Clinical trial NCT01365598: Evaluation of the Gametocytocidal Efficacy and Safety of Primaquine in Uncomplicated Falciparum Malaria in Uganda
Official title: Evaluation of the Efficacy and Safety of Primaquine for Clearance of Gametocytes in Uncomplicated Falciparum Malaria in Uganda
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Falciparum Malaria
Keywords: malaria
uncomplicated malaria
gametocytocidal drug
gametocytocidal
gametocyte
primaquine
transmission blocking
malaria transmission
sexual parasite
sexual stage
Uganda
Africa
Lead sponsor: London School of Hygiene and Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
First posted: 2011-06-03
Enrollment: 468
Sex: ALL
Minimum age (years): 1
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to evaluate the safety and efficacy of lower doses of primaquine compared to the dose recommended by the WHO for reducing P. falciparum gametocytes in the infected human host to prevent transmission of falciparum malaria to the anopheles mosquito vector.

Detailed description: A single dose of 0.75mg/kg primaquine base is recommended by the WHO to block transmission of falciparum malaria from infected humans to mosquitoes by clearing gametocytes. However, the optimal dose for safety and efficacy has not been evaluated. Dose-finding data is important because primaquine has a dose-dependent risk of causing haemolysis (destruction of blood cells) in pre-disposed individuals, such as those with G6PD deficiency. G6PD deficiency is most prevalent in malaria-endemic areas. Therefore, it is essential that data on primaquine's safety is available in such areas.

The investigators hypothesise that lower doses of primaquine have a lower risk of adverse effects compared to the WHO-recommended dose, but retain the transmission-blocking efficacy.

The investigators propose to test this hypothesis in a four-arm clinical trial with a non-inferiority design to evaluate the efficacy and a superiority design to evaluate the safety of the WHO dose (0.75mg/kg) and lower doses of primaquine for clearance of P. falciparum gametocytes in children in Uganda. The study will include a pharmacokinetic analysis.

Eligibility criteria: Inclusion Criteria:

* Age \>/= 1 year and \</= 10 years
* Weight over 10kg
* Fever \>38 degrees C (tympanic) or history of fever in the last 24 hours
* P. falciparum parasitaemia \<500 000/µl
* Normal G6PD enzyme function

Exclusion Criteria:

* Enrolled in another study
* Evidence of severe illness/ danger signs
* Known allergy to study medications
* Haemoglobin \< 8g/dL)
* Started menstruation
* Pregnancy or breastfeeding
* Primaquine taken within the last 4 weeks
* Blood transfusion within the last 90 days
* Non-falciparum malaria co-infection

Primary outcomes:
measure: Mean number of days to gametocyte clearance (gametocyte clearance time, GCT)
timeFrame: 14 days
measure: Mean (+/- SD) maximal fall in Hb (g/dL) from enrollment to day 28 of follow-up
timeFrame: 28 days
Secondary outcomes:
measure: Mean (+/- SD) area under the curve of gametocyte density per day during 14 days of follow-up
timeFrame: 14 days
measure: Requirement for blood transfusion
timeFrame: 28 days
measure: Follow-up day of Hb nadir
timeFrame: 28 days
measure: Incidence of serious adverse events by sign, symptom, laboratory parameter and relationship to taking study drug
timeFrame: 28 days
measure: Incidence of gastrointestinal symptoms after taking study drug
timeFrame: 6 days
Other outcomes:
Locations:
city: Jinja
country: Uganda
facility: Walukuba Health Centre IV
state: Eastern Region
Study officials:
affiliation: London School of Hygiene and Tropical Medicine
name: Alice C Eziefula, MBBS MCRP MRCPath
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bousema T, Okell L, Shekalaghe S, Griffin JT, Omar S, Sawa P, Sutherland C, Sauerwein R, Ghani AC, Drakeley C. Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar J. 2010 May 24;9:136. doi: 10.1186/1475-2875-9-136.
citation: Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeren M, Enevold A, Alifrangis M, Mosha F, Sauerwein R, Bousema T. Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate. PLoS One. 2007 Oct 10;2(10):e1023. doi: 10.1371/journal.pone.0001023.
citation: Schneider P, Bousema JT, Gouagna LC, Otieno S, van de Vegte-Bolmer M, Omar SA, Sauerwein RW. Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am J Trop Med Hyg. 2007 Mar;76(3):470-4.
citation: Shekalaghe SA, ter Braak R, Daou M, Kavishe R, van den Bijllaardt W, van den Bosch S, Koenderink JB, Luty AJ, Whitty CJ, Drakeley C, Sauerwein RW, Bousema T. In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals. Antimicrob Agents Chemother. 2010 May;54(5):1762-8. doi: 10.1128/AAC.01135-09. Epub 2010 Mar 1.
citation: Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, Naing AL, Nyo MY, Myint NZ, Imwong M, Ashley E, Lee SJ, White NJ. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010 Oct;10(10):673-81. doi: 10.1016/S1473-3099(10)70187-0. Epub 2010 Sep 9.
citation: Chang HH, Meibalan E, Zelin J, Daniels R, Eziefula AC, Meyer EC, Tadesse F, Grignard L, Joice RC, Drakeley C, Wirth DF, Volkman SK, Buckee C, Bousema T, Marti M. Persistence of Plasmodium falciparum parasitemia after artemisinin combination therapy: evidence from a randomized trial in Uganda. Sci Rep. 2016 May 20;6:26330. doi: 10.1038/srep26330.
citation: Eziefula AC, Bousema T, Yeung S, Kamya M, Owaraganise A, Gabagaya G, Bradley J, Grignard L, Lanke KH, Wanzira H, Mpimbaza A, Nsobya S, White NJ, Webb EL, Staedke SG, Drakeley C. Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial. Lancet Infect Dis. 2014 Feb;14(2):130-9. doi: 10.1016/S1473-3099(13)70268-8. Epub 2013 Nov 13.