title: The gametocytocidal efficacy of primaquine in malaria asymptomatic carriers treated with dihydroartemisinin-piperaquine in The Gambia (PRINOGAM): study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Finding efficacious tools to decrease and interrupt malaria transmission is essential to sustain the gains in malaria control and contain the emergence of artemisinin resistance. Primaquine is effective against Plasmodium falciparum gametocytes and recommended for treatment campaigns in (pre-)elimination settings. Safety concerns preclude its use in endemic African countries with variable proportions of glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The efficacy of the current recommended dose needs to be evaluated, particularly in individuals with an asymptomatic malaria infection.
  
  
  METHODS
  This is a four-arm, open label, randomized controlled trial that aims to determine and compare the effect of three different single doses of primaquine combined with dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, on gametocyte carriage in asymptomatic, malaria infected, G6PD-normal individuals. Approximately 1,200 participants are enrolled and followed for 42 days, with the primary endpoint being the prevalence of Plasmodium falciparum gametocyte carriage at day 7 of follow-up determined by quantitative nucleic acid sequence based amplification assay. Direct membrane feeding experiments to determine infectiousness to mosquitoes are conducted as a biological secondary endpoint.
  
  
  CONCLUSIONS
  Sub-Saharan Africa, with a relatively high but poorly characterized G6PD prevalence, could potentially benefit from the use of primaquine to further reduce or interrupt malaria transmission. However, G6PD screening may not be feasible given the cost and difficulties in interpreting test results in terms of risk of haemolysis. Because the haemolytic effect of primaquine is dose-dependent, determining the minimal gametocytocidal and transmission-blocking dose of primaquine is extremely important to help address public health concerns over its safety and validate the efficacy of lower than recommended dosages. By including infectiousness to mosquitoes, the trial provides complementary evidence for the potential of the drug to interrupt transmission to mosquitoes.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01838902 (12 April 2013).
authors.affiliation: Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. jokebe@mrc.gm.
authors.forename: Joseph
authors.initials: J
authors.lastname: Okebe
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, UK. teun.Bousema@lshtm.ac.uk.
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.affiliation: Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. maffara@mrc.gm.
authors.forename: Muna
authors.initials: M
authors.lastname: Affara
authors.affiliation: Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population health, London School of Hygiene and Tropical Medicine, London, UK. GianLuca.DiTanna@lshtm.ac.uk.
authors.forename: GianLuca
authors.initials: G
authors.lastname: DiTanna
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, UK. chi.eziefula@lshtm.ac.uk.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Eziefula
authors.affiliation: Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. mjawara@mrc.gm.
authors.forename: Musa
authors.initials: M
authors.lastname: Jawara
authors.affiliation: Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. dnwakanma@mrc.gm.
authors.forename: Davis
authors.initials: D
authors.lastname: Nwakanma
authors.affiliation: Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. angwa@mrc.gm.
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.affiliation: International Health Unit, Faculty of Medicine & Health Sciences, University of Antwerp, Antwerp, Belgium. Jean-Pierre.VanGeertruyden@ua.ac.be.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Van Geertruyden
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, UK. Chris.Drakeley@lshtm.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Drakeley
authors.affiliation: Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia. udalessandro@mrc.gm.|Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. udalessandro@mrc.gm.|Department of Public health, Institute of Tropical Medicine, Antwerp, Belgium. udalessandro@mrc.gm.
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002985:Clinical Protocols; D003627:Data Interpretation, Statistical; D004338:Drug Combinations; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D011319:Primaquine / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D018401:Sample Size; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011319:Primaquine; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines