Clinical trial NCT06191458: Postpartum Primaquine in Breast Milk
Official title: Neonatal Exposure to Primaquine Through Breast Milk During Treatment in Postpartum Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Postpartum Women
Keywords: Postpartum women
Primaquine
Pharmacokinetics
Healthy
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
First posted: 2024-01-05
Enrollment: 12
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Plasmodium vivax and ovale infections both follow chronically relapsing courses, leading to cumulative morbidity and mortality. P. vivax is the second most common malaria worldwide, with an estimated 13.8 million cases annually, and there is increasing concern about severe illness and death in vulnerable populations.

Radical cure of P.vivax and P.ovale with 8-aminoquinolines is necessary to prevent relapse. The most widely 8-aminoquinoline is primaquine (7-14 day course), which has been used for almost 75 years. Its widespread use is hampered by the potentially severe haemolysis primaquine may trigger in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common red blood cell enzyme deficiency in the world. Safe administration of primaquine requires at least 30% of normal G6PD activity to avoid significant hemolysis.

Screening for malaria is routine in pregnancy, leading to improved detection of P. vivax infections, but primaquine and is contraindicated in pregnancy. As a result, relapses of P. vivax are common in postpartum and lactating women. Normal G6PD activity levels in infants less than 6 months old have only recently been described and have only been established along the Thailand-Myanmar border. Most low-resource settings are therefore unable to determine infant G6PD status. Uncertainty about infant G6PD status means that breastfeeding women are rarely offered radical cure because of theoretical concerns about drug exposure through breast milk triggering haemolysis in breastfed infants and children with G6PD deficiency. Though neonates generally have higher G6PD activity than adults, increased haemolysis for a neonate could theoretically contribute to neonatal jaundice and anaemia.

Understanding drug exposure to a breastfeeding neonate is operationally important, as interventions that can be safely offered before women leave the hospital postpartum have higher uptake. Current World Health Organization guidelines advise against prescribing primaquine to lactating women if they are breastfeeding infants less than 6 months old, or breastfeeding infants with G6PD deficiency or unknown G6PD status.

Detailed description: This is a prospective open-label, single site, dense pharmacokinetic study of primaquine (0.5 mg/kg daily for 14 days) taken by postpartum lactating women.

The study will take place the Shoklo Malaria Research Unit (SMRU), Mahidol Oxford Tropical Medicine Research Unit, Tak Province, Thailand. Pregnant women who access care at SMRU antenatal care will be invited to participate after delivery with their breastfed children. Recruitment will prioritize women with a history of P. vivax infection without radical cure, but will also accept healthy volunteers. All 12 lactating women and their breastfed neonates 48 hours - 5 days old will be G6PD phenotypically normal, confirmed by spectrophotometry.

Following informed consent, women attending SMRU antenatal care will be pre-screened during pregnancy for potential enrolment postpartum. Full screening must be repeated postpartum before enrolment.

Similar to the mothers, neonates will be pre-screened for eligibility using biosensor and Hb/Hct. Birth history will be reviewed to determine the absence of severe neonatal disease (neonatal sepsis, severe jaundice, significant birth asphyxia etc).

Mothers and neonates will be closely monitored for safety throughout the 28 day follow up period including regular assessments of adverse events, Hb, Hct and MetHb levels. If a neonate develops jaundice, treatment will follow the clinical guidelines of the site. The study sampling will continue as long as the baby is responding normally to phototherapy and inclusion in the study is not thought to interfere with clinical care. If methemoglobinemia is detected, it will be managed according to SMRU clinical protocol. Medication will be stopped if the participant is in the primaquine arm and a severe drug related AE occurs.

Pharmacokinetic (PK)sampling plan:

* Mothers: Dense PK venous blood and breast milk sampling will be performed during day 1 and 14; two blood samples and one breast milk sample will collected at a single timepoint on days 3, 5 and 8.
* Neonate: One capillary blood sample will be collected on the same days as maternal sampling.

PK drug measurements of primaquine, and carboxyprimaquine will be performed. Drug concentrations will be quantified by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) using a validated assay according to regulatory guidelines.

This study is funded by Thrasher Research Fund, EW "Al" Thrasher award.

Eligibility criteria: Inclusion Criteria: Mothers

* Lactating woman \>= 18 years old
* Planning to breastfeed for the duration of the study
* Breastfeeding one infant 48 hours - 5 days old
* Willingness and ability to comply with the study protocol for the duration of the study
* Can understand information about the study and provide consent

Inclusion Criteria: Infants

• Healthy neonate 48 hours - 5 days old

Exclusion Criteria: Mothers

* Known hypersensitivity to Primaquine (PMQ), defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis
* Known Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in mother defined as G6PD activity \<70% of normal male population median by spectrophotometry
* 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
* Screening Hct \<33% by complete blood count (CBC)
* Known history of severe jaundice in a previous child
* Blood transfusion within the 3 months before screening

Exclusion Criteria: Infants

* Known Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in neonate defined as G6PD activity \<70% of normal male population median by spectrophotometry
* 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
* Screening Hct \<40% by CBC
* Estimated gestational age at birth \< 38 weeks
* Evidence of birth asphyxia (5 min Apgar score \<7)
* Moderate or severe jaundice as defined as total serum bilirubin above treatment line on day 1 (before maternal dose)

Primary outcomes:
measure: Area under the time-concentration curve in milk
timeFrame: 14 days
measure: Relative infant dose
timeFrame: 14 days
Secondary outcomes:
measure: Area under the time-concentration curve in plasma
timeFrame: 14 days
measure: Time to maximum concentration
timeFrame: 14 days
measure: Peak plasma concentration
timeFrame: 14 days
measure: Haematologic changes
timeFrame: 14 days
measure: Number of adverse events
timeFrame: 14 days
measure: Severity of adverse events
timeFrame: 14 days
measure: Type of adverse events
timeFrame: 14 days
Other outcomes:
Locations:
city: Mae Ramat
country: Thailand
facility: Shoklo Malaria Research Unit (SMRU)
state: Tak
Study officials:
affiliation: Shoklo Malaria Research Unit (SMRU)
name: Rose McGready, Ph.D
role: PRINCIPAL_INVESTIGATOR
References: