Review 2: "Artemether-lumefantrine-amodiaquine or Artesunate-amodiaquine Combined with Single Low-dose Primaquine to Reduce Plasmodium Falciparum Malaria Transmission in Ouelessebougou, Mali: A Five-arm, Phase 2, Single-blind, Randomised Clinical Trial"

Milijaona Randrianarivelojosia

doi:doi:10.1162/2e3983f5.44df5302

Artemether-lumefantrine-amodiaquine or artesunate-amodiaquine combined with single low-dose primaquine to reduce Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a five-arm, phase 2, single-blind, randomised clinical trial

by Almahamoudou Mahamar, Leen N Vanheer, Merel J Smit, Koualy Sanogo, Youssouf Sinaba, Sidi M. Niambele, Makonon Diallo, Oumar M Dicko, Richard S. Diarra, Seydina O Maguiraga, Ahamadou Youssouf, Adama Sacko, Sekouba Keita, Siaka Samake, Adama Dembele, Karina Teelen, Yahia Dicko, Sekou F. Traore, Arjen Dondorp, Chris Drakeley, William Stone, and Alassane Dicko

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Published on Feb 24, 2024
www.medrxiv.org

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Summary 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 uncomplicated Plasmodium falciparum malaria. 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 asymptomatic P. falciparum microscopy-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 only 31·67% (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

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: Almahamoudou Mahamar et al. report on “Artemether-lumefantrine-amodiaquine or artesunate-amodiaquine combined with single low-dose primaquine to reduce Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a five-arm, phase 2, single-blind, randomised clinical trial”.

The methodology is pertinent and the results from this phase 2 clinical trial are indeed well presented. The findings underscore the significance of combining low-dose primaquine (PQ) with ACT or TACT in reducing the spread of P. falciparum. Above all, the addition of a single PQ low-dose is an effective addition for blocking P. falciparum transmission.

I also believe that combining artesunate + amodiaquine (ASAQ) or artemether-lumefantrine (AL) with a low dose of PQ in a single dose will be pivotal for malaria control. ASAQ and AL are the most used ACTs for treating malaria in Africa where PQ low-dose is often recommended but still underutilized. Thus, Mahamar et al.'s paper deserves to be published. This is among the key papers to guide the decision-makers in improving malaria treatment policy and therapeutic efficacy survey (testing ACT + PQ).

However, the authors should correct the mistyping. For example:

Line 150: what is “23/02/2024 08:44:00”
Line 299: there were not the were

Review 2: "Artemether-lumefantrine-amodiaquine or Artesunate-amodiaquine Combined with Single Low-dose Primaquine to Reduce Plasmodium Falciparum Malaria Transmission in Ouelessebougou, Mali: A Five-arm, Phase 2, Single-blind, Randomised Clinical Trial"

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