GlycoCholic Acid Treatment for Patients With Inborn Errors in Bile Acid Synthesis

Study Overview
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Brief Summary
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The purpose of this research study is to determine the way (mechanisms) by which your defect in bile acid handling (metabolism) causes your liver disease or abnormality in absorption of vitamins and the effect of an investigational bile acid therapy (glycocholic acid) on your vitamin absorption and your liver disease. An investigational therapy is one that not approved by the United States Food and Drug Administration (FDA) and is being provided to you under an Investigational New Drug application from the FDA.

Detailed Description
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Inborn errors of bile acid metabolism have been established as a well recognized cause of neonatal cholestasis and fat-soluble vitamin malabsorption. Although there is extensive experience with metabolic defects in the biosynthetic pathway, few patients have identified with defects in conjugation with taurine or glycine that allows bile acids to become effective detergents. This protocol is designed to study the effect of defects of conjugation of bile acids on growth and fat-soluble vitamin malabsorption. Study subjects will have liver function studies performed, serum and urinary bile acid measurements, vitamin levels, growth measurements, bile acid pool size measurements made by stable isotope dilution mass-spectrometry, and measurements of absorption of two fat-soluble vitamins, tocopherol and vitamin D. Subjects will be treated orally with conjugates of cholic acid with follow-up laboratories performed as an outpatient and then subjects will have all of the initial studies repeated during an inpatient stay 3-12 months after starting treatment. Subjects with previous liver biopsies indicating the presence of significant liver disease will have a repeat liver biopsy after 3-12 months treatment to assess the histologic response to treatment.

Official Title
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Conjugated Cholic Acid for the Treatment of Inborn Errors in Bile Acid Synthesis Involving Side-Chain Conjugation

Conditions
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Bile Acid Synthesis Defect, Inborn Error of Bile Acid Metabolism, Inborn Error of Bile Acid Conjugation

Intervention / Treatment
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* Drug: Glycocholic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmation of a diagnosis of an inborn error of bile acid synthesis/conjugation based upon urine analysis by FAB-MS. Any age Participant must be willing and able to comply with study assessments and procedures. The participant and/or parent/legal guardian must have signed the written informed consent document prior to study start. Exclusion Criteria 1. No confirmed diagnosis of inborn error of bile acid synthesis/conjugation based upon urine analysis by FAB-MS.

Ages Eligible for Study
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Minimum Age: 1 Week
Maximum Age: 85 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: GlycoCholic Acid, Study Drug<br>An open label, single arm, non-randomized, non-comparative, treatment study of Glycocholic Acid in the treatment of defects of bile acid metabolism. | Drug: Glycocholic Acid<br>* 10-15mg/kg body weight/day taken orally. Supplied as either liquid or 50mg capsules.<br>* Other names: Conjugated Cholic Acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conjugated Cholic Acid (GCA) for the Treatment of Inborn Errors in Bile Acid Synthesis Involving Side-chain Conjugation. | This is the number of participants with bile acid amidation defects treated with oral glycocholic acid (15 milligrams/kilograms (mg/kg) of body weight/day (bw/day)) | Up to 10 years | 
| Evaluation of Levels of Atypical Bile Acid Metabolites After GCA Treatment Compared | Semi-quantitative descriptive evaluation of the levels of atypical bile acids in urine measured by mass spectrometry (FAB MS) based on a scale of 0 = absent or traces levels, 1 = low levels, 2 = moderate levels, 3 = high levels using the signal/noise ratio and intensity of ions. Atypical bile acids evaluated included m/z 407 (unconjugated cholic acid), m/z 471 (dihydroxy-choleanoic-sulfate) and m/z 583 (trihydroxy-choleanoic glucuronide). | Average of 6 months, average 12 months, and average of after year 1 to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Liver Function Tests of ALT From Baseline to Post-treatment | Liver function tests Alanine Aminotransferease (ALT) | Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10) | 
| Change in Liver Function Test: AST From Baseline to Post-treatment | Measure of Aspartate Aminotransferase (AST) | Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10) | 
| Change in Vitamin D, 25-OH Measure From Baseline to Post-treatment | Measure Vitamin D levels nanograms per milliliter (ng/mL) | Pre-treatment and post treatment (average of available timepoints after year 1 through year 10) |