Discussion
malaria, parasitaemia
MALARIA, DISEASE PROGRESSION, DISEASE
The contribution of artefenomel exposure (AUCGraphical explorations of the relationship between exposure and Day 28 PCR-adjusted ACPR were suggestive of a contribution of artefenomel to the efficacy of the artefenomel/ferroquine combination. In addition, parasite clearance parameters consistently demonstrated more rapid clearance with the artefenomel/ferroquine combination compared with ferroquine alone, indicating a contribution of both drugs to early parasite clearance. Importantly, for the considerably larger FALCI study, which ran in parallel, the exposure-dependent contribution of both artefenomel and ferroquine to both Day 28 PCR-adjusted ACPR and crude ACPR could be estimated, even if the overall efficacy of the exploratory dose regimens in FALCI was sub-optimal [It seems, therefore, likely that the current study was not adequately powered to identify a statistically significant contribution rather than a lack of a contribution. A possible explanation for this is the higher-than-expected response with 400 mg ferroquine alone in the current study. The clinical trial simulations used to inform the study design were based on a predicted ferroquine Day 28 PCR-adjusted ACPR of 72% (90% CI 57.0, 84.0), whereas the observed response with ferroquine alone (80.8%) was close to the upper limit of predicted efficacy. With a lower than predicted number of treatment failures across all treatment arms, it was statistically more difficult to detect a significant contribution of artefenomel.The reasons for a higher-than-expected response to ferroquine are unclear. However, this does not appear to result from higher than anticipated ferroquine or active metabolite exposures in this study population. Notably, limited exposure–response data were available for ferroquine to inform the clinical trial simulations and no efficacy data for the artefenomel/ferroquine combination were available. Consequently, there was considerable uncertainty associated with the predictions for ferroquine exposure–response. However, this uncertainty in the predicted ferroquine response was not considered in the clinical trial simulations.The upper limit for parasitaemia for enrolment in this study was 50,000 parasites/µL for ethical reasons, considerably lower than the maximum parasitaemia level used in the clinical trial simulations (316,228 parasites/µL). Both in this study and in FALCI, higher baseline parasitaemia was shown to significantly decrease the odds of Day 28 PCR-adjusted ACPR [In FALCI, there was evidence that age influenced baseline parasitaemia [Overall, eligible participants were aged 14 to 69 years, with No new safety signals were identified, and the safety findings were consistent with previous clinical studies [Although there was one case of increased ALT, there was no suggestion of a relationship between artefenomel dosing and ALT increases. No patient had a QTcB or QTcF > 500 ms or an increase from baseline > 60 ms. These findings contrast with FALCI, as increased ALT was reported in 2.1% (8/373) of patients and appeared to be associated with ferroquine [This study illustrates the challenges in designing clinical trials to demonstrate the contribution of individual drugs to the overall efficacy of a combination therapy in a disease which if not rapidly treated can progress to a serious and life-threatening condition. To explore the contribution of the individual drugs, sub-therapeutic doses must be administered. However, the risk to the patients from disease progression must also be minimized. Consequently, in this study the patient population excluded children < 14 years of age who are most at risk of severe malaria, restricted baseline parasitaemia to the range ≥ 3000 to ≤ 50,000 parasites/µL blood and used drug doses that were not substantially sub-therapeutic.