Malaria is caused by protozoan parasites of the genus Plasmodium and it is the most important parasitic disease in terms of mortality and morbidity. Estimates of 247 million malaria cases and 619.000 deaths worldwide were reported by WHO for the year 2021 (1). Plasmodium falciparum can lead to severe malaria and accounts for 90% of malaria deaths that mainly occur in children below the age of 5 years in Sub-Saharan Africa.
A simplified treatment regimen, ideally a single-day cure (or at most 2-day dosing regimen), of uncomplicated malaria due to P. falciparum would be the magic in the antimalarial armamentarium. Improving treatment adherence is one of the key factors in reducing mortality and morbidity and also the transmission of malaria, and such a regimen would substantially increase adherence. To find a new non-artemisinin combination therapy with a shorter regimen, ideally, a single-dose cure, with low resistance potential would be the aim. The two compounds tested here are ZY19489, a triaminopyrimidine, and ferroquine (FQ), a next-generation 4-aminoquinoline. Both compounds show unique features in terms of long half-life, and activity against current drug-resistant strains.
Therefore, the main goal of this clinical trial is to assess the safety of the ZY19489-FQ combination given as a 1- or 2-day dose regimen.
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1. Mixed Plasmodium infection as judged by microscopy. 2. Presence of clinically significant infectious disease or fever (e.g. Body temperature ≥38°C or 100.4°F) within the 14 days prior to enrollment.
Piperaquine, mefloquine, naphthoquine or sulfadoxine-pyrimethamine within 6 weeks prior to screening.
Amodiaquine, chloroquine within 4 weeks prior to screening.
Any artemisinin derivative (artesunate, artemether or dihydroartemisinin), quinine, lumefantrine or any other anti-malarial treatment or antibiotic with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones and azithromycin) within 14 days prior to screening.
Parallel
ZY19489 + Ferroquine (FQ)
DrugZY19489-FQ combination or placebo orally after a fasting period of at least 10 h.
Placebo
DrugZY19489-FQ combination or placebo orally after a fasting period of at least 10 h.
incidence, severity and relationship to ZY19489-FQ of treatment emergent adverse events
To evaluate the safety and tolerability of ZY19489-FQ combination in African adult asymptomatic carriers of Plasmodium falciparum mono-infections.
Area under the curve from the time of dosing to the last measurable concentration (AUC0-t).
Estimation of PK parameters of ZY19489, its major metabolite and FQ and its major metabolite using noncompartmental method.To characterize the PK of ZY19489-FQ combination in African asymptomatic adult carriers of Plasmodium falciparum mono-infections
Area under the curve from the time of dosing to the infinity (AUC0-∞)
Estimation of PK parameters of ZY19489, its major metabolite and FQ and its major metabolite using noncompartmental method.To characterize the PK of ZY19489-FQ combination in African asymptomatic adult carriers of Plasmodium falciparum mono-infections
Maximum plasma concentration (Cmax)
Estimation of PK parameters of ZY19489, its major metabolite and FQ and its major metabolite using noncompartmental method.To characterize the PK of ZY19489-FQ combination in African asymptomatic adult carriers of Plasmodium falciparum mono-infections
Time to reach maximum plasma concentration (Tmax)
Estimation of PK parameters of ZY19489, its major metabolite and FQ and its major metabolite using noncompartmental method.To characterize the PK of ZY19489-FQ combination in African asymptomatic adult carriers of Plasmodium falciparum mono-infections
Parasite reduction ratio between baseline and 48h post-treatment (PRR48) and corresponding parasite clearance half-life (PCT½).
To describe the parasite clearance capacity of ZY19489-FQ combination in African asymptomatic adult carriers of Plasmodium falciparum mono-infections
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