BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases

Jian-She Wang of Children's Hospital of Fudan University

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

Study Overview

• Status: Withdrawn
• Conditions: Cholestasis, Intrahepatic; Hereditary Diseases
• Intervention / Treatment: Drug: 4-Phenylbutyrate

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Jian-She Wang, Ph.D; Phone Number: 86-02164931171; Email: jshwang@shmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BSEP trafficking abnormal group; Patients with ABCB11 missense mutations that were speculated to affect the BSEP trafficking	Drug: 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.; Other Names: UDCA or biliary diversion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Native liver survive time	Time of patient survived with native liver will be accessed.	During follow-up (about 3 years）

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ALT(Alanine Aminotransferase)	It is a repeated measurement variable. ALT would be measured.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
DB(direct bilirubin) levels	It is a repeated measurement variable. DB would be measured.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
TB(total bilirubin)	It is a repeated measurement variable. TB would be measured.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
AST(Aspartate Aminotransferase)	It is a repeated measurement variable. AST would be measured.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Weight	It is a repeated measurement variable. The weight of the patients.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Length	It is a repeated measurement variable. The length of the patients	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Itching relief	It is a repeated measurement variable.The itching score level will be accessed using a score ranged from 0 to 10.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Liver pathological staging	It is a repeated measurement variable.Liver pathological staging will be accessed using the Batts-Ludwig system.	day 90, 180
Coagulation function	It is a repeated measurement variable.The INR(international normalized ratio)/PT(prothrombin time) levels will be followed if with coagulation function abnormal.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Hypoglycemia	It is a repeated measurement variable.The glucose wil be followed.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Hypo25-hydroxyvitamin Demia	It is a repeated measurement variable. Hypo25-hydroxyvitamin D levels will be followed.	at day 0, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
The bile acid profiling	It is a repeated measurement variable. The bile acid profiling will be checked during follow-up.	at day 30, 60, 90, 180, 360, 720 and 1080
Hypoproteinemia	It is a repeated measurement variable. The albumin wil be followed.	at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
Adverse events	It is a binary variable(1/0). If any adverse events including bleeding, fractures, tumors, and hepatic encephalopathy happended during the follow-up, the variable would be setted into "1". The incidence of each adverse events will also be calculated.	During follow-up (about 3 years）

Collaborators and Investigators

• Sponsor: Children's Hospital of Fudan University

Publications and helpful links

Helpful Links

• Targeted pharmacotherapy in ABCB11 mutation by 4-phenylbutyrate
• Pharmacological premature termination codon readthrough of ABCB11
• Functional rescue of an ABCB11 mutant by ivacaftor

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): February 8, 2023
• Primary Completion (ACTUAL): February 8, 2023
• Study Completion (ACTUAL): February 8, 2023

Study Registration Dates

• First Submitted: August 26, 2020
• First Submitted That Met QC Criteria: August 26, 2020
• First Posted (ACTUAL): August 31, 2020

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: liver biopsy; gene; BSEP; ABCB11; biliary diversion
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis; Genetic Diseases, Inborn; Cholestasis, Intrahepatic; Antineoplastic Agents; 4-phenylbutyric acid
• Other Study ID Numbers: BSEP_FudanEK_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No