Open Label, Continuation Study of Cholic Acid in Subjects With Inborn Errors of Bile Acid Synthesis

• Sponsor: Travere Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01438411
• Collaborator: (none)
• Enrollment: 53
• Location: 1
• Arm: 1
• Duration (Months): 78
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The primary purpose of the study is to evaluate the therapeutic efficacy and safety of cholic acid in subjects with identified inborn errors of bile acid synthesis.

Condition or Disease	Intervention/Treatment	Phase
Bile Acid Synthesis Defect	Drug: Cholic Acid	Phase 3

Detailed Description

This is a Phase 3, open-label, single center, nonrandomized study. This continuation protocol will consist of eligible subjects who have previously received cholic acid through the Cincinnati Children's Hospital Medical Center (CCHMC) Compassionate Use (91-10-10), CAC-001-01 study protocols and newly diagnosed subjects.

New subjects will be infants, children, adolescents identified from urine samples obtained from the clinical services of programs across the U.S., Canada, South America, Europe, and Asia. Subject or their legal representative will receive information regarding the study, and the principle investigator (PI) or designee will obtain informed consent. Serum and urine samples will be collected and sent to CCHMC to measure complete bile acid profile analysis. Clinical records including medical history, physical exams, vital signs, and laboratory assessments performed as standard of care will be reviewed to ensure subject eligibility and determine baseline values.

Subjects who have participated in Protocols conducted under IND 45,470 will be consented to continue to receive cholic acid capsules under this continuation protocol. Subjects will serve as their own controls and no placebo will be utilized.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Single Center, Nonrandomized Continuation Study of Cholic Acid Capsules to Treat Subjects With Inborn Errors of Bile Acid Synthesis
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: Cholic Acid Active drug	Drug: Cholic Acid; 10-15 mg/kg body weight/day supplied in 50 or 250 mg Cholic Acid Capsules; Other Names: Cholic Cholic Acid Capsules

Outcome Measures

Primary Outcome Measures

1. Change in Atypical Urinary Bile Acid Excretion by FAB-MS (Fast-Atom-Bombardment Ionization-Mass Spectrometry) [At baseline, then every 12 months for an average of 3.5 years]

   The level of atypical urinary bile acid secretion was scored using a scale of: 0, normal; 1, slight; 2, significant; or 3, marked. A Cochran-Mantel-Haenszel (CMH) test with modified ridit scoring was used to compare the difference between the score at baseline and the worst post-baseline score during treatment with cholic acid in this single-arm trial.

Secondary Outcome Measures

1. Evaluation of Serum Transaminases: ALT [At baseline, then every 12 months for an average of 3.5 years]

   Changes in ALT were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: <ULN; ≥1 ULN but <2 ULN; ≥2 ULN but <3 ULN; and ≥3x ULN. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented.

2. Evaluation of Serum Transaminases: AST [At baseline, then every 12 months for an average of 3.5 years]

   Changes in AST were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: <ULN; ≥1 ULN but <2 ULN; ≥2 ULN but <3 ULN; and ≥3x ULN. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented.

3. Clinical Laboratory Results: Bilirubin [At baseline, then every 12 months for an average of 3.5 years]

   Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for bilirubin. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.

4. Clinical Laboratory Results: Gamma Glutamyl Transferase (GGT) [At baseline, then every 12 months for an average of 3.5 years]

   Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for GGT. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.

5. Clinical Laboratory Results: Alkaline Phosphatase [At baseline, then every 12 months for an average of 3.5 years]

   Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for alkaline phosphatase. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.

6. Clinical Laboratory Results: Prothrombin Time [At baseline, then every 12 months for an average of 3.5 years]

   Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for prothrombin time. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.

7. Physical Examinations: Height [At baseline, then every 12 months for an average of 3.5 years]

   Changes in height percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial.

8. Physical Examinations: Body Weight [At baseline, then every 12 months for an average of 3.5 years]

   Changes in body weight percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial.

9. Incidence of Adverse Events [At baseline, then every 12 months for an average of 3.5 years]

   Number (%) of patients with any AE

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Subjects who received cholic acid through CCHMC protocols 91-10-10 or CAC-002-01 and meet the following criteria are eligible for study participation.

1. The subject and/or parent/legal guardian must have provided informed consent prior to study start.

2. The subject must have a diagnosis of an inborn error of bile acid synthesis.

3. The subject must be willing and able to comply with all study assessments and procedures.

4. Subjects with other organ dysfunction will not be excluded

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Travere Therapeutics, Inc.

Investigators

• Principal Investigator: James E 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: NCT01438411
• Other Study ID Numbers: CAC-002-01
• First Posted: Sep 22, 2011
• Last Update Posted: Aug 21, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Travere Therapeutics, Inc.: Cholic Acid; Inborn Error; Bile Acid Metabolism; Inborn Error of Bile Acid Synthesis
• Additional relevant MeSH terms: Cholic Acids

Study Results

Participant Flow

Recruitment Details	This study included subjects with inborn errors of bile acid metabolism who had previously participated in studies CAC-91-10-10 or CAC-001-01 as well as newly diagnosed subjects. Data were collected from 1 Jan 2010 through study completion on 31 Jul 2016. Note that treatment with cholic acid continues throughout a subject's lifetime.
Pre-assignment Detail	Of 53 subjects, 31 subjects rolled over from studies CAC-91-10-10 and/or CAC-001-01, while 22 patients were treatment-naive, i.e. received their first dose of cholic acid during study CAC-002-01.

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Period Title: Overall Study
STARTED	53
COMPLETED	40
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Overall Participants	53
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9 (9)
Sex: Female, Male (Count of Participants)
Female	23 43.4%
Male	30 56.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.9%
Asian	1 1.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 9.4%
White	24 45.3%
More than one race	0 0%
Unknown or Not Reported	22 41.5%
Region of Enrollment (participants) [Number]
United States	45 84.9%
Argentina	1 1.9%
Canada	1 1.9%
Chile	1 1.9%
Israel	2 3.8%
Italy	1 1.9%
Mexico	1 1.9%
Australia	1 1.9%

Outcome Measures

1. Primary Outcome

Title	Change in Atypical Urinary Bile Acid Excretion by FAB-MS (Fast-Atom-Bombardment Ionization-Mass Spectrometry)
Description	The level of atypical urinary bile acid secretion was scored using a scale of: 0, normal; 1, slight; 2, significant; or 3, marked. A Cochran-Mantel-Haenszel (CMH) test with modified ridit scoring was used to compare the difference between the score at baseline and the worst post-baseline score during treatment with cholic acid in this single-arm trial.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	51
Baseline score: normal	25 47.2%
Baseline score: slight	6 11.3%
Baseline score: significant	10 18.9%
Baseline score: marked	10 18.9%
Worst-post-BL score: normal	25 47.2%
Worst-post-BL score: slight	11 20.8%
Worst-post-BL score: significant	6 11.3%
Worst-post-BL score: marked	9 17%

2. Secondary Outcome

Title	Evaluation of Serum Transaminases: ALT
Description	Changes in ALT were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: <ULN; ≥1 ULN but <2 ULN; ≥2 ULN but <3 ULN; and ≥3x ULN. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	48
Baseline: ALT<ULN	27 50.9%
Baseline: ULN<=ALT<2 ULN	9 17%
Baseline: 2 ULN<=ALT<3 ULN	7 13.2%
Baseline: ALT>=3 ULN	5 9.4%
Worst-post-BL value: ALT<ULN	20 37.7%
Worst-post-BL value: ULN<=ALT<2 ULN	15 28.3%
Worst-post-BL value: 2 ULN<=ALT<3 ULN	9 17%
Worst-post-BL value: ALT>=3 ULN	4 7.5%

3. Secondary Outcome

Title	Evaluation of Serum Transaminases: AST
Description	Changes in AST were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: <ULN; ≥1 ULN but <2 ULN; ≥2 ULN but <3 ULN; and ≥3x ULN. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	47
Baseline: AST<ULN	17 32.1%
Baseline: ULN<=AST<2 ULN	17 32.1%
Baseline: 2 ULN<=AST<3 ULN	5 9.4%
Baseline: AST<=3 ULN	8 15.1%
Worst-post-BL value: AST<ULN	15 28.3%
Worst-post-BL value: ULN<=AST<2 ULN	17 32.1%
Worst-post-BL value: 2 ULN<=AST<3 ULN	6 11.3%
Worst-post-BL value: AST<=3 ULN	9 17%

4. Secondary Outcome

Title	Clinical Laboratory Results: Bilirubin
Description	Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for bilirubin. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	48
Baseline	3.678 (1.1427)
Worst-post-BL value	3.785 (1.1464)

5. Secondary Outcome

Title	Clinical Laboratory Results: Gamma Glutamyl Transferase (GGT)
Description	Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for GGT. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	42
Baseline	38.8 (7.13)
Worst-post-BL value	16.4 (8.28)

6. Secondary Outcome

Title	Clinical Laboratory Results: Alkaline Phosphatase
Description	Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for alkaline phosphatase. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	47
Baseline	293.7 (30.30)
Worst-post-BL value	39.6 (17.71)

7. Secondary Outcome

Title	Clinical Laboratory Results: Prothrombin Time
Description	Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial for prothrombin time. Changes from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial were presented in terms of descriptive statistics.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	46
Baseline	17.977 (2.1338)
Worst-post-BL value	1.045 (2.1442)

8. Secondary Outcome

Title	Physical Examinations: Height
Description	Changes in height percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	41
Baseline	26.767 (4.4448)
Worst-post-BL value	25.540 (4.1064)

9. Secondary Outcome

Title	Physical Examinations: Body Weight
Description	Changes in body weight percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial.
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

Patients with values

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	48
Baseline	38.030 (5.2853)
Worst-post-BL value	33.227 (4.9842)

10. Secondary Outcome

Title	Incidence of Adverse Events
Description	Number (%) of patients with any AE
Time Frame	At baseline, then every 12 months for an average of 3.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cholic Acid
Arm/Group Description	Cholic acid capsules, each containing 50 mg or 250 mg of cholic acid to be administered orally at a daily dose of 10-15 mg/kg body weight
Measure Participants	53
Count of Participants [Participants]	44 83%

Adverse Events

Time Frame	Subjects underwent assessments at baseline and every 12 months or when clinically indicated. Treatment with cholic acid will continue throughout a subject's lifetime. CAC-002-01 study reports data collected from 1 January 2010 until study completion on 31 July 2016, approximately 6.5 years.
Arm/Group Title	Cholic Acid
Arm/Group Description	Active drug Cholic Acid: 10-15 mg/kg body weight/day supplied in 50 or 250 mg Cholic Acid Capsules
All Cause Mortality
	Cholic Acid
	Affected / at Risk (%)	# Events
Total	6/53 (11.3%)
Serious Adverse Events
	Cholic Acid
	Affected / at Risk (%)	# Events
Total	19/53 (35.8%)
Blood and lymphatic system disorders
Coagulopathy	3/53 (5.7%)	3
Cardiac disorders
Bradykardia	1/53 (1.9%)	1
Cardiac arrest	1/53 (1.9%)	1
Gastrointestinal disorders
Abdominal distension	1/53 (1.9%)	1
Gastric ulcer	1/53 (1.9%)	1
General disorders
Disease progression	5/53 (9.4%)	6
Pyrexia	1/53 (1.9%)	1
Hepatobiliary disorders
Hepatic artery thrombosis	1/53 (1.9%)	1
Hepatic failure	1/53 (1.9%)	1
Hyperbilirubinaemia	1/53 (1.9%)	2
Infections and infestations
Bacteraemia	1/53 (1.9%)	1
Ear infection	1/53 (1.9%)	1
Gastroenteritis viral	1/53 (1.9%)	1
Influenza	2/53 (3.8%)	2
Pneumonia	3/53 (5.7%)	3
Sepsis	1/53 (1.9%)	1
Upper respiratory tract infection	1/53 (1.9%)	1
Injury, poisoning and procedural complications
Fracture	2/53 (3.8%)	2
Metabolism and nutrition disorders
Dehydration	1/53 (1.9%)	2
Hypoalbuminaemia	1/53 (1.9%)	1
Hypokalaemia	1/53 (1.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oesophageal carcinoma	1/53 (1.9%)	1
Nervous system disorders
Encephalopathy	2/53 (3.8%)	2
Mental impairment	1/53 (1.9%)	1
Somnolence	1/53 (1.9%)	1
Psychiatric disorders
Completed suicide	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/53 (1.9%)	1
Respiratory distress	1/53 (1.9%)	1
Respiratory failure	2/53 (3.8%)	2
Surgical and medical procedures
Adenoidectomy	1/53 (1.9%)	1
Orchidopexy	1/53 (1.9%)	1
Vascular disorders
Thrombosis	1/53 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Cholic Acid
	Affected / at Risk (%)	# Events
Total	21/53 (39.6%)
Gastrointestinal disorders
Abdominal pain	6/53 (11.3%)	8
Diarrhoea	6/53 (11.3%)	7
Infections and infestations
Nasopharyngitis	4/53 (7.5%)	4
Upper respiratory tract infection	8/53 (15.1%)	8
Investigations
Hepatic enzyme increased	4/53 (7.5%)	6
Vitamin D decreased	6/53 (11.3%)	6
Musculoskeletal and connective tissue disorders
Arthralgia	3/53 (5.7%)	3

Limitations/Caveats

[Not Specified]

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.