Efficacy and Safety of Pyronaridine-Artesunate Versus Artemether-Lumefantrine in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An open- labelled randomized controlled trial

Abstract Background: Declining responsiveness to artemether-lumefantrine (AL), the ACT of choice since 2005, has been reported in Nigeria. Pyronaridine-artesunate (PA) is a newer fixed-dose ACT recently included in the WHO list of prequalified medicines for the treatment of uncomplicated falciparum malaria. However, data from the Nigerian paediatric population is scarce. Therefore, we compared the efficacy and safety of pyronaridine-artesunate with artemether-lumefantrine using the WHO 28-day antimalarial efficacy protocol in Ibadan, southwest Nigeria.Method: In an open-labelled randomized controlled clinical trial children aged 3 to 144 months with a history of fever and microscopically confirmed Plasmodium falciparum malaria were enrolled. Enrolees were randomly assigned to receive pyronaridine–artesunate or artemether–lumefantrine at standard dosages according to bodyweight, for 3 days. Venous blood was obtained for haematology, blood chemistry and liver function tests on days 0, 3, 7, and 28 as part of safety evaluation.Results: One hundred and sixty-five (95.9%; 165/172) enrolees completed the study. About half [52.3%; 90/172] of enrolees were male. Eighty-seven (50.6%) received artemether-lumefantrine while 85 (49.4%) received pyronaridine-artesunate. Day 28 adequate clinical and parasitological response for pyronaridine-artesunate was 92.7% [(76/82) 95% CI: 83.1, 95.9] and 71.1% [(59/83) 95% CI: 60.4, 79.9] for artemether-lumefantrine (ρ<0.001). PCR-corrected cure rates were similar for PA and AL as all parasite recurrences [PA = 6 (7.3%); AL = 24 (28.9%)] were re-infections. Haematological recovery at day-28 was significantly better among pyronaridine-artesunate treated patients (34.9% ± 2.8) compared to those treated with artemether-lumefantrine (33.1% ±3.0) [ρ = 0.002]. Adverse events in both treatment arms were fever, chills and rigors, anorexia, cough and headache, similar to symptoms observed during malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise. There was no serious adverse event in both arms of the study. Conclusion: The two ACTs were well-tolerated. Pyronaridine-artesunate has a higher ACPR than artemether-lumefantrine in the per-protocol-population and a non-inferiority response after PCR correction in the treatment of uncomplicated malaria in Nigerian children. The results of this study support the inclusion of pyronaridine-artesunate in the antimalaria treatment guidelines in Nigeria.Retrospective Trial Registration in Clinicaltrials.gov: NCT05192265