Efficacy of To Be Marketed (TBM) Cholic Acid Capsules Used to Treat Children With Inborn Errors of Bile Acid Synthesis
Study Details
Study Description
Brief Summary
This is a study in a small population of children who have inborn errors of bile acid synthesis who are currently taking established doses of the currently used cholic acid capsules prepared at the Cincinnati Children's Hospital Pharmacy. The study is designed to compare the efficacy of these currently used capsules with the efficacy of the same treatment provided in a cholic acid capsule that is made by a company that will be marketed after FDA approval.
At baseline, patients receive established doses of cholic acid capsules prepared at the Cincinnati Children's Hospital Medical Center Pharmacy. During the study, patients receive the same treatment provided in the to-be-marketed (TBM) cholic acid capsule. Hence, patients serve as their own controls, with baseline values presenting the reference value (CCHMC cholic acid capsule) and values after 30 days treatment presenting the value for the investigational treatment (TBM cholic acid capsule).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Bile acids are end products of cholesterol metabolism. Individuals with inborn errors of bile acid synthesis lack the enzymes needed to synthesize the primary bile acids cholic acid and chenodeoxycholic acid (CDCA). These conditions are serious and account for approximately 1% of cases presenting as idiopathic cholestatic liver disease. The liver disease associated with these inborn errors in bile acid synthesis is progressive and, if untreated, may lead to death from cirrhosis and liver failure.
Monotherapy with cholic acid is considered the most appropriate therapeutic strategy to treat inborn errors in bile acid synthesis because it provides a stimulus for bile flow and inhibits endogenous production and accumulation of potentially hepatotoxic and cholestatic bile acid precursors, while additionally facilitating the absorption of fats and fat-soluble vitamins. At therapeutic doses, adverse effects are not generally observed and as such, cholic acid has become the treatment of choice at the Cincinnati Children's Hospital since 1994.
This study will bridge data on the effectiveness of a standardized manufactured preparation to data obtained from patients originally treated with the currently used cholic acid capsules formulated in the CCHMC Pharmacy before being switched to the manufactured preparation.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cholic Acid Capsule Manufactured cholic acid capsules |
Drug: Cholic acid
The IUPAC name for cholic acid is 3 alpha,7alpha,12 alpha-trihydroxy-5 beta-cholanoic acid. The international nonproprietary name (INN) is cholic acid.
Each patient will be given a box containing a 1 month supply of study drug. Each bottle will contain 90 capsules; each capsule will contain either 50 or 250 mg of manufactured cholic acid depending upon the child's weight. The study drug will be taken orally, in divided doses (as determined by the investigator), for a total daily dose of 10-15 mg/kg body weight. Parents of infants and young children who are unable to swallow the TBM cholic acid capsule will be instructed to sprinkle the contents of the capsule over 1-2 teaspoons of plain applesauce and feed it to the child.
|
Outcome Measures
Primary Outcome Measures
- Serum Transaminases [At baseline and after 30 days of treatment]
Concentration of serum alanine transaminase (ALT) and aspartate transaminase (AST)
- Serum and Urine Bile Acids [At baseline (BL) and after 30 days of treatment (D30)]
Concentration of bile acids in serum (S) and urine (U). (abbreviations: chol.=cholenoic; monohydro=monohydroxy; dihydro=monohydro)
Secondary Outcome Measures
- Adverse Events [Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment]
Total number of patients with any adverse events
- Blood Pressure [At baseline and after 30 days of treatment]
Systolic blood pressure (SBP) and diastolic blood pressure (DBP)
- Physical Examination [At baseline (BL) and after 30 days of treatment (D30)]
Total number of patients with abnormal findings from general physical examination
- Total Bilirubin [At baseline and after 30 days of treatment]
Concentration of total bilirubin in serum
Eligibility Criteria
Criteria
Inclusion Criteria:
-
must have stable transaminase levels within 2 times the upper limits of the normal range.
-
must have a diagnosis of an inborn error of bile acid synthesis.
-
must have signed the written informed consent/assent document before study start.
-
must be currently receiving currently used cholic acid therapy under IND 45,470.
-
must be willing and able to comply with all study assessments and procedures.
-
must be able to make two visits (Visit 1 and Visit 2) to the study site.
Exclusion Criteria:
-
is not currently receiving cholic acid therapy for inborn errors of bile acid synthesis under IND 45,470.
-
is unable or unwilling to comply with study requirements.
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
Study Documents (Full-Text)
None provided.More Information
Publications
- Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004 Jul-Aug;7(4):315-34. Epub 2004 Jul 15. Review.
- Gonzales E, Gerhardt MF, Fabre M, Setchell KD, Davit-Spraul A, Vincent I, Heubi JE, Bernard O, Jacquemin E. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009 Oct;137(4):1310-1320.e1-3. doi: 10.1053/j.gastro.2009.07.043. Epub 2009 Jul 19.
- Heubi JE, Setchell KD, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007 Aug;27(3):282-94. Review.
- Jacquemin E., Gerhardt M, Cresteil D, Fabre M, Taburet AM, Hadchouel M, Trivin F, Stechell KDR and Bernard O. Long-term effects of bile acid therapy in children with defects of primary bile acid synthesis: 3ß-Hydroxy-C27-steroid dehydrogenase/isomerase and Delta4-3-Oxosteroid 5ß-reductase deficiencies. In: van Berge Henegouwen GP, et al. (eds): Falk Symposium No 120: Biology of Bile Acids in Health and Disease. Kluwer Academic Publishers, Dordrecht/Boston/London; 2001:278-282.
- Setchell KD, Heubi JE. Defects in bile acid biosynthesis--diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006 Jul;43 Suppl 1:S17-22. Review.
- Setchell KDR, et al. A unique case of cerebrotendinous xantomatosis presenting in infancy with cholestatic liver disease further highlights bile acid synthetic defects as an important category of metabolic liver disease. In: van Berge Henegouwen GP et al. (ed): Falk Symposium No. 120: Biology of Bile Acids in Health and Disease. Boston: Kluwer Academic Publishers; 2001.
- CAC-001-01
Study Results
Participant Flow
| Recruitment Details | In this single-arm study, patients served as their own controls: Reference was presented by the baseline value, when patients received cholic acid capsules prepared by the Cincinnati Children's Hospital Medical Center; Investigational Treatment was the to-be-marketed (TBM) cholic acid capsule administered to patients for 30 days treatment duration. |
|---|---|
| Pre-assignment Detail | The study was performed in patients with inborn defects of bile acid synthesis currently receiving cholic acid capsules prepared by the Cincinnati Children's Hospital Medical Center (CCHMC) under IND 45,470. The study planned to include 25 patients; but only 16 patients fulfilled eligibility criteria and were willing to travel to the CCHMC. |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Period Title: Overall Study | |
| STARTED | 16 |
| COMPLETED | 16 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Overall Participants | 16 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
7.8
(4.6)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
5
31.3%
|
| Male |
11
68.8%
|
| Region of Enrollment (participants) [Number] | |
| United States |
16
100%
|
Outcome Measures
| Title | Serum Transaminases |
|---|---|
| Description | Concentration of serum alanine transaminase (ALT) and aspartate transaminase (AST) |
| Time Frame | At baseline and after 30 days of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients entered and treated |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Measure Participants | 16 |
| ALT, baseline |
31.4
(21.9)
|
| ALT, Day 30 |
30.9
(24.0)
|
| AST, baseline |
62.7
(27.1)
|
| AST, Day 30 |
65.0
(39.0)
|
| Title | Serum and Urine Bile Acids |
|---|---|
| Description | Concentration of bile acids in serum (S) and urine (U). (abbreviations: chol.=cholenoic; monohydro=monohydroxy; dihydro=monohydro) |
| Time Frame | At baseline (BL) and after 30 days of treatment (D30) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients entered and treated |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Measure Participants | 16 |
| U, BL: 3β,7α-dihydroxy-Δ5 sulfate m/z 469 |
12.37
(35.31)
|
| U, D30: 3β,7α-dihydroxy-Δ5 sulfate m/z 469 |
2.762
(3.955)
|
| U, BL: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485 |
14.11
(42.78)
|
| U, D30: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485 |
2.011
(2.995)
|
| U, BL: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526 |
159.85
(474.52)
|
| U, D30: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526 |
19.958
(29.341)
|
| U,BL: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z 542 |
105.43
(337.05)
|
| U,D30: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z542 |
5.421
(7.633)
|
| S,BL: Glyco-3-oxo-7-α,12α-dihydroxy-4-chol. m/z460 |
0.15
(0.07)
|
| S,D30: Glyco-3-oxo-7-α,12α-dihydroxy-4-chol.m/z460 |
0.055
(0.078)
|
| S,BL:Glyco-3-oxo-7-α,12α-monohydroxy-4-chol.m/z444 |
0.14
(0.01)
|
| S,D30:Glyco-3-oxo-7-α,12α-monohydro.-4-chol.m/z444 |
0.140
(0.184)
|
| S, BL: Tauro-3-oxo-7-α,12α-dihydroxy-4-chol.m/z510 |
0.52
(0.23)
|
| S,D30: Tauro-3-oxo-7-α,12α-dihydroxy-4-chol.m/z510 |
0.490
(0.679)
|
| S,BL:Tauro-3-oxo-7-α,12α-monohydroxy-4-chol.m/z498 |
0.05
(0.04)
|
| S,D30:Tauro-3-oxo-7-α,12α-monohydro.-4-chol.m/z498 |
0.020
(0.028)
|
| U, BL: Total 3β-hydroxy-Δ5 bile acids |
291.77
(889.56)
|
| U, D30: Total 3β-hydroxy-Δ5 bile acids |
30.148
(43.582)
|
| S, BL: Total 3-oxo-Δ4 bile acids |
0.84
(0.13)
|
| S, D30: Total 3-oxo-Δ4 bile acids |
0.705
(0.601)
|
| Title | Adverse Events |
|---|---|
| Description | Total number of patients with any adverse events |
| Time Frame | Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients entered and treated |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Measure Participants | 16 |
| Number [participants] |
9
56.3%
|
| Title | Blood Pressure |
|---|---|
| Description | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) |
| Time Frame | At baseline and after 30 days of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients entered and treated |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Measure Participants | 16 |
| SBP, baseline |
106.9
(10.2)
|
| SBP, Day 30 |
109.6
(6.6)
|
| DBP, baseline |
63.9
(6.7)
|
| DBP, Day 30 |
65.4
(6.8)
|
| Title | Physical Examination |
|---|---|
| Description | Total number of patients with abnormal findings from general physical examination |
| Time Frame | At baseline (BL) and after 30 days of treatment (D30) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients entered and treated |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Measure Participants | 16 |
| BL, N patients with abnormal physical findings |
0
0%
|
| D30, N patients with abnormal physical findings |
0
0%
|
| Title | Total Bilirubin |
|---|---|
| Description | Concentration of total bilirubin in serum |
| Time Frame | At baseline and after 30 days of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients entered and treated |
| Arm/Group Title | Cholic Acid |
|---|---|
| Arm/Group Description | All patients entered and treated |
| Measure Participants | 16 |
| Baseline, total bilirubin |
0.35
(0.37)
|
| D30, total bilirubin |
0.32
(0.28)
|
Adverse Events
| Time Frame | Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Cholic Acid | |
| Arm/Group Description | All patients entered and treated | |
All Cause Mortality |
||
| Cholic Acid | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Cholic Acid | ||
| Affected / at Risk (%) | # Events | |
| Total | 1/16 (6.3%) | |
| Gastrointestinal disorders | ||
| Vomiting | 1/16 (6.3%) | |
| General disorders | ||
| Fever | 1/16 (6.3%) | |
Other (Not Including Serious) Adverse Events |
||
| Cholic Acid | ||
| Affected / at Risk (%) | # Events | |
| Total | 9/16 (56.3%) | |
| Gastrointestinal disorders | ||
| Diarrhoea | 1/16 (6.3%) | |
| Reflux | 1/16 (6.3%) | |
| General disorders | ||
| Decreased/low 250H/Vit D | 4/16 (25%) | |
| Decreased Vitamin A | 1/16 (6.3%) | |
| Hepatobiliary disorders | ||
| Increased ALT | 1/16 (6.3%) | |
| Increased AST | 1/16 (6.3%) | |
| Musculoskeletal and connective tissue disorders | ||
| Muscle spasm | 1/16 (6.3%) | |
| Vascular disorders | ||
| Nosebleed | 1/16 (6.3%) | |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Retrophin Medical Information |
|---|---|
| Organization | Retrophin, Inc. |
| Phone | 1-877-659 ext 5518 |
| medinfo@retrophin.com |
- CAC-001-01