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

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: Administration of study drug. Collection of baseline physical exam, vital signs, blood and urine samples for laboratory tests. Collection of periodic physical exam, vital signs, blood and urine samples for laboratory tests during the period of administration of the study drug. Collection of any adverse event information. Time and Events Schedule: Baseline: Confirm eligibility Obtain written informed consent from patient and/or parents/legal guardian Collect demographic data and disease and medication history, including family history Baseline and Ongoing: Obtain body weight Record adverse events Obtain blood and urine samples for laboratory tests Initiate study drug therapy & monitor study drug therapy and adjust dose as needed

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

Patients with excretion of atypical bile acids in urine by category, from worst status before treatment (baseline, BL) to best status on treatment (OT)

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)

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.

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 and on treatment (every 1, 3, or 6 months, depending on protocol version, for an average of 2.8 years)

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.

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.