Pharmacokinetics of Antimalarials in Breastfeeding Ugandan Mother-infant Pairs (MILK Malaria)

Pharmacokinetics of Drugs Used to Treat Uncomplicated Malaria in Breastfeeding Mother-infant Pairs: An Observational Pharmacokinetic Study

Lactating women requiring treatment for uncomplicated malaria will be identified and invited for sampling. The decision to treat them with first-line treatment will have been made by the clinician, not by a member of the study team. The study team will not make any adjustments to the prescribed treatment. Artemether-lumefantrine comprises six doses of medication, with the initial two doses given 8 hours apart on Day 1, and dosing 12-hourly on Day 2 and Day 3. Intensive pharmacokinetic sampling will be undertaken after Dose 5, as indicated in the schema under Section 5: plasma and breastmilk samples will be obtained pre-dose and at 2, 4, 6, 8 hours after dose. In addition, sparse sampling will be undertaken on either of these occasions; at pre-dose and between 1 to 6 hours after the first dose; a trough (pre-dose) sample after the Dose 3 or Dose 4 and lastly at 5, 7, and up to 14-days after the first dose. A heelprick sample will also be obtained from the breastfed infants at maternal trough (prior to maternal dose) and at a random timepoint (once per infant) over the 8-hour pharmacokinetic sampling visit to characterize concentrations of these drugs over an 8-hour dosing interval. In addition, a single heelprick sample will be obtained from the infant whenever the mother returns after treatment for the late sampling time points (5, 7, and 14 days post the first dose). Due to the long half-life of lumefantrine of approximately 6 days plasma sampling will be performed up to day 14 to characterise the terminal elimination of the drug. Concentrations of total plasma and breastmilk lumefantrine and desbutyl-lumefantrine will be determined.

Study Overview

• Status: Recruiting
• Conditions: Malaria,Falciparum
• Intervention / Treatment: Drug: Artemether-lumefantrine

Detailed Description

The endpoints of this study relate to the amount of antimalarial drug present in maternal blood, breastmilk and infant blood. The study is not powered for antimalarial efficacy, and therefore formal assessment of parasitological clearance is not required. The participants will be followed up until 30-40 days after completion of antimalarial therapy, and if recurrent symptoms occur, management will be as clinically indicated. Details regarding further clinical investigations and management required by either mother or infant during the follow-up period will be recorded on the CRF.

• Study Type: Observational
• Enrollment (Anticipated): 30

Contacts and Locations

• Study Contact: Name: Ritah Nakijoba; Email: rnakijoba@idi.co.ug
• Study Contact Backup: Name: Catriona Waitt; Phone Number: +256778288217; Email: cwaitt@idi.co.ug

Study Locations

• Uganda
  • Kampala, Uganda, 22418
    • Recruiting
    • Infectious Diseases Institute
    • Contact: Tom Kakaire, BSc; Phone Number: 0778288217; Email: tkakaire@idi.co.ug
    • Contact: Richard Ssesanga, BSc; Email: rssesanga@idi.co.ug
    • Principal Investigator: Catriona Waitt, MBChB, PhD
    • Sub-Investigator: Barbara Castelnuovo, MBChB, PhD
    • Sub-Investigator: Ritah Nakijoba, RN, BSc
    • Sub-Investigator: Allan Buzibye, BSc, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Ugandan breastfeeding women requiring treatment for uncomplicated malaria

Description

Inclusion Criteria:

1. A personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Woman is aged 18 years or older, and mothers between the age of 14-17, who are considered emancipated minors.
4. Receiving treatment for uncomplicated malaria
5. Breastfeeding at enrolment

Exclusion Criteria:

1. Severe maternal or infant illness which in the opinion of the patient's clinician would interfere with her participation in the study
2. Breastfed infant is aged over 12 months
3. Partner objection to participate in the study
4. Maternal objection to infant participation

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Participants; Breastfeeding women who have been prescribed (by a clinician independent from the study team) artemether-lumefantrine to treat uncomplicated malaria	Drug: Artemether-lumefantrine; National policy recommendation for treatment of uncomplicated malaria in Uganda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-24 of lumefantrine in maternal plasma and breastmilk	Maternal plasma exposure of lumefantrine	0-24 hours after dose
AUC0-24 of lumefantrine breastmilk	Breastmilk exposure of lumefantrine	0-24 hours after dose
Milk to plasma ratio of lumefantrine	Ratio of AUC in breastmilk to maternal plasma	0-24 hours after dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC desbutyl-lumefantrine plasma	Plasma exposure of active metabolite	0-24 hours after dose
AUC desbutyl-lumefantrine breastmilk	Breastmilk exposure of active metabolite	0-24 hours after dose
Milk to plasma ratio of desbutyl-lumefantrine	Ratio of breastmilk to maternal plasma of active metabolite	0-24 hours after dose
Infant concentration lumefantrine	Infant lumefantrine exposure	0-8 hours after maternal dose
Infant concentration desbutyl-lumefantrine	Infant exposure to active metabolite	0-8 hours after maternal dose
Infant development	Infant assessment using Gross Motor Development Score (IGMDS)	0-1 year old
Depression and anxiety in mothers	Patient Health Questionnaire (PHQ9)	0-1 year postpartum
Depression and anxiety in mothers	General Anxiety Disorder (GAD7)	0-1 year postpartum
Maternal beliefs about medicines	Beliefs about Medicines questionnaire (BMQ)	0-1 year postpartum

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: Infectious Diseases Institute, Makerere University College of Health Sciences; Malawi-Liverpool-Wellcome Clinical Research Programme

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: December 13, 2022
• First Submitted That Met QC Criteria: January 4, 2023
• First Posted (Actual): January 9, 2023

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: MILK Malaria

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised data showing age, number of weeks postpartum and drug concentrations in plasma, breastmilk and infant plasma will be made available for future use following primary publication.
• IPD Sharing Time Frame: After primary publication - intention is to place anonymised data on drug concentrations on an online repository such as Zenodo
• IPD Sharing Access Criteria: Weblink not yet available.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No