NECTAR4 Randomized Controlled Trial

Related studies: 

NECTAR1
NECTAR2
NECTAR3

Background: Artemisinin-based combination therapies (ACT) are the first-line treatment for uncomplicated Plasmodium falciparum malaria. ACTs rapidly clear asexual P. falciparum parasites, responsible for clinical symptoms, but have limited activity against mature gametocytes, which are the only life stages capable of transmitting to mosquitoes. To reduce P. falciparum transmission, the World Health Organisation recommends the addition of a single low dose of primaquine (0.25 mg/kg) (SLD PQ), a potent and fast-acting gametocytocidal drug, to ACT. Although artesunate-amodiaquine (ASAQ) is a commonly used ACT, limited available data suggest poor activity against gametocytes and the added benefit of SLD PQ in combination with ASAQ remains unknown. We previously showed that artemether-lumefantrine (AL) is a more potent ACT in terms of gametocyte clearance and transmission reduction efficacy compared to dihydroartemisinin-piperaquine. Recently, triple artemisinin-based combination therapies (TACT) such as artemether-lumefantrine plus amodiaquine (ALAQ) have been proposed to delay the emergence of drug resistance and to provide efficacious treatment for multi-drug resistance P. falciparum infections. The transmission reducing efficacy of ALAQ or ALAQ-PQ has not yet been tested. We aimed to determine transmission reducing efficacy of artesunate-amodiaquine with and without a single low dose (0.25mg/kg) of primaquine and artemether-lumefantrine with and without amodiaquine and primaquine.

Objectives:

Primary objective: To assess the within-person reduction of infectivity of gametocytes following administration of ASAQ alone or with single-dose PQ and AL alone or with AQ and ALAQ alone or with single-dose PQ in children and adults at day 2 post-treatment compared to pre-treatment (day 0)

Secondary objectives:

To assess differences in other mosquito infectivity parameters (mosquito infection rate, change in infection rate, infectivity to mosquitoes, and oocyst density) following treatment with ASAQ, ASAQ-PQ, AL, ALAQ and ALAQ-PQ in children and adults at all feeding timepoints compared to pre-treatment (day 0) and between treatment matched arms (ASAQ vs ASAQ-PQ, AL vs ALAQ, ALAQ vs ALAQ-PQ)
To assess differences in gametocyte parameters (prevalence, density, circulation time, area-under-the-curve, sex-ratio) following treatment with ASAQ, ASAQ-PQ, AL, ALAQ and ALAQ-PQ in children and adults at all feeding timepoints compared to pre-treatment (day 0) and between treatment matched arms (ASAQ vs ASAQ-PQ, AL vs ALAQ, ALAQ vs ALAQ-PQ)
To assess differences in safety parameters (AE frequency, Hb density, median drop in Hb) following treatment with ASAQ, ASAQ-PQ, AL, ALAQ and ALAQ-PQ in children and adults at all feeding timepoints compared to pre-treatment (day 0) and between treatment matched arms (ASAQ vs ASAQ-PQ, AL vs ALAQ, ALAQ vs ALAQ-PQ)
To assess differences in biochemical parameters (ALT, CBC, Creatinine) following treatment with ASAQ, ASAQ-PQ, AL, ALAQ and ALAQ-PQ in children and adults at all feeding timepoints compared to pre-treatment (day 0) and between treatment matched arms (ASAQ vs ASAQ-PQ, AL vs ALAQ, ALAQ vs ALAQ-PQ)

Exploratory objectives:

To assess parasite genomic and transcriptomic variation at baseline and at select post-treatment timepoints
To assess human genomic variation (i.e., HBB type) and association with parasite measures
To assess the association of parasite and plasma biomarkers on malaria transmission efficiency
To assess the efficiency of Plasmodium transmission to mosquitoes before and after enrichment of gametocytes by MACS
To determine the association between gametocyte density and mosquito infection rates, before and after MACS enrichment, to estimate possible loss in per-gametocyte infectivity following treatment

Methodology:

Geographic Location/Study Sites:: The field site of Ouelessebougou and Malaria Research and Training Centre (MRTC) in Bamako, Mali

Dates of Data Collection: : Between 17 Oct and 28 Dec 2022 individuals were assessed for eligibility. The final follow-up visit was on Jan 26, 2023

Study Design: Five-arm, single-blind, phase 2, randomised controlled trial with follow-up up to 28 days after receiving the first dose of the study drugs

Eligibility Criteria: For participation in the trial, individuals between 10-50 years will be recruited from villages around Ouelessebougou, near Bamako in Mali. Written, informed consent will be obtained. Inclusion criteria include presence of ≥16 gametocytes/µL, absence of other non-P. falciparum species on blood film, absence of symptomatic falciparum malaria, haemoglobin ≥ 10 g/dL, and no evidence of acute severe or chronic disease or pregnancy. Exclusion criteria included use of other medication (except for paracetamol and/or aspirin), current eye disease with retinal damage, allergy to study drugs, known electrocardiogram corrected QT interval of more than 450 ms, and blood transfusion in last 90 days.

Data Collection: Blood samples will be taken pre-treatment, and at days 2, 7, 14, 21 and 28 post-treatment for parasitology, genetic, haematology and biochemistry analysis. Membrane feeding assay (MFA) will be conducted pre-treatment, and at days 2, 7 and 14 post-treatment. MFA will also be conducted at day 21 for any individuals infectious at day 7 or 14; and at day 28 for any individuals infectious at day 14 or 21. Magnetic-activated cell sorting to enrich for gametocytes will be done at two timepoints per individual to determine per-gametocyte infectivity and confirm whether PQ sterilizes gametocytes, followed by MFA.

ClinEpiDB Data Integration: Data files were provided to ClinEpiDB as excel files. These datasets were merged by unique ID and redundant or administrative columns were dropped from presentation on ClinEpiDB.org. All dates were obfuscated per participant through the application of a random number algorithm that shifted dates no more than seven days to comply with the ethical conduct of human subjects research.

Acknowledgements: Artesunate/amodiaquine, artemether-lumefantrine, and amodiaquine tablets were kindly donated by Guilin Pharmaceutical Co, Guangxi, China. Primaquine tablets were kindly donated by ACE Pharmaceuticals, Zeewolde, The Netherlands. We thank the local safety monitor, members of the data safety and monitoring board, and all MRTC study staff for their assistance. Finally, we thank the study participants and the population of Ouelessebougou, Mali, for their cooperation.

Financial Support: This work was supported by the Bill & Melinda Gates Foundation (#INV-002098). JB is supported by an award jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth and Development Office (FCDO) under the MRC/FCDO Concordat agreement, which is also part of the EDCTP2 programme supported by the EU (MR/R010161/1). TB is further supported by a fellowship from The Netherlands Organisation for Scientific Research (Vidi fellowship NWO project number 016.158.306) and a European Research Council-Consolidator Grant (ERC-CoG 864180; QUANTUM). WS is supported by a Sir Henry Wellcome fellowship (218676/Z/19/Z).

Ethics Statement: Ethical approval was granted by the Ethics Committee of the Faculty of Medicine, Pharmacy, and Dentistry of the University of Science, Techniques, and Technologies of Bamako (Bamako, Mali), and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine (London, UK).

Last Updated: October 31, 2023: A five-arm trial comparing artesunate-amodiaquine and artemether-lumefantrine-amodiaquine with or without single-dose primaquine to reduce P. falciparum transmission in Mali (NECTAR4)