Title

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
  • Phase

    Phase 3
  • Study Type

    Interventional
  • Study Participants

    85
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
Study Started
Jan 31
1992
Primary Completion
Dec 31
2009
Study Completion
Dec 31
2009
Results Posted
Jul 15
2020
Last Update
Oct 05
2020

Drug Cholic Acids

10-15 mg/kg body weight/day taken orally.

  • Other names: Cholic, Cholic Acid, Cholic Acid Capsules

Cholic Acid Other

Criteria

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.

Summary

Cholic Acid

All Events

Event Type Organ System Event Term Cholic Acid

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)

Cholic Acid

Baseline, marked atypical bile acid excretion

Baseline, no atypical bile acid excretion

Baseline, significant atypical bile acid excretion

Baseline, slight atypical bile acid excretion

On treatment, marked atypical bile acid excretion

On treatment, no atypical bile acid excretion

On treatment, slight atypical bile acid excretion

OT, significant atypical bile acid excretion

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)

Cholic Acid

Baseline, 2 ULN ≤ ALT <3 x ULN

Baseline, 2 ULN ≤ AST <3 x ULN

Baseline, ALT ≥3 x ULN

Baseline, ALT <ULN

Baseline, AST ≥3 x ULN

Baseline, AST <ULN

Baseline, ULN ≤ ALT <2 x ULN

Baseline, ULN ≤ AST <2 x ULN

On treatment, 2 ULN ≤ ALT <3 x ULN

On treatment, 2 ULN ≤ AST <3 x ULN

On treatment, ALT ≥3 x ULN

On treatment, ALT <ULN

On treatment, AST ≥3 x ULN

On treatment, AST <ULN

On treatment, ULN ≤ ALT <2 x ULN

On treatment, ULN ≤ AST <2 x ULN

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).

Cholic Acid

Bridging fibrosis at baseline, quantitative

Bridging fibrosis at BL, qualitative

Bridging fibrosis OT, qualitative

Bridging fibrosis OT, quantitative

Cholestasis at BL, qualitative

Cholestasis at BL, quantitative

Cholestasis OT, qualitative

Cholestasis OT, quantitative

Fibrosis (not specified) at BL, qualitative

Fibrosis (not specified) at BL, quantitative

Fibrosis (not specified) OT, qualitative

Fibrosis (not specified) OT, quantitative

Giant cells at BL, qualitative

Giant cells at BL, quantitative

Giant cells OT, qualitative

Giant cells OT, quantitative

Inflammation (not spec.) at BL, qualitative

Inflammation (not specified) at BL, quantitative

Inflammation (not specified) OT, quantitative

Inflammation (not spec.) OT, qualitative

Lobular inflammation at BL, qualitative

Lobular inflammation at BL, quantitative

Lobular inflammation OT, qualitative

Lobular inflammation OT, quantitative

Necrosis at BL, qualitative

Necrosis at BL, quantitative

Necrosis OT, qualitative

Necrosis OT, quantitative

Periportal inflammation at BL, qualitative

Periportal inflammation at BL, quantitative

Periportal inflammation OT, qualitative

Periportal inflammation OT, quantitative

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

Cholic Acid

Height percentile, baseline

30.1
Percentile (Mean)
Standard Error: 5.5

Height percentile, on treatment

44.0
Percentile (Mean)
Standard Error: 6.1

Weight percentile, baseline

21.3
Percentile (Mean)
Standard Error: 3.7

Weight percentile, on treatment

42.3
Percentile (Mean)
Standard Error: 4.8

Adverse Events

Number of patients with any adverse event

Cholic Acid

Patients at risk

Patients with any AE

Change in Bilirubin Measured in Serum

Bilirubin concentration in serum at baseline and on treatment

Cholic Acid

Baseline, bilirubin

0.3
mg/dL (Mean)
Standard Deviation: None

Baseline, direct bilirubin

2.2
mg/dL (Mean)
Standard Deviation: 5.6

Baseline, indirect bilirubin

0.5
mg/dL (Mean)
Standard Deviation: 0.9

Baseline, total bilirubin

2.8
mg/dL (Mean)
Standard Deviation: 10.6

On treatment, bilirubin

0.6
mg/dL (Mean)
Standard Deviation: 0.5

On treatment, direct bilirubin

0.5
mg/dL (Mean)
Standard Deviation: 1.8

On treatment, indirect bilirubin

0.2
mg/dL (Mean)
Standard Deviation: 0.2

On treatment, total bilirubin

1.5
mg/dL (Mean)
Standard Deviation: 5.2

Age, Continuous

3
years (Mean)
Standard Deviation: 4

Region of Enrollment

Sex: Female, Male

Overall Study

Cholic Acid

Drop/Withdrawal Reasons

Cholic Acid