Plasmodium vivax is the most geographically widespread malaria species and the second largest contributor to symptomatic malaria worldwide. It accounts for half of all malaria cases outside Africa, with an estimated 14.3 million clinical vivax malaria cases reported annually, contributing to an annual cost of US$359 million. Children are most vulnerable to infection, with P. vivax prevalence peaking between 2 to 6 years of age. In Papua New Guinea (PNG), there are \>1.5 million suspected P. vivax cases annually, and while P. falciparum infections are the most prevalent, P. vivax transmission is the most intense in the world. P. vivax in PNG provides a unique epidemiological setting in which to assess innovative treatments in children.The complex biology of P. vivax represents a challenge for malaria control and chemotherapy, especially dormant liver-stage parasites (hypnozoites) which can reactivate (relapse) and cause disease at a time remote from the primary infection. Hypnozoite relapse is the primary cause of vivax malaria in endemic regions and is resistant to most antimalarial drugs. Identifying effective treatments for radical cure, the complete elimination of parasites (both blood- and liver-stage), is therefore a priority. The World Health Organization (WHO) recommends a 14-day radical cure regimen for uncomplicated vivax malaria; comprised of blood stage treatment (chloroquine or artemisinin combination therapy (ACT)) and 14 days of the 8-aminoquinoline drug primaquine (PQ; 0.25-0.5 mg/kg/day) for liver-stage cure. More recently, the 8-aminoquinoline tafenoquine has garnered interest as an alternative radical cure agent to primaquine. However, there is limited data on the pharmacokinetics, tolerability and radical cure efficacy of tafenoquine in children. Furthermore, early data suggest a drug interaction between TQ and artemisinin combination therapy (ACT) drugs - which requires further investigation and confirmation. This study will generate critical paediatric safety, tolerability, pharmacokinetic, and preliminary efficacy data for TQ when administered with either artemether-lumefantrine or dihydroartemisinin-piperaquine in PNG children with uncomplicated malaria.
Have normal G6PD activity (>70% enzyme activity) as confirmed by quantitative SD Biosensor
Do not have severe malaria (by WHO criteria)
Have rapid diagnostic test and/or microscopically confirmed uncomplicated malaria (any species)
Have no significant co-morbidity
Have <70% G6PD enzyme activity, as confirmed by quantitative SD Biosensor
Have signs or symptoms of severe malaria (by WHO criteria)
Test negative for malaria by rapid diagnostic test and/or microscopy
Have signs or symptoms of a significant co-morbidity
Parallel
Single dose tafenoquine (10 mg/kg)
DrugParticipants will receive single-dose TQ as 10 mg/kg given with the first dose of ACT. Food (low-fat meal) is taken to attenuate any gastrointestinal adverse effects that are related to taking TQ on an empty stomach. Combinations of full or half-tablets will be swallowed whole or crushed lightly (tablets) or dissolved in boiled water (if dispersible tablets are available), as directly observed treatment. Children vomiting within the first 30 minutes of treatment will be withdrawn, and will receive the remaining treatment course of their randomized ACT as for PNG Standard Treatment Guidelines.
Dihydroartemisinin-piperaquine (DHA-PPQ)
DrugParticipants will receive dihydroartemisinin-piperaquine (DHA 2.5 mg/kg and PQ phosphate 20 mg/kg), once daily for 3 days with water and a low-fat meal. Combinations of full or half-tablets will be swallowed whole or crushed lightly (tablets) or dissolved in boiled water (if dispersible tablets are available), as directly observed treatment.
Artemether + Lumefantrine
DrugParticipants will receive artemether-lumefantrine (ARM 1.7 mg/kg and LUM 10 mg/kg) twice daily for 3 days with water and a low-fat meal. Combinations of full or half-tablets will be swallowed whole or crushed lightly (tablets) or dissolved in boiled water (if dispersible tablets are available). Morning doses will be observed as directly observed treatment, with evening doses dispensed to the parent/guardian each day. Parents will be asked to report approximate time of evening dosing the following morning, and return any pills that were not successfully administered.
Pharmacokinetic: Tafenoquine terminal elimination half-life
Pharmacokinetic parameters of tafenoquine and 5,6-orthoquinone tafenoquine, will be ascertained using a nonlinear mixed-effects modelling approach (NONMEM), based on drug concentrations determined from blood samples collected at baseline (Day 0) and 6 of 13 randomized collection time points (2, 4, 8, 12, 24 and 48 hours and Days 3, 4, 7, 14, 28, 42 and 56.
Pharmacokinetic: Tafenoquine distribution half-life
Pharmacokinetic parameters of tafenoquine and 5,6-orthoquinone tafenoquine, will be ascertained using a nonlinear mixed-effects modelling approach (NONMEM), based on drug concentrations determined from blood samples collected at baseline (Day 0) and 6 of 13 randomized collection time points (2, 4, 8, 12, 24 and 48 hours and Days 3, 4, 7, 14, 28, 42 and 56.
Pharmacokinetic: Tafenoquine absorption half-life
Pharmacokinetic parameters of tafenoquine and 5,6-orthoquinone tafenoquine, will be ascertained using a nonlinear mixed-effects modelling approach (NONMEM), based on drug concentrations determined from blood samples collected at baseline (Day 0) and 6 of 13 randomized collection time points (2, 4, 8, 12, 24 and 48 hours and Days 3, 4, 7, 14, 28, 42 and 56.
Pharmacokinetics: Tafenoquine clearance
Pharmacokinetic parameters of tafenoquine and 5,6-orthoquinone tafenoquine, will be ascertained using a nonlinear mixed-effects modelling approach (NONMEM), based on drug concentrations determined from blood samples collected at baseline (Day 0) and 6 of 13 randomized collection time points (2, 4, 8, 12, 24 and 48 hours and Days 3, 4, 7, 14, 28, 42 and 56.
Safety: Change in haemoglobin over 84 days
A fingerprick blood sample will be drawn at baseline to determine pre-treatment haemoglobin concentration (point-of-care HemoCue Hb201+, Radiometer, Australia). To monitor for post-treatment haemolysis, fingerprick haemoglobin samples will be taken at safety time points (4 and 24 hours, and on days 3, 7 and 28 post tafenoquine dosing) and all standardised review time points (Days 0, 1, 2, 3, 4, 7, 14, 28, 42, 56 and 84).
Safety: Change in methaemoglobin over 28 days
Methaemoglobin will be assessed by a Rad57 pulse oximeter with SpMet function (Masimo, USA) at all defined safety time points (4 and 24 hours) and standardised review time points (Days 0, 1, 2, 3, 4, 7, 14, and 28).
Safety: Change in hepatorenal function over 28 days
Hepatorenal function (creatinine, total bilirubin and alanine transaminase \[ALT\]) will be analysed on a Fuji Dri-Chem NX500 analyser (Fujifilm, Japan). 100 µL fingerprick blood samples will be collected at baseline, 4 and 24 hours, and on Days 3, 7 and 28 after tafenoquine dosing.
Safety: Change in rate corrected QTc over 28 days
A 12-lead electrocardiogram will be conducted at baseline, 4 and 24 hours, and on Days 3, 7 and 28 after tafenoquine dosing to determine change in rate corrected QTc.
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Curtin University
Lead sponsor
Papua New Guinea Institute of Medical Research
Collaborator
The University of Western Australia
Collaborator
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