Finding the best combination of drugs for curing vivax malaria in the Solomon Islands

INTERVENTION: AL+PQ (Arm 1): Artemether‐lumefantrine (2/12mg/kg) administered orally with milk twice daily for 3 days (3 morning doses directly observed by research worker, 3 evening doses self administered with adherence checked by packet return) + primaquine (0.25mg/kg) administered orally once daily with food (savory biscuit) for 14 days (co‐administered with morning dose of artemether‐lumefantrine under direct supervision of research worker on days 0, 1 and 2, administered on its own under observation of community worker on days 4, 5, 6, 8, 9, 11, 12, 13 and administered on its own under supervision of research worker on days 7, and 10. On day 14 research worker will document adherence with full 14 day course by reviewing records of community observers. DP+PQ (Arm 2): Dihydroartemisinin‐piperaquine (2.5/20mg/kg) administered orally once daily without milk in the morning (3 morning doses directly observed by research worker) + primaquine (0.25mg/kg) administered orally once daily with food (savory biscuit) for 14 days (co‐administered with dose of dihydroartemisinin‐piperaquine under direct supervision of research worker on days 0, 1 and 2, administered on its own under observation of community worker on days 4, 5, 6, 8, 9, 11, 12, 13 and administered on its own under supervision of research worker on days 7, and 10. On day 14 research worker will document adherence with full 14 day course by reviewing records of community observers. CONDITION: Plasmodium vivax malaria PRIMARY OUTCOME: Microscopically confirmed, PCR verified P.vivax infection occurring at any time during the designated 6‐month follow‐up period. This “microscopy endpoint” will require that the following criteria be met: ; ; 1. A finding of P.vivax parasitaemia on field‐based examination of a Giemsa‐stained thick and thin blood film (by a level 2 microscopist) at any scheduled or unscheduled visit between days 21 and 168, inclusive. ; 2. Confirmation of initial field microscopy diagnosis of P.vivax by a 2nd Level 2 microscopist, ; or ; 3. Confirmation of a diagnosis of P.vivax by a 3rd Level 2 microscopist (only when 1st and 2nd reads are discrepant). ; 4. Malaria species specific PCR confirms the presence of P.vivax DNA in dried blood spot taken at the same time‐point as the positive slide. ; ; In addition, the primary endpoint includes the following circumstances: ; ; 1. Both asymptomatic and symptomatic infections. ; 2. Mixed infections: PCR‐confirmed P.vivax infections where there is additional evidence of P.falciparum co‐infection (on either PCR or microscopy). ; SECONDARY OUTCOME: Parasitological/ treatment efficacy (1): ; Positive species specific PCR (from a dried blood spot sample) for P.vivax (regardless of microscopy results) at any scheduled or unscheduled visit between days 14 and 168: The “PCR endpoint”. ; Parasitological/ treatment efficacy (2): ; P.vivax recurrent parasitaemia during the follow‐up period, genotypically corrected for reinfections (based on PCR from dried blood spot samples). Following genotyping of baseline‐recurrent PCR positive paired samples, those with discrepant genotypes (suggesting re‐infection) will be censored, leaving only those recurrences with identical genotypes as meeting this endpoint: The “Genotypically‐corrected PCR endpoint”. ; Pharmacokinetic indices and surrogates of active drug exposure (2): ; Safety and toxicity (1) ; 1. Subjective side effects reported and defined as: ; a) Absent (=0) ; b) Minor (=1: not bad enough to interfere with daily activity) ; c) Moderate (=2: bad enough to interfere with daily activity) ; d) Severe or life‐threatening (=3: requiring hospitalization or associated with risk of death) ; Methaemoglobin levels (% hemoglobin saturation) measured non‐invasively by Massimo Rad57 portable spectrophotometer (pulse oximetry machine) from a finger probe applied to the finger. Pharmacokinetic indices and surrogates of drug exposure (1) ; Population pharmacokinetic model‐derived per‐treatment group estimate of primaquine AUC (0‐24hours) following 7th primaquine dose (168 hours). Primaquine measured in serum samples and in red cell pellet. ; ; Possible adverse events include symptoms of abdominal pain or cramping, vomiting and pruritus (most likely due to primaquine). These will be assessed by research nurse using a structured side effect questionnaire and graded in severity from a) to d) as above according to assessment by research nurse. Safety and toxicity (2) ; Likely drug‐induced haemolytic anaemia – defined as >25% reduction in Hb from baseline any time from day 1‐28, together with evidence of haemoglobinuria (on urinary dipstick) or jaundice. ; Safety and toxicity (3) ; Haemoglobin concentrations (g/dL): ; ; INCLUSION CRITERIA: 1. Age over 12 months 2. Weight greater than or equal to 10kg 3. Melanesian background and living in local area 4. Microscopically (based on field microscopy) or RDT confirmed P.vivax regardless of parasite density. Mixed infections (P.falciparum‐P.vivax) can be included.