BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases

NCT ID: NCT04531878

Last Updated: 2023-02-09

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2/PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-02-08
• Study Completion Date: 2023-02-08

Brief Summary

The purpose of the study is to improve the prognosis of inhereditary cholestasis caused by ABCB11 gene mutations by using BSEP function rescue drugs

Detailed Description

Bile acids function as detergents to aid digestion and as signaling molecules to regulate gene expression and metabolism. They are synthesized from cholesterol in the liver, secreted into bile and re -turned from chyme to liver in portal- vein blood 6-10 times per day (enterohepatic circulation. Enterohepatic circulation of bile acids involves more than 20 transporters among which bile salt export pump (BSEP), encoded by ABCB11 plays a key role. BSEP medi-ates the secretion of bile acids across the canalicular membrane of hepatocytes into bile to provide the osmotic pressure for bile flow. Mutations in ABCB11 can cause absence or dysfunction of BSEP leading to cholestasis. Bile acid accumulation in hepatocytes caused by BSEP dysfunction is associated with a range of liver dis-eases, ranging from transient neonatal cholestasis to fatal progressive familial intrahepatic cholestasis (PFIC), with jaundice, growth retardation, cirrhosis, liver failure and death. Our current indicates that more than 70% patents with ABCB11 mutations need liver-transplantation or dead during follow-up. In recent years, some targeted drugs including 4-phenylbutyrate(for patients with BSEP trafficking abnormal), ivacaftor(for patients with abnormal BSEP transport function), and gentamicin (for patients with none sense mutations) have emerged make it possible for individual targeted therapy possible.

Conditions

Hereditary Diseases; Cholestasis, Intrahepatic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

BSEP trafficking abnormal group

Patients with ABCB11 missense mutations that were speculated to affect the BSEP trafficking

Group Type: EXPERIMENTAL

4-Phenylbutyrate

Intervention Type: DRUG

4-phenylbutyrate therapy will be started at a daily dose of 200 mg kg/d divided in 2 oral doses of sodium phenylbutyrate (AMMONAPS, Swedish Orphan Inter AB). In order to get the best effect, the dose will be increased up to a maximum of 500 mg kg/d.

Interventions

4-Phenylbutyrate

4-phenylbutyrate therapy will be started at a daily dose of 200 mg kg/d divided in 2 oral doses of sodium phenylbutyrate (AMMONAPS, Swedish Orphan Inter AB). In order to get the best effect, the dose will be increased up to a maximum of 500 mg kg/d.

Intervention Type: DRUG

Other Intervention Names

UDCA or biliary diversion

Eligibility Criteria

Inclusion Criteria

• with signed informed consent form from the guardian, and the patient if applicable.
• aged from 2 month to 18 years old.
• with cholestatic disease caused by ABCB11 biallelic mutation.
• Long-term residence in China.

Exclusion Criteria

• Currently receiving or previously received experimental drugs.
• The child is already in the stage of liver failure, or in unstable state that are not suitable for drug treatment according to the researcher's judgment: serious complications such as bleeding tendency and skin rash.
• accompany with other chronic liver disease (viral hepatitis B and C, autoimmune hepatitis, wilson disease, cystic fibrosis, primary biliary cirrhosis, biliary atresia, sclerosing cholangitis, bile acid synthesis defects, and infections, cholestasis caused by space-occupying and other reasons).
• Suffered from congenital TORCHES infection, including toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, EB virus, syphilis, HIV, etc.
• With any other major medical conditions that may affect drug absorption, metabolism, or excretion based on the researcher's judgment.
• Known or suspected hypersensitivity to any experimental drugs or their indigents.
• Patients with alcohol or drug dependence.
• In receiving any investigational drugs or within 60 days before enrollment.

• Minimum Eligible Age: 2 Months
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Fudan University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jian-She Wang, Ph.D

Role: STUDY_CHAIR

Children's hospital of Fudan Unviersity

Related Links

http://www.ncbi.nlm.nih.gov/pubmed/25716872

Targeted pharmacotherapy in ABCB11 mutation by 4-phenylbutyrate

http://www.ncbi.nlm.nih.gov/pubmed/32702170

Pharmacological premature termination codon readthrough of ABCB11

http://www.ncbi.nlm.nih.gov/pubmed/32433800

Functional rescue of an ABCB11 mutant by ivacaftor

Other Identifiers

BSEP_FudanEK_001

Identifier Type: -

Identifier Source: org_study_id