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

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

Tracking Information

• First Submitted Date: January 30, 2019
• First Posted Date: March 26, 2019
• Last Update Posted Date: January 25, 2023
• Estimated Study Start Date: December 2023
• Estimated Primary Completion Date: March 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 24, 2019)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 24, 2019)

• 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.
• 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.
• 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.
• 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.
• 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..

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intestinal Microbiome Composition in Infants With Biliary Atresia (BA)
• Official Title: Intestinal Microbiome Composition in Infants With Biliary Atresia

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.

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 Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

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.

• 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.

Condition

• Biliary Atresia
• Intrahepatic Cholestases
• Normal Controls

• Intervention: Not Provided

Study Groups/Cohorts

• 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.

Publications *

• Balistreri WF, Grand R, Hoofnagle JH, Suchy FJ, Ryckman FC, Perlmutter DH, Sokol RJ. Biliary atresia: current concepts and research directions. Summary of a symposium. Hepatology. 1996 Jun;23(6):1682-92. doi: 10.1002/hep.510230652.
• Bessho K, Bezerra JA. Biliary atresia: will blocking inflammation tame the disease? Annu Rev Med. 2011;62:171-85. doi: 10.1146/annurev-med-042909-093734.
• Mack CL, Feldman AG, Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis. 2012 Nov;32(4):307-16. doi: 10.1055/s-0032-1329899. Epub 2013 Feb 8.
• Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013 Jul;58(1):120-7. doi: 10.1002/hep.26319. Epub 2013 May 14.
• Tabibian JH, Talwalkar JA, Lindor KD. Role of the microbiota and antibiotics in primary sclerosing cholangitis. Biomed Res Int. 2013;2013:389537. doi: 10.1155/2013/389537. Epub 2013 Oct 22.
• Kane M, Case LK, Kopaskie K, Kozlova A, MacDearmid C, Chervonsky AV, Golovkina TV. Successful transmission of a retrovirus depends on the commensal microbiota. Science. 2011 Oct 14;334(6053):245-9. doi: 10.1126/science.1210718.
• Kuss SK, Best GT, Etheredge CA, Pruijssers AJ, Frierson JM, Hooper LV, Dermody TS, Pfeiffer JK. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science. 2011 Oct 14;334(6053):249-52. doi: 10.1126/science.1211057.
• Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, Sahl JW, Stres B, Thallinger GG, Van Horn DJ, Weber CF. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009 Dec;75(23):7537-41. doi: 10.1128/AEM.01541-09. Epub 2009 Oct 2.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: March 24, 2019): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2032
• Estimated Primary Completion Date: March 2029 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Day to 2 Years (Child)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Jorge A Bezerra, MD; 513-636-4928; jorge.bezerra@cchmc.org

Contact: Reena R Mourya, MSc; 513-636-9731; reena.mourya@cchmc.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03890536
• Other Study ID Numbers: CIN001-Microbiome study in BA
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Jorge Bezerra. MD, Children's Hospital Medical Center, Cincinnati
• Original Responsible Party: Jorge Bezerra, Children's Hospital Medical Center, Cincinnati, Professor of Pediatrics
• Current Study Sponsor: Children's Hospital Medical Center, Cincinnati
• Original Study Sponsor: Same as current
• Collaborators: Wuhan Union Hospital, China

Investigators

• Principal Investigator: Jorge A Bezerra, MD; Professor of Pediatrics

• PRS Account: Children's Hospital Medical Center, Cincinnati
• Verification Date: January 2023