Tafenoquine and Primaquine in Colostrum and Breast Milk

NCT04984759 | Withdrawn Phase 4 DMC

• 1 other identifier: MAL21004
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Each year almost a million infants are born small for gestational age due to malaria infection in pregnancy. These infants are at risk for stillbirth or neonatal death, and being born too small predisposes the survivors to increased metabolic diseases later in life. Plasmodium vivax (PV) is the second most common malaria species globally. Its relapsing nature results in multiple episodes of PV in a single pregnancy, compounding growth restriction and stillbirth risk. Women with PV in one pregnancy may harbor dormant parasites (hypnozoites) in their liver the cause illness and poor fetal growth in a subsequent pregnancy. Only radical cure with 8-aminoquinolines (8AQ)- primaquine (PMQ) or tafenoquine (TQ) - can eliminate hypnozoites, but these drugs are contraindicated in pregnancy. The postpartum period presents a key window of opportunity for giving radical cure to women of childbearing age with PV. Pharmacokinetic data is needed to support safe use of these drugs postpartum and World Health Organization has identified pharmacokinetic studies of 8AQ in lactation as a research priority. Primaquine is excreted minimally in mature breast milk, at \<1% of the weight-adjusted relative infant dose (RID). As the main adverse event associated with both 8AQ - hemolysis glucose-6-phosphate dehydrogenase (G6PD) deficient individuals - is dose-dependent and negligible at low doses, this finding strongly supports its safe use in later lactation. This study is needed to determine if primaquine can also be given safely in the early postpartum period. There is no published data on tafenoquine excretion in breastmilk, and this study would quantify safety throughout early and late lactation. Drug safety studies in lactation are essential to ensure medications are not denied and unnecessary interruption of breastfeeding is avoided. Demonstration of safety of radical cure for breastfeeding women in the postpartum period would allow women with PV in pregnancy and lactation to receive 8AQ after delivery, preventing illnesses in the postpartum period and subsequent pregnancies. Improved uptake of radical cure through elimination of unnecessary contraindications supports malaria elimination and community health. The main purpose of this study is to characterize the transfer of tafenoquine and primaquine in breast milk of mothers receiving radical cure doses of 8AQ throughout the different phases of lactation - colostrum, transitional milk, and mature milk - in order to determine the degree of infant exposure.

Conditions

Healthy Lactating Women

Keywords

Healthy lactating women; Tafenoquine; Primaquine; Plasmodium Vivax; Pharmacokinetic

Outcome Measures

Primary Outcomes (1)

• To characterize the excretion of tafenoquine and primaquine (with its main metabolite, carboxyprimaquine) in colostrum, transitional milk and mature milk in order to determine the degree of infant exposure

  End points: Area under the time-concentration curve (AUC) for 8-aminoquinolines in colostrum, transitional milk and mature milk. Relative infant dose (RID) for 8-aminoquinolines calculated using AUCs for drug in maternal plasma and colostrum, transitional milk and mature milk.

  Days 1-14 for primaquine, Days 1-75 for tafenoquine

Secondary Outcomes (5)

• To evaluate the pharmacokinetics (PK) of primaquine and tafenoquine in lactating women and their breastfed children at different time points following delivery.

  Days 1-14 for primaquine, Days 1-75 for tafenoquine

• To evaluate the pharmacokinetics (PK) of primaquine and tafenoquine in lactating women and their breastfed children at different time points following delivery.

  Days 1-14 for primaquine, Days 1-75 for tafenoquine

• To evaluate the pharmacokinetics (PK) of primaquine and tafenoquine in lactating women and their breastfed children at different time points following delivery.

  Days 1-14 for primaquine, Days 1-75 for tafenoquine

• To describe hematologic changes in mothers and breastfeed children during maternal ingestion of radical cure doses of 8-aminoquinolines.

  Days 1-75

• To assess adverse events of maternal radical cure doses of 8-aminoquinolines in mothers and their breastfeeding children.

  Days 1-75

Study Arms (3)

Primaquine in colostrum and transitional milk (mother-neonate pairs)

EXPERIMENTAL

12 women who are breast feeding neonates ≤5 days old will be recruited into the primaquine arm. They will receive primaquine 0.5 mg/kg daily for 14 days directly observed in the clinic.

Drug: Primaquine

Tafenoquine in mature milk (mother-child pairs)

EXPERIMENTAL

24 women who are breast feeding infants or young children \> 14 days will be recruited into Arm 2. They will receive a single 300 mg dose of tafenoquine directly observed in the clinic. Investigators will begin with recruiting 2-4 women breastfeeding young children ≥12 months old.

Drug: Tafenoquine

Tafenoquine in colostrum and transitional milk (mother-neonate pairs)

EXPERIMENTAL

12 women who are breast feeding neonates ≤ 5 days old will be recruited into Arm 3. They will receive a single 300 mg dose of tafenoquine directly observed in the clinic.

Drug: Tafenoquine

Interventions

Primaquine DRUG

Primaquine GPO® (Government Pharmaceutical Organization (GPO), Thailand) 0.5 mg/kg will be given once daily with food for 14 days. This is the dose recommended for radical cure of P. vivax in tropical areas with high rates of relapse, such as the study design setting. Doses will be directly supervised (DOT).

Also known as: Primaquine GPO®

Primaquine in colostrum and transitional milk (mother-neonate pairs)

Tafenoquine DRUG

Tafenoquine (Kodatef, Biocelect Pty Ltd.) 300 mg will be given as a directly observed single dose with food. This is the standard dose recommended globally for radical cure of P. vivax.

Also known as: Kodatef

Tafenoquine in colostrum and transitional milk (mother-neonate pairs); Tafenoquine in mature milk (mother-child pairs)

Eligibility Criteria

• Age: 16 Years+
• Gender Eligibility Details: Lactating women \>= 16 years old who are breast feeding one child who fits the time window for the respective study arm
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Mother
• Lactating women \>= 16 years old who are breast feeding one child who fits the time window for the respective study arm
• Planning to breastfeed for the duration of the study
• Willingness and ability to comply with the study protocol for the duration of the study
• Willingness to delay pregnancy until the end of the period of drug exposure (14 days for PMQ and 90 days for TQ)
• Current pregnancy excluded by urine pregnancy test and ultrasound OR immediate postpartum status (≤2 months)
• Can understand information about the study and provide consent
• Children
• Healthy children falling into the time window for the respective study arm
• ≤ 5 days for Arms 1 \& 3
• \> 14 days for Arm 2

You may not qualify if:

• Mothers
• Known hypersensitivity to PMQ or TQ, 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
• Alkaline phosphatase (ALT) \> 2x the upper limit of normal (ULN)
• Pregnancy
• Screening hematocrit (Hct) \<33%
• Known history of severe jaundice in a previous child
• Known history of psychiatric illness or abnormal depression screening score
• Blood transfusion within the 3 months before screening
• Children
• Known hypersensitivity to primaquine or tafenoquine, defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis
• Known Glucose-6-phosphate-dehydrogenase (G6PD) deficiency in child defined as G6PD activity \<70% of normal male population median by spectrophotometry in children
• 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%

Sponsors & Collaborators

• University of Oxford: lead
• Mahidol Oxford Tropical Medicine Research Unit: collaborator

Study Sites (1)

Shoklo Malaria Research Unit (SMRU)

Mae Sot, Changwat Tak, 63110, Thailand

Location

MeSH Terms

Conditions

Malaria, Vivax

Interventions

Primaquine; tafenoquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Rose McGready, Ph.D

  Shoklo Malaria Research Unit (SMRU), PO Box 46, 68/30 Ban Toong Road, Mae Sot, Tak 63110

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This is a prospective open-label study in which both participants and investigators know the identity of the treatment and its dosage.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Arms 1 and 2 will enroll first as preliminary data from Arms 1 and 2 is needed before Arm 3 can begin enrolment. All eligible and consenting women who are immediately postpartum will be enrolled in Arm 1 until it is completed. Arm 2 will enroll eligible women breastfeeding older infants and young children. If there are no safety concerns after 2-4 mother-child dyads have been enrolled in Arm 2, successively younger infants will be enrolled to a minimum of 14 days old. If there are no safety concerns with Arms 1 and 2, Arm 3 will begin enrolment.

Study Record Dates

• First Submitted: July 14, 2021
• First Posted: August 2, 2021
• Study Start: July 1, 2023
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: April 4, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: After completion of the study
• Access Criteria: SMRU and MORU Data Sharing Policies The criteria for authorship will be consistent with the international guidelines (http://www.icmje.org/#author).

Locations

TH (1)