Tafenoquine Drug Levels in Small Children

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.

Inclusion criteria

• P. vivax mono-infection as diagnosed by RDT or microscopy
• Quantitative G6PD activity ≥70%
• Age >28 days old and weight ≤12kg
• The parent/guardian can understand the study instructions and provide written informed consent
• Willing to return with the participant for 4 months to follow up

Exclusion criteria

• Hb < 8 g/dL
• Severe malaria
• Blood transfusion in the last 3 months
• Any previous history of severe anaemia or haemolysis
• If age is <6 months old today: gestational age at birth <37wk or birth weight <2.5kg
• Use of tafenoquine within the last 4 months
• History of allergic response to an 8-aminoquinoline or the nationally recommended schizonticide (e.g., chloroquine, artemether-lumefantrine)
• Use of drugs that are substrates of organic cation transporter-2 (OCT2) or multidrug and toxin extrusion (MATE) transporters, and drugs that affect chloroquine metabolism
• Presence of any condition which in the judgement of the investigator would place the participant at undue risk or interfere with the results of the study (e.g. chronic disease, failure to thrive, severe malnutrition)