Project: Single low-dose primaquine efficacy and safety for treatment of uncomplicated Plasmodium falciparum Malaria based on cytochrome P450 2D6 activity in Bagamoyo district, Tanzania.

Acronym	ESSLDPQ P4502D6 (Reference Number: TMA2016CDF-1555)
Duration	01/08/2018 - 31/01/2021
Project Topic	Background: The World Health Organization (WHO) has now recommended addition of a 0.25 mg/kg single-dose primaquine (PQ) to standard artemisinin-based combination therapy (ACT) for elimination of Plasmodium falciparum malaria in low transmission-settings and for containment in areas threatened by artemisinin resistance. The dose has shown to be safe even in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and is efficacious for clearance of P. falciparum gametocytes. However, some individuals with normal G6PD status have developed AEs including acute hemolysis following treatment with this single low-dose PQ. Furthermore, a failure rate of =5 has also been reported in gametocyte clearance and transmission blocking after treatment with even high doses of PQ suggesting involvement of other factors in determining PQ safety and efficacy. Due to these safety concerns most of the malaria endemic sub-Saharan African countries have failed to adopt the PQ recommendation. However, PQ metabolism depends on a highly polymorphic cytochrome P450 (CYP) 2D6 isoenzyme, which probably compromises the drug’s safety and efficacy, particularly in individuals with reduced isoenzyme activity. Nonetheless, there is no enough information regarding the effect of CYP2D6 isoenzyme polymorphism on PQ safety and its efficacy in sterilizing mature P. falciparum gametocytes. This trial aims to assess the safety and efficacy of 0.25 mg/kg single-dose PQ when added to standard artemetherlumefantrine regimen for clearance and blocking transmission of P. falciparum gametocytes in patients with CYP2D6 reduced/null activity as compared to those with normal/increased enzyme activity. Methods: One hundred and fifty-five children aged between 1 and 10 years and with uncomplicated P. falciparum malaria will be enrolled, treated with standard artemether-lumefantrine regimen plus a 0.25 mg/kg single-dose of PQ and then followed up on days 0, 1, 2, 3, 7, 14, 21 and 28 for clinical and laboratory assessment. Primaquine will be administered together with the first dose of artemether-lumefantrine. Safety assessment will be performed using the Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT). Gametocytes will be detected and quantified by microscopy and Pfs25 mRNA quantitative nucleic acid sequence based amplification (QT-NASBA) on days 0 and 7. For a subset of 100 participants, post-treatment infectiousness will be assessed by mosquito feeding assays on day 7. The CYP2D6 status will be determined using a polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analyses. The primary outcome will be the safety of 0.25 mg/kg single-dose PQ for clearance and transmission-blocking of P. falciparum gametocytes in patients with CYP2D6 reduced/null activity compared to those with normal/increased activity. Expected outcomes: The findings will provide the much-needed information on the safety and efficacy of 0.25 mg/kg single-dose PQ for clearance and transmission-blocking of P. falciparum gametocytes in individuals with reduced/null compared to those with normal/increased CYP450 2D6 isoenzyme activity prior to the implementation of the PQ policy, particularly in Africa. The project will also equip the applicant with required knowledge and skills in running clinical trials, and also prepare him to become an independent researcher.
Network	EDCTP2
Call	Career Development Fellowships 2016

Project partner

Number	Name	Role	Country
1	Tropical Pesticides Research Institute	Coordinator	Tanzania