In East Asia and Oceania Plasmodium vivax is the most common cause of malaria. Relapses occur in over half
the infections and comprise the main burden of P. vivax malaria. Relapses are the major cause of morbidity,
particularly in children and pregnant women. In recent years targeted malaria elimination has driven down
Plasmodium falciparum malaria in these populous regions, but P. vivax malaria has re-emerged rapidly
because of relapse. Preventing relapse (radical cure) requires administration of an 8-aminoquinoline – which
until recently meant a 7-14 day course of primaquine. Tafenoquine is a recently registered slowly eliminated 8-
aminoquinoline with the substantial operational advantage of providing single dose radical cure. However,
Phase 3 randomized controlled trials showed that the currently recommended 300mg adult dose (~ 5mg/kg) of
tafenoquine had low radical curative efficacy against P. vivax malaria. Tafenoquine doses up to 14mg/kg have
proved safe and well tolerated in adults and children with >70% G6PD activity. We obtained the individual
participant (N= 1102) data from the Phase 3 pre-registration trials (DETECTIVE and GATHER; see
Bibliography, references 22-24). Individual patient data meta-analysis (see Bibliography, reference 32) shows
clearly that a) the dose response curve is steep around the currently recommended dose (5mg/kg) and b) the
odds ratio for P. vivax recurrence (<4 months) is 0.69 (95% CI 0.64 to 0.75; p=10-21) for each mg/kg increase in
dose. Thus, increasing the dose by half (i.e., to 7.5mg/kg) is predicted to result in an overall >90% reduction of
P. vivax recurrence. To test this prediction, we propose conducting a multi-center double-blind randomized
clinical trial in five countries in the Greater Mekong sub-Region. Aim 1 compares the radical curative efficacies
of the current tafenoquine dose and a 50% higher dose (e.g., 300mg versus 450mg in persons =35kg) in adults
and children with acute vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) activity >70%.
Relapses will be distinguished from reinfections probabilistically based on parasite genotyping and time to
event information. To detect very low-density P. vivax parasitemias which might be suppressed by tafenoquine,
ultrasensitive polymerase chain reaction (uPCR) will be performed. Aim 2 assesses plasma, urine, and red
blood cell tafenoquine concentrations and explores potential tafenoquine metabolites. Genotyping for CYP2D6
mutations and measurements of methemoglobinemia will be included as exposure correlates of radical
curative efficacy. Aim 3 assesses safety and tolerability of the higher tafenoquine dose. Tolerability,
gastrointestinal symptoms, hematocrit, and elevated blood methemoglobin concentrations will be monitored.
This study will provide definitive evidence to guide tafenoquine dosing for the radical cure of P. vivax malaria.
An efficacious, safe and well tolerated single dose anti-relapse therapeutic will substantially improve the
treatment of P. vivax malaria and accelerate malaria elimination.