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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GlycoCholic Acid, Study Drug | Experimental | An open label, single arm, non-randomized, non-comparative, treatment study of Glycocholic Acid in the treatment of defects of bile acid metabolism. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glycocholic Acid | Drug | 10-15mg/kg body weight/day taken orally. Supplied as either liquid or 50mg capsules. |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria
1. No confirmed diagnosis of inborn error of bile acid synthesis/conjugation based upon urine analysis by FAB-MS.
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| Name | Affiliation | Role |
|---|---|---|
| Kenneth D. Setchell, Ph.D. | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| James E. Heubi, M.D. | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23415802 | Result | 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. | |
| 25163551 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Glycocholic Acid | 15 milligrams/kilograms (mg/kg) of body weight/day (bw/day) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Glycocholic Acid | 15 milligrams/kilograms (mg/kg) of body weight/day (bw/day) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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)) | Posted | Count of Participants | Participants | Up to 10 years |
|
|
Adverse events were assessed while patients were receiving investigational agent; up to 10 years.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Glycocholic Acid | 15 mg/kg bw/day | 0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ken Setchell, PhD | Cincinnati Children's Hospital Medical Center | 5136364548 | kenneth.setchell@cchmc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 31, 2018 | Apr 19, 2022 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 31, 2018 | Apr 19, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D006000 | Glycocholic Acid |
| ID | Term |
|---|---|
| D002793 | Cholic Acids |
| D001647 | Bile Acids and Salts |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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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) |
| 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. |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| 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). | Posted | Median | Full Range | score on a scale | Average of 6 months, average 12 months, and average of after year 1 to 10 years |
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| Secondary | Changes in Liver Function Tests of ALT From Baseline to Post-treatment | Liver function tests Alanine Aminotransferease (ALT) | Posted | Mean | Standard Error | units per liter (U/L) | Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10) |
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| Secondary | Change in Liver Function Test: AST From Baseline to Post-treatment | Measure of Aspartate Aminotransferase (AST) | Posted | Median | Standard Error | units per liter (U/L) | Comparison between baseline and post-treatment (average of available timepoints after year 1 through year 10) |
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| Secondary | Change in Vitamin D, 25-OH Measure From Baseline to Post-treatment | Measure Vitamin D levels nanograms per milliliter (ng/mL) | Missing data on Vitamin D from 2 participants. | Posted | Mean | Standard Error | nanograms per milliliter (ng/mL) | Pre-treatment and post treatment (average of available timepoints after year 1 through year 10) |
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| D011083 |
| Polycyclic Compounds |
| D002757 | Cholanes |
| D034442 | N-substituted Glycines |
| D005998 | Glycine |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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| average of year 1 to 10 |
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