Tafenoquine Drug Levels in Small Children

Overview

This study is an open label, single arm, pharmacokinetic trial. A total of 20 participants (children ≤12kg and \>28 days old) will be enrolled. Enrollment will be competitive between Thailand and Vietnam study sites (each site will enroll as many patients that are eligible until the sample size is reached). Tafenoquine will be given concomitantly with the schizonticidal agent, chloroquine, on the day of enrolment. The participant will be admitted to hospital for observation and until the malaria smear is negative for asexual parasites on 2 consecutive days or until the schizonticidal treatment is completed, which will be approximately 3-7 days. All treatment doses will be supervised. Follow up will continue on days 7, 14, 21, and 28 then every month until month 4. Parent/guardian of participants will be instructed to follow up in between visits if participants are feeling unwell. Participants who are lost to follow up (any missed visit), who require drug re-administration after vomiting, or where at least 3 pharmacokinetic samples are not successfully drawn, will be replaced. Participants being replaced will continue in the study for safety assessments and to ensure the treatment of recurrences. The total blood drawn for this study will be 3.76 mL if the participant has no recurrences.

Objectives: Primary Objective: * Characterise the pharmacokinetic profile of tafenoquine in G6PD normal (G6PD activity ≥70%) children ≤12kg and \>28 days old with P. vivax mono-infection Secondary Objectives: * Characterise the safety and tolerability of tafenoquine in children ≤12kg and \>28 days old * Correlate day 7 methaemoglobin levels to the tafenoquine pharmacokinetic profile * Correlate the CYP2D6 metaboliser status and genotype with tafenoquine concentrations in vivo Recruitment Potential participants will be recruited from the outpatient setting at the following sites: * Shoklo Malaria Research Unit (SMRU), Thailand * Oxford University Clinical Research Unit (OUCRU), Vietnam This study recruits P. vivax patients who seek treatment at public or local health facilities. The malaria diagnosis will be performed by designated staff (such as the research team or government health care staff) at each facility. The patients who are diagnosed with P. vivax malaria by blood rapid diagnostic test (RDT) or malaria smear will be invited to participate in the study. The trained study staff will explain the following; 1) The nature of the study; 2) The nature of the data collected; 3) Confidentiality and vulnerability; 4) Safety and alternatives; 5) The potential risks involved; 6) The potential benefits to the participants. A properly signed consent form by the parent/guardian of the patient will be obtained before participation. Following written informed consent from a parent/guardian, participants will undergo screening with finger-prick haemoglobin and G6PD enzyme activity testing to confirm eligibility. Age-adjusted G6PD activity thresholds, based on 70% of the median activity for children aged 28 days to 4 months, will be applied for participants \>28 days to 6 months and ≥6 months to 2 years of age. Eligible participants will be enrolled and undergo venous blood collection (3.14 mL on Day 0) using standard sterile venipuncture procedures. Blood samples will be labelled according to study requirements. Total blood volume collected during the study will be approximately 3.76 mL for participants without recurrence. All study drug administrations will be directly observed by study staff to ensure adherence. Tafenoquine dosing will be weight-based: \<5 kg, 25 mg; ≥5 kg to \<10 kg, 50 mg; and ≥10 kg to 12 kg, 100 mg. Participants will be observed during dosing and compliance monitored throughout the study. If vomiting occurs within 30 minutes of administration, the full dose will be re-administered; if vomiting occurs 31 to 60 minutes after administration, half the dose will be re-administered. At each observed dosing visit, study staff will record adverse events, vital signs, and the date and time of study drug administration, and review available laboratory results before dosing. After enrolment, participants will be admitted for observation and supervised treatment until malaria smears are negative on two consecutive days or schizonticidal treatment is completed (approximately 3 to 7 days). Follow-up visits will occur on Days 7, 14, 21, and 28, and Months 2, 3, and 4. Scheduled assessments include medication and concomitant medication review, adverse event monitoring, vital signs, physical examination, collection of protocol-specified blood and urine samples, and review of laboratory results. Visit windows are ±3 days for Days 7, 14, and 21; +2 weeks/-3 days for Day 28; and ±2 weeks for Months 2, 3, and 4. At Month 4, participants with unresolved adverse events will be referred for appropriate clinical follow-up. Participants experiencing Plasmodium vivax recurrence will be treated according to national guidelines and will repeat study assessments from Day 0, excluding complete blood count and biochemistry testing. Additional assessments will include haemoglobin (Hemocue® Hb 301), malaria smear, methaemoglobin, and chloroquine and tafenoquine drug level measurements. Follow-up will then continue according to the Day 0 schedule, without extending the overall study duration. The study will end after completion of the last study visit of the last participant. This project is funded by the National Institutes of Health (NIH), award number U01AI195203.