BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases

Sponsor

Children's Hospital of Fudan University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04531878

Collaborator

(none)

Enrollment

Arm

12.9

Anticipated Duration (Months)

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Hereditary Diseases Cholestasis, Intrahepatic	Drug: 4-Phenylbutyrate	Phase 2/Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Dec 3, 2022

Anticipated Primary Completion Date :

Dec 30, 2023

Anticipated Study Completion Date :

Dec 30, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Native liver survive time [During follow-up (about 3 years）]
Time of patient survived with native liver will be accessed.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Months to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.