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

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

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.

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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breastfeeding

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.



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.


Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03397108


Locations
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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
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Principal Investigator: Shinya Ito, MD The Hospital for Sick Children
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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    Key Record Dates
Last Update Posted: October 20, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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Crohn Disease
Colitis
Colitis, Ulcerative
Intestinal Diseases
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases