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BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases

Primary Purpose

Hereditary Diseases, Cholestasis, Intrahepatic

Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
4-Phenylbutyrate
Sponsored by
Children's Hospital of Fudan University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hereditary Diseases focused on measuring BSEP, ABCB11, biliary diversion, liver biopsy, gene

Eligibility Criteria

2 Months - 18 Years (Child, Adult)All SexesDoes not accept 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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    BSEP trafficking abnormal group

    Arm Description

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

    Outcomes

    Primary Outcome Measures

    Native liver survive time
    Time of patient survived with native liver will be accessed.

    Secondary Outcome Measures

    ALT(Alanine Aminotransferase)
    It is a repeated measurement variable. ALT would be measured.
    DB(direct bilirubin) levels
    It is a repeated measurement variable. DB would be measured.
    TB(total bilirubin)
    It is a repeated measurement variable. TB would be measured.
    AST(Aspartate Aminotransferase)
    It is a repeated measurement variable. AST would be measured.
    Weight
    It is a repeated measurement variable. The weight of the patients.
    Length
    It is a repeated measurement variable. The length of the patients
    Itching relief
    It is a repeated measurement variable.The itching score level will be accessed using a score ranged from 0 to 10.
    Liver pathological staging
    It is a repeated measurement variable.Liver pathological staging will be accessed using the Batts-Ludwig system.
    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.
    Hypoglycemia
    It is a repeated measurement variable.The glucose wil be followed.
    Hypo25-hydroxyvitamin Demia
    It is a repeated measurement variable. Hypo25-hydroxyvitamin D levels will be followed.
    The bile acid profiling
    It is a repeated measurement variable. The bile acid profiling will be checked during follow-up.
    Hypoproteinemia
    It is a repeated measurement variable. The albumin wil be followed.
    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.

    Full Information

    First Posted
    August 26, 2020
    Last Updated
    February 7, 2023
    Sponsor
    Children's Hospital of Fudan University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04531878
    Brief Title
    BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases
    Official Title
    Jian-She Wang of Children's Hospital of Fudan University
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    February 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    lack of funding
    Study Start Date
    February 8, 2023 (Anticipated)
    Primary Completion Date
    February 8, 2023 (Actual)
    Study Completion Date
    February 8, 2023 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Children's Hospital of Fudan University

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. 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
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hereditary Diseases, Cholestasis, Intrahepatic
    Keywords
    BSEP, ABCB11, biliary diversion, liver biopsy, gene

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2, Phase 3
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    BSEP trafficking abnormal group
    Arm Type
    Experimental
    Arm Description
    Patients with ABCB11 missense mutations that were speculated to affect the BSEP trafficking
    Intervention Type
    Drug
    Intervention Name(s)
    4-Phenylbutyrate
    Other Intervention Name(s)
    UDCA or biliary diversion
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Native liver survive time
    Description
    Time of patient survived with native liver will be accessed.
    Time Frame
    During follow-up (about 3 years）
    Secondary Outcome Measure Information:
    Title
    ALT(Alanine Aminotransferase)
    Description
    It is a repeated measurement variable. ALT would be measured.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    DB(direct bilirubin) levels
    Description
    It is a repeated measurement variable. DB would be measured.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    TB(total bilirubin)
    Description
    It is a repeated measurement variable. TB would be measured.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    AST(Aspartate Aminotransferase)
    Description
    It is a repeated measurement variable. AST would be measured.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Weight
    Description
    It is a repeated measurement variable. The weight of the patients.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Length
    Description
    It is a repeated measurement variable. The length of the patients
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Itching relief
    Description
    It is a repeated measurement variable.The itching score level will be accessed using a score ranged from 0 to 10.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Liver pathological staging
    Description
    It is a repeated measurement variable.Liver pathological staging will be accessed using the Batts-Ludwig system.
    Time Frame
    day 90, 180
    Title
    Coagulation function
    Description
    It is a repeated measurement variable.The INR(international normalized ratio)/PT(prothrombin time) levels will be followed if with coagulation function abnormal.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Hypoglycemia
    Description
    It is a repeated measurement variable.The glucose wil be followed.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Hypo25-hydroxyvitamin Demia
    Description
    It is a repeated measurement variable. Hypo25-hydroxyvitamin D levels will be followed.
    Time Frame
    at day 0, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    The bile acid profiling
    Description
    It is a repeated measurement variable. The bile acid profiling will be checked during follow-up.
    Time Frame
    at day 30, 60, 90, 180, 360, 720 and 1080
    Title
    Hypoproteinemia
    Description
    It is a repeated measurement variable. The albumin wil be followed.
    Time Frame
    at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080
    Title
    Adverse events
    Description
    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.
    Time Frame
    During follow-up (about 3 years）

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    2 Months
    Maximum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    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.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jian-She Wang, Ph.D
    Organizational Affiliation
    Children's hospital of Fudan Unviersity
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Links:
    URL
    http://www.ncbi.nlm.nih.gov/pubmed/25716872
    Description
    Targeted pharmacotherapy in ABCB11 mutation by 4-phenylbutyrate
    URL
    http://www.ncbi.nlm.nih.gov/pubmed/32702170
    Description
    Pharmacological premature termination codon readthrough of ABCB11
    URL
    http://www.ncbi.nlm.nih.gov/pubmed/32433800
    Description
    Functional rescue of an ABCB11 mutant by ivacaftor

    Learn more about this trial

    BSEP Function Rescue During Childhood Inhereditary Cholestatic Diseases

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