Abstract:
Background: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose
treatments are expected to increase compliance and improve treatment outcomes, and thereby may
slow the development of resistance. The efficacy and safety of a single-dose combination of
artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of
uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years)
and Asia.
Methods: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in
patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were
followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary
efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and
parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African
patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and
prevalence of kelch-13 mutations were explored.
Results: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African
patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy
criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%).
PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7%
[81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese
patients, ranging from 20 to 40%. A clear relationship was found between drug exposure
(artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher
concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were
detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated
with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h
of initial artefenomel administration was common (24.6%) and associated with lower drug
exposures.
Conclusion: The efficacy of artefenomel/ferroquine combination was suboptimal in African
children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact
on efficacy.