Parasite clearance and protection from Plasmodium falciparum infection (PCPI): a two-arm, parallel, double-blinded, placebo-controlled, randomised trial of presumptive sulfadoxine-pyrimethamine versus artesunate monotherapy among asymptomatic children 3-5 years of age in Zambia

Background: The 2022 malaria chemoprevention guidelines of the World Health Organization (WHO) recommend the provision of a full treatment course of an antimalarial medicine at predefined intervals, regardless of whether the child is infected with malaria, to prevent illness in moderate to high perennial malaria transmission settings. Sulfadoxine-pyrimethamine (SP) is usually used for this intervention, now called perennial malaria chemoprevention (PMC). The K540E mutation in the dihydropteroate synthase ( dhps ) gene circulating in Africa is thought to be associated with treatment failure and reduced chemoprevention efficacy in children but the exact effect remains unclear. Methods: This protocol is for a two-arm, parallel, double-blind, placebo-controlled, randomised trial in Zambia that is designed to evaluate the effect of parasite genotypes on the efficacy of single-dose SP among asymptomatic children between 3-5 years of age. Children are randomly allocated to one of two groups for directly observed treatment. Over seven consecutive days (days -7 to -1), children in the SP group (n=400) receive placebo artesunate (AS), then active SP (day 0). In contrast, children in the AS group (n=200) receive active artesunate for seven consecutive days, followed by placebo SP (day 0). Then, on days 0, 2, 5, 7, and weekly thereafter until day 28, children provide blood for thick smear slides. Dried blood spots are collected on the same days and weekly from day 28 to day 63 for quantitative polymerase chain reaction (qPCR) and genotype analyses using a platform based on PCR followed by targeted next-generation sequencing. Discussion: Our aim is to measure the effect of the parasite genotypes associated with SP resistance on parasite clearance and protection from new infection when exposed to SP chemoprevention. We will report unblinded results including: (i) time-to-parasite clearance among SP recipients who were positive on day 0 by qPCR and measured to day 63; (ii) mean duration of SP protection against infection, and (iii) mean duration of symptom-free status among SP recipients who were parasite free on day 0 by qPCR. Our conclusions will reflect on the utility of WHO’s new malaria chemoprevention efficacy study protocol with its follow-up to day 28 versus day 63. Trial Registration: ClinicalTrials.gov NCT06166498; 11/12/2023.