Intestinal Microbiome Composition in Infants With Biliary Atresia (BA)

Biliary Atresia Clinical Trial

— BA  

Official title:

Intestinal Microbiome Composition in Infants With Biliary Atresia

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03890536
• Other study ID #: CIN001-Microbiome study in BA
• Status: Not yet recruiting
• Start date: December 2023
• Est. completion date: March 2032

Study information

• Verified date: January 2023
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: Jorge A Bezerra, MD
• Phone: 513-636-4928
• Email: jorge.bezerra[@]cchmc.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: March 2032
• Est. primary completion date: March 2029
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Day to 2 Years

Eligibility

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

Related Conditions & MeSH terms

• Biliary Atresia
• Cholestasis
• Cholestasis, Intrahepatic
• Intrahepatic Cholestases
• Normal Controls

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati	Wuhan Union Hospital, China

Country where clinical trial is conducted

United States, 

References & Publications (8)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in intestinal microbiome signature.	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.	Through study completion, an average of 24 months.
Secondary	Microbiome signature and serum direct/ conjugated bilirubin.	Correlation between the microbiome signature and normalization of serum direct/ conjugated bilirubin 3months after HPE.	Through study completion, an average of 24 months.
Secondary	Microbiome signature and survival at 1 yr of age.	Correlation between the microbiome signature and survival with the native liver at 1 yr of age.	Through study completion, an average of 36 months.
Secondary	Microbiome signature and survival at 2 yr of age.	Correlation between the microbiome signature and survival with the native liver at 2 yr of age.	Through study completion, an average of 48 months.
Secondary	Microbiome signature and ascending cholangitis.	Change in intestinal microbiome signature specific for ascending cholangitis up to and include 2 yr of age.	Through study completion, an average of 48 months.
Secondary	Change in microbiome signature and liver transplant.	Change in microbiome signature specific for end-stage liver disease (liver transplant) up to and include 2 yr of age..	Through study completion, an average of 48 months.