Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial

Despite the development and application of vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) around the world, the scientific community is still trying to find therapies to avoid or ameliorate the fatal evolution of Coronavirus disease 2019 (COVID-19). Since the publication of the potential use of ivermectin as a treatment against the disease [1], much information about it has been published. However, the evidence is not strong or weak enough to conclude its usefulness in the clinical evolution of patients infected with SARS-CoV-2 [2]. Ivermectin has been described as a broad-spectrum antiviral, inhibiting nuclear import due to its ability to inactivate host nuclear transport proteins, such as integrase and NS5, limiting the ability of West Nile virus to infect at low concentrations [5]. It also inhibits the replication of yellow fever virus and other viruses, such as dengue, likely by attacking nonstructural helicase 3 activity [4].

The aim of the study was to evaluate the efficacy and safety of ivermectin in the treatment of patients with asymptomatic and mild COVID-19 in a three-day administration in comparison to placebo.

In this clinical trial of patients with asymptomatic and mild COVID-19, those who were randomized to receive ivermectin for 3 days in the early stages of diagnosis at a dose of 12 mg/day presented a reduction on viral load within the five days after starting treatment in relation to the group that received placebo.

These results agree with those observed by Ahmed et al. [11], who evaluated the effect of ivermectin alone and in combination with doxycycline compared to placebo in hospitalized COVID-19 patients. They observed that treatment with ivermectin for 5 days resulted in earlier viral clearance (9.7 days) than the group treated in combination (11.5 days) or with placebo (12.7 days). A significant difference was observed against placebo at 7 and 14 days. In concordance, Pott-Junior et al. [12] found shorter times for obtaining two consecutive negative SARS-CoV-2 RT–PCR tests in subjects treated with ivermectin compared to those who received standard of care at hospital admission.

Chaccour et al. [13] published a pilot study of 24 patients, where they observed no difference in viral clearance after treatment with ivermectin at a single dose of 400 mcg/day or placebo in patients with mild symptoms. They reported that 7 days after treatment, all subjects remained with a positive SARS-CoV-2 test in the N gene; however, in both the N and E genes, a decrease in viral load was observed in those treated with ivermectin on days 4 and 7 post-treatment compared to placebo. These observations were accompanied by lower IgG antibody titters in the ivermectin group on Day 21 post-treatment. Similar results were reported in Lebanon by Samaha et al. [14] in a pilot clinical trial. They described a significant difference in Ct values between patients who received ivermectin compared to placebo from Day 0 to Day 3.

This effect could be associated in a directly proportional way to the dose, since a preliminary report indicated that providing ivermectin two times the dose that we administered (24 mg/day) for a single day translated into a higher proportion of subjects negative for COVID-19 at day five compared to 12 mg/day or placebo. In this trial, no statistical significance was observed; thus, it could be assumed that an indication of ivermectin for more days is required to reach such significance [15]. However, our study did not show a correlation between the calculated dose (12 mg between weight in kilograms) and the Ct value of the N gene (data not shown). According to Schmith et al. [16] report, single repeated doses of 200 mcg/kg, 120 mg weekly, or 60 mg every 72 h were not enough to reach the concentrations relative to the 50% inhibition (IC₅₀) established by Caly et al. [3], but they did not intend consecutive daily doses as we did. The diverse results with similar or different posology could be explained considering the pharmacokinetics (PK) of ivermectin [17]. Absorption is intestinal, and diarrhea is a common clinical manifestation of COVID-19. This finding decreases the absorption rate and bioavailability and therefore the effect. Moreover, the elimination is principally in feces. However, there is no report of individual results of the effect or presence of diarrhea, and our data did not show any differences in Ct value between those who presented diarrhea and those who did not on any of the evaluated days (data not shown).

Similarly, a randomized study in hospitalized patients showed a benefit in the Ct value of patients treated with ivermectin for 7 days (100, 200, or 400 mcg/kg) in relation to those who did not receive ivermectin, with no-dose behavior.

Our findings and the others previously mentioned can potentially be translated into avoiding progression to severe disease. According to Liu's and Samaha's report, there is a relationship between the Ct value and the intensity of the disease [14]. Furthermore, other studies have shown that receiving ivermectin as part of COVID-19 treatment is associated with a lower mortality rate, accompanied by lower levels of inflammatory biomarkers, such as C-reactive protein, ferritin, and D-dimer [18].

In this study, an evaluation of the presence of symptoms associated with COVID-19 was carried out through the delivery of a diary; in general, the participants had an adherence to the completion of the symptom diary greater than 80%. The analysis revealed that the subjects who received ivermectin presented a higher frequency of symptoms from basal evaluation, of which fatigue and diarrhea were reported as adverse events expected from receiving ivermectin in the Food and Drug Administration (FDA) technical data sheet. In addition, in the same document, muscle pain and headache have also been observed in clinical trials [21]. Therefore, we could assume that these may be due to the drug and not the disease.

These findings do not correspond to the results by Chaccour et al. [13] in his pilot study, since they observed a lower frequency of the following symptoms in those treated with ivermectin: cough, anosmia, hyposmia, and shortness of breath. They did not observe any differences in the frequency of fever or an increase in the frequency of gastrointestinal symptoms by 3.5 times [11]. Recently, a randomized clinical trial by Shahbaznejad et al. [22] reported that patients who used ivermectin at a single dose, calculated according to weight, decreased the hospital stay and duration of symptoms compared to the control group.

On the other hand, a randomized trial with 400 patients, in which the time to resolution of symptoms was evaluated in subjects who received ivermectin (300 mcg/kg) for 5 days, did not observe a significant difference between groups, with a time to resolution slightly lower in the placebo arm (10 vs. 12 days) [23].

The evidence available to date seems to indicate that there is little or no benefit in the resolution of symptoms associated with the consumption of ivermectin at a standard dose [24].

Regarding safety issues, no relationship was found between the drug and any adverse event. The encephalitis event that occurred in the subject who received ivermectin was diagnosed as secondary to SARS-CoV-2 infection, a phenomenon that has been previously documented [25].

Taken together, these data do not show that ivermectin is effective in the treatment of COVID-19 by "accelerating" viral clearance in the first week, which may translate into a lower rate of complications. However, clinical trials with a larger number of participants are required at different doses and times of administration to elucidate the treatment with greater efficacy and a better safety profile. A limitation of the present study was the small sample size, especially for the interpretation of safety outcomes.

At standard doses, ivermectin is not effective to prevent progression to a severe state or reducing symptoms in adults with mild COVID-19.