Inborn Errors of Bile Acid Synthesis
Conditions
Keywords
Inborn Errors, Bile Acid, Pediatrics, Liver Disease
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).
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.
Interventions
DRUGCholic 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.
Sponsors
Mirum Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Cholic Acid All patients entered and treated | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Cholic Acid |
|---|---|
| Age, Continuous | 7.8 years STANDARD_DEVIATION 4.6 |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 16 |
| serious Total, serious adverse events | 1 / 16 |
Outcome results
Primary
Serum and Urine Bile Acids
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)
Population: All patients entered and treated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholic Acid | Serum and Urine Bile Acids | U, D30: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526 | 19.958 mmol/L | Standard Deviation 29.341 |
| Cholic Acid | Serum and Urine Bile Acids | U, BL: 3β,7α-dihydroxy-Δ5 sulfate m/z 469 | 12.37 mmol/L | Standard Deviation 35.31 |
| Cholic Acid | Serum and Urine Bile Acids | U, D30: 3β,7α-dihydroxy-Δ5 sulfate m/z 469 | 2.762 mmol/L | Standard Deviation 3.955 |
| Cholic Acid | Serum and Urine Bile Acids | U, BL: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485 | 14.11 mmol/L | Standard Deviation 42.78 |
| Cholic Acid | Serum and Urine Bile Acids | U, D30: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485 | 2.011 mmol/L | Standard Deviation 2.995 |
| Cholic Acid | Serum and Urine Bile Acids | U, BL: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526 | 159.85 mmol/L | Standard Deviation 474.52 |
| Cholic Acid | Serum and Urine Bile Acids | U,BL: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z 542 | 105.43 mmol/L | Standard Deviation 337.05 |
| Cholic Acid | Serum and Urine Bile Acids | U,D30: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z542 | 5.421 mmol/L | Standard Deviation 7.633 |
| Cholic Acid | Serum and Urine Bile Acids | S,BL: Glyco-3-oxo-7-α,12α-dihydroxy-4-chol. m/z460 | 0.15 mmol/L | Standard Deviation 0.07 |
| Cholic Acid | Serum and Urine Bile Acids | S,D30: Glyco-3-oxo-7-α,12α-dihydroxy-4-chol.m/z460 | 0.055 mmol/L | Standard Deviation 0.078 |
| Cholic Acid | Serum and Urine Bile Acids | S,BL:Glyco-3-oxo-7-α,12α-monohydroxy-4-chol.m/z444 | 0.14 mmol/L | Standard Deviation 0.01 |
| Cholic Acid | Serum and Urine Bile Acids | S,D30:Glyco-3-oxo-7-α,12α-monohydro.-4-chol.m/z444 | 0.140 mmol/L | Standard Deviation 0.184 |
| Cholic Acid | Serum and Urine Bile Acids | S, BL: Tauro-3-oxo-7-α,12α-dihydroxy-4-chol.m/z510 | 0.52 mmol/L | Standard Deviation 0.23 |
| Cholic Acid | Serum and Urine Bile Acids | S,D30: Tauro-3-oxo-7-α,12α-dihydroxy-4-chol.m/z510 | 0.490 mmol/L | Standard Deviation 0.679 |
| Cholic Acid | Serum and Urine Bile Acids | S,BL:Tauro-3-oxo-7-α,12α-monohydroxy-4-chol.m/z498 | 0.05 mmol/L | Standard Deviation 0.04 |
| Cholic Acid | Serum and Urine Bile Acids | S,D30:Tauro-3-oxo-7-α,12α-monohydro.-4-chol.m/z498 | 0.020 mmol/L | Standard Deviation 0.028 |
| Cholic Acid | Serum and Urine Bile Acids | U, BL: Total 3β-hydroxy-Δ5 bile acids | 291.77 mmol/L | Standard Deviation 889.56 |
| Cholic Acid | Serum and Urine Bile Acids | U, D30: Total 3β-hydroxy-Δ5 bile acids | 30.148 mmol/L | Standard Deviation 43.582 |
| Cholic Acid | Serum and Urine Bile Acids | S, BL: Total 3-oxo-Δ4 bile acids | 0.84 mmol/L | Standard Deviation 0.13 |
| Cholic Acid | Serum and Urine Bile Acids | S, D30: Total 3-oxo-Δ4 bile acids | 0.705 mmol/L | Standard Deviation 0.601 |
Primary
Serum Transaminases
Concentration of serum alanine transaminase (ALT) and aspartate transaminase (AST)
Time frame: At baseline and after 30 days of treatment
Population: All patients entered and treated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholic Acid | Serum Transaminases | ALT, baseline | 31.4 U/L | Standard Deviation 21.9 |
| Cholic Acid | Serum Transaminases | ALT, Day 30 | 30.9 U/L | Standard Deviation 24 |
| Cholic Acid | Serum Transaminases | AST, baseline | 62.7 U/L | Standard Deviation 27.1 |
| Cholic Acid | Serum Transaminases | AST, Day 30 | 65.0 U/L | Standard Deviation 39 |
Secondary
Adverse Events
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
Population: All patients entered and treated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cholic Acid | Adverse Events | 9 participants |
Secondary
Blood Pressure
Systolic blood pressure (SBP) and diastolic blood pressure (DBP)
Time frame: At baseline and after 30 days of treatment
Population: All patients entered and treated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholic Acid | Blood Pressure | SBP, baseline | 106.9 mmHg | Standard Deviation 10.2 |
| Cholic Acid | Blood Pressure | SBP, Day 30 | 109.6 mmHg | Standard Deviation 6.6 |
| Cholic Acid | Blood Pressure | DBP, baseline | 63.9 mmHg | Standard Deviation 6.7 |
| Cholic Acid | Blood Pressure | DBP, Day 30 | 65.4 mmHg | Standard Deviation 6.8 |
Secondary
Physical Examination
Total number of patients with abnormal findings from general physical examination
Time frame: At baseline (BL) and after 30 days of treatment (D30)
Population: All patients entered and treated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cholic Acid | Physical Examination | BL, N patients with abnormal physical findings | 0 participants |
| Cholic Acid | Physical Examination | D30, N patients with abnormal physical findings | 0 participants |
Secondary
Total Bilirubin
Concentration of total bilirubin in serum
Time frame: At baseline and after 30 days of treatment
Population: All patients entered and treated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholic Acid | Total Bilirubin | Baseline, total bilirubin | 0.35 mg/dL | Standard Deviation 0.37 |
| Cholic Acid | Total Bilirubin | D30, total bilirubin | 0.32 mg/dL | Standard Deviation 0.28 |