NECTAR3 Randomized Controlled Trial

Related studies: 

NECTAR1
NECTAR2
NECTAR4

Background: Artemether-lumefantrine accounts for more than 75% of all artemisinin-based combination therapy used worldwide, there is currently no reliable data on malaria transmission post- artemether-lumefantrine. We aimed to determine the efficacy of artemether-lumefantrine with or without SLD of primaquine and sulfadoxine-pyrimethamine and amodiaquine with and without single low-dose tafenoquine for reducing gametocyte density and transmission to mosquitoes.

Objectives:

Primary objective: Assess the reduction of infectivity of gametocytes following administration of AL alone or with single dose PQ and SPAQ alone or with single-dose TQ in children and adults without G6PD deficiency at day 2 (AL, AL-PQ) and 7 (SPAQ, SPAQ-TQ) post-treatment compared to pre-treatment (day 0)

Secondary objectives:

Assess differences in other mosquito infectivity parameters (mosquito infection rate, change in infection rate, infectivity to mosquitoes, and oocyst density) following treatment with AL, AL-PQ, SPAQ & SPAQ-TQ in children and adults without G6PD deficiency at all feeding timepoints compared to pre-treatment (day 0) and between treatment matched arms (AL vs AL-PQ, SPAQ vs SPAQ-TQ)
Assess differences in gametocyte parameters (prevalence, density, circulation time, area-under the curve, sex-ratio) following treatment with AL, AL-PQ, SPAQ & SPAQTQ in children and adults without G6PD deficiency compared to pre-treatment (day 0) and between treatment matched arms (AL vs AL-PQ, SPAQ vs SPAQ-TQ)
Assess differences in safety parameters (AE frequency, Hb density, median drop in Hb) following treatment with AL, AL-PQ, SPAQ & SPAQ-TQ in children and adults without G6PD deficiency compared to pre-treatment (day 0) and between treatment matched arms (AL vs AL-PQ, SPAQ vs SPAQ-TQ)
Assess differences in biochemical parameters (ALT, AST, CBC, Creatine, Methaemoglobin) following treatment with AL, AL-PQ, SPAQ & SPAQ-TQ in children and adults without G6PD deficiency compared to pre-treatment (day 0) and between treatment matched arms (AL vs AL-PQ, SPAQ vs SPAQ-TQ)

Exploratory objectives:

Assess parasite genomic and transcriptomic variation at baseline and at select post-treatment timepoints
Assess human genomic variation (i.e., HBB type) and association with parasite measures
Assess the impact of plasma biomarkers on malaria transmission efficiency
Estimate the carbon footprint of different components of the trial

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 13 Oct and 16 Dec 2021, 1290 individuals were assessed for eligibility. The final follow-up visit was on Jan 13, 2022

Study Design: Four-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: Before the commencement of screening, the study team composed of clinicians and technicians met with community leaders, village health workers, and heads of households from each village to explain the study and obtain approval to conduct the study. Village health workers then used a door-to-door approach to inform households of the date and location where consenting and screening would take place. Participants were included in the trial if they met the following criteria: positive for P. falciparum gametocytes by microscopy (i.e. ≥1 gametocytes recorded in a thick film against 500 white blood cells, equating to 16 gametocytes/µL with a standard conversion of 8000 white blood cells (WBC)/µL blood); absence of other non-P. falciparum species on blood film; haemoglobin density of ≥ 10g/dL; G6PD normal (male >4 IU/g Hb, female >6 IU/g Hb); aged between 10-50 years; weighed ≤80kg; no clinical signs of malaria, defined by fever (≥37·5°C); no signs of acute, severe or chronic disease; no allergies to any study drugs; reported no use of antimalarial drugs over the past week; consistent with the long half-life of tafenoquine, use of effective contraception for 5 half-lives (3 months) after the end of TQ treatment. Exclusion criteria included pregnancy (tested at enrolment by urine test) or lactation, use of other medication (except for paracetamol and/or aspirin), family history of congenital prolongation of the corrected QT (QTc) interval, current/recent treatment with drugs known to extend QTc interval and blood transfusion in last 90 days. Prior to screening and prior to study enrolment, participants provided written informed consent (≥18 years) or assent with written parental consent (12-17 years).

Data Collection: Participants received a full clinical and parasitological examination on days 1, 2, 5, 7, 14, 21 and 28 after receiving the first dose of the study drugs. Additional venous blood samples were taken for biochemical and infectivity assessments on day 0, 2, 5, 7 and 14 in all arms. For each assessment of infectivity, ~75 locally reared Anopheles gambiae were allowed to feed for 15-20 minutes on venous blood samples through a prewarmed glass membrane feeder system. All surviving mosquitoes were dissected on the 7th day after feeding assay; midguts were stained in 1% mercurochrome and examined for the presence and density of oocysts by expert microscopists

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: Primaquine tablets were kindly donated by ACE Pharmaceuticals, Zeewolde, The Netherlands. Tafenoquine tablets were kindly donated by 60° Pharmaceuticals Ltd, USA. We would like to thank the study participants and the population of Ouelessebougou, Mali for their cooperation. Finally, we would like to thank the local safety monitor, members of the data safety and monitoring board for their assistance.

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: July 14, 2023NECTAR3 is a four-arm trial comparing artemether-lumefantrine with or without single-dose primaquine and sulphadoxine-pyrimethamine/amodiaquine with or without single-dose tafenoquine to reduce P. falciparum transmission in Mali.