A randomised, double-blind, placebo-controlled, non-inferiority trial to assess the safety of age-dosed single low dose primaquine in falciparum-infected African children with G6PD deficiency
Background: The WHO recommends gametocytocidal, single low dose primaquine (SLDPQ) for blocking Plasmodium falciparum transmission but safety concerns have hampered implementation in Sub-Saharan Africa. We, therefore, investigated the safety of age-dosed SLDPQ. Methods: We conducted a randomised, double-blind, placebo-controlled, non-inferiority trial of SLDPQ combined with either artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHAPP) in Ugandan and Congolese children aged 6m−11y with acute uncomplicated P. falciparum and haemoglobin (Hb) concentrations ≥ 6 g/dL. A comorbid illness requiring inpatient treatment, on haemolysing drugs in glucose-6-phosphate dehydrogenase deficiency (G6PDd), allergy to study drugs, and enrolment in another trial excluded participation. G6PD status was defined by genotyping for the c.202T A- G6PDd allele. Randomisation was stratified by age and G6PD status. The development of profound (Hb <4 g/dL) or severe anaemia (Hb <5 g/dL) with severity features, within 21 days of treatment, defined the primary end point. The sample size assumed a 1·5% incidence in the placebo arm and a 3% non-inferiority margin. Analysis was by intention to treat. Findings: 1,137 children, median age 5y, were recruited: 286 AL+SLDPQ, 286 AL+Placebo, 283 DHAPP+SLDPQ and 282 DHAPP+Placebo (266, 272, 264, 264 completed the study, respectively): 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (G6PDd group), 119 heterozygous females, 418 G6PD-c.202C normal males (n=418) and females (n=299), and unknown status 17. None developed profound anaemia and three severe anaemia: G6PDd group 0/133 (0%, Placebo) vs. 1/151 (0·66%, SLDPQ): ∆= -0·66% (95% CI -1·96%, 0·63%, p=0·35), and nonG6PDd group: 1/430 (0·23%, Placebo) vs. 1/407 (0·25%, SLDPQ): ∆= -0·014% (95% CI -0·68%, 0·65%; p=0·97). Ten [0·88 (0·42, 1·61%)] patients were transfused in the first week; four had G6PDd. Early vomiting rates (p=0·525) were 22/568 [3·9 (2·4, 5·8)%, Placebo] vs. 18/569 [3·2 (1·9, 5·0)%, SLDPQ]. Interpretation: Gametocytocidal, age-dosed SLDPQ was well tolerated in falciparum-infected African children and had a similar safety profile as placebo. These data support the wider implementation of SLDPQ in Africa. Funding: The study was funded by the Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (Grant Ref: MR/P006973/1
