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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cholic Acid | Other | Active drug |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cholic Acid | Drug | 10-15 mg/kg body weight/day supplied in 50 or 250 mg Cholic Acid Capsules |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | At baseline, then every 12 months for an average of 3.5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluation of Serum Transaminases: ALT | Changes in ALT were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: \ | At baseline, then every 12 months for an average of 3.5 years |
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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.
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| Name | Affiliation | Role |
|---|---|---|
| James E Heubi, MD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Kenneth Setchell, PhD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31899729 | Derived | Heubi JE, Setchell KDR. Open-label Phase 3 Continuation Study of Cholic Acid in Patients With Inborn Errors of Bile Acid Synthesis. J Pediatr Gastroenterol Nutr. 2020 Apr;70(4):423-429. doi: 10.1097/MPG.0000000000002618. |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Patients with values | Posted | Count of Participants | Participants | At baseline, then every 12 months for an average of 3.5 years |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cholic Acid | Active drug Cholic Acid: 10-15 mg/kg body weight/day supplied in 50 or 250 mg Cholic Acid Capsules |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Coagulopathy | Blood and lymphatic system disorders | MedDRA 11.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Retrophin Medical Information | Retrophin, Inc. | 1-877-659 | 5518 | medinfo@retrophin.com |
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| ID | Term |
|---|---|
| D019826 | Cholic Acid |
| ID | Term |
|---|---|
| D002793 | Cholic Acids |
| D001647 | Bile Acids and Salts |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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| Evaluation of Serum Transaminases: AST | Changes in AST were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: \ | At baseline, then every 12 months for an average of 3.5 years |
| Clinical Laboratory Results: Bilirubin | 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. | At baseline, then every 12 months for an average of 3.5 years |
| Clinical Laboratory Results: Gamma Glutamyl Transferase (GGT) | 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. | At baseline, then every 12 months for an average of 3.5 years |
| Clinical Laboratory Results: Alkaline Phosphatase | 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. | At baseline, then every 12 months for an average of 3.5 years |
| Clinical Laboratory Results: Prothrombin Time | 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. | At baseline, then every 12 months for an average of 3.5 years |
| Physical Examinations: Height | Changes in height percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial. | At baseline, then every 12 months for an average of 3.5 years |
| Physical Examinations: Body Weight | Changes in body weight percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial. | At baseline, then every 12 months for an average of 3.5 years |
| Incidence of Adverse Events | Number (%) of patients with any AE | At baseline, then every 12 months for an average of 3.5 years |
| Withdrawal by Subject |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Evaluation of Serum Transaminases: ALT | Changes in ALT were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: \ | Patients with values | Posted | Count of Participants | Participants | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Evaluation of Serum Transaminases: AST | Changes in AST were evaluated in terms of elevations above the upper limit of normal (ULN) and were categorized as: \ | Patients with values | Posted | Count of Participants | Participants | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Clinical Laboratory Results: Bilirubin | 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. | Patients with values | Posted | Mean | Standard Error | mg/dL | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Clinical Laboratory Results: Gamma Glutamyl Transferase (GGT) | 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. | Patients with values | Posted | Mean | Standard Error | U/L | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Clinical Laboratory Results: Alkaline Phosphatase | 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. | Patients with values | Posted | Mean | Standard Error | U/L | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Clinical Laboratory Results: Prothrombin Time | 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. | Patients with values | Posted | Mean | Standard Error | sec | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Physical Examinations: Height | Changes in height percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial. | Patients with values | Posted | Mean | Standard Error | Height percentiles | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Physical Examinations: Body Weight | Changes in body weight percentiles from baseline to the worst post-baseline value during treatment with cholic acid in this single-arm trial. | Patients with values | Posted | Mean | Standard Error | Body weight percentiles | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| Secondary | Incidence of Adverse Events | Number (%) of patients with any AE | Posted | Count of Participants | Participants | At baseline, then every 12 months for an average of 3.5 years |
|
|
|
| 6 |
| 53 |
| 19 |
| 53 |
| 21 |
| 53 |
| Bradykardia | Cardiac disorders | MedDRA 11.0 | Systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | MedDRA 11.0 | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Gastric ulcer | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Disease progression | General disorders | MedDRA 11.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 11.0 | Systematic Assessment |
|
| Hepatic artery thrombosis | Hepatobiliary disorders | MedDRA 11.0 | Systematic Assessment |
|
| Hepatic failure | Hepatobiliary disorders | MedDRA 11.0 | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 11.0 | Systematic Assessment |
|
| Bacteraemia | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Ear infection | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Fracture | Injury, poisoning and procedural complications | MedDRA 11.0 | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 11.0 | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA 11.0 | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 11.0 | Systematic Assessment |
|
| Oesophageal carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 11.0 | Systematic Assessment |
|
| Encephalopathy | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
|
| Mental impairment | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
|
| Completed suicide | Psychiatric disorders | MedDRA 11.0 | Systematic Assessment |
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| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Adenoidectomy | Surgical and medical procedures | MedDRA 11.0 | Systematic Assessment |
|
| Orchidopexy | Surgical and medical procedures | MedDRA 11.0 | Systematic Assessment |
|
| Thrombosis | Vascular disorders | MedDRA 11.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
|
| Hepatic enzyme increased | Investigations | MedDRA 11.0 | Systematic Assessment |
|
| Vitamin D decreased | Investigations | MedDRA 11.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 11.0 | Systematic Assessment |
|
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| D011083 |
| Polycyclic Compounds |
| D002757 | Cholanes |
| Title | Measurements |
|---|---|
|
| Baseline: ALT>=3 ULN |
|
| Worst-post-BL value: ALT<ULN |
|
| Worst-post-BL value: ULN<=ALT<2 ULN |
|
| Worst-post-BL value: 2 ULN<=ALT<3 ULN |
|
| Worst-post-BL value: ALT>=3 ULN |
|
| Title | Measurements |
|---|---|
|
| Baseline: AST<=3 ULN |
|
| Worst-post-BL value: AST<ULN |
|
| Worst-post-BL value: ULN<=AST<2 ULN |
|
| Worst-post-BL value: 2 ULN<=AST<3 ULN |
|
| Worst-post-BL value: AST<=3 ULN |
|