Adrenoleukodystrophy, Cholestasis, Infantile Refsum's Disease, Peroxisomal Disorders, Zellweger Syndrome
Conditions
Brief summary
OBJECTIVES: I. To Evaluate the therapeutic efficacy of cholic acid during provision of compassionate treatment to patients with identified inborn errors of bile acid synthesis and metabolism II. To assess the safety and tolerability of cholic acid
Detailed description
Investigational Plan: A Phase III, open label, single arm, nonrandomized, non-comparative, compassionate treatment study of cholic acid in the treatment of defects of bile acid metabolism. The study was begun with a single study site at Cincinnati Children's Hospital Medical Center (CCHMC), but in 2005 was expanded so that compassionate treatment could be provided to additional patients who had been identified with inborn errors of bile metabolism through the center's screening/diagnostic program. Patients who were screened were contacted and evaluated with respect to the inclusion/exclusion criteria. Signed informed consent by the patient and/or parents/legal guardian was obtained as soon as it is confirmed that the patient met inclusion/exclusion criteria and the parents/guardian would agree for the child to participate in the study. The primary interventions for the study were: 1. Administration of study drug. 2. Collection of baseline physical exam, vital signs, blood and urine samples for laboratory tests. 3. Collection of periodic physical exam, vital signs, blood and urine samples for laboratory tests during the period of administration of the study drug. 4. Collection of any adverse event information. Time and Events Schedule: Baseline: 1. Confirm eligibility 2. Obtain written informed consent from patient and/or parents/legal guardian 3. Collect demographic data and disease and medication history, including family history Baseline and Ongoing: 4. Obtain body weight 5. Record adverse events 6. Obtain blood and urine samples for laboratory tests 7. Initiate study drug therapy & monitor study drug therapy and adjust dose as needed
Interventions
DRUGCholic Acids
10-15 mg/kg body weight/day taken orally.
Sponsors
Children's Hospital Medical Center, Cincinnati
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
PROTOCOL ENTRY CRITERIA: --Disease Characteristics-- Clinical or biochemical evidence of liver disease, unexplained fat-soluble vitamin malabsorption, or peroxisomal dysfunction that compromises bile acid biosynthesis Inclusion criteria for enrollment were: * Infants \< age 3 months * Children presenting for evaluation of cholestasis defined as a conjugated bilirubin \> 2mg/dl or increased serum bile acids * Older subjects of any age with cholestatic liver disease if urine screens suggested that they had inborn errors of bile acid metabolism * Confirmation of a diagnosis of an inborn error of bile acid synthesis based upon urine analysis by FAB-MS to determine whether specific abnormalities in bile acid synthesis are indicated * The patient and/or parent/legal guardian must have signed the written informed consent document before study start. * The patient must be willing and able to comply with all study assessments and procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years | Patients with excretion of atypical bile acids in urine by category, from worst status before treatment (baseline, BL) to best status on treatment (OT) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years | Patients with elevations of liver function tests (alanine transaminase \[ALT\], aspartate transaminase \[AST\]) measured as multiples of the upper limit of normal (ULN) at baseline (worst value) and on treatment (best value) |
| Liver Histology | At baseline (if no historical data were available) and between 1 and 6 months following treatment start. | Patients (number, percentage) with pathological findings for qualitative (the presence of inflammation, fibrosis, necrosis, giant cells and cholestasis) and quantitative (the degrees of the aforementioned histologic features) liver histopathology at baseline (BL) and on treatment (OT). |
| Height and Weight | Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years | Change in height/weight percentiles from baseline (worst value) to the best on-treatment value, based on CDC (Centres for Disease Control and Prevention, US) growth chart percentiles |
| Adverse Events | Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years | Number of patients with any adverse event |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Bilirubin Measured in Serum | Baseline and on treatment (every 1, 3, or 6 months, depending on protocol version, for an average of 2.8 years) | Bilirubin concentration in serum at baseline and on treatment |
Countries
United States
Participant flow
Recruitment details
A total of 85 patients were enrolled.
Pre-assignment details
Of the patients diagnosed with a defect in bile acid synthesis during routine diagnostic procedures at the Cincinnati Children's Hospital Medical Center (CCHMC) Mass Spectrometry Laboratory, 85 patients were invited to participate in the study.
Participants by arm
| Arm | Count |
|---|---|
| Cholic Acid All patients entered into the study | 85 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 16 |
| Overall Study | Lost to Follow-up | 13 |
| Overall Study | No evidence of treatment | 6 |
| Overall Study | Pt cared for by outside physician | 4 |
| Overall Study | Pt withdrawn (liver transplant) | 4 |
| Overall Study | Pt withdrawn (worsening cholestasis) | 1 |
Baseline characteristics
| Characteristic | Cholic Acid |
|---|---|
| Age, Continuous | 3 years STANDARD_DEVIATION 4 |
| Region of Enrollment United States | 85 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 79 |
| other Total, other adverse events | 35 / 79 |
| serious Total, serious adverse events | 20 / 79 |
Outcome results
Primary
Number of Participants With Excretion of Atypical Bile Acids in Urine by Category
Patients with excretion of atypical bile acids in urine by category, from worst status before treatment (baseline, BL) to best status on treatment (OT)
Time frame: Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Population: Patients treated and with at least 1 pre-treatment and 1 post-treatment assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | On treatment, no atypical bile acid excretion | 51 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | Baseline, no atypical bile acid excretion | 10 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | Baseline, slight atypical bile acid excretion | 11 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | On treatment, slight atypical bile acid excretion | 9 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | Baseline, significant atypical bile acid excretion | 16 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | OT, significant atypical bile acid excretion | 4 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | Baseline, marked atypical bile acid excretion | 33 Participants |
| Cholic Acid | Number of Participants With Excretion of Atypical Bile Acids in Urine by Category | On treatment, marked atypical bile acid excretion | 6 Participants |
Secondary
Adverse Events
Number of patients with any adverse event
Time frame: Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Population: Patients entered into the study and treated
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cholic Acid | Adverse Events | Patients at risk | 79 Participants |
| Cholic Acid | Adverse Events | Patients with any AE | 38 Participants |
Secondary
Change in Liver Function Tests (LFTs) Measured in Serum
Patients with elevations of liver function tests (alanine transaminase \[ALT\], aspartate transaminase \[AST\]) measured as multiples of the upper limit of normal (ULN) at baseline (worst value) and on treatment (best value)
Time frame: Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Population: Patients treated and with at least 1 pre-treatment and 1 post-Treatment assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, ALT <ULN | 14 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, ALT <ULN | 49 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, ULN ≤ ALT <2 x ULN | 16 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, ULN ≤ ALT <2 x ULN | 13 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, 2 ULN ≤ ALT <3 x ULN | 8 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, 2 ULN ≤ ALT <3 x ULN | 2 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, ALT ≥3 x ULN | 29 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, ALT ≥3 x ULN | 3 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, AST <ULN | 9 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, AST <ULN | 38 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, ULN ≤ AST <2 x ULN | 14 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, ULN ≤ AST <2 x ULN | 15 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, 2 ULN ≤ AST <3 x ULN | 7 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, 2 ULN ≤ AST <3 x ULN | 4 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | Baseline, AST ≥3 x ULN | 35 Participants |
| Cholic Acid | Change in Liver Function Tests (LFTs) Measured in Serum | On treatment, AST ≥3 x ULN | 9 Participants |
Secondary
Height and Weight
Change in height/weight percentiles from baseline (worst value) to the best on-treatment value, based on CDC (Centres for Disease Control and Prevention, US) growth chart percentiles
Time frame: Baseline, then every 1, 3, or 6 months (depending on protocol version) for an average of 2.8 years
Population: Patients treated and with at least 1 pre-treatment and 1 post-treatment assessment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholic Acid | Height and Weight | Height percentile, baseline | 30.1 Percentile | Standard Error 5.5 |
| Cholic Acid | Height and Weight | Height percentile, on treatment | 44.0 Percentile | Standard Error 6.1 |
| Cholic Acid | Height and Weight | Weight percentile, baseline | 21.3 Percentile | Standard Error 3.7 |
| Cholic Acid | Height and Weight | Weight percentile, on treatment | 42.3 Percentile | Standard Error 4.8 |
Secondary
Liver Histology
Patients (number, percentage) with pathological findings for qualitative (the presence of inflammation, fibrosis, necrosis, giant cells and cholestasis) and quantitative (the degrees of the aforementioned histologic features) liver histopathology at baseline (BL) and on treatment (OT).
Time frame: At baseline (if no historical data were available) and between 1 and 6 months following treatment start.
Population: All patients entered into the study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cholic Acid | Liver Histology | Giant cells at BL, quantitative | 13 Participants |
| Cholic Acid | Liver Histology | Periportal inflammation at BL, qualitative | 19 Participants |
| Cholic Acid | Liver Histology | Periportal inflammation OT, qualitative | 16 Participants |
| Cholic Acid | Liver Histology | Lobular inflammation at BL, qualitative | 5 Participants |
| Cholic Acid | Liver Histology | Lobular inflammation OT, qualitative | 4 Participants |
| Cholic Acid | Liver Histology | Inflammation (not spec.) at BL, qualitative | 3 Participants |
| Cholic Acid | Liver Histology | Inflammation (not spec.) OT, qualitative | 0 Participants |
| Cholic Acid | Liver Histology | Bridging fibrosis at BL, qualitative | 25 Participants |
| Cholic Acid | Liver Histology | Bridging fibrosis OT, qualitative | 31 Participants |
| Cholic Acid | Liver Histology | Fibrosis (not specified) at BL, qualitative | 6 Participants |
| Cholic Acid | Liver Histology | Fibrosis (not specified) OT, qualitative | 6 Participants |
| Cholic Acid | Liver Histology | Cholestasis at BL, qualitative | 20 Participants |
| Cholic Acid | Liver Histology | Cholestasis OT, qualitative | 10 Participants |
| Cholic Acid | Liver Histology | Giant cells at BL, qualitative | 18 Participants |
| Cholic Acid | Liver Histology | Giant cells OT, qualitative | 12 Participants |
| Cholic Acid | Liver Histology | Necrosis at BL, qualitative | 14 Participants |
| Cholic Acid | Liver Histology | Necrosis OT, qualitative | 2 Participants |
| Cholic Acid | Liver Histology | Periportal inflammation at BL, quantitative | 18 Participants |
| Cholic Acid | Liver Histology | Periportal inflammation OT, quantitative | 15 Participants |
| Cholic Acid | Liver Histology | Lobular inflammation at BL, quantitative | 5 Participants |
| Cholic Acid | Liver Histology | Lobular inflammation OT, quantitative | 4 Participants |
| Cholic Acid | Liver Histology | Inflammation (not specified) at BL, quantitative | 3 Participants |
| Cholic Acid | Liver Histology | Inflammation (not specified) OT, quantitative | 0 Participants |
| Cholic Acid | Liver Histology | Bridging fibrosis at baseline, quantitative | 22 Participants |
| Cholic Acid | Liver Histology | Bridging fibrosis OT, quantitative | 27 Participants |
| Cholic Acid | Liver Histology | Fibrosis (not specified) at BL, quantitative | 3 Participants |
| Cholic Acid | Liver Histology | Fibrosis (not specified) OT, quantitative | 5 Participants |
| Cholic Acid | Liver Histology | Cholestasis at BL, quantitative | 15 Participants |
| Cholic Acid | Liver Histology | Cholestasis OT, quantitative | 7 Participants |
| Cholic Acid | Liver Histology | Giant cells OT, quantitative | 9 Participants |
| Cholic Acid | Liver Histology | Necrosis at BL, quantitative | 13 Participants |
| Cholic Acid | Liver Histology | Necrosis OT, quantitative | 2 Participants |
Other Pre-specified
Change in Bilirubin Measured in Serum
Bilirubin concentration in serum at baseline and on treatment
Time frame: Baseline and on treatment (every 1, 3, or 6 months, depending on protocol version, for an average of 2.8 years)
Population: All available bilirubin laboratory data are collected then grouped by bilirubin test type and collection time points (baseline vs. on treatment). Not all participant had available data, and each participant may have more than one type of bilirubin collected at a time point, and may have multiple on-treatment collections.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholic Acid | Change in Bilirubin Measured in Serum | Baseline, bilirubin | 0.3 mg/dL | — |
| Cholic Acid | Change in Bilirubin Measured in Serum | On treatment, bilirubin | 0.6 mg/dL | Standard Deviation 0.5 |
| Cholic Acid | Change in Bilirubin Measured in Serum | Baseline, direct bilirubin | 2.2 mg/dL | Standard Deviation 5.6 |
| Cholic Acid | Change in Bilirubin Measured in Serum | On treatment, direct bilirubin | 0.5 mg/dL | Standard Deviation 1.8 |
| Cholic Acid | Change in Bilirubin Measured in Serum | Baseline, indirect bilirubin | 0.5 mg/dL | Standard Deviation 0.9 |
| Cholic Acid | Change in Bilirubin Measured in Serum | On treatment, indirect bilirubin | 0.2 mg/dL | Standard Deviation 0.2 |
| Cholic Acid | Change in Bilirubin Measured in Serum | Baseline, total bilirubin | 2.8 mg/dL | Standard Deviation 10.6 |
| Cholic Acid | Change in Bilirubin Measured in Serum | On treatment, total bilirubin | 1.5 mg/dL | Standard Deviation 5.2 |