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

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

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.

Study Overview

• Status: Completed
• Conditions: Bile Acid Synthesis Defect; Inborn Error of Bile Acid Metabolism; Inborn Error of Bile Acid Conjugation
• Intervention / Treatment: Drug: Glycocholic Acid

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 83 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmation of a diagnosis of an inborn error of bile acid synthesis/conjugation based upon urine analysis by FAB-MS.
2. Any age
3. Participant must be willing and able to comply with study assessments and procedures.
4. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GlycoCholic Acid, Study Drug; 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; 10-15mg/kg body weight/day taken orally. Supplied as either liquid or 50mg capsules.; Other Names: Conjugated Cholic Acid

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Kenneth D. Setchell, Ph.D., Children's Hospital Medical Center, Cincinnati; Principal Investigator: James E. Heubi, M.D., Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Setchell KD, Heubi JE, Shah S, Lavine JE, Suskind D, Al-Edreesi M, Potter C, Russell DW, O'Connell NC, Wolfe B, Jha P, Zhang W, Bove KE, Knisely AS, Hofmann AF, Rosenthal P, Bull LN. Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology. 2013 May;144(5):945-955.e6; quiz e14-5. doi: 10.1053/j.gastro.2013.02.004. Epub 2013 Feb 13.
• Heubi JE, Setchell KD, Jha P, Buckley D, Zhang W, Rosenthal P, Potter C, Horslen S, Suskind D. Treatment of bile acid amidation defects with glycocholic acid. Hepatology. 2015 Jan;61(1):268-74. doi: 10.1002/hep.27401. Epub 2014 Dec 23.

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): January 22, 2019
• Study Completion (Actual): January 22, 2019

Study Registration Dates

• First Submitted: April 3, 2012
• First Submitted That Met QC Criteria: April 30, 2012
• First Posted (Estimate): May 2, 2012

Study Record Updates

• Last Update Posted (Actual): June 8, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Gastrointestinal Agents; Cholagogues and Choleretics; Cholic Acids; Glycocholic Acid
• Other Study ID Numbers: 2009-0780