The TOGETHER trial of ivermectin against covid has finally been published. While the authors argue that ivermectin failed, the data once again indicates that ivermectin may be moderately effective in the early treatment of high-risk patients. (See update below).
A full seven months after completion of the trial, the Gates-funded TOGETHER study of ivermectin against covid has finally been published in the New England Journal of Medicine.
In terms of trial design and execution, the TOGETHER trial has some important limitations and weaknesses, such as a low dosage (initially just one single dose of ivermectin, later three single doses); a rather late treatment (hospitalization on average just one day after treatment course); mostly low-risk participants (younger than 50); low protocol adherence; and missing data.
It is quite likely that none of the available covid drugs, including Pfizer’s Paxlovid and monoclonal antibodies, could have achieved a significant result in this trial. In fact, both Paxlovid and monoclonal antibodies failed to reach significance among standard-risk patients (vs. high-risk patients, i.e. 65+ and/or with preconditions), or if started later than five days after symptom onset.
Despite these limitations and weaknesses, the TOGETHER trial once again found a non-significant advantage in the ivermectin group: hospitalizations were 17% lower, mechanical ventilation was 23% lower, and deaths were 12% lower. These differences were even more pronounced in people over 50, as one would expect if ivermectin is assumed to be effective. The probability of superiority of ivermectin compared to a placebo was calculated as about 80%. These results are quite similar to previous randomized controlled trials (e.g. the recent Malaysian I-TECH trial).
Randomized trials that claimed much higher effectiveness turned out to be fraudulent; however, these “trials” had been run almost entirely by groups from Arab countries, which unfortunately are known to produce a disproportionate share of fraudulent medical studies. Furthermore, studies that tried to show protection against infection (PCR+) were misguided to begin with, as this would have required a very strong mucosal anti-viral effect.
If the moderate effectiveness of ivermectin against covid is real, how can it be explained?
There are two options: the known immuno-modulatory effects of ivermectin, or a more speculative anti-viral effect. A direct anti-viral effect was found in computational and cell culture studies at high doses, but couldn’t be confirmed in animal or human studies. In contrast, a beneficial immuno-modulatory effect was confirmed in a covid animal study by the French Institute Pasteur, and it was found in various pre-covid studies, including against asthma. Theoretically, it could be that ivermectin indirectly affects viral load by improving the immune response in high-risk patients.
Another question concerns the relationship between ivermectin and other covid treatments: is the effect of ivermectin unique and additive to other medications, or is ivermectin better replaced with more effective anti-viral or anti-inflammatory drugs? In general, it appears likely that a multi-modal treatment might be most effective against covid; for instance, aspirin was recently once again found to be moderately effective against covid in a large US study (-20% mortality in patients 60+).
If ivermectin indeed shows an effectiveness of about 15% to 25% against covid mortality, its professional use could have saved two to five million lives so far. Given these figures, it is perhaps understandable that those who tried to disparage ivermectin – including some scientists, journalists, and health authorities – will likely continue to do so. This is despite the fact that, in view of limited vaccine protection, early treatment options against covid remain as important as ever.
TOGETHER trial lead investigator, Prof. Edward Mills, has made some remarkable comments on the ivermectin study: “I actually think it is quite positive. I presented this a couple weeks ago at the NIH Collaboratory Rounds and () I advocate that actually, there is a clear signal that IVM works in COVID patients, just that our study didn’t achieve significance. In particular, there was a 17% reduction in hospitalizations that would be significant if more patients were added. I really don’t view our study as negative and, also in that talk, you will hear me retract previous statements where I had been previously negative. I think if we had continued randomizing a few hundred more patients, it would have likely been significant.”
References: The TOGETHER Ivermectin study (NEJM)
Read more: The Ivermectin Debate (SPR)