CTX
Conditions
Keywords
Cerebrotendinous xanthomatosis, CTX, Cholestanol, Leukodystrophy, CYP27A1
Brief summary
The study is made up of two cohorts: a randomized double-blind crossover (placebo withdrawal with rescue) study among patients ≥ 16 years of age (adult cohort) and an open-label dose titration study among pediatric patients ≥1 month and \<16 years of age (pediatric cohort)
Interventions
DRUGBlinded CDCA 250 mg TID
Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
DRUGPlacebo
Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
DRUGOpen-Label CDCA 250 mg TID
Adult cohort patients will receive open-label 250 mg CDCA TID during the run-in and washout periods of the study or as rescue medication during the double-blind periods, if needed, based on clinical symptoms.
DRUGRescue Medication CDCA 250 mg TID
CDCA 250 mg TID will be provided as rescue medication during the double-blind periods, if needed, based on laboratory results.
DRUGCDCA Weight-Based Dose TID
Patients in the pediatric cohort will complete a weight-based dose titration to a tolerated dose and will maintain that tolerated dose for the remainder of the study. Pediatric cohort dosing of CDCA will not exceed an equivalent dose of 750 mg/day.
Sponsors
Mirum Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Two-cohort study. One cohort is for adult patients with a double-blind placebo withdrawal (with CDCA rescue) crossover. Second cohort will dose titrate pediatric patients into a stable, open-label treatment.
Eligibility
Sex/Gender
ALL
Age
1 Months to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female at least 1 month or older at screening. 2. Clinical diagnosis of CTX with biochemical confirmation. 3. Women of childbearing potential must agree to the use of one highly reliable method of contraception during the study, plus one additional barrier method during sexual activity. 4. Males must be surgically sterile, or males and their sexual partners must together agree to use medically accepted methods of contraception that are considered highly reliable during the course of the study.
Exclusion criteria
1. Genetic testing does not confirm CTX. 2. Malabsorption disorder or confounding inflammatory gastrointestinal condition (for example, irritable bowel syndrome). 3. Documented history of heart failure. 4. Treated with medications which impact bile acid absorption such as bile acid sequestering agents (eg, cholestyramine, colestipol, aluminum-based antacids. 5. Treated with cholic acid medication. 6. Female patient who is pregnant, plans to become pregnant during the course of the study, or is breastfeeding. 7. Positive at screening for the human immunodeficiency virus (HIV) or markers indicating acute or chronic hepatitis B infection or hepatitis C infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16 | Primary Analysis of Change from Baseline in Urine 23S-Pentol (Natural Log-Transformed) during the Two Double-blind Periods- Paired T-test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16 | Primary Analysis of Change from Baseline Plasma Cholestanol (Natural Log-transformed) at the End of the Two Double-Blind Periods- Paired T-test |
| Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16 | Primary Analysis of Change from Baseline Plasma 7αC4 (Natural Log-Transformed) During the Two Double-Blind Periods |
| Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16 | Proportion of Participants Who Received Rescue Treatment during Two Double-Blind Periods - Prescott's Method |
Countries
Brazil, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence AB Patients in the adult cohort will participate in a randomized, double-blind, placebo-controlled, 2 period × 2-treatment crossover study with rescue medication and open-label run-in to assess the efficacy and safety of CDCA.
Patients randomized to sequence AB will receive blinded CDCA TID for 4 weeks or until open-label rescue medication criteria are triggered
Blinded CDCA 250 mg TID: Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
Placebo: Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
Open-Label CDCA 250 mg TID: Adult cohort patients will receive open-label 250 mg CDCA TID during the run-in and washout periods of the study or as rescue medication during the double-blind periods, if needed, based on clinical symptoms. | 6 |
| Sequence BA Patients in the adult cohort will participate in a randomized, double-blind, placebo-controlled, 2 period × 2-treatment crossover study with rescue medication and open-label run-in to assess the efficacy and safety of CDCA.
Patients randomized to sequence BA will receive placebo TID for 4 weeks or until either the blinded and/or open-label rescue medication criteria are triggered.
Blinded CDCA 250 mg TID: Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
Placebo: Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
Open-Label CDCA 250 mg TID: Adult cohort patients will receive open-label 250 mg CDCA TID during the run-in and washout periods of the study or as rescue medication during the double-blind periods, if needed, based on clinical symptoms.
Rescue Medication CDCA 250 mg TID: CDCA 250 mg TID will be provided as rescue medication during the double-blind periods, if needed, based on laboratory results. | 7 |
| Pediatric Cohort Pediatric cohort patients (≥1 month and \<16 years) will participate in a 24-week, open-label cohort with an 8-week titration period and a 16-week treatment period at the tolerated dose.
CDCA Weight-Based Dose TID: Patients in the pediatric cohort will complete a weight-based dose titration to a tolerated dose and will maintain that tolerated dose for the remainder of the study. Pediatric cohort dosing of CDCA will not exceed an equivalent dose of 750 mg/day. | 5 |
| Total | 18 |
Baseline characteristics
| Characteristic | Sequence BA | Pediatric Cohort | Sequence AB | Total |
|---|---|---|---|---|
| Age, Customized Number Analyzed | 38.6 years STANDARD_DEVIATION 11.73 | 8.2 years STANDARD_DEVIATION 3.96 | 43 years STANDARD_DEVIATION 7.4 | 29.9 years STANDARD_DEVIATION 3.9 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 5 Participants | 5 Participants | 13 Participants |
| Region of Enrollment Brazil | 3 participants | 2 participants | 3 participants | 8 participants |
| Region of Enrollment United States | 4 participants | 3 participants | 3 participants | 10 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 5 |
| other Total, other adverse events | 13 / 13 | 13 / 13 | 5 / 5 |
| serious Total, serious adverse events | 0 / 13 | 1 / 13 | 0 / 5 |
Outcome results
Primary
Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods
Primary Analysis of Change from Baseline in Urine 23S-Pentol (Natural Log-Transformed) during the Two Double-blind Periods- Paired T-test
Time frame: Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16
Population: All adult cohort participants who were randomized and took at least one dose of randomized study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CDCA TID | Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Pooled Double Blind Baseline | 7.18 natural log of ng/mL | Standard Deviation 0.797 |
| CDCA TID | Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Pooled last non missing postbaseline Double Blind record | 7.45 natural log of ng/mL | Standard Deviation 0.675 |
| CDCA TID | Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Pooled change from baseline to last non missing postbaseline Double Blind record | 0.20 natural log of ng/mL | Standard Deviation 0.732 |
| Placebo TID | Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Pooled Double Blind Baseline | 6.96 natural log of ng/mL | Standard Deviation 1.076 |
| Placebo TID | Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Pooled last non missing postbaseline Double Blind record | 10.34 natural log of ng/mL | Standard Deviation 0.788 |
| Placebo TID | Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods | Pooled change from baseline to last non missing postbaseline Double Blind record | 3.38 natural log of ng/mL | Standard Deviation 1.111 |
p-value: <0.000195% CI: [-3.794, -2.331]paired t-test
Secondary
Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods
Primary Analysis of Change from Baseline Plasma 7αC4 (Natural Log-Transformed) During the Two Double-Blind Periods
Time frame: Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16
Population: All adult cohort participants who were randomized and took at least one dose of randomized study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CDCA TID | Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Pooled Double Blind baseline | 4.02 natural log of ng/mL | Standard Deviation 0.519 |
| CDCA TID | Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Pooled last non missing postbaseline Double Blind record | 3.97 natural log of ng/mL | Standard Deviation 0.572 |
| CDCA TID | Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Pooled change from baseline to last non missing postbaseline Double Blind record | -0.08 natural log of ng/mL | Standard Deviation 0.717 |
| Placebo TID | Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Pooled Double Blind baseline | 4.00 natural log of ng/mL | Standard Deviation 0.526 |
| Placebo TID | Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Pooled last non missing postbaseline Double Blind record | 7.60 natural log of ng/mL | Standard Deviation 0.511 |
| Placebo TID | Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods | Pooled change from baseline to last non missing postbaseline Double Blind record | 3.60 natural log of ng/mL | Standard Deviation 0.742 |
p-value: <0.000195% CI: [-4.193, -3.207]paired t-test
Secondary
Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods
Primary Analysis of Change from Baseline Plasma Cholestanol (Natural Log-transformed) at the End of the Two Double-Blind Periods- Paired T-test
Time frame: Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16
Population: All adult cohort participants who were randomized and took at least one dose of randomized study medication, and who had been on CDCA for at least 2 months prior to the open-label run-in period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CDCA TID | Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Pooled Double Blind baseline | 1.13 natural log of μg/mL | Standard Deviation 0.791 |
| CDCA TID | Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Pooled last non missing post baseline Double Blind record | 1.10 natural log of μg/mL | Standard Deviation 0.728 |
| CDCA TID | Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Pooled change from baseline to last non missing post baseline Double Blind record | -0.12 natural log of μg/mL | Standard Deviation 0.542 |
| Placebo TID | Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Pooled Double Blind baseline | 1.14 natural log of μg/mL | Standard Deviation 0.534 |
| Placebo TID | Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Pooled last non missing post baseline Double Blind record | 1.88 natural log of μg/mL | Standard Deviation 0 |
| Placebo TID | Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods | Pooled change from baseline to last non missing post baseline Double Blind record | 0.75 natural log of μg/mL | Standard Deviation 0.865 |
p-value: 0.008395% CI: [-1.64, -0.399]paired t-test
Secondary
Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods
Proportion of Participants Who Received Rescue Treatment during Two Double-Blind Periods - Prescott's Method
Time frame: Two double-blind periods: Week 0 to Week 4, Week 12 to Week 16
Population: All adult cohort participants who were randomized and took at least one dose of randomized study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CDCA TID | Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Double Blind Period 1 Proportion of participants who required rescue medication, % | 0 participants |
| CDCA TID | Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Double Blind Period 2 Proportion of participants who required rescue medication, % | 1 participants |
| CDCA TID | Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Pooled Proportion of participants who required rescue medication, % | 1 participants |
| Placebo TID | Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Double Blind Period 1 Proportion of participants who required rescue medication, % | 2 participants |
| Placebo TID | Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Double Blind Period 2 Proportion of participants who required rescue medication, % | 6 participants |
| Placebo TID | Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods | Pooled Proportion of participants who required rescue medication, % | 8 participants |
p-value: 0.000695% CI: [0, 0.36]Prescott's
p-value: 0.000695% CI: [0.32, 0.86]Prescott's