Bile Acid Synthesis Defect, Inborn Error of Bile Acid Conjugation, Inborn Error of Bile Acid Metabolism
Conditions
Brief summary
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
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.
Interventions
DRUGGlycocholic Acid
10-15mg/kg body weight/day taken orally. Supplied as either liquid or 50mg capsules.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Weeks to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Conjugated Cholic Acid (GCA) for the Treatment of Inborn Errors in Bile Acid Synthesis Involving Side-chain Conjugation. | Up to 10 years | 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)) |
| Evaluation of Levels of Atypical Bile Acid Metabolites After GCA Treatment Compared | Average of 6 months, average 12 months, and average of after year 1 to 10 years | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Liver Function Tests of ALT From Baseline to Post-treatment | Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10) | Liver function tests Alanine Aminotransferease (ALT) |
| Change in Liver Function Test: AST From Baseline to Post-treatment | Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10) | Measure of Aspartate Aminotransferase (AST) |
| Change in Vitamin D, 25-OH Measure From Baseline to Post-treatment | Pre-treatment and post treatment (average of available timepoints after year 1 through year 10) | Measure Vitamin D levels nanograms per milliliter (ng/mL) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glycocholic Acid 15 milligrams/kilograms (mg/kg) of body weight/day (bw/day) | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Glycocholic Acid |
|---|---|
| Age, Categorical <=18 years | 5 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 5 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
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))
Time frame: Up to 10 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 15 mg/Kg Body Weight/Day | Conjugated Cholic Acid (GCA) for the Treatment of Inborn Errors in Bile Acid Synthesis Involving Side-chain Conjugation. | 5 Participants |
Primary
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).
Time frame: Average of 6 months, average 12 months, and average of after year 1 to 10 years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 15 mg/Kg Body Weight/Day | Evaluation of Levels of Atypical Bile Acid Metabolites After GCA Treatment Compared | 6 months average | 1.4 score on a scale |
| 15 mg/Kg Body Weight/Day | Evaluation of Levels of Atypical Bile Acid Metabolites After GCA Treatment Compared | 12 months average | 1 score on a scale |
| 15 mg/Kg Body Weight/Day | Evaluation of Levels of Atypical Bile Acid Metabolites After GCA Treatment Compared | average of year 1 to 10 | 1 score on a scale |
Secondary
Change in Liver Function Test: AST From Baseline to Post-treatment
Measure of Aspartate Aminotransferase (AST)
Time frame: Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10)
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 15 mg/Kg Body Weight/Day | Change in Liver Function Test: AST From Baseline to Post-treatment | Baseline | 65 units per liter (U/L) | Standard Error 14.2 |
| 15 mg/Kg Body Weight/Day | Change in Liver Function Test: AST From Baseline to Post-treatment | average of available timepoints after year 1 through year 10 | 39 units per liter (U/L) | Standard Error 3.5 |
p-value: 0.116t-test, 2 sided
Secondary
Change in Vitamin D, 25-OH Measure From Baseline to Post-treatment
Measure Vitamin D levels nanograms per milliliter (ng/mL)
Time frame: Pre-treatment and post treatment (average of available timepoints after year 1 through year 10)
Population: Missing data on Vitamin D from 2 participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 15 mg/Kg Body Weight/Day | Change in Vitamin D, 25-OH Measure From Baseline to Post-treatment | Baseline | 1.0 nanograms per milliliter (ng/mL) | Standard Error 0.8 |
| 15 mg/Kg Body Weight/Day | Change in Vitamin D, 25-OH Measure From Baseline to Post-treatment | average of available timepoints after year 1 through year 10 | 25.7 nanograms per milliliter (ng/mL) | Standard Error 5.9 |
p-value: 0.065t-test, 2 sided
Secondary
Changes in Liver Function Tests of ALT From Baseline to Post-treatment
Liver function tests Alanine Aminotransferease (ALT)
Time frame: Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 15 mg/Kg Body Weight/Day | Changes in Liver Function Tests of ALT From Baseline to Post-treatment | Baseline | 43.8 units per liter (U/L) | Standard Error 10.5 |
| 15 mg/Kg Body Weight/Day | Changes in Liver Function Tests of ALT From Baseline to Post-treatment | average of available timepoints after year 1 through year 10 | 31.7 units per liter (U/L) | Standard Error 2.2 |
p-value: 0.342t-test, 2 sided