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Intestinal Microbiome Composition in Infants With Biliary Atresia (BA) (BA)

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ClinicalTrials.gov Identifier: NCT03890536
Recruitment Status : Not yet recruiting
First Posted : March 26, 2019
Last Update Posted : January 25, 2023
Sponsor:
Collaborator:
Wuhan Union Hospital, China
Information provided by (Responsible Party):
Jorge Bezerra. MD, Children's Hospital Medical Center, Cincinnati

Study Description
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Brief Summary:

A prospective observational study in infants with biliary atresia and controls to determine whether the composition of the intestinal microbiome is specific for biliary atresia will be conducted.

The hypothesis of the study is "infants with biliary atresia have a unique microbiome signature at the time of diagnosis and changes in population dynamics occur during disease progression". The microbiome will be determined at diagnosis and at well-defined time points during the natural history of the disease.


Condition or disease
Biliary Atresia Intrahepatic Cholestases Normal Controls

Detailed Description:

Biliary atresia, the most common cause of neonatal cholestasis, results from a fibrosing and inflammatory obstruction of extrahepatic bile ducts of unknown etiology. Infants with neonatal cholestasis will be enrolled at the time of diagnosis. Those that undergo exploratory laparotomy and are diagnosed with biliary atresia will form the "biliary atresia".

The development of the normal bacterial flora is a dynamic process that varies in early postnatal ages and may be influenced by disease states. To control for age differences, the composition of the microbiome in subjects with other causes of neonatal liver diseases (non-biliary atresia or disease-controls) and age-matched healthy subjects (normal controls) will be determined.

Subjects with biliary atresia will be enrolled at diagnosis, at which time a stool sample and a 2 mL blood sample will be obtained. Thereafter, a stool sample will be obtained at 3±1 months after hepatoportoenterostomy (HPE) and at 24±6 months of age. A stool sample and a 2 ml blood sample will also be obtained if/when subjects are admitted to the hospital for an evaluation and treatment of presumed infection (example: ascending cholangitis) and at the time of liver transplantation.

Similar samples will also be obtained from healthy subjects (normal controls) and patients diagnosed with other cholestatic syndromes (non-biliary atresia or disease-controls) at ages that match those of subjects with biliary atresia. Samples will be used for bacterial DNA isolation, which will be used for bacterial and mammalian gene sequencing using next-generation sequencing methods, followed by statistical analysis to identify unique microbiome compositions or alterations that are associated with particular disease (biliary atresia or non-BA controls) or clinical outcomes including response to HPE, ascending cholangitis and progression of liver disease.

Study Design
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Study Type : Observational
Estimated Enrollment : 50 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Intestinal Microbiome Composition in Infants With Biliary Atresia
Estimated Study Start Date : December 2023
Estimated Primary Completion Date : March 2029
Estimated Study Completion Date : March 2032

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort
Biliary atresia
Biliary atresia is an obstructive cholangiopathy of infancy. It is the most common cause of neonatal cholestasis and the most frequent indication for liver transplantation in children. Patients with biliary atresia have conjugated hyperbilirubinemia (serum direct bilirubin > 1mg/dL) AND are scheduled for/undergo exploratory laparotomy for diagnosis and Kasai portoenterostomy for surgical treatment of BA.
Non-BA=disease controls
All infants with other cholestatic syndromes (except biliary atresia) will be eligible for study enrollment in disease controls/non-biliary atresia. This involves the diagnosis of liver diseases caused by syndromes of intrahepatic cholestasis with or without hyperbilirubinemia.
Normal
All healthy infants with no acute or chronic liver related illness.


Outcome Measures
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Primary Outcome Measures :
  1. Change in intestinal microbiome signature. [ Time Frame: Through study completion, an average of 24 months. ]
    Change in intestinal microbiome signature at the time of diagnosis of biliary atresia (up to 3 months of age/ at HPE) as compared with disease control and normal.


Secondary Outcome Measures :
  1. Microbiome signature and serum direct/ conjugated bilirubin. [ Time Frame: Through study completion, an average of 24 months. ]
    Correlation between the microbiome signature and normalization of serum direct/ conjugated bilirubin 3months after HPE.

  2. Microbiome signature and survival at 1 yr of age. [ Time Frame: Through study completion, an average of 36 months. ]
    Correlation between the microbiome signature and survival with the native liver at 1 yr of age.

  3. Microbiome signature and survival at 2 yr of age. [ Time Frame: Through study completion, an average of 48 months. ]
    Correlation between the microbiome signature and survival with the native liver at 2 yr of age.

  4. Microbiome signature and ascending cholangitis. [ Time Frame: Through study completion, an average of 48 months. ]
    Change in intestinal microbiome signature specific for ascending cholangitis up to and include 2 yr of age.

  5. Change in microbiome signature and liver transplant. [ Time Frame: Through study completion, an average of 48 months. ]
    Change in microbiome signature specific for end-stage liver disease (liver transplant) up to and include 2 yr of age..


Biospecimen Retention:   Samples With DNA
Stool specimens will be collected from infants with Biliary atresia, non-biliary atresia liver disease and control subjects with no disease. Bacterial genomic DNA will be isolated from stool samples of the above-mentioned subjects.

Eligibility Criteria
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Ages Eligible for Study:   1 Day to 2 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Biliary atresia, the most common cause of neonatal cholestasis, results from a fibrosing and inflammatory obstruction of extrahepatic bile ducts of unknown etiology. Infants with neonatal cholestases due to other causes and age-matched healthy controls will be enrolled.

This is a prospective study that starts at the time of evaluation of neonatal cholestasis and will collect samples and clinical data during the progression of liver disease. A subject will be eligible for study once it is determined that the subject meets entry criteria either into the study or disease-control cohorts or the normal control cohort.

Criteria

Inclusion Criteria:

  1. Age:

    -Birth to 5 months

  2. Disease state: Must meet either (a), (b), or (c) for eligibility.

    a) Biliary atresia:

    • Conjugated hyperbilirubinemia (serum direct bilirubin > 1mg/dL) AND demonstration of obstruction of extra hepatic bile ducts by examination of histological sections of extra hepatic bile ducts

      b) Neonatal cholestasis secondary to other causes of liver disease:

    • Diagnosis of liver disease caused by syndromes of intrahepatic cholestasis with or without hyperbilirubinemia

      c) Normal controls:

    • No acute or chronic liver related illness
  3. Signed informed consent/assent

Exclusion Criteria:

  1. Evidence of multi-organ system failure (e.g. combined liver and kidney failure)
  2. For subjects < 5 months old, treatment with antibiotics prior to enrollment into study
Contacts and Locations
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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): NCT03890536


Contacts
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Contact: Jorge A Bezerra, MD 513-636-4928 jorge.bezerra@cchmc.org
Contact: Reena R Mourya, MSc 513-636-9731 reena.mourya@cchmc.org

Locations
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United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Contact: Jorge A Bezerra, MD    513-636-4928    jorge.bezerra@cchmc.org   
Contact: Reena R Mourya, MSc    513-636-9731    reena.mourya@cchmc.org   
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Wuhan Union Hospital, China
Investigators
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Principal Investigator: Jorge A Bezerra, MD Professor of Pediatrics
More Information
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Publications:

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Responsible Party: Jorge Bezerra. MD, Professor of Pediatrics, Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT03890536    
Other Study ID Numbers: CIN001-Microbiome study in BA
First Posted: March 26, 2019    Key Record Dates
Last Update Posted: January 25, 2023
Last Verified: January 2023
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 Jorge Bezerra. MD, Children's Hospital Medical Center, Cincinnati:
Microbiome
Additional relevant MeSH terms:
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Cholestasis
Biliary Atresia
Cholestasis, Intrahepatic
Bile Duct Diseases
Biliary Tract Diseases
 Digestive System Diseases
Digestive System Abnormalities
Congenital Abnormalities
Liver Diseases