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

• Change in Liver Function Test (serum transaminases) [ Time Frame: Standard of Care ] [ Designated as safety issue: No ]
• Change in Liver Histology (for patients in whom biopsy was performed) [ Time Frame: Standard of Care ] [ Designated as safety issue: No ]
• Safety Assessments (Incidence and Severity of Adverse Events) [ Time Frame: Each visit as standard of care ] [ Designated as safety issue: Yes ]
• Height and Weight [ Time Frame: Standard of Care ] [ Designated as safety issue: No ]

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

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

• Infantile Refsum's Disease
• Zellweger Syndrome
• Adrenoleukodystrophy
• Peroxisomal Disorders
• Cholestasis

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.