Compassionate Treatment of Patients With Inborn Errors of Bile Acid Metabolism With Cholic Acid

Investigation in the Pathogenesis of Liver Disease in Patients With Inborn Errors of Bile Acid Metabolism

OBJECTIVES:

I. To Evaluate the therapeutic efficacy of cholic acid during provision of compassionate treatment to patients with identified inborn errors of bile acid synthesis and metabolism

II. To assess the safety and tolerability of cholic acid

Study Overview

• Status: Completed
• Conditions: Cholestasis; Peroxisomal Disorders; Adrenoleukodystrophy; Zellweger Syndrome; Infantile Refsum's Disease
• Intervention / Treatment: Drug: Cholic Acids

Detailed Description

Investigational Plan:

A Phase III, open label, single arm, nonrandomized, non-comparative, compassionate treatment study of cholic acid in the treatment of defects of bile acid metabolism.

The study was begun with a single study site at Cincinnati Children's Hospital Medical Center (CCHMC), but in 2005 was expanded so that compassionate treatment could be provided to additional patients who had been identified with inborn errors of bile metabolism through the center's screening/diagnostic program.

Patients who were screened were contacted and evaluated with respect to the inclusion/exclusion criteria. Signed informed consent by the patient and/or parents/legal guardian was obtained as soon as it is confirmed that the patient met inclusion/exclusion criteria and the parents/guardian would agree for the child to participate in the study.

The primary interventions for the study were:

1. Administration of study drug.
2. Collection of baseline physical exam, vital signs, blood and urine samples for laboratory tests.
3. Collection of periodic physical exam, vital signs, blood and urine samples for laboratory tests during the period of administration of the study drug.
4. Collection of any adverse event information.

Time and Events Schedule:

Baseline:

1. Confirm eligibility
2. Obtain written informed consent from patient and/or parents/legal guardian

3. Collect demographic data and disease and medication history, including family history

   Baseline and Ongoing:

4. Obtain body weight
5. Record adverse events
6. Obtain blood and urine samples for laboratory tests
7. Initiate study drug therapy & monitor study drug therapy and adjust dose as needed

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Clinical or biochemical evidence of liver disease, unexplained fat-soluble vitamin malabsorption, or peroxisomal dysfunction that compromises bile acid biosynthesis

Inclusion criteria for enrollment were:

• Infants < age 3 months
• Children presenting for evaluation of cholestasis defined as a conjugated bilirubin > 2mg/dl or increased serum bile acids
• Older subjects of any age with cholestatic liver disease if urine screens suggested that they had inborn errors of bile acid metabolism
• Confirmation of a diagnosis of an inborn error of bile acid synthesis based upon urine analysis by FAB-MS to determine whether specific abnormalities in bile acid synthesis are indicated
• The patient and/or parent/legal guardian must have signed the written informed consent document before study start.
• The patient must be willing and able to comply with all study assessments and procedures.

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
Other: Cholic Acid	Drug: Cholic Acids; 10-15 mg/kg body weight/day taken orally.; Other Names: Cholic; Cholic Acid; Cholic Acid Capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Excretion of Atypical Bile Acids in Urine by Category	Patients with excretion of atypical bile acids in urine by category, from worst status before treatment (baseline, BL) to best status on treatment (OT)	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Liver Function Tests (LFTs) Measured in Serum	Patients with elevations of liver function tests (alanine transaminase [ALT], aspartate transaminase [AST]) measured as multiples of the upper limit of normal (ULN) at baseline (worst value) and on treatment (best value)	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Liver Histology	Patients (number, percentage) with pathological findings for qualitative (the presence of inflammation, fibrosis, necrosis, giant cells and cholestasis) and quantitative (the degrees of the aforementioned histologic features) liver histopathology at baseline (BL) and on treatment (OT).	At baseline (if no historical data were available) and between 1 and 6 months following treatment start.
Height and Weight	Change in height/weight percentiles from baseline (worst value) to the best on-treatment value, based on CDC (Centres for Disease Control and Prevention, US) growth chart percentiles	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Adverse Events	Number of patients with any adverse event	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Bilirubin Measured in Serum	Bilirubin concentration in serum at baseline and on treatment	Baseline and on treatment (every 1, 3, or 6 months, depending on protocol version, for an average of 2.8 years)

Collaborators and Investigators

• Sponsor: Mirum Pharmaceuticals, Inc.
• Collaborators: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: James Heubi, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Kenneth Setchell, PhD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Heubi JE, Bove KE, Setchell KDR. Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders. J Pediatr Gastroenterol Nutr. 2017 Sep;65(3):321-326. doi: 10.1097/MPG.0000000000001657.

Study record dates

Study Major Dates

• Study Start: January 1, 1992
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: December 6, 2000
• First Submitted That Met QC Criteria: December 6, 2000
• First Posted (Estimated): December 7, 2000

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: September 29, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Kidney Diseases; Urologic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Congenital Abnormalities; Liver Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Biliary Tract Diseases; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Nervous System Malformations; Abnormalities, Multiple; Leukoencephalopathies; Bile Duct Diseases; Adrenal Gland Diseases; Polyneuropathies; Hereditary Central Nervous System Demyelinating Diseases; Adrenal Insufficiency; Hereditary Sensory and Motor Neuropathy; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cholestasis; Peroxisomal Disorders; Adrenoleukodystrophy; Refsum Disease; Zellweger Syndrome; Refsum Disease, Infantile; Gastrointestinal Agents; Cholic Acids
• Other Study ID Numbers: CAC-91-10-10; CCHMC-91-10-10 (Other Identifier: Cincinnati Children's Hospital Medical Center); NCRR-M01RR08084-0009 (Other Identifier: National Center For Research Resources (NCRR))