Standard Dose Ivermectin for COVID-19

To the Editor:

The article by Ceplowicz Rajter et al¹ published in CHEST (January 2021), which presents a significant effect of ivermectin at standard dose on COVID-19 mortality rates, raises once again important questions on the significance of observational studies that report posttreatment outcome for COVID-19. Uncontrolled, observational studies have already created confusion in the medical community’s response to the pandemics, the example of hydroxychloroquine being the most obvious one.² For instance, in their article, the criteria for treatment with ivermectin are not specified, and a bias due to treatment indication is not addressed completely. Moreover, despite the use of a propensity score matching aimed at reducing confounders, relevant variables might have been measured inadequately. As an example, the authors did not find a benefit associated with the use of steroids (which were given in a significantly higher proportion of patients in the ivermectin group of the unmatched cohort) and suppose that this finding, in contrast to what has been demonstrated by the RECOVERY clinical trial,³ might be due to a propensity to save this treatment for the most critically ill patients.

In addition to the limitations due to the study design, we would like to point out the concerns about the dose of ivermectin that has been used.

Indeed, based on the article by Caly et al,⁴ the potential drug efficacy in vitro was observed at high ivermectin concentration. The IC-50 reported (2,190 ng/mL) was at least 50 times higher than the maximal concentration achievable with the standard dose of 200 μg/kg, which is the one reported by Ceplowicz Rajter et al.¹ A potential clinical efficacy of this dose was not even plausible; thus, introducing ivermectin as a treatment for COVID-19 patients was (and is) not justified.

We currently are coordinating a randomized, Phase 2, double-blind clinical trial on ivermectin at high dose (600 or 1200 μg/kg for 5 consecutive days) for COVID-19 early stage in patients with mild symptoms who do not need hospitalization.⁵ We did not even consider to include an arm with a standard dose, precisely because of implausibility.

We humbly argue that, if reported results of an observational study are not plausible, unrecognized confounders are the most likely explanation.

Ivermectin is being used already in an uncontrolled way in Latin American countries.⁶ We do not need an improper use of the drug to be further promoted, unless well-designed randomized controlled trials will be able to prove an efficacy, presumably with the use of much higher doses of ivermectin.