NECTAR2 Randomized Controlled Trial

Related studies: 

NECTAR1
NECTAR3
NECTAR4

Background: Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin–piperaquine for reducing gametocyte density and transmission to mosquitoes.

Objectives:

Primary objective: Assess the change of infectivity of gametocytes following the administration of different doses of tafenoquine (TQ) combined with dihydroartemisinin-piperaquine (DP) in children and adults without G6PD deficiency at day 2 post-treatment compared to pre-treatment (day 0)

Secondary objectives:

Assess the safety (AE frequency, median drop in Hb) of different doses of TQ combined with DP in children and adults without G6PD deficiency
Assess the change of infectivity of gametocytes following the administration of different doses of TQ combined with DP in children and adults without G6PD deficiency at day 7 post treatment compared to pre-treatment (day 0)
Assess the change of gametocyte carriage and density following the administration of different doses of TQ combined with DP in children and adults without G6PD deficiency compared to pre-treatment (day 0)
Assess the difference in gametocytocidal activity (assessed as gametocyte area under the curve) between study arms
Assess the difference in safety outcomes (AE frequency, median drop in Hb) between study arms
Assess the difference in infectivity (prevalence and density of oocysts at day 2, 7 and 14 compared to baseline) between study arms

Methodology:

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

Dates of Data Collection: From Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility. The final follow-up visit was on Dec 23, 2020

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, our study team 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 (ie, ≥1 gametocytes recorded in a thick film against 500 white blood cells, equating to 16 gametocytes per μL with a standard conversion of 8000 white blood cells per μL blood); absence of other non-P falciparum species on blood film; haemoglobin density of 10 g/dL or more; normal G6PD (male >4 IU/g haemoglobin, female >6 IU/g haemoglobin); aged between 12–50 years; bodyweight 80 kg or less; 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 five half-lives (3 months) after the end of tafenoquine treatment. Exclusion criteria included pregnancy (tested at enrolment by urine and serum test) or lactation, use of other medication (except for paracetamol or aspirin), family history of congenital prolongation of the corrected QT interval, current or recent treatment with drugs known to extend the corrected QT interval, and blood transfusion in the past 90 days.

Data Collection: Participants received a full clinical and parasitological examination on days 1, 2, 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 days 0, 2, 7, and 14 in all treatment groups. For each assessment of infectivity, approximately 75 locally reared Anopheles gambiae were allowed to feed for 15–20 min on venous blood samples through a prewarmed glass membrane feeder system. All surviving mosquitoes were dissected on the seventh day after the 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: Tafenoquine tablets were kindly donated by 60° Pharmaceuticals, USA. We thank Judith Meta, Maria Luisa Simoes, and Marta Moreno Leirana for the abstract translations. 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 & Tropical Medicine (London, UK).

Last Updated: July 14, 2023The NECTAR2 trial evaluated single low dose tafenoquine to reduce P. falciparum transmission in Mali.