Study to Evaluate Patients With Cerebrotendinous Xanthomatosis (RESTORE)

• Blinded CDCA 250 mg TID (Drug): Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment.
• Placebo (Drug): 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 (Drug): 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 (Drug): CDCA 250 mg TID will be provided as rescue medication during the double-blind periods, if needed, based on laboratory results.
• CDCA Weight-Based Dose TID (Drug): 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.

Primary outcomes

• 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 outcomes

• 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

Sex: All, ages: 1 Month to any

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.

Participant flow

Outcome results

• Change From Baseline in Urine 23S-Pentol During the Two Double-Blind Periods (Primary), Mean, natural log of ng/mL: CDCA TID 7.18 +/- 0.797; Placebo TID 6.96 +/- 1.076 (p <0.0001)
• Change From Baseline Plasma Cholestanol During the Two Double-Blind Periods (Secondary), Mean, natural log of μg/mL: CDCA TID 1.13 +/- 0.791; Placebo TID 1.14 +/- 0.534 (p 0.0083)
• Change From Baseline Plasma 7αC4 During the Two Double-Blind Periods (Secondary), Mean, natural log of ng/mL: CDCA TID 4.02 +/- 0.519; Placebo TID 4.00 +/- 0.526 (p <0.0001)
• Proportion of Participants Who Received Rescue Treatment During Two Double-Blind Periods (Secondary), Number, participants: CDCA TID 0; Placebo TID 2 (p 0.0006)

Adverse events

Time frame: AEs (including SAEs) were captured from the time informed consent was signed to the patient's final visit. In addition, AEs (including SAEs) were to be collected for all patients via a follow-up phone call 30 (±7) days after the last dose of study medication to assess patient safety. Adult Cohort: 24 weeks duration Pediatric Cohort: 16 week duration

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2023-04-04)
• Statistical Analysis Plan (PDF, 2023-07-17)