Abstract
BackgroundChildren are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.MethodsThis phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.ResultsOf 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy’s law definition).ConclusionsThe pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.Trial registrationClinicalTrials.gov: identifier NCT00541385
Highlights
The World Health Organization (WHO) generally recommends artemisinin-containing combination therapy (ACT) for the treatment of P. falciparum malaria [3]. Of those medicines included on the WHO list of prequalified medicinal products, only artemether-lumefantrine dispersible tablets and artesunateamodiaquine water-soluble tablets are available for oral liquid administration to children [4]
In two Phase III trials of pyronaridine-artesunate tablets, both conducted in adults and children in Africa and Asia with P. falciparum malaria, day-28 adequate clinical and parasitological response (ACPR) rates in the per-protocol population were 99.5% (780/784) and 99.2% (743/749) when corrected for re-infection with polymerase chain reaction genotyping (PCR-corrected) [5,6]
This paper reports outcomes from a Phase III comparative, open-label, randomized, multi-center clinical study assessing the safety and efficacy of a fixed-dose oral pyronaridine-artesunate granule formulation (60:20 mg) versus artemether-lumefantrine crushed tablets in infants and children with acute uncomplicated P. falciparum malaria
Summary
A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria. Plasmodium falciparum malaria kills approximately 850,000 children annually, most are under five years old [1,2]. The World Health Organization (WHO) generally recommends artemisinin-containing combination therapy (ACT) for the treatment of P. falciparum malaria [3]. Of those medicines included on the WHO list of prequalified medicinal products, only artemether-lumefantrine dispersible tablets and artesunateamodiaquine water-soluble tablets are available for oral liquid administration to children [4]. Pyronaridine-artesunate (3:1 ratio) is an ACT being developed for the treatment of uncomplicated P. falciparum and Plasmodium vivax malaria [5,6,7]. The adverse event profile of pyronaridine-artesunate in these trials has been generally favorable, though liver transaminases were increased in some patients [5,6]
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