BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hereditary Diseases, Cholestasis, Intrahepatic

Intervention / Treatment
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* Drug: 4-Phenylbutyrate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BSEP trafficking abnormal group<br>Patients with ABCB11 missense mutations that were speculated to affect the BSEP trafficking | Drug: 4-Phenylbutyrate<br>* 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.<br>* Other names: UDCA or biliary diversion;|

What is the study measuring?
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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） | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BSEP, ABCB11, biliary diversion, liver biopsy, gene