Artemether-lumefantrine-amodiaquine or artesunate-amodiaquine combined with single low-dose primaquine to reducePlasmodium falciparummalaria transmission in Ouélessébougou, Mali: a five-arm, phase 2, single-blind, randomised clinical trial
Authors: Mahamar Almahamoudou , Vanheer Leen N , Smit Merel J , Sanogo Koualy , Sinaba Youssouf , Niambele Sidi M. , Diallo Makonon , Dicko Oumar M , Diarra Richard S. , Maguiraga Seydina O , Youssouf Ahamadou , Sacko Adama , Keita Sekouba , Samake Siaka , Dembele Adama , Teelen Karina , Dicko Yahia , Traore Sekou F. , Dondorp Arjen , Drakeley Chris , Stone William , Dicko Alassane 
Published: December 2024

Background

Triple artemisinin-based combination therapies, such as artemether-lumefantrine-amodiaquine, can delay the spread of antimalarial drug resistance; artesunate-amodiaquine is widely used for uncomplicatedPlasmodium falciparummalaria. We aimed to determine the efficacy of artemether-lumefantrine-amodiaquine and artesunate-amodiaquine with and without single low-dose primaquine for reducing gametocyte carriage and transmission to mosquitoes.

Methods

We conducted a five-arm, single-blind, phase 2, randomised clinical trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Sciences, Techniques and Technologies of Bamako (Bamako, Mali). Eligible participants aged 10-50 years, with asymptomaticP. falciparummicroscopy-detected gametocyte carriage, were randomised (1:1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine-amodiaquine, artemether-lumefantrine-amodiaquine plus primaquine, artesunate-amodiaquine, or artesunate-amodiaquine plus primaquine. Treatment allocation was computer randomised and concealed to all study staff other than the trial pharmacist. The primary outcome was the within-person percentage reduction in mosquito infection rate at 48 hours after treatment initiation compared to pre-treatment, assessed by direct membrane feeding assay. Data were analysed per protocol. This study is registered with ClinicalTrials.gov,NCT05550909.

Findings

Between Oct 16 and Dec 28, 2022, 1249 individuals were screened for eligibility, 100 of which were enrolled and randomly assigned to one of five treatment groups (n=20 per group). Before treatment, 61 (61%) of 100 participants were infectious to mosquitoes, with a median of 7·3%(IQR 3·2-23·5) of mosquitoes becoming infected. Among infectious individuals, the median percentage reduction in mosquito infection rate between pre-treatment and 2 days post-treatment was 100% (IQR 100-100) in the artemether-lumefantrine (p=0·0018), artemether-lumefantrine-amodiaquine (p=0·0018), and artemether-lumefantrine-amodiaquine plus primaquine (p=0·0009) treatment groups. In the artesunate-amodiaquine group the median percent reduction in mosquito infection rate was only31·67% (IQR -10·9-100, p=0·1927), whereas there was 100% reduction in the artesunate-amodiaquine plus primaquine group (p=0·0009). At day 2, 10% (2/20) of participants in the artemether-lumefantrine group, 11% (2/19) in the artemether-lumefantrine-amodiaquine group, and 75% (15/20) in the artesunate-amodiaquine group infected any number of mosquitoes whilst no infected mosquitoes were observed at this time-point in the primaquine arms. No serious adverse events occurred.

Interpretation

These data support the effectiveness of artemether-lumefantrine alone or as part of triple combination therapy for preventing nearly all human-mosquito malaria parasite transmission within 48 hours. In contrast, substantial transmission was observed following treatment with artesunate-amodiaquine. The addition of a single low-dose of primaquine blocks transmission to mosquitoes rapidly regardless of schizonticide.

Funding

Bill & Melinda Gates Foundation