Conditions: Malaria, Vivax
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 851
Healthy volunteers: no

Brief summary:
The purpose of this two part study is to test the safety and efficacy of Tafenoquine (with Cholorquine) as a radical cure for Plasmodium vivax (P.vivax) malaria relative to the control Chloroquine.Part 1 aims to select an efficacious and well tolerated dose that can be co-administered with Chloroquine. Part 2 will investigate the safety and efficacy of the selected dose (300 mg tafenoquine) in the treatment and radical cure of Plasmodium Vivax Malaria.

Detailed description:
Plasmodium vivax represents 50-80% of all malarial cases in Latin America and South East Asia. It is able to establish a dormant liver stage called the hypnozoite. Hypnozoite activation after initial infection can cause a relapse. Currently the only widely available drug is primaquine which requires administration over 14 days, resulting in poor compliance and treatment failure. Tafenoquine (an 8-aminoquinoline anti-malarial drug) has been shown to possess activity against all stages of the plasmodium life cycle, including the dormant stage in the liver. This is a multi-centre, double dummy, double blind, parallel group, randomized, active control study which is conducted in two parts. For both parts, subjects are treated with Chloroquine on days 1 to 3 (600mg, 600mg, and 300mg) to treat the blood stage vivax malaria. Part 1 will include at least 324 subjects and part 2 at least 600 subjects. Part 1 has 6 treatment arms, arms 1 to 4 contain different doses of Tafenoquine (50mg, 100mg, 300mg, and 600mg) dosed on day 1 or 2, arm 5 contains primaquine (15mg) dosing over 14 days (days 2-15 (15mg)) and arm 6 contains chloroquine only. The aim of this is to find a dose of Tafenoquine which meets the defined dose criteria. Based on Part 1 efficacy and safety, a single Tafenoquine dose (300 mg) will be studied in the pivotal Part 2. Part 2 contains 3 treatment arms one with the selected Tafenoquine dose (300 mg), the second arm will be 15mg Primaquine which will again be dosed over 14 days and the final arm contains chloroquine only dosed days 1-3 (600mg, 600mg, 300mg). Therefore as with Part 1, in Part 2 all subjects will receive Chloroquine. The aim of Part 2 is to investigate the safety and efficacy of the selected Tafenoquine/Chloroquine dose in the treatment and radical cure of Plasmodium vivax malaria. In addition to the Primary and Secondary endpoints stated below we will also be collecting; other efficacy endpoints (gametocyte clearance time, Recrudescence defined as any Plasmodium vivax parasitemia occurring on or before Day 29 (blood stage treatment failure), Incidence of Plasmodium falciparum malaria and Incidence of recrudescence and new Plasmodium vivax infection, determined by Polymerase Chain Reaction (PCR), safety endpoints (clinically relevant haemolysis leading to drops in haemoglobin / haematocrit or complications thereof (required transfusions, acute renal failure), changes in methaemoglobin, gastrointestinal (GI) tolerability - incidence of abdominal pain, heartburn, diarrhoea, constipation, nausea and vomiting and ophthalmic safety - incidence of corneal deposits, retinal and visual field abnormalities. Data collected at up to four centres . Additionally, the incidence and severity of adverse events and abnormal laboratory observations will be presented).Pharmacokinetic endpoints (Population pharmacokinetic parameters for tafenoquine including but not limited to oral clearance (CL/F) and volume of distribution (V/F)and Pharmacokinetic/Pharmacodynamic endpoints (e.g. tafenoquine plasma concentrations) and selected Pharmacodynamic endpoints (e.g. relapse efficacy, change in methaemoglobin) if appropriate, will be explored.

Arms:
arm 1: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 50mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed. arm 2: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 100mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed. arm 3: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed. arm 4: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 600mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed. arm 5: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15. arm 6: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. arm 7: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed. arm 8: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15 arm 9: On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered

Interventions: intervention 1: Chloroquine 600mg intervention 2: Chloroquine 300mg intervention 3: Tafenoquine 50mg intervention 4: Tafenoquine 100mg intervention 5: Tafenoquine 300mg intervention 6: Tafenoquine 600mg intervention 7: Primaquine 15mg intervention 8: Chloroquine 600mg (Part 2 ) intervention 9: Chloroquine 300mg (Part 2 ) intervention 10: Tafenoquine 300mg (Part 2) intervention 11: Primaquine 15mg (Part2 )
Intervention descriptions: intervention 1: 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial intervention 2: 300mg Chloroquine given to each subject on Day 3 of the trial intervention 3: single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2 intervention 4: single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2 intervention 5: single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2 intervention 6: single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2 intervention 7: 15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15. intervention 8: 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial. intervention 9: 300mg Chloroquine given to each subject on Day 3 of the trial. intervention 10: single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2. intervention 11: 15mg Primaquine given once daily to subject on treatment arm 3 on Days 2 to 15.

Protocol document: