NECTAR1 Randomized Controlled Trial

Related studies: 

NECTAR2
NECTAR3
NECTAR4

Background: Pyronaridine–artesunate is the most recently licensed artemisinin-based combination therapy. WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance. We aimed to determine the efficacy of pyronaridine–artesunate and dihydroartemisinin–piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes.

Objectives:

The study had the following primary scientific objective: Assess the change of infectivity of gametocytes from malaria infected patients following the administration of pyronaridine-artesunate (PA), PA plus single low dose primaquine (PA-PQ), dihydroartemisinin-piperaquine (DP), and DP plus single low dose primaquine (DP-PQ) in P. falciparum gametocyte carriers at day 2 post-treatment.

The study had the following secondary scientific objectives:

Assess the change of infectivity of gametocytes from malaria infected patients following the administration of pyronaridine-artesunate (PA), PA plus single low dose primaquine (PA-PQ), dihydroartemisinin-piperaquine (DP), and DP plus single low dose primaquine (DP-PQ) in P. falciparum gametocyte carriers at day 7 post treatment.
Compare the duration and intensity of infectivity to mosquitoes up to day 7 post-treatment between all study arms.
Assess the total duration of human infectivity to mosquitoes following DP and PA treatment, and its association with molecular and serological markers of gametocyte density, fitness, and infectivity.
Assess the association of P. falciparum gametocyte density, RDT detectability, infectivity, and HRP persistence between P. falciparum infected individuals with (DP and PA arms) and without (DP-PQ and PA-PQ arms) gametocytes post-treatment, with and without adjustment for baseline HRP-2 concentration.
Assess the safety of DP and PA when given with or without low single dose of primaquine.

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 Sept 10 to Nov 19, 2019, 1044 individuals were screened for eligibility. The final follow-up visit was on Jan 7, 2020.

Study Design: Four-arm, single-blind, phase 2/3, randomized controlled trial with follow-up up to 49 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. The study population will be derived from individuals aged 5-50 years with asymptomatic P. falciparum malaria who agree to be screened for malaria infection at the clinic. The maximum weight of individuals is 80kg, to allow adequate dosing of DP (for which no dose recommendations are available for individuals >100kg). Eligible individuals will have microscopically detectable P. falciparum asexual parasites at densities of 16-2000/µL, with gametocyte densities of ≥16 gametocytes/µL.

Study Arms:

Arm 1: Dihydroartemisinin-piperaquine

Arm 2: Dihydroartemisinin-piperaquine + primaquine

Arm 3: Pyronaridine-artesunate

Arm 4: Pyronaridine-artesunate + primaquine

Data Collection: Each participant will be followed for 49 days. Participants will receive a full clinical and parasitological examination on days 1, 2, 7, 14, 21, 28, 35, 42 and 49 after receiving the first dose of the study drug. Blood samples will be taken for parasitology (microscopy, and whole blood for qRT-PCR), serology (dried blood spots and whole serum), and HRP-2 detection and quantification (RDT, uRDT, and Luminex/Quansys for concentration). All participants will be treated with DP again at day 21, to ensure adequate prophylaxis for the full duration of follow-up. Infectivity to locally reared mosquitoes will be assessed with membrane feeding assays at baseline, on the final day of DP treatment (day 2) and at day 7 for all participants. In the DP and PA arms, infectivity will continue to be assessed at day 10, 14 and then weekly until no infectivity is observed for 2 sequential visits (from and including day 10) or until day 49. The minimum volume of blood for infectivity assays will be 3*2mL blood samples (days 0, 2 and 7), and the maximum will be 10*2mL blood samples to establish infectivity over the entire 6 week period, if infectivity is assessed at all-time points.

ClinEpiDB Data Integration: Data files were provided to ClinEpiDB as flat, tsv files. These datasets were merged by unique ID and redundant or administrative columns were dropped from presentation on ClinEpiDB.org. All dates were obfuscated to comply with the ethical conduct of human subjects research.

Financial Support: This work was supported by the Gates Foundation (INV-002098). JB received support from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID; MR/K012126/1) under the MRC–DFID Concordat agreement and as part of the EDCTP2 programme supported by the EU. TB is 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: Ethics 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 NECTAR1 trial evaluated the efficacy of pyronaridine–artesunate and dihydroartemisinin–piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes in Mali