Discussion
malaria, blood stage infection, semi-immunity, parasitaemia
MALARIA, ONCHOCERCIASIS, DISEASE, DRUG EFFECT, SECONDARY, LYMPHATIC FILARIASIS
Ivermectin is given for mass drug administration to whole communities to control lymphatic filariasis and onchocerciasis. It has been observed in some studies that ivermectin can kill Within seven days of follow-up, more than 90% participants reduced parasite load by 90% in both ivermectin and placebo groups. The time to achieve 90% parasite reduction was 24 h vs. 32 h in ivermectin and placebo groups, respectively. However, this was not statistically significant as confidence intervals overlapped. The finding of similar reduction of parasite count between the intervention and control group suggests that in the study population, 90% parasite reduction within seven days could be achieved without use of ivermectin. The 90% parasite reduction in placebo group is likely driven by the fact that the study participants were semi-immune adults. This therefore challenges our sample size calculation assumption that only 25% of participants in the placebo group would achieve 90% parasite reduction. Nonetheless, there are indications that parasite reduction might be quicker in the ivermectin (24 h) than in the placebo group (32 h). Confidence intervals of the median time to 90% parasite reduction for ivermectin range from 8 h to 32 h while in the placebo group they range from 24 h to more than 115 h suggesting a trend for ivermectin. The hazard ratio of 1.38 is also in favour of an effect of ivermectin above that of placebo. There was statistically no evidence to support the superiority of ivermectin from either per protocol or ITT analyses suggesting there was no attrition bias that could affect that assessment. Also, it cannot be ruled out that the slightly slower parasite reduction in the placebo group might be due to the higher baseline parasitaemia. No subgroup analysis was deemed necessary because of the small sample size, the lack of statistically significant differences between the randomized groups and because a recent PK study that showed no association between ivermectin pharmacokinetics and sex, or BMI.The secondary outcomes analyses support the primary outcome results as there are some trends that the parasite clearance time is shorter in the ivermectin group compared to the placebo group. The same is shown for the area under the curve of parasitaemia that is smaller for ivermectin. However, all these findings do not show strong statistical evidence that would comfort any conclusion and rule out the role of chance.A clear differentiation between asymptomatic and pre-symptomatic participants cannot be made. Therefore, some participants developed malaria symptoms only hours after inclusion in the trial. Indeed, semi-immunity that is characterized by the host's ability to tolerate and, to an extent, supress blood stage infection, is assumed to be acquired over the course of several disease episodes.In a clinical study investigating the efficacy of ivermectin against onchocerciasis before the drug was licensed (1985–1987), the lack of efficacy of ivermectin against The stringent application of a randomized, placebo-controlled clinical trial design supports the solidity of the presented results. The drop-out rate was low with only one participant lost to follow-up and three participants having discontinued the intervention. None of the participants in the trial had missing outcome data. As microscopy was the primary diagnostic tool, these results should be easily reproducible across research centres in malaria-endemic areas.The findings on safety showed a good tolerability of ivermectin at the doses of 200 μg/kg once daily up to three days and 300 μg/kg once daily for three days. This is in line with reports of higher doses showing that ivermectin is well tolerated in humans up to 2000 μg/kg.There are a few limitations to this study. These include a small error in the sample size calculation as it occurs after post-hoc checks that with the assumptions made, the number per arm should have been approximately 16, 19 to be exact, while it was set to 17. Nonetheless, that mistake is believed not to significantly affect the findings providing the assumptions were correct. However, the assumption to have 25% and 75% achieving the outcome in the ivermectin and placebo groups, respectively, was not confirmed as more than 90% reduced the parasite load up to 90% in both arms. This suggest that the sample size could have been underpowered and thus the study was too small to detect the real effect. There is a need to adjust power and sample size calculation for future trials. Considering our observed hazard ratio of 1.378 as well as the rate of parasite reduction in the placebo group were true, setting conventional 5% α and 80% power, a sample size of 260 participants would be needed. However, as discussed, our sample size hypothesis and endpoint might not have been adequate. Our findings and findings from other studies on asymptomatic volunteers will be helpful in better defining the variability of parasites in this population, thus providing more robust hypothesises for power and sample size calculation of trials investigating blood-schizonticidal effect of ivermectin.The single centre study design limits the external validity and thus the generalization of the findings. This is an early phase, proof of concept study, so internal validity might be most important at this stage.As no quality analysis was performed on the drug batches used, it cannot be ruled out that the absence of drug effect may have been due to sub-standard drug quality. Placebo and ivermectin were sourced from good manufacturing practice-certified manufacturers in batches produced for commercial delivery. Having procured these drugs from accredited pharmacies, we assume they have not been sub-standard.This is an in-human trial evaluating the efficacy of ivermectin against 