Postpartum 8-aminoquinoline Breast Milk Study

Global malaria eradication requires universal and equitable access to effective antimalarial treatment. More than 2.5 billion people are at risk of infection with Plasmodium vivax. Unlike falciparum malaria, P. vivax forms dormant liver-stage parasites (hypnozoites) that can reactivate (relapse) causing recurrent febrile illness after the initial infection. Women are at increased risk of vivax malaria during pregnancy and postpartum, when they are at higher risk of P. vivax infections than P. falciparum malaria. Over 80% of these infections are relapses, rather than new infections but pregnant and lactating women cannot be treated with the available anti-relapse drugs. This is because the 8-aminoquinolones, primaquine (PQ) and tafenoquine (TQ), can cause potentially life-threatening haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient babies, and there is concern that the drugs are transferred in breast milk. If anti-relapse treatment could be given immediately on delivery and before discharge, it would dramatically reduce the risk of vivax relapses which currently affect ~10% of women in countries like Papua New Guinea (PNG).

This study aims to accelerate maternal access to PQ/TQ by confirming minimal transfer of PQ or TQ not only in mature breast milk (>2 weeks postpartum; current data available from a pharmacokinetic (PK) study in Thailand), but also in colostrum and transitional breast milk in the first two weeks after birth. Generating PK data for TQ is also critical. Maternal treatment could then be initiated before hospital discharge to prevent postpartum relapses and maximise benefit for health outcomes and malaria control.

This open-label study has the following objectives and hypothesis:

Primary Objective: To determine the transfer of primaquine (and primary metabolite carboxyprimaquine) and tafenoquine in breast milk (colostrum and transitional milk) and determine associated relative infant exposure.

Secondary objectives include; i) To compare haematological and hepatorenal indices in exposed and unexposed mother-infant pairs as a measure of safety, and ii) to assess maternal tolerability of early postpartum primaquine (PQ) and tafenoquine (TQ) treatment.

Hypothesis: i) Negligible concentrations of PQ and TQ will be detected in colostrum and transitional milk, or breastfed infants, when mothers are treated with PQ or TQ and ii) Maternal administration of therapeutic doses of PQ or TQ immediately after birth does not result in clinically significant haematological or hepatorenal changes in breastfed neonates.

To do this, once eligibility is confirmed, and appropriate informed consent obtained, a sample of 60 postpartum mother-infant pairs will be recruited into one of four study treatment groups (n=15 per treatment group).

Due to the nature of the research, a conservative approach will be taken to treatment allocation, with groups (n=15) of participants to be allocated treatment doses in a stepwise design as follows: Group 1 - non-intervention (control) group; Group 2 - PQ14 (0.5 mg/kg/day for 14 days); Group 3 - PQ7 (1 mg/kg/day for 7 days); and Group 4 - TQ (300 mg single dose).

Review of mother and neonate for safety and PK procedures across all groups will be scheduled on days 0, 1, 3, 6, 8, 15, 20 and 28 (and 56 for Group 4). At each scheduled time point a symptom questionnaire (capturing both maternal symptoms and the mother's observations of her child) will be conducted, along with a physical examination of both mother and infant. Samples for PK (maternal venous blood, maternal dried blood spot, fore- and hind-breast milk, infant dried blood spot) and safety assessment (haemoglobin, methaemoglobin, hepatorenal biochemistry) will also be collected at specified time points to confirm safety and characterise the transfer and PK profile of PQ/TQ in breast milk and associated infant exposure.

After completion of procedures (Day 28 for Groups 1-3 and Day 59 for Group 4) standardized review of each mother and infant will be conducted monthly for 6 months after initial treatment to monitor P. vivax recurrence and other indicators of maternal and infant health. These study review visits will be timed to coincide with the national infant immunisation schedule at 1, 2, 3 and 6 months. Examination of the infant by study staff will complement assessment of developmental milestones, and maternal assessment could include family planning.

Inclusion criteria

• ≥18 years of age
• Both mother and infant have G6PD activity >70% (normal activity; SD Biosensor)
• They have no significant co-morbidity
• Delivered a live singleton baby within past 48-hours
• Rapid diagnostic test negative for malaria
• No history of hypersensitivity to 8-aminoquinoline drugs
• Plan to exclusively breastfeed for at least two months
• History of vivax malaria (as per health book)
• They can attend follow-up assessments for the duration of the study

Exclusion criteria

• Either mother/infant have G6PD activity <70% (SD Biosensor)
• Either mother/infant have significant co-morbidity
• Mother did not deliver a live singleton within past 48-hours
• Mother/infant are rapid diagnostic test positive for malaria
• Mother has a history of hypersensitivity to 8-aminoquinoline drugs
• Mother does not plan to exclusively breastfeed for at least two months
• Mother does not have a history of vivax malaria (as per health book)
• Cannot or are not willing to attend follow-up assessments for the duration of the study