Postpartum 8-aminoquinoline Breast Milk Study

NCT ID: NCT07060404

Last Updated: 2025-07-11

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-08-31
• Study Completion Date: 2026-12-31

Brief Summary

In Papua New Guinea, administration of primaquine (PQ) or tafenoquine (TQ) to breastfeeding mothers is contraindicated during the first six months postpartum, when infants are recommended to be exclusively breastfed, because of a lack of comprehensive pharmacokinetic data on PQ/TQ neonatal and infant exposure via breast milk. The therapeutic restriction of PQ/TQ use in lactating women during the first six months postpartum effectively translates into ~10% of females being excluded from radical cure in endemic areas at any time. This is because many at risk women live in remote areas, are frequently lost to follow-up, or may have conceived again before they reattend. As a result, radical cure is rarely achieved and women are exposed to recurrent infections and cumulative risk of anaemia. Relapses may occur for years, placing subsequent pregnancies at risk and perpetuating intergenerational failure of fetal growth. They also contribute to malaria transmission, thus household and community exposure to vivax malaria.

The goal of the present study is to determine how much PQ/TQ is transferred to a suckling baby, if a mother receives a treatment course of PQ/TQ at time of delivery. We also want to confirm that this treatment is safe and has no major side effects for babies in Papua New Guinea.

The study Interventions areas follows: Group 1 - Participants receive PNG standard of care; PQ given 6-months postpartum; Group 2 - Participants receive a 14-day treatment regimen of PQ, at the standard dose prescribed in PNG for vivax radical cure (0.5 mg/kg/day for 14 days); Group 3 - Participants receive an accelerated high-dose 7-day treatment regimen of PQ, as per current WHO recommendations (1.0 mg/kg/day for 7 days); Group 4 - Participants receive a single dose of 300mg tafenoquine.

All participants will be monitored for a total duration of 6 months, with the safety, tolerability, pharmacokinetics and preliminary relapse efficacy of PQ/TQ evaluated at standardised time points over this period (Day 0, 1, 3, 6, 8, 15, 20, 28, and Month 2, 3, 4, 5 and 6). At each of these time points, participants will be asked to describe any symptoms they may be experiencing, participate in a medical examination, and provide a blood and breast milk sample for drug analysis and safety (biochemistry and haematology testing). The investigators will also collect a small blood sample (heel prick) from the infant to measure drug concentrations and safety testing.

Detailed Description

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.

Conditions

Drug Pharmacokinetics in Healthy Volunteers

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Group1 - control

Participants will receive no intervention at time of delivery. As per standard care in PNG, each participant will receive primaquine at 6-months postpartum (completion of study procedures).

Group Type: NO_INTERVENTION

No interventions assigned to this group

Group 2 - PQ14

Daily oral primaquine as 0.5 mg/kg per day for 14 days, taken with food and water

Group Type: EXPERIMENTAL

Daily primaquine (0.5 mg/kg per day) for 14 days given with food food and water

Intervention Type: DRUG

Women will receive daily doses of PQ (0.5 mg/kg per day) for 14 days at a total treatment dose of 7 mg/kg PQ. All doses will be to the nearest full tablet, with food and water to prevent gastrointestinal discomfort, as directly observed treatment. Women vomiting within 30 minutes of administration of any dose will be re-treated.

Group 3 - PQ7

Daily oral primaquine 1 mg/kg per day for 7 days, taken with food and water

Group Type: EXPERIMENTAL

Daily primaquine 1 mg/kg per day for 7 days given with food and water

Intervention Type: DRUG

Women will receive daily doses of PQ (1 mg/kg per day) for 7 days at a total treatment dose of 7 mg/kg PQ. All doses will be to the nearest full tablet, with food and water to prevent gastrointestinal discomfort, as directly observed treatment. Women vomiting within 30 minutes of administration of any dose will be re-treated.

Group 4 - TQ

Single dose tafenoquine as 300mg taken with food and water

Group Type: EXPERIMENTAL

Single-dose tafenoquine given with food and water to prevent gastrointestinal discomfort

Intervention Type: DRUG

Women will receive a single dose of 300mg tafenoquine. Treatment will be given with food and water to prevent gastrointestinal discomfort, as directly observed treatment. Women vomiting within 30 minutes of administration of any dose will be re-treated.

Interventions

Daily primaquine (0.5 mg/kg per day) for 14 days given with food food and water

Women will receive daily doses of PQ (0.5 mg/kg per day) for 14 days at a total treatment dose of 7 mg/kg PQ. All doses will be to the nearest full tablet, with food and water to prevent gastrointestinal discomfort, as directly observed treatment. Women vomiting within 30 minutes of administration of any dose will be re-treated.

Intervention Type: DRUG

Daily primaquine 1 mg/kg per day for 7 days given with food and water

Women will receive daily doses of PQ (1 mg/kg per day) for 7 days at a total treatment dose of 7 mg/kg PQ. All doses will be to the nearest full tablet, with food and water to prevent gastrointestinal discomfort, as directly observed treatment. Women vomiting within 30 minutes of administration of any dose will be re-treated.

Intervention Type: DRUG

Single-dose tafenoquine given with food and water to prevent gastrointestinal discomfort

Women will receive a single dose of 300mg tafenoquine. Treatment will be given with food and water to prevent gastrointestinal discomfort, as directly observed treatment. Women vomiting within 30 minutes of administration of any dose will be re-treated.

Intervention Type: DRUG

Other Intervention Names

Primacin; Primaquine phosphate; Primacin; Primaquine phosphate; Tafenoquine succinate; Kodatef

Eligibility Criteria

Inclusion Criteria

1. ≥18 years of age

2. Both mother and infant have G6PD activity >70% (normal activity; SD Biosensor)

3. They have no significant co-morbidity

4. Delivered a live singleton baby within past 48-hours

5. Rapid diagnostic test negative for malaria

6. No history of hypersensitivity to 8-aminoquinoline drugs

7. Plan to exclusively breastfeed for at least two months

8. History of vivax malaria (as per health book)

9. They can attend follow-up assessments for the duration of the study

Exclusion Criteria

1. Either mother/infant have G6PD activity <70% (SD Biosensor)

2. Either mother/infant have significant co-morbidity

3. Mother did not deliver a live singleton within past 48-hours

4. Mother/infant are rapid diagnostic test positive for malaria

5. Mother has a history of hypersensitivity to 8-aminoquinoline drugs

6. Mother does not plan to exclusively breastfeed for at least two months

7. Mother does not have a history of vivax malaria (as per health book)

8. Cannot or are not willing to attend follow-up assessments for the duration of the study

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Menzies School of Health Research

OTHER

Sponsor Role: collaborator

Papua New Guinea Institute of Medical Research

OTHER_GOV

Sponsor Role: collaborator

Curtin University

OTHER

Sponsor Role: lead

Responsible Party

Brioni Moore

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brioni Moore, PhD

Role: PRINCIPAL_INVESTIGATOR

Curtin University

Locations

Alexishafen Health Centre

Madang, Madang Province, Papua New Guinea

Countries

Papua New Guinea

Central Contacts

Brioni Moore, PhD

Role: CONTACT

brioni.moore@curtin.edu.au

+61 8 9266 2956

Paula Tesine, MD

Role: CONTACT

paula.tesine@pngimr.org.pg

+675 434 0208

Facility Contacts

Paula Tesine, Dr

Role: primary

+675 434 02058

Other Identifiers

RES68007

Identifier Type: -

Identifier Source: org_study_id