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

• Sponsor: Travere Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00007020
• Collaborator: Children's Hospital Medical Center, Cincinnati (Other)
• Enrollment: 85
• Location: 1
• Arm: 1
• Duration (Months): 215
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

OBJECTIVES:

1. 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

2. To assess the safety and tolerability of cholic acid

Condition or Disease	Intervention/Treatment	Phase
Infantile Refsum's Disease; Zellweger Syndrome; Adrenoleukodystrophy; Peroxisomal Disorders; Cholestasis	Drug: Cholic Acids	Phase 3

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:

1. Obtain body weight

2. Record adverse events

3. Obtain blood and urine samples for laboratory tests

4. Initiate study drug therapy & monitor study drug therapy and adjust dose as needed

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Investigation in the Pathogenesis of Liver Disease in Patients With Inborn Errors of Bile Acid Metabolism
• Study Start Date: Jan 1, 1992
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Excretion of Atypical Bile Acids in Urine by Category [Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years]

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

Secondary Outcome Measures

1. Change in Liver Function Tests (LFTs) Measured in Serum [Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years]

   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)

2. Liver Histology [At baseline (if no historical data were available) and between 1 and 6 months following treatment start.]

   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).

3. Height and Weight [Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years]

   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

4. Adverse Events [Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years]

   Number of patients with any adverse event

Other Outcome Measures

1. Change in Bilirubin Measured in Serum [Baseline and on treatment (every 1, 3, or 6 months, depending on protocol version, for an average of 2.8 years)]

   Bilirubin concentration in serum at baseline and on treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039

Sponsors and Collaborators

• Travere Therapeutics, Inc.
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Travere Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT00007020
• Other Study ID Numbers: CAC-91-10-10; CCHMC-91-10-10; NCRR-M01RR08084-0009
• First Posted: Dec 7, 2000
• Last Update Posted: Oct 5, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Cholestasis; Zellweger Syndrome; Adrenoleukodystrophy; Refsum Disease; Refsum Disease, Infantile; Peroxisomal Disorders; Cholic Acids

Study Results

Participant Flow

Recruitment Details	A total of 85 patients were enrolled.
Pre-assignment Detail	Of the patients diagnosed with a defect in bile acid synthesis during routine diagnostic procedures at the Cincinnati Children's Hospital Medical Center (CCHMC) Mass Spectrometry Laboratory, 85 patients were invited to participate in the study.

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 250 mg of cholic acid, or a liquid preparation of 15 mg/mL cholic acid, to be administered orally in a dose of 15 mg/kg body weight/day.
Period Title: Overall Study
STARTED	85
COMPLETED	41
NOT COMPLETED	44

Baseline Characteristics

Arm/Group Title	Cholic Acid
Arm/Group Description	All patients entered into the study
Overall Participants	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3 (4)
Sex: Female, Male (Count of Participants)
Female	31 36.5%
Male	50 58.8%
Region of Enrollment (Count of Participants)
United States	85 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients treated and with at least 1 pre-treatment and 1 post-treatment assessment

Arm/Group Title	Cholic Acid
Arm/Group Description	Patients treated
Measure Participants	70
Baseline, no atypical bile acid excretion	10 11.8%
On treatment, no atypical bile acid excretion	51 60%
Baseline, slight atypical bile acid excretion	11 12.9%
On treatment, slight atypical bile acid excretion	9 10.6%
Baseline, significant atypical bile acid excretion	16 18.8%
OT, significant atypical bile acid excretion	4 4.7%
Baseline, marked atypical bile acid excretion	33 38.8%
On treatment, marked atypical bile acid excretion	6 7.1%

2. Secondary Outcome

Title	Change in Liver Function Tests (LFTs) Measured in Serum
Description	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)
Time Frame	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years

Outcome Measure Data

Analysis Population Description

Patients treated and with at least 1 pre-treatment and 1 post-Treatment assessment

Arm/Group Title	Cholic Acid
Arm/Group Description	Patients treated
Measure Participants	70
Baseline, ALT <ULN	14 16.5%
On treatment, ALT <ULN	49 57.6%
Baseline, ULN ≤ ALT <2 x ULN	16 18.8%
On treatment, ULN ≤ ALT <2 x ULN	13 15.3%
Baseline, 2 ULN ≤ ALT <3 x ULN	8 9.4%
On treatment, 2 ULN ≤ ALT <3 x ULN	2 2.4%
Baseline, ALT ≥3 x ULN	29 34.1%
On treatment, ALT ≥3 x ULN	3 3.5%
Baseline, AST <ULN	9 10.6%
On treatment, AST <ULN	38 44.7%
Baseline, ULN ≤ AST <2 x ULN	14 16.5%
On treatment, ULN ≤ AST <2 x ULN	15 17.6%
Baseline, 2 ULN ≤ AST <3 x ULN	7 8.2%
On treatment, 2 ULN ≤ AST <3 x ULN	4 4.7%
Baseline, AST ≥3 x ULN	35 41.2%
On treatment, AST ≥3 x ULN	9 10.6%

3. Secondary Outcome

Title	Liver Histology
Description	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).
Time Frame	At baseline (if no historical data were available) and between 1 and 6 months following treatment start.

Outcome Measure Data

Analysis Population Description

All patients entered into the study

Arm/Group Title	Cholic Acid
Arm/Group Description	All patients entered into the study
Measure Participants	85
Periportal inflammation at BL, qualitative	19 22.4%
Periportal inflammation OT, qualitative	16 18.8%
Lobular inflammation at BL, qualitative	5 5.9%
Lobular inflammation OT, qualitative	4 4.7%
Inflammation (not spec.) at BL, qualitative	3 3.5%
Inflammation (not spec.) OT, qualitative	0 0%
Bridging fibrosis at BL, qualitative	25 29.4%
Bridging fibrosis OT, qualitative	31 36.5%
Fibrosis (not specified) at BL, qualitative	6 7.1%
Fibrosis (not specified) OT, qualitative	6 7.1%
Cholestasis at BL, qualitative	20 23.5%
Cholestasis OT, qualitative	10 11.8%
Giant cells at BL, qualitative	18 21.2%
Giant cells OT, qualitative	12 14.1%
Necrosis at BL, qualitative	14 16.5%
Necrosis OT, qualitative	2 2.4%
Periportal inflammation at BL, quantitative	18 21.2%
Periportal inflammation OT, quantitative	15 17.6%
Lobular inflammation at BL, quantitative	5 5.9%
Lobular inflammation OT, quantitative	4 4.7%
Inflammation (not specified) at BL, quantitative	3 3.5%
Inflammation (not specified) OT, quantitative	0 0%
Bridging fibrosis at baseline, quantitative	22 25.9%
Bridging fibrosis OT, quantitative	27 31.8%
Fibrosis (not specified) at BL, quantitative	3 3.5%
Fibrosis (not specified) OT, quantitative	5 5.9%
Cholestasis at BL, quantitative	15 17.6%
Cholestasis OT, quantitative	7 8.2%
Giant cells at BL, quantitative	13 15.3%
Giant cells OT, quantitative	9 10.6%
Necrosis at BL, quantitative	13 15.3%
Necrosis OT, quantitative	2 2.4%

4. Secondary Outcome

Title	Height and Weight
Description	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
Time Frame	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years

Outcome Measure Data

Analysis Population Description

Patients treated and with at least 1 pre-treatment and 1 post-treatment assessment

Arm/Group Title	Cholic Acid
Arm/Group Description	Patients treated
Measure Participants	70
Height percentile, baseline	30.1 (5.5)
Height percentile, on treatment	44.0 (6.1)
Weight percentile, baseline	21.3 (3.7)
Weight percentile, on treatment	42.3 (4.8)

5. Secondary Outcome

Title	Adverse Events
Description	Number of patients with any adverse event
Time Frame	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years

Outcome Measure Data

Analysis Population Description

Patients entered into the study and treated

Arm/Group Title	Cholic Acid
Arm/Group Description	All patients entered into the study and treated
Measure Participants	79
Patients at risk	79 92.9%
Patients with any AE	38 44.7%

6. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

All available bilirubin laboratory data are collected then grouped by bilirubin test type and collection time points (baseline vs. on treatment). Not all participant had available data, and each participant may have more than one type of bilirubin collected at a time point, and may have multiple on-treatment collections.

Arm/Group Title	Cholic Acid
Arm/Group Description	All patients entered into the study
Measure Participants	60
Measure Number of Test Results	689
Baseline, bilirubin	0.3
On treatment, bilirubin	0.6 (0.5)
Baseline, direct bilirubin	2.2 (5.6)
On treatment, direct bilirubin	0.5 (1.8)
Baseline, indirect bilirubin	0.5 (0.9)
On treatment, indirect bilirubin	0.2 (0.2)
Baseline, total bilirubin	2.8 (10.6)
On treatment, total bilirubin	1.5 (5.2)

Adverse Events

Time Frame	Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Arm/Group Title	Cholic Acid
Arm/Group Description	All patients entered into the study and treated with Cholic Acid. 85 patients enrolled in the study and 79 received treatment (safety set).
All Cause Mortality
	Cholic Acid
	Affected / at Risk (%)	# Events
Total	13/79 (16.5%)
Serious Adverse Events
	Cholic Acid
	Affected / at Risk (%)	# Events
Total	20/79 (25.3%)
Blood and lymphatic system disorders
Coagulopathy	1/79 (1.3%)	1
Gastrointestinal disorders
Diarrhoea	2/79 (2.5%)	2
Gastric ulcer	1/79 (1.3%)	1
Gastrointestinal haemorrhage	1/79 (1.3%)	2
Pneumoperitoneum	1/79 (1.3%)	1
General disorders
Disease progression	7/79 (8.9%)	7
Hepatobiliary disorders
Jaundice	1/79 (1.3%)	1
Infections and infestations
Gastroenteritis	1/79 (1.3%)	1
Gastroenteritis viral	1/79 (1.3%)	2
Infection	1/79 (1.3%)	1
Nasopharyngitis	1/79 (1.3%)	1
Rotavirus infection	1/79 (1.3%)	1
Urinary tract infection	2/79 (2.5%)	2
Investigations
Nutritional condition abnormal	1/79 (1.3%)	1
Metabolism and nutrition disorders
Dehydration	2/79 (2.5%)	2
Nervous system disorders
Convulsion	1/79 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/79 (1.3%)	1
Respiratory disorder	1/79 (1.3%)	1
Respiratory distress	1/79 (1.3%)	2
Other (Not Including Serious) Adverse Events
	Cholic Acid
	Affected / at Risk (%)	# Events
Total	35/79 (44.3%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/79 (1.3%)	1
Gastrointestinal disorders
Abdominal discomfort	1/79 (1.3%)	1
Abdominal pain	2/79 (2.5%)	2
Anal fistula	1/79 (1.3%)	1
Ascites	2/79 (2.5%)	2
Constipation	2/79 (2.5%)	2
Diarrhoea	4/79 (5.1%)	4
Enteritis	1/79 (1.3%)	1
Gastrointestinal haemorrhage	1/79 (1.3%)	1
Inguinal hernia	1/79 (1.3%)	1
Vomiting	1/79 (1.3%)	1
General disorders
Disease progression	1/79 (1.3%)	1
Injection site inflammation	1/79 (1.3%)	1
Malaise	1/79 (1.3%)	1
Pyrexia	7/79 (8.9%)	7
Hepatobiliary disorders
Cholelithiasis	1/79 (1.3%)	1
Cholestasis	1/79 (1.3%)	1
Jaundice	1/79 (1.3%)	1
Portal hypertension	1/79 (1.3%)	1
Infections and infestations
Bronchopneumonia	2/79 (2.5%)	2
Ear infection	1/79 (1.3%)	1
Gastroenteritis viral	2/79 (2.5%)	2
Otitis media	2/79 (2.5%)	2
Pneumonia	1/79 (1.3%)	1
Respiratory tract infection	1/79 (1.3%)	1
Upper respiratory tract infection	5/79 (6.3%)	5
Varicella	1/79 (1.3%)	1
Injury, poisoning and procedural complications
Contusion	1/79 (1.3%)	1
Fracture	4/79 (5.1%)	6
Investigations
Amino acid level increased	1/79 (1.3%)	1
Occult blood	1/79 (1.3%)	1
Weight decreased	1/79 (1.3%)	1
Metabolism and nutrition disorders
Decreased appetite	1/79 (1.3%)	1
Dehydration	1/79 (1.3%)	1
Iron deficiency	1/79 (1.3%)	1
Malnutrition	1/79 (1.3%)	1
Vitamin D deficiency	1/79 (1.3%)	1
Vitamin E deficiency	2/79 (2.5%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/79 (1.3%)	1
Scoliosis	1/79 (1.3%)	1
Nervous system disorders
Convulsion	4/79 (5.1%)	6
Hypotonia	1/79 (1.3%)	1
Lethargy	3/79 (3.8%)	3
Psychiatric disorders
Hallucination	1/79 (1.3%)	1
Reproductive system and breast disorders
Ovarian cyst	1/79 (1.3%)	1
Ovarian failure	1/79 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
Apnoea	1/79 (1.3%)	1
Cough	2/79 (2.5%)	2
Epistaxis	2/79 (2.5%)	2
Nasal congestion	1/79 (1.3%)	1
Pulmonary congestion	1/79 (1.3%)	1
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/79 (1.3%)	1
Rash	1/79 (1.3%)	1

Limitations/Caveats

CAC-91-10-10 includes data from patients enrolled from 1992-2009. The study end date was arbitrarily chosen as data cut-off point; the disease requires life-long treatment, no final study visit was done. Many patients continued onto study CAC-002-01

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.