The Malaysian ivermectin trial: what does it really show?
JAMA Internal Medicine has published the Malaysian I-TECH open-label randomized trial of ivermectin, comprising a total of 490 patients. The trial found no significant benefit of ivermectin regarding disease progression or death. But things are more complex than this.
On the positive side, the trial included mostly participants with an elevated risk of severe covid (50+ with comorbidities). But on the negative side, 68% of the participants were already vaccinated (52% were double vaccinated), leaving only 159 unvaccinated participants. Moreover, treatment began on average 5.1 days after symptom onset, and mostly in patients already hospitalized.
Thus, most of these patients would not even have been eligible for the covid drug trials run by Pfizer (Paxlovid) and Merck (Molnupiravir), which required unvaccinated outpatients and a treatment delay of no more than 3 days (or 5 days at most), since swift action is crucial against a viral disease.
To make matters worse, the primary endpoint of the Malaysian study was hypoxia (95% oxygen saturation), an endpoint that was reached on average already 8 days after symptom onset or just 3 days after start of treatment, i.e. before the treatment was even completed (5 days).
Thus, the study was “designed to fail”: “The study design was such that any other antiviral, such as Paxlovid or Molnupiravir [or monoclonal antibodies], would also have failed.”
Interestingly, if one considers the secondary endpoint of 28-day in-hospital mortality, ivermectin once again showed an apparent benefit: 3 deaths (1.2%) vs 10 deaths (4.0%) overall and 1 death (1.3%) vs. 4 deaths (4.8%) in the unvaccinated subgroup, but the study was too small to reach statistical significance (risk ratio 0.31, p=0.09). Regarding ICU admission and ventilation, too, the ivermectin group showed a non-significant 20% to 60% advantage.
In addition, more people in the ivermectin group quickly progressed to hypoxia (21.6% vs. 17.3%; difference is not significant), which indicates that patients in the ivermectin group may have been in worse shape to begin with (but, after treatment, showed rather lower mortality).
Thus, while many propagandists and weak analysts quickly jumped to a negative conclusion, the study is in fact consistent with previous high-quality RCTs that found a non-significant mortality benefit of up to 30% (i.e. 5 million prevented deaths globally). As professor David Boulware noted, this could also be due to an indirect effect (parasite hyperinfection due to steroid treatment).
In conclusion, it will be very interesting to see the results of the remaining high-quality ivermectin trials, and an updated meta-analysis of these trials, even though high vaccination rates and omicron (90% lower lethality) may increasingly impact results.
Postscriptum: The Malaysian trial data is not very positive with regards to vaccine protection: unadjusted death rates in fully vaccinated vs. unvaccinated participants were 3.8% (5 people) vs. 4.8% (4 people) in the control group and 1.6% (2) vs. 1.3% (1) in the ivermectin group. In other words, ivermectin had a bigger (unadjusted) impact on mortality than vaccination…
See also: The Ivermectin Debate