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

Abstract

Background: The World Health Organization 2022 malaria chemoprevention guidelines recommend providing a full course of antimalarial treatment at pre-defined intervals, regardless of malaria status to prevent illness among children resident in moderate to high perennial malaria transmission settings as perennial malaria chemoprevention (PMC) with sulfadoxine-pyrimethamine (SP). The dhps I431V mutation circulating in West Africa has unknown effect on SP protective efficacy.

Methods: This protocol is for a three-arm, parallel, double-blinded, placebo-controlled, randomised trial in Cameroon among children randomly assigned to one of three directly-observed treatment groups: (i) Group 1 (n = 450) receives daily artesunate (AS) placebo on days - 7 to -1, then active SP plus placebo amodiaquine (AQ) on day 0, and placebo AQ on days 1 and 2; (ii) Group 2 (n = 250) receives placebo AS on days - 7 to -1, then active SP and AQ on day 0, and active AQ on days 1 and 2; and (iii) Group 3 (n = 200) receives active AS on days - 7 to -1, then placebo SP on day 0 and placebo AQ on days 0 to 2. On days 0, 2, 5, 7, and thereafter weekly 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.

Discussion: Our aim is to quantify the chemopreventive efficacy of SP, and SP plus AQ, and measure the effect of the parasite genotypes associated with SP resistance on parasite clearance and protection from infection when exposed to SP chemoprevention. We will report unblinded results including: (i) time-to-parasite clearance among SP and SP plus AQ recipients who were positive on day 0 by qPCR and followed to day 63; (ii) mean duration of SP and SP plus AQ protection against infection, and (iii) mean duration of symptom-free status among SP and SP plus AQ recipients who were parasite free on day 0 by qPCR. Our study is designed to compare the 28-day follow-up of the new WHO malaria chemoprevention efficacy study protocol with extended follow-up to day 63.

Trial registration: ClinicalTrials.gov NCT06173206; 15/12/2023.

Keywords: Antimalarial resistance; Intermittent preventive treatment; Perennial malaria chemoprevention.

Fig. 1

Publicly available historical data on dhps mutations in Cameroon. Legend: The prevalence of the dhps I431V genotype has risen since 2010, along with mutations in the dhps A581G and A613S

Fig. 2

Combined published and unpublished data on frequency of dhps genotypes in Cameroon. Legend: The denominators shown exclude mixed infections at any of the six dhps loci, as well as samples with incomplete haplotype information. The red and orange sections in the pie charts show the proportion of those samples that contain the novel dhps 431V genotype. The question mark symbol within the haplotypes denotes a dhps genotype that is either 436S or 436A

Fig. 3

Incidence of infection per person per year across the year. Legend: Incidence was obtained by calibrating a malaria transmission model (developed by Imperial College) to a parasite prevalence 40% reported for Ngounso. The model uses historical data on intervention coverage at first administrative level (West Region) obtained from MIS and DHS surveys. The functional form for seasonality in malaria cases are based on rainfall data from the Climate Hazards Group InfraRed Precipitation with Station (CHIRPS)