Assessing the Drug Exposure Risk of Infants Breastfed by Women With Inflammatory Bowel Disease

• ClinicalTrials.gov Identifier: NCT03397108
• Recruitment Status: Active, not recruiting
• First Posted: January 11, 2018
• Last Update Posted: October 20, 2021
• Sponsor: The Hospital for Sick Children
• Collaborators: MOUNT SINAI HOSPITAL; Crohn's and Colitis Foundation
• Information provided by (Responsible Party): Shinya Ito, The Hospital for Sick Children

Study Description

Brief Summary:

Breastfeeding is beneficial to both mother and baby. However, many breastfeeding women are affected by long-term health conditions and need to take medications. Sometimes, concerns about transfer of drugs to infants via breast milk lead the mothers to either avoid breastfeeding or stop their medication.

Inflammatory Bowel Disease (IBD) is a chronic condition that is marked by an abnormal response of the body's immune system, and high levels of certain proteins that cause inflammation (Cytokines like Tumor Necrosis Factor-alpha or TNFα). A group of drugs called "biologics" target and stop these proteins from causing inflammation, and have been successfully used to treat this condition. Inflammatory proteins may be present in breast milk of healthy women in variable levels, and may play a role in development of infant's brain and immune system.

This study is being conducted to investigate:

• Concentration of some of the inflammatory proteins in breast milk of mothers with IBD and healthy controls
• Interaction between these proteins and biologics in breast milk of women with IBD
• Potential role of these proteins (and their interaction with biologics) on development of infant learning and memory function It has been presumed that concentrations of TNFα and some other cytokines are higher in breast milk of women with IBD, and the biologics can normalize these high levels.

Due to precautions for COVID-19, the study now consists of only two mandatory study visits and two optional study visits. The mandatory visits include two home visits in the first 4 months postpartum to complete a participant questionnaire and collect a small sample of breast milk at each visit. The optional study visits consist of two visits at the Hospital for Sick Children for evaluation of learning and memory function of the infant at the ages of 12 and 18 months. Additionally, mothers will be required to complete for their infant subscales of The Ages and Stages Questionnaires®, Third Edition (ASQ®-3) either in person or over the telephone at the ages of 12 months and 18 months.

Condition or disease
Crohn's Disease; Ulcerative Colitis; Healthy Controls

Detailed Description:

The inflammatory bowel disease (IBD) shows the highest incidence among people of childbearing age. Indeed, it is not uncommon that pregnant or lactating women with IBD require drug therapy, including monoclonal antibodies against Tumor Necrosis Factor-alpha (TNFα). However, these patients face challenges, because information on pregnancy and breastfeeding safety of these new medications is lacking due to exclusion of pregnant and breastfeeding women from drug development processes. Whereas the data necessary for fetal safety assessment is accumulating gradually, significant gaps in the research efforts and the understanding on excretion of TNFα inhibitors into milk remain. Experts generally consider it acceptable to use the TNFα inhibitors during breastfeeding, because the previous studies found relatively low levels of these drugs in milk. However, the existing data on milk levels of these drugs are highly inconsistent, probably because previous reports gave no consideration to potential interference from high levels of endogenous TNFα in milk. As a result, a comprehensive picture of TNFα inhibitors in breast milk remains obscure. Moreover, in a recent mouse study, transfer of TNFα-dependent chemokines through milk has been shown to play a role in shaping the postnatal programming of brain development, implying that altered disposition of endogenous TNFα and other chemokines in milk during anti-TNFα therapy has an impact on brain development of the offspring.

This is an observational cohort study with comparison group, which describes the first step to address the issue by uncovering the TNFα-dependent 'lactocrine' pathway and disposition of TNFα inhibitors in milk. The study will also investigate the pharmacokinetics of TNFα inhibitors in breast milk (as a sub-study), using the population pharmacokinetic (popPK) approach.

Study Design

• Study Type: Observational
• Estimated Enrollment: 160 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Assessing the Drug Exposure Risk of Infants Breastfed by Women With Inflammatory Bowel Disease
• Actual Study Start Date: July 4, 2017
• Estimated Primary Completion Date: November 30, 2021
• Estimated Study Completion Date: March 31, 2022

Groups and Cohorts

Group/Cohort
Women with IBD; This group is composed of breastfeeding women aged over 18 years and in their first 4-month postpartum period, who are diagnosed with Crohn's disease or Ulcerative Colitis.
Healthy breastfeeding women; This group is composed of healthy breastfeeding women aged over 18 years and in their first 4-month postpartum period.

Outcome Measures

Primary Outcome Measures :

1. Levels of TNFα and its downstream chemokines (CCL2, CCL4, CCL7, and CXCL10) in breast milk of women with IBD and healthy controls by Multiplex assay [ Time Frame: 4 years ]
   Multiplex assay will be used to measure TNFα and downstream chemokines including CCL2, CCL4, CCL7, CXCL10 in breast milk of two groups of participants (women with IBD and healthy controls). (The unit of measurement is the same for all these cytokines)

Secondary Outcome Measures :

1. Milk concentration of TNFα inhibitors (infliximab, adalimumab) at different time-points between two doses of medication, in lactating women with IBD by ELISA assay [ Time Frame: 4 years ]
   ELISA assay will be used to measure total and free drug levels (bound and unbound to TNFα) in breast milk of lactating women with IBD. (The unit of measurement is the same for infliximab and adalimumab).
2. Scores on cognitive subset of Bayley Scales of Infant and Toddler development- Third Version (Bayley-III) in infants of healthy controls and women with IBD [ Time Frame: 4 years ]
   The infants of women with IBD and healthy controls will be examined for cognitive development using Bayley-III
3. Scores on the "Problem-solving" and "Communication" subscales of The Ages and Stages Questionnaire (ASQ®-3) in infants of healthy controls and women with IBD [ Time Frame: 4 years ]
   Infants of healthy controls and women with IBD will be examined for communication and problem-solving development using the ASQ®-3. This supplementary measure is intended to provide additional data as an alternative to Bayley test under unprecedented circumstances which preclude participants to complete Bayley test at the Hospital for Sick Children
4. Simulated/predicted profiles of TNFα inhibitors (infliximab, adalimumab) in breast milk in a large population of lactating women with IBD by population pharmacokinetic modelling [ Time Frame: 4 years ]
   An estimation of the population distribution of anti-TNFα antibodies (infliximab and adalimumab) in breast milk of women with IBD will be made, using population pharmacokinetic modelling

Biospecimen Retention:   Samples Without DNA

Human milk samples will be collected and analyzed for TNF alpha, TNF alpha-dependent chemokines, and infliximab/adalimumab levels.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

The study participants are required to live in the Greater Toronto Area. The IBD group will be selected from IBD clinics, while the healthy controls will be selected from the community samples who volunteer to participate.

Criteria

Inclusion Criteria:

• Breastfeeding women with IBD or healthy breastfeeding women in the first 4-month postpartum period

Exclusion Criteria:

• unable to communicate in English
• Present illness of chronic inflammatory conditions (except IBD)
• Mastitis
• Present acute or chronic infection
• use of a different anti-TNFα drug within the last 2 months

Contacts and Locations

Locations

Canada, Ontario

Mount Sinai Hospital

Toronto, Ontario, Canada, M5G 1X5

The Hospital for Sick Children

Toronto, Ontario, Canada, M5G 1X8

Sponsors and Collaborators

The Hospital for Sick Children

MOUNT SINAI HOSPITAL

Crohn's and Colitis Foundation

Investigators

• Principal Investigator: Shinya Ito, MD; The Hospital for Sick Children

More Information

• Responsible Party: Shinya Ito, Principal Investigator, Head of Clinical Pharmacology & Toxicology, The Hospital for Sick Children
• ClinicalTrials.gov Identifier: NCT03397108
• Other Study ID Numbers: 1000056982
• First Posted: January 11, 2018
• Last Update Posted: October 20, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shinya Ito, The Hospital for Sick Children:

Inflammatory Bowel Disease; Crohn disease; Colitis; TNF; Breast milk; monoclonal antibody

Additional relevant MeSH terms:

Crohn Disease; Colitis; Intestinal Diseases; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases