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

An Open Label, Single Center, Nonrandomized Continuation Study of Cholic Acid Capsules to Treat Subjects With Inborn Errors of Bile Acid Synthesis

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01438411

Enrollment

Registered

2011-09-22

Start date

2010-01-31

Completion date

2016-07-31

Last updated

2023-10-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bile Acid Synthesis Defect

Keywords

Cholic Acid, Inborn Error, Bile Acid Metabolism, Inborn Error of Bile Acid Synthesis

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.

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.

Interventions

DRUGCholic Acid

10-15 mg/kg body weight/day supplied in 50 or 250 mg Cholic Acid Capsules

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

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

Countries

United States

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 details

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.

Participants by arm

Arm	Count
Cholic Acid 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	53
Total	53

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	8
Overall Study	Lack of Efficacy	1
Overall Study	Lost to Follow-up	1
Overall Study	Withdrawal by Subject	3

Baseline characteristics

Characteristic	Cholic Acid
Age, Continuous	9 years STANDARD_DEVIATION 9
Race (NIH/OMB) American Indian or Alaska Native	1 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	5 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	22 Participants
Race (NIH/OMB) White	24 Participants
Region of Enrollment Argentina	1 participants
Region of Enrollment Australia	1 participants
Region of Enrollment Canada	1 participants
Region of Enrollment Chile	1 participants
Region of Enrollment Israel	2 participants
Region of Enrollment Italy	1 participants
Region of Enrollment Mexico	1 participants
Region of Enrollment United States	45 participants
Sex: Female, Male Female	23 Participants
Sex: Female, Male Male	30 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	6 / 53
other Total, other adverse events	21 / 53
serious Total, serious adverse events	19 / 53

Outcome results

Primary

Change in Atypical Urinary Bile Acid Excretion by FAB-MS (Fast-Atom-Bombardment Ionization-Mass Spectrometry)

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.