Clinical trial NCT04531878: BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases
Official title: Jian-She Wang of Children's Hospital of Fudan University
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
PHASE3
Conditions: Hereditary Diseases
Cholestasis, Intrahepatic
Keywords: BSEP
ABCB11
biliary diversion
liver biopsy
gene
Lead sponsor: Children's Hospital of Fudan University
Sponsor class: OTHER
First posted: 2020-08-31
Enrollment: 0
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Native liver survive time
timeFrame: During follow-up (about 3 years）
Secondary outcomes:
measure: ALT(Alanine Aminotransferase)
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: DB(direct bilirubin) levels
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: TB(total bilirubin)
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: AST(Aspartate Aminotransferase)
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Weight
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Length
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Itching relief
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Liver pathological staging
timeFrame: day 90, 180
measure: Coagulation function
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Hypoglycemia
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Hypo25-hydroxyvitamin Demia
timeFrame: at day 0, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: The bile acid profiling
timeFrame: at day 30, 60, 90, 180, 360, 720 and 1080
measure: Hypoproteinemia
timeFrame: at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
measure: Adverse events
timeFrame: During follow-up (about 3 years）
Other outcomes:
Locations:
Study officials:
affiliation: Children's hospital of Fudan Unviersity
name: Jian-She Wang, Ph.D
role: STUDY_CHAIR
References: