title: Study protocol for a randomised controlled double-blinded trial of the dose-dependent efficacy and safety of primaquine for clearance of gametocytes in children with uncomplicated falciparum malaria in Uganda.
abstract: OBJECTIVE
  For the purpose of blocking transmission of Plasmodium falciparum malaria from humans to mosquitoes, a single dose of primaquine is recommended by the WHO as an addition to artemisinin combination therapy. Primaquine clears gametocytes but causes dose-dependent haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Evidence is needed to inform the optimal dosing of primaquine for malaria elimination programmes and for the purpose of interrupting the spread of artemisinin-resistant malaria. This study investigates the efficacy and safety of reducing doses of primaquine for clearance of gametocytes in participants with normal G6PD status.
  
  
  METHODS
  In this prospective, four-armed randomised placebo-controlled double-blinded trial, children aged 1-10 years, weighing over 10 kg, with haemoglobin ≥8 g/dl and uncomplicated P falciparum malaria are treated with artemether lumefantrine and randomised to receive a dose of primaquine (0.1, 0.4 or 0.75 mg base/kg) or placebo on the third day of treatment. Participants are followed up for 28 days. Gametocytaemia is measured by quantitative nucleic acid sequence-based analysis on days 0, 2, 3, 7, 10 and 14 with a primary endpoint of the number of days to gametocyte clearance in each treatment arm and secondarily the area under the curve of gametocyte density over time. Analysis is for non-inferiority of efficacy compared to the reference dose, 0.75 mg base/kg. Safety is assessed by pair-wise comparisons of the arithmetic mean (±SD) change in haemoglobin concentration per treatment arm and analysed for superiority to placebo and incidence of adverse events. Ethics and dissemination Approval was obtained from the ethical committees of Makerere University School of Medicine, the Ugandan National Council of Science and Technology and the London School of Hygiene and Tropical Medicine.
  
  
  RESULTS
  These will be disseminated to inform malaria elimination policy, through peer-reviewed publication and academic presentations.
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Alice Chijioke
authors.initials: AC
authors.lastname: Eziefula
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.forename: Shunmay
authors.initials: S
authors.lastname: Yeung
authors.forename: Emily
authors.initials: E
authors.lastname: Webb
authors.forename: Moses
authors.initials: M
authors.lastname: Kamya
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.forename: Chris
authors.initials: C
authors.lastname: Drakeley
references.citation: Blood. 1968 Nov;32(5):816-8
references.pmid: 4386875
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2):219-25
references.pmid: 16896122
references.citation: Bull World Health Organ. 1968;38(4):625-32
references.pmid: 4876731
references.citation: Malar J. 2010 May 24;9:136
references.pmid: 20497536
references.citation: J Infect Dis. 2006 Apr 15;193(8):1151-9
references.pmid: 16544256
references.citation: PLoS One. 2012;7(8):e42821
references.pmid: 22936993
references.citation: Trans R Soc Trop Med Hyg. 2006 Feb;100(2):176-83
references.pmid: 16257026
references.citation: Am J Trop Med Hyg. 2007 Oct;77(4):779-89
references.pmid: 17978087
references.citation: Infect Immun. 2000 Jun;68(6):3455-62
references.pmid: 10816498
references.citation: Trans R Soc Trop Med Hyg. 1981;75(1):103-5
references.pmid: 7022784
references.citation: Bull World Health Organ. 1961;24:650-3
references.pmid: 13709766
references.citation: PLoS Med. 2008 Nov 25;5(11):e226; discussion e226
references.pmid: 19067479
references.citation: Mol Biochem Parasitol. 2004 Sep;137(1):35-41
references.pmid: 15279949
references.citation: Lancet Infect Dis. 2012 Nov;12(11):851-8
references.pmid: 22940027
references.citation: Exp Parasitol. 1999 Jan;91(1):101-3
references.pmid: 9920049
references.citation: J Infect Dis. 2001 Apr 15;183(8):1254-9
references.pmid: 11262208
references.citation: PLoS Clin Trials. 2006 Jul 21;1(3):e15
references.pmid: 16871318
references.citation: PLoS One. 2007 Oct 10;2(10):e1023
references.pmid: 17925871
references.citation: Clin Infect Dis. 2013 Mar;56(5):694-6
references.pmid: 23175557
references.citation: Am J Hyg. 1956 Jul;64(1):1-11
references.pmid: 13339773
references.citation: Trans R Soc Trop Med Hyg. 1949 Mar;42(5):455-63
references.pmid: 18118367
references.citation: Malar J. 2008 Nov 18;7:237
references.pmid: 19017387
references.citation: Trop Med Int Health. 2004 Jan;9(1):53-61
references.pmid: 14728607
references.citation: Bull World Health Organ. 1961;24:451-6
references.pmid: 13689019
references.citation: Emerg Infect Dis. 2012 Sep;18(9):1547-9
references.pmid: 22932762
references.citation: PLoS One. 2009 Dec 22;4(12):e8410
references.pmid: 20027314
references.citation: Bull World Health Organ. 1960;22:621-31
references.pmid: 13793053
references.citation: Ann Trop Med Parasitol. 1960 Dec;54:460-70
references.pmid: 13692485
references.citation: Trop Med Int Health. 2005 Mar;10(3):251-62
references.pmid: 15730510
references.citation: Curr Opin Infect Dis. 2006 Dec;19(6):623-31
references.pmid: 17075340
references.citation: PLoS Med. 2011 Jan 25;8(1):e1000406
references.pmid: 21311579
references.citation: Malar J. 2010 Feb 23;9:57
references.pmid: 20175930
references.citation: Nat Commun. 2012;3:1237
references.pmid: 23212366
references.citation: Malar J. 2004 Jul 14;3:24
references.pmid: 15253774
references.citation: Cochrane Database Syst Rev. 2012 Sep 12;(9):CD008152
references.pmid: 22972117
references.citation: Am J Trop Med Hyg. 1993 May;48(5):700-6
references.pmid: 8517489
references.citation: Antimicrob Agents Chemother. 2004 Apr;48(4):1329-34
references.pmid: 15047537
references.citation: J Trop Med Hyg. 1992 Oct;95(5):349-51
references.pmid: 1404560
references.citation: N Engl J Med. 2009 Jul 30;361(5):455-67
references.pmid: 19641202
references.citation: Clin Microbiol Rev. 2011 Apr;24(2):377-410
references.pmid: 21482730
references.citation: Clin Infect Dis. 2013 Mar;56(5):685-93
references.pmid: 23175563
references.citation: Malar J. 2012 Oct 30;11:360
references.pmid: 23130957
references.citation: Parasitology. 1977 Feb;74(1):1-8
references.pmid: 320542
references.citation: Southeast Asian J Trop Med Public Health. 1980 Sep;11(3):408-12
references.pmid: 7003735
references.citation: Lancet Infect Dis. 2010 Oct;10(10):673-81
references.pmid: 20832366
references.citation: Malar J. 2012 Dec 14;11:418
references.pmid: 23237606
references.citation: Curr Infect Dis Rep. 2009 Jan;11(1):59-65
references.pmid: 19094826
references.citation: PLoS Med. 2010 Aug 10;7(8):
references.pmid: 20711482
references.citation: PLoS One. 2011;6(5):e20179
references.pmid: 21629651
references.citation: Antimicrob Agents Chemother. 2010 May;54(5):1762-8
references.pmid: 20194698
references.citation: Am J Trop Med Hyg. 2006 Oct;75(4):640-4
references.pmid: 17038686
references.citation: Trop Med Int Health. 2000 Jan;5(1):3-8
references.pmid: 10672199
references.citation: N Engl J Med. 2011 Sep 22;365(12):1073-5
references.pmid: 21992120
references.citation: Southeast Asian J Trop Med Public Health. 1989 Sep;20(3):351-9
references.pmid: 2699082
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):E1214-23
references.pmid: 22042867
references.citation: PLoS One. 2007 Dec 12;2(12):e1311
references.pmid: 18074034
references.citation: Trends Parasitol. 2013 Feb;29(2):53-9
references.pmid: 23273727
references.citation: Int J Parasitol. 2006 Apr;36(4):403-8
references.pmid: 16500657
references.citation: Science. 2011 Feb 4;331(6017):596-8
references.pmid: 21292978