Evaluation of the efficacy and safety of primaquine for clearance of gametocytes in uncomplicated falciparum malaria in Uganda

Background: After standard effective antimalarial treatment with artemisinin-based combination therapy (ACT), a proportion of individuals remain infectious to mosquitoes, enabling onward transmission. This is due to persisting gametocytes, the sexual stage of the malaria parasite. Primaquine, an 8-aminoquinoline drug, sterilizes and clears gametocytes. The World Health Organization recommends that, in areas where malaria elimination is targeted, a single dose of primaquine should be given in addition to standard antimalarial treatment. Despite its recommendation in WHO guidelines since the 1970s, the optimal dose of primaquine for this purpose had not been determined. Primaquine is associated with haemolytic toxicity in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition that is prevalent in malaria-endemic regions. This thesis presents the first dose ranging trial to assess the safety and efficacy of reducing doses of primaquine in combination with ACT to treat children with uncomplicated falciparum malaria infection. Methods: A literature review was conducted to inform a novel, evidence-based trial design. Based in Jinja, Uganda, this randomised, double-blind, and placebo-controlled trial had four parallel treatment groups of reducing doses of primaquine plus ACT. Results: For trial participants, a single dose of 0.4mg/kg primaquine base had non-inferior efficacy (measured by gametocyte clearance) to the WHO-recommended dose of 0.75mg/kg, whereas a dose of 0.1mg/kg was not non-inferior. There was no significant haemolysis in any of the treatment arms and the fall in haemoglobin was not associated with the dose of primaquine. However, a sub-analysis showed a dose-dependent reduction in haemoglobin in participants who were G6PD deficient (heterozygous or hemi-/homozygous genotype). Subsequently, the WHO reduced the recommended dose to 0.25mg/kg primaquine base