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Review 1: "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"

The reviewers found the evidence and study results to be strong and significant, respectively. However, they note the need for clarification and corrections.

Published onJun 06, 2024
Review 1: "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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key-enterThis Pub is a Review of
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
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
Description

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: This is an important research project as transmission blocking interventions are crucial to reduce the  reduce the risk of spreading parasites that have acquired resistance and reducing the transmission will become increasingly necessary when moving towards elimination of malaria.

The present study is  demonstrating the utility of single dose of primaquine when treatments are administered that have no intrinsic gametocidal activity. Please see below for comments and questions to the  current version of the manuscript:

  • The title is misleading as it only mentions two of the five the treatment arms (ALAQ with and without primaquine)

  • Line 41 and section “randomization and masking”: treatment with AL consists of 6 doses and treatment with ASAQ of 3 doses, were participants blinded?  Same question on primaquine administration some arms received single low dose of primaquine some not. If the participants were not blinded by using placebo this should be clearly mentioned in the abstract and randomization section of the manuscript.

  • Please state how compliance to study treatment was ascertained, how did you determine that participants adhered to a full course of allocated study medication .

  • Nomenclature of Study Days: To make design of this study (and other malaria studies) better comprehensible, the terminology used in other indications should be adopted. Day of Study Drug Administration is Study Day 1 (and not SD0)

  • Why was the  primary endpoint set at  48h after first drug administration, ie before full course of treatment is administered, (for 6 doses of AL (or ALAQ) this would be 60 h after first administration).

  • Interpretation of “median percent of reduction” on 48h post treatment vs “any mosquito infected” at this time. The benefit of adding PQ to AL and ALAQ should also be discussed even if the intrasubject reduction is  100% , there are still gametocytes and mosquito infection of the lumefantrine treatment arms (without primaquine).

  • Mali is one of the countries implementing Seasonal Malaria Chemoprotection with SP&amondiaquine, using an amodiaquine containing malaria treatment is not supported by WHO guidance, please comment why ASAQ and ALAQ were used in this country.

  • Please comment why MACS was used to enrich gametocytes in blood samples before feeding, increase of infectivity was limited. Would other methods, such as Percoll gradient centrifugation be better suited? (A controlled human malaria infection model enabling evaluation of transmission-blocking interventions  (Katharine A. Collins, et al. J Clin Invest. 2018;128(4):1551-1562. https://doi.org/10.1172/JCI98012.)  )

  • Inclusion criteria : I noted that participants with clinical signs of malaria were excluded, was there a limit of asexual parasite counts at screening.

Minor points:

  • Line 150 “23/02/2024 08:44:00” is probably a time stamp, please remove.

  • Line 160: Please state the name of the biochemistry analyser, I assume it was the HumaStar100 manufactured by Human, Wiesbaden Germany

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