Single dose primaquine for clearance of Plasmodium falciparum gametocytes in
children with uncomplicated malaria in Uganda: a randomised, controlled,
double-blind, dose-ranging trial.
Author(s): Eziefula AC(1), Bousema T(2), Yeung S(3), Kamya M(4), Owaraganise A(4), Gabagaya
G(4), Bradley J(5), Grignard L(6), Lanke KH(7), Wanzira H(4), Mpimbaza A(8),
Nsobya S(4), White NJ(9), Webb EL(5), Staedke SG(3), Drakeley C(6).
Affiliation(s): Author information:
(1)Department of Immunology and Infection, London School of Hygiene and Tropical
Medicine, London, UK. Electronic address: chi.eziefula@gmail.com.
(2)Department of Immunology and Infection, London School of Hygiene and Tropical
Medicine, London, UK; Department of Medical Microbiology, Radboud University
Nijmegen Medical Centre, Nijmegen, Netherlands.
(3)Department of Clinical Research, London School of Hygiene and Tropical Medicine,
London, UK.
(4)Infectious Disease Research Collaboration, Kampala, Uganda.
(5)Department of Infectious Disease Epidemiology, London School of Hygiene and
Tropical Medicine, London, UK.
(6)Department of Immunology and Infection, London School of Hygiene and Tropical
Medicine, London, UK.
(7)Department of Medical Microbiology, Radboud University Nijmegen Medical Centre,
Nijmegen, Netherlands.
(8)Infectious Disease Research Collaboration, Kampala, Uganda; Child Health and
Development Centre, College of Health Sciences, Makerere University, Kampala,
Uganda.
(9)Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine,
Mahidol University, Bangkok, Thailand.
Publication date & source: 2014, Lancet Infect Dis. , 14(2):130-9
BACKGROUND: Primaquine is the only available drug that clears mature Plasmodium
falciparum gametocytes in infected human hosts, thereby preventing transmission
of malaria to mosquitoes. However, concerns about dose-dependent haemolysis in
people with glucose-6-phosphate dehydrogenase (G6PD) deficiencies have limited
its use. We assessed the dose-response association of single-dose primaquine for
gametocyte clearance and for safety in P falciparum malaria.
METHODS: We undertook this randomised, double-blind, placebo-controlled trial
with four parallel groups in Jinja district, eastern Uganda. We randomly
allocated Ugandan children aged 1-10 years with uncomplicated falciparum malaria
and normal G6PD enzyme function to receive artemether-lumefantrine, combined with
either placebo or with 0.1 mg/kg, 0.4 mg/kg, or 0.75 mg/kg (WHO reference dose)
primaquine base. Randomisation was done with computer-generated four-digit
treatment assignment codes allocated to random dose groups in block sizes of 16.
Study staff who provided care or assessed outcomes and the participants remained
masked to the intervention group after assignment. The primary efficacy endpoint
was the non-inferiority of the mean duration of gametocyte carriage in the test
doses compared with the reference group of 0.75 mg primaquine per kg, with a
non-inferiority margin of 2.5 days. The primary safety endpoint was the
superiority of the arithmetic mean maximum decrease in haemoglobin concentration
from enrolment to day 28 of follow-up in the primaquine treatment groups compared
with placebo, with use of significance testing of pairwise comparisons with a
cutoff of p=0.05. The trial is registered with ClinicalTrials.gov, number
NCT01365598.
FINDINGS: We randomly allocated 468 participants to receive
artemether-lumefantrine combined with placebo (119 children) or with 0.1 mg/kg
(116), 0.4 mg/kg (116), or 0.75 mg/kg (117) primaquine base. The mean duration of
gametocyte carriage was 6.6 days (95% CI 5.3-7.8) in the 0.75 mg/kg reference
group, 6.3 days (5.1-7.5) in the 0.4 mg/kg primaquine group (p=0.74), 8.0 days
(6.6-9.4) in the 0.1 mg/kg primaquine group (p=0.14), and 12.4 days (9.9-15.0) in
the placebo group (p<0.0001). No children showed evidence of treatment-related
haemolysis, and the mean maximum decrease in haemoglobin concentration was not
associated with the dose of primaquine received-it did not differ significantly
compared with placebo (10.7 g/L, SD 11.1) in the 0.1 mg/kg (11.4 g/L, 9.4;
p=0.61), 0.4 mg/kg (11.3 g/L, 10.0; p=0.67), or 0.75 mg/kg (12.7 g/L, 8.2;
p=0.11) primaquine groups.
INTERPRETATION: We conclude that 0.4 mg/kg primaquine has similar gametocytocidal
efficacy to the reference 0.75 mg/kg primaquine dose, but a dose of 0.1 mg/kg was
inconclusive for non-inferiority. Our findings call for the prioritisation of
further trials into the efficacy and safety of doses of primaquine between 0.1
mg/kg and 0.4 mg/kg (including the dose of 0.25 mg/kg recently recommended by
WHO), in view of the potential for widespread use of the drug to block malaria
transmission.
FUNDING: Wellcome Trust and the Bill & Melinda Gates Foundation.
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