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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cholic Acid Capsule | Experimental | Manufactured cholic acid capsules |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cholic acid | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Serum Transaminases | Concentration of serum alanine transaminase (ALT) and aspartate transaminase (AST) | At baseline and after 30 days of treatment |
| Serum and Urine Bile Acids | Concentration of bile acids in serum (S) and urine (U). (abbreviations: chol.=cholenoic; monohydro=monohydroxy; dihydro=monohydro) | At baseline (BL) and after 30 days of treatment (D30) |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events | Total number of patients with any adverse events | Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment |
| Blood Pressure | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| James E Heubi, MD | 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 |
|---|---|---|---|
| 15383928 | Background | 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. doi: 10.1007/s10024-002-1201-8. Epub 2004 Jul 15. | |
| 19622360 | Background | 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. |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cholic Acid | All patients entered and treated |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cholic Acid | All patients entered and treated |
| 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 | Serum Transaminases | Concentration of serum alanine transaminase (ALT) and aspartate transaminase (AST) | All patients entered and treated | Posted | Mean | Standard Deviation | U/L | At baseline and after 30 days of treatment |
|
|
Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment
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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 | All patients entered and treated |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA (11.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Decreased/low 250H/Vit D | General disorders | MedDRA (11.1) | Non-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 |
|---|---|
| D008107 | Liver Diseases |
| ID | Term |
|---|---|
| D004066 | Digestive System Diseases |
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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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|
| At baseline and after 30 days of treatment |
| Physical Examination | Total number of patients with abnormal findings from general physical examination | At baseline (BL) and after 30 days of treatment (D30) |
| Total Bilirubin | Concentration of total bilirubin in serum | At baseline and after 30 days of treatment |
| 17682975 | Background | Heubi JE, Setchell KD, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007 Aug;27(3):282-94. doi: 10.1055/s-2007-985073. |
| Background | 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. |
| 16819396 | Background | Setchell KD, Heubi JE. Defects in bile acid biosynthesis--diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006 Jul;43 Suppl 1:S17-22. doi: 10.1097/01.mpg.0000226386.79483.7b. |
| Background | 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. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
| Primary | Serum and Urine Bile Acids | Concentration of bile acids in serum (S) and urine (U). (abbreviations: chol.=cholenoic; monohydro=monohydroxy; dihydro=monohydro) | All patients entered and treated | Posted | Mean | Standard Deviation | mmol/L | At baseline (BL) and after 30 days of treatment (D30) |
|
|
|
| Secondary | Adverse Events | Total number of patients with any adverse events | All patients entered and treated | Posted | Number | participants | Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment |
|
|
|
| Secondary | Blood Pressure | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) | All patients entered and treated | Posted | Mean | Standard Deviation | mmHg | At baseline and after 30 days of treatment |
|
|
|
| Secondary | Physical Examination | Total number of patients with abnormal findings from general physical examination | All patients entered and treated | Posted | Number | participants | At baseline (BL) and after 30 days of treatment (D30) |
|
|
|
| Secondary | Total Bilirubin | Concentration of total bilirubin in serum | All patients entered and treated | Posted | Mean | Standard Deviation | mg/dL | At baseline and after 30 days of treatment |
|
|
|
| 1 |
| 16 |
| 9 |
| 16 |
| Fever | General disorders | MedDRA (11.1) | Non-systematic Assessment |
|
| Decreased Vitamin A | General disorders | MedDRA (11.1) | Non-systematic Assessment |
|
| Nosebleed | Vascular disorders | MedDRA (11.1) | Non-systematic Assessment | In the clinical study Report, the Event was counted towards the Body System "Eye, ear, nose, throat" |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (11.1) | Non-systematic Assessment |
|
| Reflux | Gastrointestinal disorders | MedDRA (11.1) | Non-systematic Assessment |
|
| Increased ALT | Hepatobiliary disorders | MedDRA (11.1) | Non-systematic Assessment |
|
| Increased AST | Hepatobiliary disorders | MedDRA (11.1) | Non-systematic Assessment |
|
| Muscle spasm | Musculoskeletal and connective tissue disorders | MedDRA (11.1) | Non-systematic Assessment |
|
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| D011083 |
| Polycyclic Compounds |
| D002757 | Cholanes |
|
| U, D30: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485 |
|
| U, BL: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526 |
|
| U, D30: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526 |
|
| U,BL: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z 542 |
|
| U,D30: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z542 |
|
| S,BL: Glyco-3-oxo-7-α,12α-dihydroxy-4-chol. m/z460 |
|
| S,D30: Glyco-3-oxo-7-α,12α-dihydroxy-4-chol.m/z460 |
|
| S,BL:Glyco-3-oxo-7-α,12α-monohydroxy-4-chol.m/z444 |
|
| S,D30:Glyco-3-oxo-7-α,12α-monohydro.-4-chol.m/z444 |
|
| S, BL: Tauro-3-oxo-7-α,12α-dihydroxy-4-chol.m/z510 |
|
| S,D30: Tauro-3-oxo-7-α,12α-dihydroxy-4-chol.m/z510 |
|
| S,BL:Tauro-3-oxo-7-α,12α-monohydroxy-4-chol.m/z498 |
|
| S,D30:Tauro-3-oxo-7-α,12α-monohydro.-4-chol.m/z498 |
|
| U, BL: Total 3β-hydroxy-Δ5 bile acids |
|
| U, D30: Total 3β-hydroxy-Δ5 bile acids |
|
| S, BL: Total 3-oxo-Δ4 bile acids |
|
| S, D30: Total 3-oxo-Δ4 bile acids |
|
|
| DBP, Day 30 |
|