptom count and hospitalization/death measured daily until
This outcome is not reported. The closest reported outcome is clinical
progression at 14 days, which shows superiority of ivermectin, OR 0.73
[0.52-0.98], posterior probability of efficacy 98%, exceeding the
Very late treatment. Patients were
treated a median of 6 days late, with 25+% 8+ days late. Extensive research
for COVID-19 and other viral diseases show that early antiviral treatment is
critical. While authors recommend (and are performing) further study, they do
not recommend or perform the obvious step of doing an early treatment trial,
as is done for NIH recommended treatments like Paxlovid, suggesting a strong
negative bias with a goal of maintaining late treatment and obtaining poor
Outcomes reported do not match
The reported outcomes are very different to the trial
The trial registration shows three primary outcomes, of which zero are
reported in the paper. The protocol shows the primary outcome using a
longitudinal statistical model with an ordinal variable based on symptom count
and hospitalization/death measured daily until day 14.
No response to data request. Authors
have not responded to a request for the data.
No COVID-19 mortality/hospitalization
Authors only report all-cause mortality and hospitalization.
Notably, the baseline hospitalization and mortality rate for non-COVID-19
causes may account for the death and many of the hospitalizations. This may
also explain why authors report only 28 day mortality/hospitalization in
violation of the protocol where the primary outcomes specify 14 days
adverse events show only one case of aggravated COVID-19 pneumonia for
ivermectin, versus 3 for placebo.
Many pre-specified outcomes missing.
not report [fnih.org]
•OR describing the overall difference in symptoms and clinical events over 14 days (primary outcome)
•Overall clinical progression OR (only specific day 7, 14, 28 values are provided)
•Time to first urgent care, emergency care, hospitalization or death
•Risk and time to event for each component of the composite
•Mean and median time to symptom freedom
•Overall QOL OR
•Day 7, 14, 28, 90 QOL OR
•Mean difference in QOL scores at day 7, 14, 28, 90
•Mean and median time to symptom resolution (only a new sustained resolution measure is reported, which is not in the protocol)
•Day 90 mean and median symptom count
protocol is available. For example, the Bayesian threshold for significance is
not known and appears to be withheld. A typical posterior efficacy threshold
of 97.6% is met by the clinical progression on the ordinal outcome scale at
day 14, OR 0.73 [0.52-0.98] 0.98. Notably, the discussion includes vague and
arbitrary "clinical relevance" and "substantial clinical benefit" rather than
statistical significance. Update: partial protocol located
threshold was exceeded. The protocol appendix is still unavailable which includes
contraindications, exclusions, formulation, appearance, packaging, dispensing,
dosing, and dose rationale.
Reported primary outcome low
relevance. The reported primary outcome (which matches neither the
trial registration or the protocol) is of relatively low relevance being based
on sustained absence of all symptoms, where symptoms includes many things that
may be found after viral clearance and may be unrelated to COVID-19, including
fatigue, headache, and cough (which may remain for some time). Authors may
have searched for the outcome that shows the least benefit. The 3-day
sustained definition further adds two days for all participants, reducing
efficacy. Authors should report data for more significant symptoms such as
dyspnea, fever, and loss of sense of taste/smell.
Patients with symptoms >7 days
included. The trial specifies symptoms ≤7 days, however subgroup
results show symptoms ≤9, 11, and 13 days, and the Q3 for the ivermectin arm
was 8 days, indicating 25% of patients with a treatment delay of ≥8 days. The
difference is likely due to the authors not considering receipt of medication
or treatment time in inclusion, i.e., due to shipping delays. However, ≤7 days
treatment delay already makes the results inapplicable to real-world usage
where antivirals are used early.
Asymptomatic patients included.
Study inclusion required >2 symptoms, however the subgroup analysis includes
109 patients with no symptoms, where results favored placebo. The primary
outcome may reach statistical significance without these patients.
Shipping and PCR delays largely enforce late
treatment. Authors required positive PCR before randomization, and
shipped medication to participants. The delay before PCR results become
positive, delay in receiving PCR results, and the shipping delay largely
ensure that patients will not be treated early.
Extreme conflicts of interest.
trial has extreme conflicts of interest, being funded by an organization that
chose not to recommend treatment while providing no quantitative analysis, no
reference to the majority of the research, and no updates for new research for
a very long period [ivmmeta.com]
. Further, a majority of
the panel providing the recommendation has major conflicts of interest
. Also see
[trialsitenews.com, trialsitenews.com (B)]
Subgroup results for treatment delays 13, 11, 9, 7, and
5 show monotonically improving results (less than 1% probability due to
chance). ≤3 days may have very few patients, and is within confidence limits
for monotonically improving results. Improved efficacy for earlier treatment
matches extensive results for ivermectin and other COVID-19 treatments
, however authors ignore this trend, claiming
only a lack of statistical significance for one specific binary threshold
(which may have few patients on one side), and authors have not initiated an
early treatment trial.
Randomization failure. The
placebo arm includes participants selected for other drugs, with drug specific
exclusions. This breaks the randomization because the populations for each
drug are different.
Blinding failure. The
placebo arm included multiple regimens matching different treatment arms,
hence some participants will know they are not in the ivermectin arm, and
others will know that there is a higher probability of them being in the
ivermectin arm than the placebo arm. This may be more important given the
politicization in the study country. The fluticasone arm and matching placebo
use an inhaler, the fluvoxamine arm uses 10 days treatment. Mached placebo
analysis should be provided.
Disingenuous conclusion. The
conclusion states that treatment did not lower mortality of hospitalization,
however it is impossible to lower zero mortality. While authors do not
indicate COVID-19 versus other hospitalization, statistically significant
reduction in hospitalization would require at minimum 79% efficacy, but for
COVID-19 hospitalization it is likely impossible based on expected
non-COVID-19 hospitalizations. The trial is underpowered by design due to
selection of a low-risk population. Note that among the 90 severe cases,
statistically significant efficacy is reported.
Up to 6 days shipping delay. The ≤7
days inclusion criterion and the 13 days subgroup suggests there was up to 6
days shipping delay (in part due to no weekend shipping). COVID-19 is an acute
disease (which may or may not be mild). Participants cannot be expected to
wait 1-2 days or longer for treatment. Chances are that patients feel better
by the time medication arrives and do not take the medication, which may
explain why adherence is not reported, or their condition became worse and
they found alternative immediate care elsewhere.
IDMC not independent.
The IDMC vice
chair was reportedly on the NIH panel that did not recommend treatment despite
strong evidence, and provided no quantitative analysis, no reference to the
majority of the research, and no updates for new research for a very long
No adherence data. Authors provide
no adherence data. Non-adherence may de-power the trial and may harm
Low risk patients. Authors focus on
patients at low risk of COVID-19 severe outcomes, which ensures an
underpowered trial, with only one death which may not be due to COVID-19.
All-cause mortality and hospitalization become less meaningful, with a
significant contribution from non-COVID-19 causes.
Subject to participant
fraud. The self-reported design, partial blinding, and absence of
professional medical examination opens the trial to participant fraud, which
may be significant due to extreme politicization in the study country.
Not enough tablets provided.
Participants were supplied 15 7mg tablets and instructed to take the number of
tablets to approximate 400μg/kg, however not enough tablets were provided for
patients with higher weights, indicating that higher risk patients received
lower dosage. 41% of patients had BMI > 30 and subgroups include BMI 50.
Over 2x greater severe dyspnea at baseline
for ivermectin. There was over 2x greater severe dyspnea in the
ivermectin arm at baseline (1.65% vs. 0.71%), which may be very important for
analyzing mortality and hospitalization.
Authors suggest high-income country
healthcare is better, however almost all patients received no active
SOC. Authors suggest the operation in a high-income country with an
associated healthcare system is a notable strength, however the study country
provided no active treatment for almost all patients in the study, in contrast
to many lower income countries that provide multiple treatments. Remdesivir,
monoclonal antibodies, and paxlovid are very difficult to obtain and rarely
used for outpatients in the study country. High income countries also may have
significantly higher conflicts of interest.
Authors do not specify placebo details, only that packaging was identical.
If the tablets were not identical, this would be an additional reason for
No breakdown of severe outcomes.
Notably, no details are provided for the hospitalization and mortality events,
which may have been more likely among patients with extremely late treatment,
or influenced by the higher baseline severity in the ivermectin arm. No severe
outcome results are provided for (relatively) early treatment.
Monotherapy with no SOC for most
patients. Authors perform monotherapy and the standard of care for
most patients in the study country included no active treatments. Other
treatments were very rare - remdesivir 0.3%, monoclonal antibodies 3%, and
paxlovid 0.1%. However, extensive and growing research shows greater and
synergistic benefits from polytherapy. Many studies use polytherapy and/or the
standard of care includes multiple active treatments.
No subgroup counts for treatment
delay. Notably, no subgroup counts are provided for treatment delay,
while they are provided for baseline symptoms and vaccination status. The
number of patients with symptoms ≤3 days may have been very small given the
design of the trial.
Skeptical prior not
justified. The skeptical prior, which reduces the observed efficacy in
the post-hoc primary outcome, is not justified based on the studies to date.
The skeptical prior was pre-specified. Authors may argue that the prior is
justified because the trial was designed to avoid showing efficacy.
What can be done better? This long list of issues
details the flaws prohibiting any negative conclusion about early treatment.
In fact, the results are extremely positive given the conditions. Despite
extreme and obvious measures used to avoid showing efficacy, efficacy was
still found. Running a better trial is a simple matter of avoiding the issues
above. How do you ensure early treatment with high-risk patients? One example
would be pre-enrolling nursing home patients, providing treatment packages in
advance, and instructing local medical staff to initiate randomization,
treatment, and monitoring immediately on symptoms. This would likely be
cheaper to run, and easily extended to also study prophylaxis.