Almost half of the 239 million population of Indonesia live in malaria-endemic areas. According to recent WHO estimates, the number of new cases of malaria in Indonesia is approximately two million per year [Murray, 2014]. The ratio of P. falciparum: P.vivax infections among diagnosed and reported cases is around 1:1. From a global malaria control and eradication perspective, P. vivax presents the greatest challenge, due to its ability to establish a dormant liver stage, the hypnozoite. Relapsing P.vivax malaria is caused by hypnozoite activation after initial infection. Severe anaemia, malnutrition and respiratory distress are among the symptoms caused by P.vivax infections and cases of severe malaria resulting in fatal outcome can occur [Price, 2009, Baird, 2013].
The current standard of care for radical cure of P. vivax malaria in most endemic countries is chloroquine for clearance of acute parasitemia plus primaquine (15mg or 30mg once daily for 14 days) to clear the liver stages of the parasite and prevent disease relapse. In Indonesia, chloroquine has been replaced by artemisinin-based combination therapies (ACTs) for the treatment of blood stage disease due to widespread chloroquine resistance. The Indonesian national treatment policy recommends co-administration of primaquine (PQ) with an ACT for radical cure of P.vivax malaria.
Tafenoquine (TQ, SB-252263 and WR 238605) is an 8-aminoquinoline anti-malarial drug being co-developed by GlaxoSmithKline and Medicines for Malaria Venture with historical support of the Walter Reed Army Institute of Research. It is a synthetic analogue of primaquine in development for the radical cure of P. vivax malaria, as a single dose co-administered in other studies with standard doses of chloroquine. The shorter course of tafenoquine offers the potential for improved compliance and thus effectiveness of relapse prevention, compared with the longer duration regimen for primaquine. Tafenoquine has been evaluated in >4000 subjects for the treatment and prevention of plasmodial infections during Phase I, II and III clinical studies.
This study will evaluate the efficacy and safety of a single dose of tafenoquine (300mg) co-administered with an Artemisinin Combination Therapy (ACT) in the radical treatment of P. vivax malaria in order to support registration of tafenoquine in Indonesia and other countries where ACTs are first line therapy. Dihydroartemisinin-piperaquine (DHA-PQP) has been selected as the ACT for this study since it is highly efficacious against the chloroquine resistant P.vivax of Eastern Indonesia. Subjects who are glucose6-phosphate dehydrogenase (G6PD) deficient will be excluded due to the hemolytic risk associated with 8-aminoquinoline drugs.
We have performed a tafenoquine/ACT interaction study (GSK Study 200951). This drug-drug interaction (DDI) study assessed the pharmacokinetics and safety of tafenoquine when co-administered with DHA-PQP in healthy subjects and demonstrated no interactions requiring dose adjustment. However, given the piperaquine-induced QTc elongation observed, DHA-PQP will be dosed and ECGs monitored, in accordance with the product label.
This is a double-blind, double-dummy, randomized, parallel group, placebo controlled superiority study. The study will be conducted as a collaboration between the Eijkman Institute of Molecular Biology (Jakarta), Eijkman Oxford Clinical Research Unit (within the Eijkman Institute, Jakarta), Faculty of Medicine, University of Indonesia (Jakarta) and the Indonesian army.
To determine the efficacy of tafenoquine co-administered with DHA-PQP for the radical cure of P. vivax malaria, relative to DHA-PQP alone at 6 months.
Coordinator: John Kevin Baird