Clinical trial NCT04270682
Conditions: CTX
Keywords: Cerebrotendinous xanthomatosis CTX Cholestanol Leukodystrophy CYP27A1
Sponsor: Mirum Pharmaceuticals, Inc.
Start date: 2020-01-31; Completion date: 2023-10-04
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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)

Detailed description:

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Blinded CDCA 250 mg TID intervention 2: Placebo intervention 3: Open-Label CDCA 250 mg TID intervention 4: Rescue Medication CDCA 250 mg TID intervention 5: CDCA Weight-Based Dose TID
Intervention descriptions: intervention 1: Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment. intervention 2: Adult cohort patients will receive blinded 250 mg CDCA TID or placebo during the double-blind periods based upon their treatment assignment. intervention 3: 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. intervention 4: CDCA 250 mg TID will be provided as rescue medication during the double-blind periods, if needed, based on laboratory results. intervention 5: 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.

Protocol documents:
Prot_000.pdf: 
A PHASE 3 STUDY TO EVALUATE THE EFFECTS OF 
CHENODEOXYCHOLIC ACID IN ADULT AND 
PEDIATRIC PATIENTS WITH CEREBROTENDINOUS 
XANTHOMATOSIS (RESTORE) 
Investigational Medicinal Product:
Chenodeoxycholic Acid (CDCA)
Protocol Number: 
Cheno-CTX-301 
IND Number: 
IND 124960 
NCT Number: 
NCT04270682 
Developmental Phase: 
Phase 3 
Amendment 6 04 April 2023 
Amendment 5 23 August 2021 
Amendment 4 15 April 2020 
Amendment 3 22 July 2019 
Amendment 2 05 April 2019 
Amendment 1 19 December 2018 
Original Protocol 13 November 2018 
Sponsor:
Travere Therapeutics, Inc.
3611 Valley Centre Drive, Suite 300 
San Diego, CA 92130 
USA 
+1 888-969-7879
CONFIDENTIAL 
This document is the property of Travere Therapeutics, Inc. and contains information that is of 
a confidential, trade secret, and/or proprietary nature. It is intended for use by Travere 
Therapeutics, Inc. and its designees, and no portion may be photocopied, disclosed, or 
transmitted to any unauthorized person without the written approval of 
Travere Therapeutics, Inc. 
 
 
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INVESTIGATOR’S AGREEMENT 
This protocol was designed and will be conducted, recorded, and reported in accordance with 
the principles of GCP as stated in the ICH of Technical Requirements for Registration of 
Pharmaceuticals for Human Use and any applicable national and regional laws. 
I have read and agree to abide by the requirements of this protocol. 
Investigator’s Signature 
Date 
Investigator’s Name: 
Institution Name: 
Institution Address: 
Institution Phone Number: 
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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Travere Therapeutics, Inc. 
Name of Investigational Product: 
Chenodeoxycholic Acid (CDCA) 
Name of Active Ingredient: 
chenodeoxycholic acid; 3α, 7α-dihydroxy-5β-cholan-24-oic acid 
Protocol No.:  Cheno-CTX-301 
Phase: 3 
Country: Global 
Title of Study:  
A Phase 3 Study to Evaluate the Effects of Chenodeoxycholic Acid in Adult and Pediatric Patients with 
Cerebrotendinous Xanthomatosis (RESTORE) 
Study Center(s):  
Approximately 10 investigational study centers globally will participate in this study. 
Studied Period (years):  
Estimated date first patient enrolled:  
November 2019 
Estimated date last patient completed:  December 2023 
Phase of Development:  
Phase 3 
Objectives:  
Efficacy Objective:  
• 
Determine the effects of chenodeoxycholic acid (CDCA), compared with placebo, on biomarkers 
and clinical symptoms of cerebrotendinous xanthomatosis (CTX) in adult patients with CTX. 
Safety Objective:  
• 
Assess the safety and tolerability of CDCA in adult and pediatric patients. 
Exploratory Objectives: 
• 
Characterize the relationship among biomarkers in adult and pediatric patients. 
• 
Characterize steady-state pharmacokinetics (PK) of CDCA and 2 conjugated forms of CDCA, 
GlycoChenodeoxycholic Acid (gCDCA) and TauroChenodeoxycholic Acid (tCDCA) in adult 
patients. 
• 
Characterize the relationship between dose and PK concentration among pediatric patients. 
• 
Assess biomarkers and health status among pediatric patients treated with CDCA. 
Methodology:  
This study is made up of 2 designs: a randomized, double-blind (DB), crossover study design among 
patients ≥16 years of age at Screening (adult cohort) and an open-label (OL), dose-titration, and 
maintenance study design among pediatric patients ≥1 month and <16 years of age at Screening 
(pediatric cohort).  
 
 
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4-Week DB1: On Day 1, patients will be randomized to treatment sequence AB or BA. Patients
randomized to sequence AB will receive blinded 250 mg CDCA TID for 4 weeks or until rescue
medication criteria are triggered; patients randomized to sequence BA will receive placebo TID for
4 weeks or until rescue medication criteria are triggered. Should rescue medication criteria be met,
patients will receive 250 mg CDCA TID until the end of DB1. Patients will return to the clinic on
Day 8 and weekly thereafter for the remaining 3 weeks.
8-Week OL2: Upon completion of DB1, patients will receive open-label 250 mg CDCA TID for
8 weeks and return to the clinic for biweekly scheduled visits.
4-Week DB2: At Week 12, patients who were randomized to sequence AB will crossover into DB2
and receive placebo treatment TID for 4 weeks or until rescue medication criteria are triggered;
patients who were randomized to sequence BA will receive blinded 250 mg CDCA TID treatment for
4 weeks or until the rescue medication criteria are triggered. Should rescue medication criteria be met,
patients will receive 250 mg CDCA TID until the end of DB2. Patients will return to the clinic on
Day 92 (7 days after the first day of the DB2 period), and weekly thereafter for the remaining 3 weeks.
Rescue Medication Criteria in the Adult Cohort: 
Blinded or open-label 250 mg CDCA TID rescue medication will be provided during the DB periods, 
if needed, based on blinded biomarkers (blinded rescue) and/or clinical CTX-related symptoms 
(open-label rescue). Patients who require blinded and/or open-label CDCA rescue medication in a 
given period will remain on the rescue medication for the remainder of the respective DB period. 
Patients who require rescue medication during DB1 but otherwise remain eligible should continue to 
OL2 and then to DB2.  
Blinded CDCA will be provided to patients who meet the following criterion: increase of 10 times the 
baseline value for a given period (ie, Visits 6 and 14) in urine 23S-pentol. Blinded CDCA will be 
assigned through the Interactive Voice/Web Response System (IxRS) at the next scheduled in-clinic 
visit. The Investigator and patient will remain blinded to biomarker data, treatment assignment, and if 
blinded rescue medication criteria are met.  
Patients receiving either blinded CDCA or blinded placebo during the DB period will be rescued with 
open-label CDCA at the discretion of the Investigator if they present with new or worsening 
CTX-related symptoms relative to their respective pretreatment assessments as defined in the protocol. 
The Investigator is responsible for evaluating patients to determine if they meet the criteria for rescue 
medication at each follow-up visit during DB1 and DB2 (Appendix 1). 
Extension of an Open-Label Period as a Result of COVID-19: 
An adult cohort patient’s participation in an OL period (ie, OL1 or OL2) may be extended to delay the 
start of a DB withdrawal period (ie, DB1 or DB2) if study and/or site operations are disrupted as a 
result of the Coronavirus Disease 2019 (COVID-19) pandemic. The decision to postpone the start of a 
DB period will be at the discretion of both the Investigator and Medical Monitor. If it is decided to 
extend an OL period, the patient will return to the study site once a month from the Visit 4 (OL1) or 
Visit 12 (OL2) date or last dispensation of OL study medication during the respective OL period. 
During these extension visits, the Investigator will ensure patient safety monitoring and dispensation of 
additional OL study medication is performed. Efficacy assessments during the extension visits are 
optional. See Appendix 6 for the Schedule of Assessments. 
Patients will continue to receive 250 mg open-label CDCA TID during the extension periods. Details 
within the clinical study protocol regarding study medication in the OL1 and OL2 periods are 
applicable for the extension periods. A patient's total duration on treatment may extend beyond 
24 weeks if an extension visit is required because of COVID-19. 
A patient may proceed with the start of a DB withdrawal period when the Investigator and Medical 
Monitor agree that the impact to site and/or study operations because of COVID-19 has stabilized. The 
Investigator and Medical Monitor will consider the site’s ability to perform study visits without 
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interruption and the timely reporting of necessary study results. A patient will resume the patient 
schedule as detailed in Appendix 1 when starting a DB period. 
If a patient completes 2 or more extension visits in 1 OL period, the patient must complete a study 
Visit 2 weeks prior to the start of a DB period to complete all safety and efficacy assessments that were 
otherwise required during a visit in the OL period. 
Visits at an alternative site by a trained medical professional (eg, licensed nurse) will be permitted to 
reduce the travel burden for patients. The visits that qualify for being conducted at an alternative site by 
a home health vendor are indicated in the Schedule of Assessments (Appendix 6). 
Study Design Diagram for Extension of Open-Label Period in the Adult Cohort: 
 
PEDIATRIC COHORT: 
Pediatric cohort patients (≥1 month and <16 years at Screening) will participate in a 24-week, 
open-label cohort with an 8-week titration period to identify a safe and tolerable dose and a 16-week 
treatment period at the safe and tolerated dose as maintenance. Patients will be screened at Visit 1 
(Appendix 2) and those who satisfy all the inclusion criteria and none of the exclusion criteria will be 
eligible to participate in this cohort to evaluate safety, PK, and biomarkers in this population. Patients 
will have visits every week during the titration period and every 4 weeks during the treatment period.  
During the dose-titration period, dose escalation decisions will be based on safety and tolerability 
(Section 6.5.1). 
Dosing will be as follows: 
• 
Treatment-naïve pediatric cohort patients will receive doses of 5 mg/kg/day (TID), 10 mg/kg/day 
(TID), or 15 mg/kg/day (TID) titrated up every 2 weeks based on safety and tolerability over a 
period of 8 weeks. 
• 
Treatment-experienced pediatric cohort patients currently taking a dose ≥5 mg/kg/day of CDCA 
will start at their current dose and titrate up every 2 weeks to the next dose level up to 
15 mg/kg/day based on safety and tolerability over a period of 8 weeks. Patients with a history 
demonstrating intolerance at higher doses will not be required to dose escalate.  
• 
Pediatric dosing of CDCA will not exceed an equivalent dose of 750 mg/day.  
• 
Pediatric cohort patients who are able to take an equivalent weight-based dose of 750 mg/day and 
are capable of swallowing a tablet will have the option to dose with CDCA 250 mg tablets TID or 
the liquid suspension form of CDCA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
   
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
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treatment-naïve patients, serum cholestanol and urine 23S-pentol levels will be obtained prior 
to initiating open-label CDCA.  
4. If the patient is currently being treated with CDCA at a dose different than the 
protocol-specified dose, the patient must be willing to change his or her current dose. 
5. With Medical Monitor approval, patients currently taking CDCA and riluzole for the treatment 
of ataxia are eligible, provided their ataxia is well controlled and they have been on a stable 
dose of riluzole for a minimum of 6 months. 
6. Women of childbearing potential (WOCBP), beginning at menarche, must agree to the use of 
1 highly reliable (ie, can achieve a failure rate of <1% per year) method of contraception 
during the course of the study. Highly reliable contraception methods include stable oral, 
implanted, transdermal, or injected contraceptive hormones associated with inhibition of 
ovulation, or an intrauterine device (IUD) in place for at least 3 months. One additional barrier 
method must also be used during sexual activity, such as a diaphragm with spermicide or male 
partner’s use of male condom with spermicide, during the course of the study. WOCBP are 
defined as those who are fertile, following menarche and until becoming postmenopausal 
unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea 
for more than 24 consecutive months without an alternative medical cause; women on 
hormone replacement therapy must have a documented plasma follicle-stimulating hormone 
level >40 mIU/mL. All WOCBP must have a negative serum pregnancy test at Screening. 
NOTE: Prior to menarche, pregnancy testing and contraceptive use is not required. However, 
the patient and their parent/legal guardian must be advised that, immediately upon menarche, 
the patient will be required to begin pregnancy testing and initiate contraceptive use. This 
requirement cannot be avoided. 
7. Males must be surgically sterile (more than 3 months post-vasectomy) or males and their 
sexual partners must together agree to the use of medically accepted methods of contraception 
that are considered highly reliable during the course of the study. 
8. The patient and/or his/her parent/legal guardian is willing and able to comply with the 
protocol. 
Exclusion Criteria: 
A patient who meets any of the following criteria will be excluded from this study: 
1. The patient has a negative genetic sequencing result for CTX. 
2. The patient is known to have another malabsorption disorder or confounding inflammatory 
gastrointestinal condition (eg, irritable bowel syndrome). 
3. The patient has been diagnosed with New York Heart Association (NYHA) Class II – IV heart 
failure. 
4. If the patient is receiving anticoagulants and, in the judgment of the Investigator, is not 
well-controlled. 
5. The patient is taking medications which impact bile acid absorption such as bile acid 
sequestering agents (eg, cholestyramine, colestipol, aluminum-based antacids). 
6. The patient is taking cholic acid medication. 
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7. The patient is pregnant or lactating or presents with a positive serum pregnancy test at 
Screening or a positive urine pregnancy test at the first day of OL1 for adult cohort or Titration 
Start for pediatric cohort. 
8. The patient has been (or is currently) enrolled in a clinical study involving study medication or 
device within 30 days prior to Screening. 
9. The patient has other prior or ongoing medical conditions, physical findings, or laboratory 
abnormalities that, in the Investigator’s opinion, could adversely affect the safety of the patient, 
make it unlikely that the course of treatment or follow up would be completed, or impair the 
assessment of study results. 
10. The patient has a history of drug or alcohol abuse within the past year that, in the judgment of 
the Investigator, could affect participation in or adherence to the requirements of the study. 
11. The patient has a positive serologic test for hepatitis B virus surface antigen, hepatitis C, or 
human immunodeficiency virus at Screening. 
12. The patient and/or his/her parent/legal guardian, in the opinion of the Investigator, is unable to 
adhere to the requirements of the study. 
Inclusion Criteria Pre-Randomization for the Adult Cohort: 
Patients in the adult cohort who meet all inclusion criteria and none of the exclusion criteria for 
participation into the run-in period AND 
1. Tolerate CDCA treatment, in the judgment of the Investigator. 
2. Have not developed any condition that, in the judgment of the Investigator, warrants 
discontinuation of CDCA. 
Patients who fail screening may be rescreened as needed. 
Study Medication, Dosage and Mode of Administration:  
Adult cohort patients (≥16 years): CDCA tablets, 250 mg TID, oral 
Pediatric cohort patients (≥1 month and <16 years): CDCA tablets will be carefully crushed by the 
pharmacist, added to a sodium bicarbonate solution 8.4% (1 mmol/mL) to create a 10 mg/mL liquid 
suspension (ie, one 250 mg tablet per 25 mL) and supplied for oral administration. Patients who are 
able to take an equivalent weight-based dose of 750 mg/day and are capable of swallowing a tablet will 
have the option to take CDCA 250 mg tablets TID or the liquid suspension form of CDCA. 
Doses will be 5 mg/kg/day (TID), 10 mg/kg/day (TID), and 15 mg/kg/day (TID) depending upon the 
safe and tolerated titrated dose.  
• 
Treatment-naïve pediatric cohort patients will receive doses of 5 mg/kg/day (TID), 10 mg/kg/day 
(TID), or 15 mg/kg/day (TID) titrated up every 2 weeks based on safety and tolerability over a 
period of 8 weeks. 
• 
Treatment-experienced pediatric cohort patients currently taking a dose ≥5 mg/kg/day of CDCA 
will start at their current dose and titrate up every 2 weeks to the next dose level up to 
15 mg/kg/day based on safety and tolerability over a period of 8 weeks. Patients with a history 
demonstrating intolerance at higher doses will not be required to dose escalate. Pediatric dosing of 
CDCA will not exceed an equivalent dose of 750 mg/day. 
Patients currently taking Chenodal® and/or an alternative therapy for CTX are required to stop their 
medication/therapy prior to the start of study medication in OL1 for the adult cohort or the titration 
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period for the pediatric cohort. Patients may resume or start taking Chenodal® and/or an alternative 
therapy for CTX after completing the study (ie, EOS visit) or permanently discontinuing study 
medication. 
Duration of Study: 
The adult cohort will be approximately 24 to 28 weeks in duration, including an up to 4-week 
screening period; an 8-week, open-label run-in period (OL1); two 4-week, DB treatment periods (DB1 
and DB2); and an 8-week open-label treatment period (OL2) in between DB1 and DB2. The duration 
of the adult cohort may extend beyond 28 weeks if the start of a double-blind period is delayed due to 
COVID-19. 
The pediatric cohort will be approximately 24 to 28 weeks in duration, including an up to 4-week 
screening period; an 8-week, open-label dose-titration period; and a 16-week, open-label treatment 
period at the identified safe and tolerated dose as maintenance.  
If genetic results are still pending after 28 days, the screening window for both cohorts may be 
extended up to 2 additional weeks, with approval by the Medical Monitor, which will bring the 
maximum total duration of the study to 30 weeks. 
For both cohorts, a safety follow-up phone call will be conducted 30 (±7) days after the last dose of 
study medication. 
Reference Therapy, Dosage and Mode of Administration:  
CDCA will be compared with placebo in the adult cohort. There is no reference therapy. 
Criteria for Evaluation: 
Efficacy: Urine bile alcohols (23S-pentol), plasma bile alcohols (tetrol glucuronide), plasma 
cholestanol, plasma7αC4, and plasma 7α12αC4. 
Rescue or Disease Progression: Patient diary and health status questionnaire, clinician global 
impression of change, and developmental milestones (pediatric cohort only). 
Safety: Evaluation of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
vital signs, safety laboratory tests (hematology, chemistry, coagulation [adult cohort only], lipid profile 
[including cholesterol], and urinalysis), 12-lead electrocardiogram (ECG), electroencephalogram 
(EEG), and physical examination (including body weight). 
Primary Efficacy Endpoint for the Adult Cohort: 
• 
Change from baseline in loge-transformed urine 23S-pentol at the end of each DB 
treatment period 
Key Secondary Efficacy Endpoints for the Adult Cohort: 
• 
Proportion of patients requiring rescue medication during the DB periods 
• 
Percent change from baseline in plasma cholestanol levels at the end of each DB treatment 
period 
• 
Percent change from baseline in plasma 7αC4 at the end of each DB treatment period 
Other Secondary Efficacy Endpoints for the Adult Cohort: 
• 
Change from baseline in plasma cholestanol to cholesterol ratio during the DB periods 
• 
Percent change from baseline in plasma 7α12αC4 at the end of each DB treatment period 
• 
Proportion of patients with negative net change in symptoms and manifestations reported 
in the diary during the DB periods 
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Safety Endpoints for both Adult and Pediatric Cohorts: 
• 
Change from baseline in body weight, vital signs, physical examinations, EEG, 12-lead 
ECG, clinical laboratory parameters (hematology, chemistry, coagulation [adult cohort 
only], lipid profile [including cholesterol]), and urinalysis laboratory parameters at each 
visit where parameters are collected 
• 
Incidence of TEAEs, including SAEs, adverse events (AEs) leading to discontinuation of 
study medication, and AEs of interest (AEOI) 
Exploratory Endpoints for Both Adult and Pediatric Cohorts: 
Adult cohort patients: 
• 
Percent change from baseline in plasma bile alcohol at the end of each DB treatment 
period  
• 
Steady-state PK parameters of 3 bile acids that include CDCA, gCDCA, and tCDCA and 
total CDCA (summed CDCA, gCDCA, and tCDCA). (AUCss, Cmax,ss, Cmin,ss, tmax,ss, CL/F)  
• 
Relationships among biomarkers (urine and plasma bile alcohols, plasma cholestanol, 
plasma 7αC4, and plasma 7α12αC4) 
• 
Relationships between PK exposure parameters (AUCss, Cmax,ss or Cmin,ss) and changes in 
biomarker levels (urine and plasma bile alcohols, plasma cholestanol, plasma 7αC4 and 
plasma 7α12αC4) 
• 
Relationships between PK exposure parameters (AUCss, Cmax,ss, or Cmin,ss) and safety 
endpoints 
• 
Change in disease severity as assessed by the CGI-C during each DB treatment period 
• 
Change in health status questionnaire 
Pediatric cohort patients: 
• 
Relationships among biomarkers (urine and plasma bile alcohols, plasma cholestanol, 
plasma 7αC4, and plasma 7α12αC4) 
• 
Steady-state PK concentration of CDCA, gCDCA, and tCDCA and total CDCA (summed 
CDCA, gCDCA, and tCDCA) 
• 
Mean biomarker levels (urine and plasma bile alcohols, plasma cholestanol, plasma 7αC4, 
and plasma 7α12αC4) 
• 
Change in disease severity as assessed by the CGI-C during the treatment period 
• 
Change in health status questionnaire 
• 
Change in developmental milestones 
 
Statistical Methods: 
Descriptive statistics will be produced separately for adult and pediatric cohorts. The following 
sections describe inferential statistical testing procedures for efficacy endpoints collected during the 
double-blind period among adult cohort patients.  
Analysis of Efficacy Endpoints: 
The primary analysis of the primary endpoint of change from baseline in loge-transformed urine 
23S-pentol at the end of each DB treatment period will be conducted via a paired t-test comparing 
CDCA with placebo using the Full Analysis Set (FAS; adult cohort). Log-transformation is performed 
due to the anticipated wide range of urine 23S-pentol levels among CTX patients. Urine 23S-pentol 
will be determined using first morning void urine samples and will be calculated as the geometric mean 
of 3 first morning void urine samples collected within 5 days prior to each visit at which urine 
23S-pentol is assessed. The baseline value for the first double-blind period is the measurement taken 
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for Day 1; the baseline value for the second double-blind period is the measurement taken at Day 85 at 
the beginning of the second double-blind period. Measurements obtained after initiation of rescue 
medication will be considered “missing” for purposes of the primary analysis. An appropriate multiple 
imputation method will be used to impute missing values and the values after initiating rescue 
medication, under the assumption of missing at random. The imputed values, not the actual values 
obtained after the initiation of the rescue medication, will be used in the analysis. Further information 
on imputation of missing data methods and sensitivity analyses will be described in the Statistical 
Analysis Plan (SAP). Percent change from baseline in plasma cholestanol levels, and plasma 7αC4 and 
7α12αC4 levels at the end of each DB treatment period will be analyzed in a similar way as for the 
primary endpoint.  
The proportion of patients requiring rescue treatment and the corresponding exact 95% confidence 
interval (CI) will be presented for each treatment. Patients who require blinded and/or open-label 
CDCA during the DB periods will be considered to have met the event (ie, received rescue medication) 
for the primary analysis. The difference in proportions, the corresponding exact CI, and exact p-values 
will be calculated and presented using Prescott's method (Prescott 1981). This analysis will be 
performed on the FAS. 
Other continuous efficacy endpoints will be analyzed using the same approach described for the 
primary endpoint. Other binary efficacy endpoints (such as incidence of new or worsening in 
CTX-related clinical manifestations) will be analyzed using the same approach described for the 
proportion of patients requiring rescue treatment. 
Control of Type 1 Error 
The primary endpoint of urine 23S-pentol will be tested at the final analysis at an α = 0.05. If the test is 
significant, the Family One is rejected and the entire α = 0.05 is preserved and then passed onto Family 
Two of hypotheses (ie, key secondary endpoints) for testing at the final analysis. Otherwise, there is no 
remaining α to be passed onto Family Two, and therefore, the key secondary endpoints will not be 
formally tested, and nominal p-values will be reported instead. 
Analysis of Safety Endpoints: 
Descriptive statistics will be used to summarize the safety data by randomized treatment group among 
adult cohort patients based on the safety analysis set (SAS) and by administered dose among pediatric 
cohort patients based on the pediatric safety analysis set (PSAS). 
Clinical laboratory parameters will be measured at baseline and postbaseline visits. Each continuous 
laboratory variable will be summarized in terms of changes from baseline by treatment group. 
Laboratory data will also be classified as low, normal, or high relative to the parameter’s reference 
range. Laboratory abnormalities for each treatment will also be summarized using shift tables.  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary by 
System Organ Class and Preferred Term. AEs that begin after the first administration of study 
medication, or existing AEs that worsen after the first dose of study medication, are considered TEAEs. 
The number and percentage of patients reporting TEAEs will be summarized for each treatment group 
by MedDRA System Organ Class and Preferred Term, by severity, and by relationship to study 
medication. The number and percentage of patients reporting serious TEAEs, TEAEs leading to 
treatment discontinuation, and AEOIs will also be summarized for each treatment group by MedDRA 
System Organ Class and Preferred Term. 
Sample Size Justification for Adult Cohort: 
The hypothesis to be tested is H0: Δ = 0 against Ha: Δ ≠ 0, where Δ is the true paired treatment 
difference between CDCA and placebo for the change from baseline in loge-transformed urine 
23S-pentol. The planned sample size is expected to provide at least 90% power at the final analysis 
(approximately 12 patients; 2-sided nominal α = 0.0436).  
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For the proportion of patients requiring rescue medication (secondary endpoint), the planned sample 
size of approximately 12 patients at the final analysis is expected to provide at least 85% power with 
two sided nominal α = 0.0436. This assumes that 85% of patients (approximately 10/12) on placebo 
and 15% of patients (approximately 2/12) on CDCA will need rescue treatment, with a discordance of 
80%, based on McNemar’s test.  
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6.3.5.2. 
Pediatric Cohort Patients ............................................................................................35 
6.4. 
Treatment Assignment ................................................................................................35 
6.5. 
Dose Adjustment Criteria ...........................................................................................35 
6.5.1. 
Dose Titration in Pediatric Cohort ..............................................................................35 
6.6. 
Interruption or Permanent Discontinuation of Study Medication ..............................36 
6.6.1. 
Study Medication Interruption ....................................................................................36 
6.6.2. 
Permanent Discontinuation of Study Medication .......................................................37 
6.7. 
Discontinuation of the Patient from the Study ...........................................................38 
6.8. 
Early Termination Visit and Withdrawal Procedures .................................................39 
6.9. 
Lost to Follow-up .......................................................................................................39 
7. 
SELECTION OF PATIENTS .....................................................................................40 
7.1. 
Inclusion Criteria ........................................................................................................40 
7.2. 
Exclusion Criteria .......................................................................................................41 
7.3. 
Inclusion Criteria Pre-Randomization for the Adult Cohort ......................................41 
8. 
TREATMENT OF PATIENTS ..................................................................................42 
8.1. 
Study Medication ........................................................................................................42 
8.2. 
Description of Study Medication ................................................................................42 
8.3. 
Rescue Medication Criteria in the Adult Cohort ........................................................43 
8.4. 
Concomitant Medications ...........................................................................................44 
8.5. 
Prohibited Medications ...............................................................................................44 
8.6. 
Treatment Compliance ................................................................................................44 
8.7. 
Randomization and Blinding for the Adult Cohort ....................................................45 
9. 
STUDY MEDICATION MATERIALS AND MANAGEMENT .............................46 
9.1. 
Chenodeoxycholic Acid ..............................................................................................46 
9.1.1. 
CDCA Packaging and Labeling ..................................................................................46 
9.1.2. 
CDCA Storage ............................................................................................................46 
9.1.3. 
CDCA Preparation ......................................................................................................46 
9.1.4. 
Blinded CDCA and Open-Label CDCA .....................................................................46 
9.2. 
Placebo in Adult Cohort .............................................................................................46 
9.3. 
Blinded CDCA and Placebo Administration in Adult Cohort ....................................47 
9.4. 
Open-Label CDCA Administration in Pediatric Cohort ............................................47 
9.5. 
Study Medication Accountability ...............................................................................47 
9.6. 
Blinded CDCA and Placebo Handling .......................................................................48 
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9.7. 
Study Medication During the Adult and Pediatric Open-Label Periods and 
Adult Open-Label Rescue Period ...............................................................................48 
10. 
STUDY PROCEDURES ............................................................................................48 
10.1. 
Study Visits in the Adult Cohort ................................................................................48 
10.2. 
Study Visits in the Pediatric Cohort ...........................................................................49 
11. 
SCREENING ASSESSMENTS .................................................................................49 
12. 
ASSESSMENT OF EFFICACY OR DISEASE PROGRESSION ............................50 
12.1. 
Biomarker Efficacy Assessments ...............................................................................50 
12.1.1. 
Urine 23S-Pentol ........................................................................................................50 
12.1.2. 
Plasma Bile Alcohols (plasma tetrol-glucuronide) .....................................................50 
12.1.3. 
Plasma 7αC4 and 7α12αC4 ........................................................................................50 
12.1.4. 
Plasma Cholestanol .....................................................................................................51 
12.2. 
Assessments in the Patient Diary ................................................................................51 
12.3. 
Assessments Performed at Clinic Visits .....................................................................51 
12.3.1. 
Clinician Global Impression Scale .............................................................................51 
12.3.2. 
Health Status Questionnaire .......................................................................................52 
12.3.3. 
Motor Developmental Milestones (Pediatric Cohort Patients) ...................................52 
12.4. 
Documentation of Rationale for Rescue Treatment Based Upon 
Investigator’s Clinical Judgment ................................................................................52 
13. 
PHARMACOKINETIC ASSESSMENTS .................................................................52 
13.1. 
Adult Cohort ...............................................................................................................52 
13.2. 
Pediatric Cohort ..........................................................................................................54 
14. 
ASSESSMENT OF SAFETY .....................................................................................54 
14.1. 
Safety Parameters .......................................................................................................54 
14.1.1. 
Demographic/Medical History ...................................................................................54 
14.1.2. 
Vital Signs ..................................................................................................................54 
14.1.3. 
Weight and Height ......................................................................................................54 
14.1.4. 
Physical Examination .................................................................................................54 
14.1.5. 
Electroencephalogram (EEG) .....................................................................................55 
14.1.6. 
Electrocardiogram (ECG) ...........................................................................................55 
14.1.7. 
Laboratory Assessments .............................................................................................55 
14.2. 
Adverse Event Reporting ............................................................................................56 
14.2.1. 
Adverse Event (AE) ....................................................................................................56 
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14.2.2. 
Serious Adverse Event (SAE) ....................................................................................57 
14.2.3. 
Evaluation of Adverse Events/Serious Adverse Events .............................................57 
14.2.3.1. 
Causality Assessment .................................................................................................57 
14.2.3.2. 
Severity .......................................................................................................................58 
14.2.3.3. 
Outcome ......................................................................................................................58 
14.2.3.4. 
Action Taken Regarding the Study Medication .........................................................58 
14.2.3.5. 
Assessment of Expectedness ......................................................................................59 
14.2.4. 
Adverse Events of Interest ..........................................................................................59 
14.2.5. 
Reporting Adverse Events and Serious Adverse Events and Adverse Events 
of Interest ....................................................................................................................60 
14.2.5.1. 
Reporting Adverse Events ..........................................................................................60 
14.2.5.2. 
Reporting Serious Adverse Events .............................................................................61 
14.2.6. 
Pregnancy Reporting ..................................................................................................62 
15. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ..........63 
15.1. 
Recording of Data .......................................................................................................63 
15.2. 
Data Quality Assurance ..............................................................................................63 
15.3. 
Data Management .......................................................................................................63 
16. 
STATISTICS ..............................................................................................................64 
16.1. 
Sample Size Justification and Power Analysis for Adult Cohort ...............................64 
16.2. 
Analysis Sets ...............................................................................................................64 
16.2.1. 
Adult Cohort ...............................................................................................................64 
16.2.2. 
Pediatric Cohort ..........................................................................................................65 
16.3. 
Demographics and Baseline Characteristics ...............................................................65 
16.4. 
Analysis of Efficacy Endpoints ..................................................................................65 
16.4.1. 
Analysis of Primary Efficacy Endpoint of Urine 23S-Pentol .....................................65 
16.4.2. 
Analysis of Key Secondary Efficacy Endpoints .........................................................66 
16.4.3. 
Analysis of Other Secondary Endpoints .....................................................................66 
16.5. 
Control of Type 1 Error ..............................................................................................67 
16.6. 
Analysis of Safety Endpoints ......................................................................................68 
16.7. 
Analysis of Pharmacokinetics Endpoints ...................................................................68 
16.8. 
Interim Analysis ..........................................................................................................68 
17. 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................69 
17.1. 
Unblinded Data Monitoring Committee .....................................................................69 
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17.2. 
Changes to the Conduct of the Study or Protocol .......................................................70 
17.3. 
Investigator’s Responsibilities ....................................................................................70 
17.3.1. 
Patient Informed Consent ...........................................................................................71 
17.3.2. 
Case Report Forms .....................................................................................................71 
17.3.3. 
Record Retention ........................................................................................................72 
17.3.4. 
Monitoring ..................................................................................................................72 
17.3.5. 
Study or Site Termination ...........................................................................................73 
17.3.6. 
Study Medication Control ...........................................................................................73 
17.3.6.1. 
Receipt of Study Medication ......................................................................................73 
17.3.6.2. 
Disposition of Unused Study Medication ...................................................................74 
17.3.7. 
Product Handling and Complaints Reporting .............................................................74 
17.3.8. 
Insurance .....................................................................................................................74 
17.3.9. 
Data Confidentiality ....................................................................................................74 
17.3.10. 
Clinical Study Report .................................................................................................75 
18. 
PUBLICATION POLICY ..........................................................................................75 
19. 
REFERENCES ...........................................................................................................76 
20. 
APPENDICES ............................................................................................................78 
 
LIST OF TABLES 
Table 1: 
Dose Titration Criteria for 8-Week Titration Period in Pediatric Cohort ...................36 
Table 2: 
Study Medication ........................................................................................................43 
Table 3: 
Timing of Standardized Low-fat Meal, Pharmacokinetic Sample Draws, and 
Study Medication Administration for the Adult and Pediatric Cohorts .....................53 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram for Adult Cohort ....................................................................31 
Figure 2: 
Study Design Diagram for Extension of Open-Label Period in the Adult 
Cohort .........................................................................................................................32 
Figure 3: 
Study Design Diagram for Pediatric Cohort ...............................................................33 
Figure 4: 
The Multiple Comparison Procedure for Type 1 Error Control .................................67 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviations used throughout the protocol should not be used by the site when documenting 
adverse events, medical history, etc. on source documents. 
Abbreviation 
Definition 
AE 
Adverse event 
AEOI 
Adverse event of interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANDA 
Abbreviated New Drug Application 
API 
Active Pharmaceutical Ingredient 
AST 
Aspartate aminotransferase 
AUCss 
Area under the plasma concentration-time curve at steady state 
BCVA 
Best-corrected visual acuity 
BLQ 
Below the level of quantification 
BM 
Bowel movement 
BMI 
Body Mass Index 
BSFS 
Bristol Stool Form Scale 
C24H40O4 
3α, 7α-dihydroxy-5β-cholan-24-oic acid (CDCA chemical formula) 
7αC4 
7-alpha-hydroxy-4-cholesten-3-one 
7α12αC4 
7-alpha,12-alpha-dihydroxy-4-cholesten-3-one 
CDCA 
Chenodeoxycholic acid 
CFR 
Code of Federal Regulations 
CGI-C 
Clinician Global Impression of Change 
CGI-S 
Clinician Global Impression of Severity 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences  
CL/F 
Apparent total clearance of the drug from plasma after oral administration 
Cmax,ss 
Maximum (peak) steady-state plasma drug concentration during a dosage 
interval 
Cmin,ss 
Minimum steady-state plasma drug concentration during a dosage interval 
COVID-19 
Coronavirus Disease 2019 
CRO 
Clinical Research Organization 
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Abbreviation 
Definition 
CTX 
Cerebrotendinous xanthomatosis 
CV 
Coefficient of variation 
DB 
Double-blind 
DB1 
Double-blind period 1 
DB2 
Double-blind period 2 
DMC 
Data Monitoring Committee 
EAS 
Enrolled analysis set 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEG 
Electroencephalogram 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
ET 
Early termination 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FTT 
Failure to thrive 
GC-MS 
Gas chromatography-mass spectrometry 
gCDCA 
GlycoChenodeoxycholic acid 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDL 
High-density lipoprotein 
HEENT 
Head, eyes, ears, nose, and throat 
HEP 
Hepatitis 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
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Abbreviation 
Definition 
IUD 
Intrauterine device 
IxRS 
Interactive voice/web response system 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDL 
Low density lipoprotein 
LFT 
Liver function test 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NA 
Not applicable 
NIFAS 
Newly-initiated Full Analysis Set 
NYHA 
New York Heart Association 
OL 
Open-label 
OL1 
Open-label period 1 
OL2 
Open-label period 2 
PE 
Physical Examination 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PKAS 
Pharmacokinetic Analysis Set 
PPAS 
Per Protocol Analysis Set 
PRO 
Patient-reported Outcomes 
PSAS 
Pediatric Safety Analysis Set 
PT 
Prothrombin time 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Standard deviation 
SE 
Standard error 
SED 
Single enzyme defect 
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Abbreviation 
Definition 
SOA 
Schedule of assessments 
SoC 
Standard of care 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
Total bilirubin 
tCDCA 
TauroChenodeoxycholic acid 
TEAE 
Treatment-emergent adverse event 
TEFAS 
Treatment-experienced Full Analysis Set 
TID 
Three times a day 
tmax,ss 
Time to reach maximum (peak) plasma concentration following drug 
administration at steady state 
UBA 
Urinary bile alcohols  
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 
 
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4.
INTRODUCTION
Cerebrotendinous xanthomatosis (CTX) is an inborn metabolic disorder of bile acid synthesis 
caused by a single enzyme defect (SED) (sterol 27-hydroxylase). To date, only a few hundred 
patients with CTX have been identified, but the exact prevalence of CTX is unknown 
(DeBarber 2014b). Clinical manifestations of CTX occur in multiple organ systems (including 
enterohepatic, tendon, ocular, and peripheral and central nervous systems) with the onset of 
neurologic impairment in the second and third decades of life and early death in the fifth or sixth 
decades of life if the condition goes undiagnosed (Duell 2018; Salen 1975; Salen 1987; 
Salen 2017; Berginer 1984). 
CTX is caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of 
a defective sterol 27-hydroxylase enzyme (Salen 2017). This enzyme is critical for the synthesis 
of bile acids, including chenodeoxycholic acid (CDCA). This deficiency leads to a virtual 
absence (<5%) of CDCA in bile (Shefer 1975), resulting in an increase in the production of 
atypical bile acids, bile alcohols (including urine 23S-pentol), and cholestanol. 
CTX is associated with elevated levels of cholestanol in the blood and deposition of cholestanol 
and cholesterol in the brain, tendon xanthomas, and bile (Salen 2017); these abnormalities 
represent the primary mechanisms for many of the neurological and motor symptoms associated 
with the disease (Keren 2009). 
There is a significant unmet need in CTX in that currently there is no labeled medication that is 
indicated for treatment of CTX. Over the past 35 years, the understanding of the pathophysiology 
of CTX has led to the use of CDCA as a direct replacement therapy option. Exogenous 
administration of CDCA restores the physiologic bile acid pool and provides the necessary 
feedback to reduce the production of cholestanol and bile alcohols, potentially altering the rate of 
disease progression (Berginer 2009; Price Evans 2007; Yahalom 2013). 
Although Chenodal® (chenodiol) is the standard of care (SoC) in the United States (US) for 
CTX, it has not received marketing approval for treatment of CTX but is currently supplied 
under medical necessity (Abbreviated New Drug Application [ANDA] 091019). The chemical 
name for chenodiol is 3α, 7α-dihydroxy-5β-cholan-24-oic acid (C24H40O4). Additional 
information on the study medication and nonclinical studies conducted for the approval of 
Chenix (chenodeoxycholic acid), now marketed under the proprietary name Xenbilox, for the 
treatment of radiolucent gallstones can be found in the Investigator’s Brochure (IB). No 
prospectively designed clinical study has been conducted for the CTX indication. 
4.1. 
Rationale for Study Design 
4.1.1. 
Adult Cohort 
For patients in the adult cohort, this study will be a randomized, double-blind (DB), placebo-
controlled, 2-period × 2-treatment crossover trial with rescue medication to assess the efficacy 
and safety of CDCA in patients with CTX who are ≥16 years of age. The rationale for including 
adolescents who are at least 16 years of age in the adult cohort is based upon the likelihood that 
most patients of this age would be prescribed the adult dose of 250 mg 3 times a day (TID). The 
50th percentile of weight for males and females at 191.5 months of age as indicated in the Center 
for Disease Control weight-for-age charts is 60.7 kg for males and 53.8 kg for females 
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(https://www.cdc.gov/growthcharts/html_charts/wtage.htm). At 15 mg/kg/day, the dose for both 
males and females in the 50th percentile for weight would be above 750 mg. Additionally, there 
is past experience with treating pediatric and adolescent patients with the adult dose of 250 mg 
TID (Berginer 2009; Duell 2018). Most adolescents who are 16 and 17 years old are essentially 
fully grown, and drug metabolism is more similar to adults than children at this point. Patients in 
the adult cohort are also followed closely with assessments so any progression of disease or 
change in biomarkers will be identified quickly during the withdrawal period. Parent or legal 
guardian consent and patient assent, if in the Investigator’s opinion the patient is able to 
understand and provide assent, will still be required for all patients less than 18 years old 
regardless of cohort assignment unless otherwise directed by a reviewing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC).  
Approximately 12 male and/or female CDCA-naïve or CDCA-treated patients with CTX 
meeting all inclusion criteria and none of the exclusion criteria and whose clinical symptoms are 
stable during the open-label run-in period are planned to be randomized in the study. The 
randomized withdrawal design is intended to directly assess the impact of withdrawing CDCA 
treatment on biomarkers and symptoms. Owing to CDCA being the treatment of choice (or SoC) 
for CTX, treating physicians are extremely hesitant to take patients off CDCA treatment for any 
period. Extensive consultation with treating physicians and experts also indicates that appropriate 
measures to protect a patient’s well-being and unnecessary progression due to withholding 
CDCA treatment should be established within the study. A maximal duration of placebo 
withdrawal of 4 weeks with available CDCA rescue is planned to ensure the safety of 
participating patients.  
The crossover design with 2 double-blind periods allows for patients to be their own controls to 
account for the heterogeneity of disease manifestations across patients. Multiple measurements 
are planned to be taken within each period to account for intra-patient variability. 
The 8-week open-label periods are intended to establish baseline levels of biomarkers and 
determine individual patient symptoms and clinical manifestations while on CDCA. 
Analyses of bile alcohols reported in the published literature (data on file) showed a mean 
reduction from baseline to end of treatment (EOT) of 91% with very low variability (standard 
deviation [SD] = 13.4%). Every individual had a significant reduction in bile alcohol; the 
smallest reduction was 52.9%. This observation indicates a consistent and dramatic effect of 
CDCA on reduction of bile alcohols. Reductions in bile alcohols were present after less than 
1 month of treatment with CDCA with a mean reduction from baseline to EOT of 94% 
(SD = 1.042%) observed (n = 4). The effect appeared to be sustained in patients with a treatment 
duration between >1 month and >48 months. 
CDCA reduced cholestanol levels in patients with CTX. Reductions were observed within 
1 month of treatment and the reduction was even greater with longer term treatment. Evidence 
supports the stability of the response with treatment durations of more than 4 years 
(Koopman 1985).  
Patients from the published literature with available baseline cholestanol levels had a mean (SD) 
baseline cholestanol level of 3.132 (3.4307) mg/dL. At EOT, a mean percent reduction from 
baseline of 75.3% was observed with low variability (SD = 19.6%). Following treatment 
initiation, no patients with CTX had an increase in cholestanol levels, while in some patients, 
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cholestanol levels were undetectable. The only patients whose cholestanol level did not decrease 
were those with normal cholestanol levels at baseline (Koopman 1985).  
Consistent results were observed when data was broken down by treatment duration. After less 
than a month of treatment, a mean percent reduction from baseline of 64.7% was observed with a 
low variability (SD = 22.7%). Similar reductions were observed between 1 month and 48 months 
of treatment and after 48 months or more of treatment with CDCA (approximately 71.7% and 
84.5%, respectively). Results suggest that a sustainable change in cholestanol levels could be 
observed shortly after treatment initiation and occurs independently of age (Koopman 1985).  
Serum 7-alpha-hydroxy-4-cholesten-3-one (7αC4) and 7-alpha-12-alpha-dihydroxy-4-cholesten-
3-one (7α12αC4) have been proposed as important markers for diagnosis and monitoring of 
replacement therapy in CTX (DeBarber 2010; DeBarber 2014a; DeBarber 2014b;
Bjorkhem 2013). Circulating 7αC4 closely mirrors cholesterol 7α-hydroxylation rate, thus 
reflecting the activity of the “classic” pathway of bile acid synthesis (Bertolotti 2008). 
Furthermore, 7αC4 is strictly correlated with the accumulation of cholestanol in the brain in both 
CTX patients (Panzenboeck 2007) and mice with disruption of sterol 27-hydroxylase
(Båvner 2010). In a study of 19 previously untreated CTX patients followed over 4 years, the 
patients had significantly elevated (from 100-fold to 200-fold increased) plasma concentration of 
7αC4 compared to controls (p<0.01) (Mignarri 2016). Serum levels of 7αC4 consistently 
decreased after CDCA treatment; however, 7αC4 never normalized in half of patients, and some 
degree of accumulation appeared to persist in most patients. A significant positive correlation 
was found between plasma values of 7αC4 and cholestanol (ρ=0.78; p<0.01). In addition to 
7αC4, 7α12αC4 will also be assessed. 7α12αC4 is an intermediate of bile acid synthesis 
downstream from 7αC4. Circulating levels of 7αC4 are indicative of regulation of the bile acid 
synthetic pathway and show a degree of natural diurnal variation with variation observed in 
individuals without disease. In contrast, 7α12αC4 is almost undetectable in individuals without 
CTX and marked elevations are seen in patients with CTX. Thus, 7α12αC4 has emerged as a 
sensitive marker of misregulation of this pathway and is used in the diagnosis of the disease
(DeBarber 2014b).
This study will be conducted in accordance with the protocol and with the following: 
•
Declaration of Helsinki
•
Council for International Organizations of Medical Sciences (CIOMS) International
Ethical Guidelines
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice
(GCP) Guidelines
•
Applicable laws and regulations
4.1.2. 
Extension of an Open-Label Period as a Result of COVID-19
In December 2019, a novel coronavirus (SARS-CoV-2) was identified in hospitalized patients in 
Wuhan, China. Since then, the Coronavirus Disease 2019 (COVID-19) has spread to thousands 
of international locations, including the United States, and was declared a global pandemic by 
the World Health Organization in March 2020. 
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COVID-19 has had a global impact disrupting supply chains, transportation lanes, resource 
allocation within service providers, and day-to-day operations at health institutions. Successful 
study operations are dependent on these components – any disruption carries the risk of 
hindering the ability to properly manage patient safety and negatively impacting the integrity of 
resulting study data. COVID-19 has forced many health institutions to limit nonessential on-site 
visitors, consistent with local and national social distancing guidelines. While clinical trial visits 
are permitted at most institutions, there is risk that visit restrictions may continue, thereby 
affecting an Investigator’s ability to complete study visits and perform necessary safety 
evaluations.  
As the world faces a viral pandemic, it is critical that patient safety is preserved. Since the key 
risks previously noted may impact the dispensation of blinded and/or open-label rescue 
medication, an extension to each open-label period will be added to the investigational plan to 
delay the start of a double-blind withdrawal period until, in the opinion of the Investigator and 
Medical Monitor, the regional impact of this global health emergency has stabilized and study 
visits can proceed without interruption. The extension of the open-label periods will also ensure 
that patients continue to receive open-label study medication while completing appropriate safety 
monitoring. 
The extension visits in an open-label period will occur on a monthly basis, which aligns with the 
dispensation schedule of open-label study medication. Additionally, the monthly visit schedule 
reduces the burden placed on patients to travel to a health institution during a viral pandemic. 
Finally, monthly laboratory assessments are part of the standard of care for patients with CTX 
who are treated with CDCA. 
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4.1.3. 
Pediatric Cohort 
For patients in the pediatric cohort, this is a 24-week, open-label study with an 8-week titration 
period to identify a safe and tolerable dose and a 16-week treatment period at the safe and 
tolerated dose as maintenance treatment to assess the safety and pharmacokinetics (PK) of 
CDCA in pediatric cohort patients ≥1 month of age to <16 years of age with CTX. The limit of at 
least 1 month of age is to allow for molecular genetic sequencing confirmation of the CTX 
diagnosis.  
CDCA-naïve or CDCA-treated pediatric patients with CTX meeting all inclusion criteria and 
none of the exclusion criteria are planned to be enrolled. The main objective for this part of the 
study is to explore dosing, exposure, and safety in this important population.  
4.2. 
Rationale for Dose 
4.2.1. 
Adult Cohort 
CDCA is currently the SoC in the US for CTX and the proposed dose is 750 mg per day (as 
250 mg TID) in adults. These doses were chosen empirically by clinicians based on the need to 
optimize the absorption of CDCA. Free CDCA is absorbed in the gut, transported to the liver, 
and then conjugates with glycine and taurine. Glyco-CDCA and Tauro-CDCA conjugates 
circulate in the enterohepatic circulation. Additionally, dividing the total dose into three portions 
maximizes the body’s ability to absorb CDCA from the gut in adults. Available data indicate that 
treatment with CDCA 750 mg/day (typically administered as 250 mg TID) or higher is 
anticipated to result in maximal inhibition of bile acid synthesis. Further information on the 
rationale for the dose is provided in the IB. 
4.2.2. 
Pediatric Cohort 
Doses for pediatric patients are consistent with doses currently prescribed in practice and 
reported extensively in the literature (Salen 2017). As pediatric patients tend to weigh less than 
adult patients, their dose is a weight-based dosing regimen at doses up to 15 mg/kg/day TID, as 
frequently prescribed to pediatric patients (van Heijst 1998).  
A weight-based dose titration of 5, 10, and 15 mg/kg based on safety and tolerability followed by 
treatment at the maximum tolerated dose has been proposed for treatment-naïve pediatric cohort 
patients who participate in this study. Treatment-experienced pediatric cohort patients who 
participate in the study will initiate treatment at their current dosing regimen and titrate up to a 
maximum dose of 15 mg/kg/day TID based on safety and tolerability. Pediatric cohort dosing of 
CDCA will not exceed an equivalent dose of 750 mg/day.  
4.3. 
Rationale for Comparator Group-Adult Cohort 
In patients with CTX, Chenodal is considered a medical necessity and the SoC in the US. There 
is no other available treatment that is appropriate to use as a comparator in assessing the effects 
of CDCA treatment in the general CTX population. The use of a placebo over a short duration as 
a comparator is justified as it presents the most efficient way to evaluate the efficacy and safety 
of SoC therapy in this withdrawal study, with rescue measures in place to protect patient safety. 
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5. 
STUDY OBJECTIVES AND PURPOSE 
The purpose of this study is to investigate the efficacy and safety of CDCA in patients with CTX 
in comparison with placebo. 
5.1. 
Efficacy Objective 
• Determine the effects of CDCA, compared with placebo, on biomarkers and clinical 
symptoms of CTX in adult patients with CTX. 
5.2. 
Safety Objective 
• Assess the safety and tolerability of CDCA in adult and pediatric patients. 
5.3. 
Exploratory Objectives 
• Characterize the relationship among biomarkers in adult and pediatric patients. 
• Characterize steady-state pharmacokinetics (PK) of CDCA and 2 conjugated forms of 
CDCA, GlycoChenodeoxycholic Acid (gCDCA) and TauroChenodeoxycholic Acid 
(tCDCA) in adult patients.  
• Characterize the relationship between dose and PK concentration among pediatric 
patients. 
• Assess biomarkers and health status among pediatric patients treated with CDCA. 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This study is made up of 2 designs: a randomized, double-blind, crossover study design among 
patients ≥16 years of age at Screening (adult cohort) and an OL, dose-titration and maintenance 
study design among pediatric patients ≥1 month and <16 years of age at Screening (pediatric 
cohort). 
6.1.1. 
Adult Cohort 
Patients in the adult cohort will participate in a randomized, double-blind, placebo-controlled, 
2-period × 2-treatment crossover study with rescue medication to assess the efficacy and safety 
of CDCA in the treatment of CTX. Approximately 12 male and/or female CDCA-naïve or 
CDCA-treated patients ≥16 years of age at Screening with CTX meeting all inclusion criteria and 
none of the exclusion criteria and whose clinical symptoms are stable during the OL run-in 
period (open-label period 1 [OL1]) are planned to be randomized in the study. At least 6 of the 
patients randomized in the study will be treatment-experienced (ie, those who have been on a 
stable dose of CDCA for at least 2 months prior to the run-in period). Patients who are either 
CDCA-naïve or those with less than 2 months of treatment prior to the run-in period are 
considered newly initiated patients. 
The study design is summarized in Figure 1.  
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Patients will be screened at Visit 1 (Screening; Appendix 1) and those who satisfy all the 
inclusion and none of the exclusion criteria will participate in the 8-week OL1 to establish 
reliable baseline measurements for biomarkers and other efficacy assessments. Patients who fail 
screening may be rescreened as needed. 
Adult cohort patients (≥16 years of age) will receive 250 mg open-label CDCA TID during the 
OL periods of the study (ie, OL1 and open-label period 2 [OL2]). During the DB periods 
(double-blind period 1 [DB1] and double-blind period 2 [DB2]), adult cohort patients will 
receive either blinded CDCA 250 mg TID or matching placebo TID.  
Following the OL1 period, patients will be reassessed for eligibility before randomization 
(Day 1, Visit 6 [Appendix 1]). To be randomized, patients are required to have tolerated CDCA 
and not have developed any condition that, in the judgment of the Investigator, warranted 
discontinuation of CDCA treatment. 
Adult cohort patients will be randomized on Day 1 at a 1:1 ratio to 1 of 2 treatment sequences 
(AB or BA) to enter a 4-week DB period (DB1), an 8-week OL period (OL2), and then a second 
4-week DB period (DB2).
Blinded or open-label 250 mg CDCA TID rescue medication will be provided during the DB 
periods, if needed, based on blinded biomarkers (blinded rescue) and/or clinical CTX-related 
symptoms (open-label rescue). Patients who require blinded and/or open-label CDCA rescue 
medication in a given period will remain on the rescue medication for the remainder of the 
respective DB period. Patients who require rescue medication during DB1 but otherwise remain 
eligible should continue to OL2 and then to DB2.  
Visits at an alternative site by a trained medical professional (eg, licensed nurse) will be 
permitted to reduce the travel burden for patients. The visits that qualify for being conducted at 
an alternative site by a home health vendor are indicated in the Adult Cohort Schedule of 
Assessments (SOA, Appendix 1). 
After the last dose of study medication, patients may transition to treatment for CTX per the 
guidance of the Investigator or prescribing physician. A safety follow-up phone call will be 
conducted for all patients 30 (±7) days after last dose of study medication.  
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Patients will continue to receive 250 mg open-label CDCA TID during the extension periods. 
Details within the clinical study protocol regarding study medication in the OL1 and OL2 
periods are applicable for the extension periods. A patient's total duration on treatment may 
extend beyond 24 weeks if an extension visit is required because of COVID-19. 
A patient may proceed with the start of a DB withdrawal period when the Investigator and 
Medical Monitor agree that the impact to site and/or study operations because of COVID-19 has 
stabilized. The Investigator and Medical Monitor will consider the site’s ability to perform study 
visits without interruption and the timely reporting of necessary study results. A patient will 
resume the patient schedule as detailed in Appendix 1 when starting a DB period. 
If a patient completes 2 or more extension visits in 1 OL period, the patient must complete a 
study visit 2 weeks prior to the start of a DB period to complete all safety and efficacy 
assessments that were otherwise required during a visit in the OL period. 
Visits at an alternative site by a trained medical professional (eg, licensed nurse) will be 
permitted to reduce the travel burden for patients. The visits that qualify for being conducted at 
an alternative site by a home health vendor are indicated in the Schedule of Assessments 
(Appendix 6). 
The modified study design is summarized in Figure 2. 
Figure 2: Study Design Diagram for Extension of Open-Label Period in the Adult Cohort 
6.1.3. 
Pediatric Cohort 
Pediatric cohort patients (≥1 month and <16 years at Screening) will participate in a 24-week, 
open-label cohort with an 8-week titration period to identify a safe and tolerable dose and a 
16-week treatment period at the safe and tolerated dose as maintenance. Patients will be screened
at Visit 1 (Appendix 2) and those who satisfy all the inclusion criteria and none of the exclusion
criteria will be eligible to participate in this cohort to evaluate safety, PK, and biomarkers in this
population. Patients will have visits every week during the titration period and every 4 weeks
during the treatment period. A safety follow-up phone call will be conducted for all patients
30 (±7) days after the last dose of study medication.
During the dose-titration period, dose escalation decisions will be based on safety and tolerability 
(Section 6.5.1).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
  
  
 
  
  
 
  
  
 
  
  
 
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• Percent change from baseline in plasma 7αC4 at the end of each DB treatment period 
6.3.3. 
Other Secondary Efficacy Endpoints for the Adult Cohort 
• Change from baseline in plasma cholestanol to cholesterol ratio during the DB 
periods 
• Percent change from baseline in plasma 7α12αC4 at the end of each DB treatment 
period 
• Proportion of patients with negative net change in symptoms and manifestations 
reported in the diary during the DB periods 
6.3.4. 
Safety Endpoints for Both Adult and Pediatric Cohorts  
• Change from baseline in body weight, vital signs, physical examinations (PE), 
electroencephalogram (EEG), 12-lead electrocardiogram (ECG), clinical laboratory 
parameters (hematology, chemistry, coagulation [adult cohort only], lipid profile 
[including cholesterol]) and urinalysis laboratory parameters at each visit where 
parameters are collected 
• Incidence of treatment-emergent adverse events (TEAEs), including serious adverse 
events (SAEs), adverse events (AEs) leading to discontinuation of study medication, 
and AEs of interest (AEOI) 
6.3.5. 
Exploratory Endpoints for Both Adult and Pediatric Cohorts 
6.3.5.1. 
Adult Cohort Patients 
• Percent change from baseline in plasma bile alcohol at the end of each DB treatment 
period 
• Steady-state PK parameters of 3 bile acids that include CDCA, gCDCA, and tCDCA 
and total CDCA (summed CDCA, gCDCA, and tCDCA). (AUCss, Cmax,ss, Cmin,ss, 
tmax,ss, [CL/F])  
• Relationships among biomarkers (urine and plasma bile alcohols, plasma cholestanol, 
plasma 7αC4, and plasma 7α12αC4 
• Relationships between PK exposure parameters (AUCss, Cmax,ss, or Cmin,ss) and 
changes in biomarker levels (urine and plasma bile alcohols, plasma cholestanol, 
plasma 7αC4, and plasma 7α12αC4)  
• Relationships between PK exposure parameters (AUCss, Cmax,ss, or Cmin,ss) and safety 
endpoints 
• Change in disease severity as assessed by the Clinician Global Impression of Change 
(CGI-C) during each DB treatment period 
• Change in health status questionnaire  
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6.3.5.2. 
Pediatric Cohort Patients 
• Relationships among biomarkers (urine and plasma bile alcohols, plasma cholestanol, 
plasma 7αC4, and plasma 7α12αC4) 
• Steady-state PK concentration of CDCA, gCDCA, and tCDCA and total CDCA 
(summed CDCA, gCDCA, and tCDCA) 
• Mean biomarker levels (urine and plasma bile alcohols, plasma cholestanol, plasma 
7αC4, and plasma 7α12αC4) 
• Change in disease severity as assessed by the CGI-C during the treatment period 
• Change in health status questionnaire 
• Change in developmental milestones 
6.4. 
Treatment Assignment 
Adult cohort patients meeting the prerandomization inclusion criteria (Section 7.3) will be 
randomized on Day 1 in a 1:1 ratio to 1 of 2 treatment sequences (AB or BA) to enter a 4-week 
DB period (DB1), an 8 week open-label period (OL2), and then a second 4-week DB period 
(DB2). 
Treatment assignment does not apply to the open-label pediatric cohort. All pediatric cohort 
patients will receive the safe and tolerated dose as determined during the titration period of the 
study. 
6.5. 
Dose Adjustment Criteria 
Dose adjustment for adult cohort patients is not allowed at any point during the study. 
6.5.1. 
Dose Titration in Pediatric Cohort 
Dose adjustment during the 8-week dose-titration period in the pediatric cohort will be based on 
safety and tolerability (Table 1 and Appendix 2). 
• Treatment-naïve pediatric cohort patients will receive doses of 5 mg/kg/day (TID), 
10 mg/kg/day (TID), or 15 mg/kg/day (TID) titrated up every 2 weeks based on 
safety and tolerability over a period of 8 weeks. 
• Treatment-experienced pediatric cohort patients currently taking a dose ≥5 mg/kg/day 
of CDCA will start at their current dose and titrate up every 2 weeks to the next dose 
level up to 15 mg/kg/day based on safety and tolerability over a period of 8 weeks. 
Patients with a history demonstrating intolerance at higher doses will not be required 
to dose escalate.  
• Pediatric dosing of CDCA will not exceed an equivalent dose of 750 mg/day.  
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Table 1: 
Dose Titration Criteria for 8-Week Titration Period in Pediatric Cohort 
Clinical or Laboratory 
Observations 
Pediatric Cohort Patient 
Treatment-Naïve 
Treatment-Experienced 
Initiate treatment at 
5 mg/kg/day 
Start at their current dose 
• <1.5× ULN of AST, ALT and
TBL
• and no clinical symptoms
Titrate up to the next dose level 
every 2 weeks  
(up to 15 mg/kg/day). Pediatric 
dosing of CDCA will not exceed an 
equivalent dose of 750 mg/day.   
Titrate up to the next dose level 
every 2 weeks 
(up to 15 mg/kg/day)  
(if already at 15 mg/kg/day, then 
maintain dose). Pediatric dosing of 
CDCA will not exceed an 
equivalent dose of 750 mg/day.   
• ≥1.5 to <3× ULN of AST or ALT
• or ≥1.5 to <2× ULN TBL
• Maintain at current dose
• If asymptomatic, retest one week
later
• If the elevation(s) returns to
baseline, consider dose increase
• If the AST and/or ALT
elevation(s) remain 1.5 to
<3× ULN, and/or the total
bilirubin remains ≥1.5 to
<2× ULN, then maintain and
continue to monitor closely and
draw LFTs weekly
• Maintain at current dose
• If asymptomatic, retest one week
later
• If the elevation(s) returns to
baseline, consider dose increase
• If the AST and/or ALT
elevation(s) remain 1.5 to
<3× ULN, and/or the total
bilirubin remains ≥1.5 to
<2× ULN, then maintain and
continue to monitor closely for
symptoms and draw LFTs
weekly
• ≥3× ULN of AST or ALT
• or ≥2× ULN TBL
• or diarrhea >48 hours
• Temporary Dose interruption
• See Section 6.6.1
• See Section 14.2.4
• Temporary Dose interruption
• See Section 6.6.1
• See Section 14.2.4
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CDCA = chenodeoxycholic 
acid; LFT = liver function tests; TBL = total bilirubin; ULN = upper limit of normal 
Note: Patients with a history demonstrating intolerance at higher doses will not be required to dose escalate. 
6.6. 
Interruption or Permanent Discontinuation of Study Medication 
6.6.1. 
Study Medication Interruption 
Patients may temporarily interrupt study medication if diarrhea lasts for more than 48 hours 
or due to elevated liver function tests (LFTs) (Section 14.2.4):  
•
3-fold or greater elevations above the upper limit of normal (ULN) of alanine
aminotransferase (ALT) or aspartate aminotransferase (AST)
•
2-fold increase in ALT or AST above the baseline value in patients who have
elevated values prior to starting study medication
•
elevation of total serum bilirubin to ≥2× ULN
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If a patient’s LFTs are elevated according to any of the above criteria, the patient should be 
monitored as described in Section 14.2.4. If the diarrhea or LFT elevation(s) resolve(s) as 
described in Section 14.2.4 and after consultation between Investigator and Medical Monitor, 
treatment may resume at the same dose for the patients in the adult cohort and at the same dose 
or an appropriately adjusted dose for the patients in the pediatric cohort. If the LFT elevation(s) 
or the diarrhea do not resolve, study medication should be permanently discontinued 
(Section 6.6.2 and Section 14.2.4). 
Patients may temporarily interrupt study medication if deemed necessary in the clinical 
judgement of the Investigator. The patient may restart the study medication at the discretion of 
the Investigator after consulting with the Sponsor’s Medical Monitor.  
Patients who temporarily interrupt study medication prior to completion of the study will 
continue with study visits and assessments according to the schedules of assessments 
(Appendix 1 and Appendix 2). 
6.6.2. 
Permanent Discontinuation of Study Medication 
DB study medication may be discontinued if the adult cohort patient requires rescue with 
open-label CDCA per Investigator judgment. Patients who discontinue DB study medication 
prematurely will be asked to remain on the study. In particular, patients who discontinue DB 
study medication during DB1 should still undergo DB2 unless an eligibility criterion is no longer 
satisfied. 
During the course of this study patients may permanently discontinue study medication for any 
of the following reasons: 
•
Any SAE, treatment-emergent AEOI (Section 14.2.4), clinically significant AE,
clinically significant laboratory abnormality, intercurrent illness or other medical
condition that indicates to the Investigator that continuation on study medication is
not in the best interest of the patient
•
Investigator discretion
•
Patient and/or caregiver decision to discontinue study medication
•
Patient pregnancy
•
Diagnosis of New York Heart Association (NYHA) Class II-IV Class of Heart Failure
•
Other
Patients who permanently discontinue study medication early should be encouraged to continue 
study visits through Week 16 for the adult and pediatric cohorts for continued collection of 
safety and efficacy data despite stopping study medication, but may withdraw consent at any 
time (see Section 6.7).  
Patients who agree to continue regularly scheduled study visits will complete the EOT 
assessments listed in the Schedule of Assessments (Appendix 1 or Appendix 2) as close as 
possible to the patient’s last dose of study medication. The visit data, including the primary 
reason for discontinuation of study medication, will be recorded on the EOT electronic case 
report form (eCRF). Subsequent study visit data will be recorded on the visit-specific eCRF. 
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If the patient completed their last dose of study medication ≥23 days prior to their EOT visit, 
then patient safety may be ascertained during the EOT visit, and a safety follow-up phone call is 
not required.  
Patients who permanently discontinue study medication should transition to treatment for CTX 
per the guidance of the Investigator or the prescribing physician, including treatment with 
appropriate medications, as deemed necessary. Patients permanently discontinuing study 
medication who are not willing to continue with regular study visits, but who are willing to 
continue for their information to be used for this study, will be encouraged to remain in the 
study. The Investigator will contact the Sponsor’s designee to determine the best approach based 
on the patient’s situation. 
6.7. 
Discontinuation of the Patient from the Study 
Patients are free to withdraw consent and/or discontinue participation in the study at any time 
without prejudice to subsequent standard of care treatment. A patient’s participation in the study 
may also be discontinued at any time at the discretion of the Investigator or Sponsor. Patients 
may also be discontinued from the study if the study is terminated (see Section 17.3.5). 
Patients may be permanently discontinued from the study for any of the following reasons: 
•
Death
•
Withdrawal of patient consent
•
Withdrawal of Parent/Legal Guardian consent
•
Adverse events, including:
−
Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient
•
Investigator decision, including:
−
Investigator determines continued participation is not in the patient’s best interests 
due to occurrence of any medical condition or circumstance that exposes the 
patient to substantial risk and/or does not allow the patient to adhere to the 
requirements of the protocol
−
Requirement of prohibited concomitant medication
•
Pregnancy
•
Protocol deviation, including patient failure to comply with protocol requirements or 
study-related procedures
•
Site terminated by Sponsor
•
Study terminated by the Sponsor, US Food and Drug Administration (FDA), or other 
regulatory authorities (see Section 17.3.5)
•
Screen failure (eg, at re-screening prior to starting OL1)
•
Lost to follow-up (see Section 6.9)
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•
Other
In general, patients should be encouraged to remain in the study until they complete the study. A 
patient who permanently discontinues from the study will complete the ET assessments listed in 
the SOA (Appendix 1 or Appendix 2) as close as possible to the patient’s last dose of study 
medication or as soon as possible for those patients who had previously completed an EOT visit. 
The visit data, including the primary reason for premature discontinuation from the study, will be 
recorded on the early termination (ET) eCRF.  
Patients discontinuing from the study will not be replaced. 
6.8. 
Early Termination Visit and Withdrawal Procedures 
The end of study for patients completing the study is on Visit 18 both for the adult and pediatric 
cohorts.   
For patients in the adult and pediatric cohorts who are withdrawn from the study prior to 
completion, all ET procedures will be performed at an ET visit, as indicated in the SOA 
(Appendix 1 and Appendix 2). In addition to the ET visit, patients who discontinue the study 
prior to completion will be contacted (via telephone call) 30 (±7) days after the last dose of study 
medication to ascertain patient safety. If the patient who has discontinued the study prior to 
completion completed their last dose of study medication ≥23 days prior to their ET visit, then 
patient safety may be ascertained during the ET visit rather than a safety phone call. The 
completion of the ET visit will mark the end of study for that patient. 
6.9. 
Lost to Follow-up 
The Investigator must make every effort to contact patients who fail to return for scheduled visits 
so that they will not be declared “lost to follow-up.”  Patients will be considered “lost to 
follow-up” only after reasonable, documented attempts to reach the patient prove 
unsuccessful. These attempts include, but are not limited to, the following: 
1. Contact all telephone numbers for the patient and his/her listed contacts (to be collected
in the source at the patient’s entry into the study), as applicable.
2. Contact the patient’s primary care physician, referring specialist, or other healthcare
professional, as applicable.
3. Send email, text, and postal mail with certified letters to all the patient’s addresses and
contacts, as applicable.
4. Review available medical records/notes for details of hospitalizations, clinic visits, or
other procedures that may indicate the status of the patient, as applicable.
5. Utilize the internet to search for additional contact information, as applicable.
6. Check local, regional, and national public records to locate the patient or search for
mortality status as allowed by law, as applicable.
The information and dates of attempted contact must be recorded in the patient’s records and the 
patient’s final status recorded in the appropriate eCRF. Once these actions have been exhausted 
and documented, the Sponsor or Sponsor’s designee should be contacted for additional guidance. 
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7.
SELECTION OF PATIENTS
Eligibility must be confirmed and signed/dated informed consent must be obtained prior to any 
study-related procedure from the patient or from the parent/legal guardian if the patient is 
<18 years or mentally incapacitated. Assent must be obtained prior to any study-related 
procedure from patients who are <18 years old or patients who are mentally incapacitated if, in 
the Investigator’s opinion, the patient is able to understand and provide assent. 
7.1. 
Inclusion Criteria 
Male and female patients with a clinical diagnosis of CTX are eligible for this study if they meet 
all of the following criteria: 
1. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed
informed consent, and where required, the patient is willing to provide assent, prior to
any screening procedures.
2. The patient is ≥1 month of age at the time of signing the informed consent and assent, as
applicable.
3. Clinical diagnosis of CTX with biochemical confirmation. For treatment-experienced
patients, documented historical confirmation of serum cholestanol and/or bile alcohol is
acceptable. For treatment-naïve patients, serum cholestanol and urine 23S-pentol levels
will be obtained prior to initiating open-label CDCA.
4. If the patient is currently being treated with CDCA at a dose different than the
protocol-specified dose, the patient must be willing to change his or her current dose.
5. With Medical Monitor approval, patients currently taking CDCA and riluzole for the
treatment of ataxia are eligible, provided their ataxia is well controlled and they have
been on a stable dose of riluzole for a minimum of 6 months.
6. Women of childbearing potential (WOCBP), beginning at menarche, must agree to the
use of 1 highly reliable (ie, can achieve a failure rate of <1% per year) method of
contraception during the course of the study. Highly reliable contraception methods
include stable oral, implanted, transdermal, or injected contraceptive hormones associated
with inhibition of ovulation, or an intrauterine device (IUD) in place for at least
3 months. One additional barrier method must also be used during sexual activity, such as
a diaphragm with spermicide or male partner’s use of male condom with spermicide,
during the course of the study. WOCBP are defined as those who are fertile, following
menarche and until becoming postmenopausal unless permanently sterile; permanent
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy. A postmenopausal state is defined as amenorrhea for more than
24 consecutive months without an alternative medical cause; women on hormone
replacement therapy must have a documented plasma follicle-stimulating hormone level
>40 mIU/mL. All WOCBP must have a negative serum pregnancy test at Screening.
NOTE: Prior to menarche, pregnancy testing and contraceptive use is not required.
However, the patient and their parent/legal guardian must be advised that, immediately
upon menarche, the patient will be required to begin pregnancy testing and initiate
contraceptive use. This requirement cannot be avoided.
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7. Males must be surgically sterile (more than 3 months post vasectomy) or males and their
sexual partners must together agree to the use of medically accepted methods of
contraception that are considered highly reliable during the course of the study.
8. The patient and/or his/her parent/legal guardian is willing and able to comply with the
protocol.
7.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study: 
1. The patient has a negative genetic sequencing result for CTX.
2. The patient is known to have another malabsorption disorder or confounding
inflammatory gastrointestinal condition (eg, irritable bowel syndrome).
3. The patient has been diagnosed with NYHA Class II – IV heart failure.
4. If the patient is receiving anticoagulants and, in the judgment of the Investigator, is not
well-controlled.
5. The patient is taking medications that impact bile acid absorption, such as bile acid
sequestering agents (eg, cholestyramine, colestipol, aluminum-based antacids).
6. The patient is taking cholic acid medication.
7. The patient is pregnant or lactating or presents with a positive serum pregnancy test at
Screening, or a positive urine pregnancy test at the first day of OL1 for adult cohort or
Titration Start for pediatric cohort.
8. The patient has been (or is currently) enrolled in a clinical study involving study
medication or device within 30 days prior to Screening.
9. The patient has other prior or ongoing medical conditions, physical findings, or
laboratory abnormalities that, in the Investigator’s opinion, could adversely affect the
safety of the patient, make it unlikely that the course of treatment or follow up would be
completed, or impair the assessment of study results.
10. The patient has a history of drug or alcohol abuse within the past year that, in the
judgment of the Investigator, could affect participation in or adherence to the
requirements of the study.
11. The patient has a positive serologic test for hepatitis B virus surface antigen, hepatitis C,
or human immunodeficiency virus at Screening.
12. The patient and/or his/her parent/legal guardian, in the opinion of the Investigator, is
unable to adhere to the requirements of the study.
7.3. 
Inclusion Criteria Pre-Randomization for the Adult Cohort 
Patients in the adult cohort who meet all inclusion criteria and none of the exclusion criteria for 
participation into the run-in period AND 
1. Tolerate CDCA treatment, in the judgment of the Investigator.
2. Have not developed any condition that, in the judgment of the Investigator, warrants
discontinuation of CDCA.
Patients who fail screening may be rescreened as needed. 
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8. 
TREATMENT OF PATIENTS 
8.1. 
Study Medication 
Study medication refers to: 
• Open-label CDCA, which is received during the run-in period, open-label period, and 
for open-label rescue CDCA for the adult cohort and all study medication in the 
pediatric cohort 
• Blinded CDCA, which is received during a double-blind period or as blinded rescue 
CDCA in the adult cohort 
• Blinded placebo in the adult cohort 
8.2. 
Description of Study Medication 
Adult cohort patients will receive 250 mg CDCA TID during the open-label periods of the study 
(ie, OL1 and OL2). During the double-blind periods (DB1 and DB2), adult cohort patients will 
receive either CDCA 250 mg TID or matching placebo TID based upon their treatment 
assignment, either AB or BA (Table 2). Those assigned to AB will receive blinded 250 mg 
CDCA TID during DB1 period and placebo TID during the DB2 period. Those assigned to BA 
will receive placebo TID during DB1 period and blinded 250 mg CDCA TID during the DB2 
period.  
Rescue 250 mg CDCA TID (blinded or unblinded) will be administered, if needed, based upon 
criteria described in Section 8.3. 
Pediatric cohort patients will receive open-label CDCA. Pediatric cohort patients who turn 
16 years of age while participating in the study will remain in the pediatric cohort and continue 
dosing with open-label CDCA. Patients who are able to take an equivalent weight-based dose of 
750 mg/day and are capable of swallowing a tablet will have the option to take CDCA 250 mg 
tablets TID or the liquid suspension form of CDCA. 
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Table 2: 
Study Medication  
 
CDCAa 
Placebo 
 
Adult Cohort 
(≥16 years of age) 
Pediatric Cohort 
(≥1 month and <16 years of age) 
Adult Cohort 
(≥16 years of age) 
Product Name 
CDCA 
CDCA 
NA 
Dosage Form 
Tablet 
Liquid suspension or tablet 250 mg TID 
Tablet 
Dose 
250 mg, TID 
5 mg/kg/day (TID) 
10 mg/kg/day (TID) 
15 mg/kg/day (TID) 
Pediatric dosing of CDCA will not exceed 
an equivalent dose of 750 mg/day. 
TID 
Route of 
Administration 
oral 
Oral 
For pediatric cohort patients, the CDCA 
tablet(s) will be carefully crushed by the 
pharmacist and added to a 
sodium bicarbonate solution 8.4% 
(1 mmol/mL) to create a 10 mg/mL liquid 
suspension (ie, one 250 mg tablet per 
25 mL) and supplied to the patient for 
oral administration. Patients who are able 
to take an equivalent weight-based dose 
of 750 mg/day and are capable of 
swallowing a tablet will have the option 
to take CDCA 250 mg tablets TID or the 
liquid suspension form of CDCA. 
Oral 
Physical 
Description 
White film-coated 250 mg tablets, imprinted “MP” on one side 
and “250” on the other 
White film-coated tablets, 
imprinted “MP” on one side 
and “250” on the other 
Manufacturer 
LGM Pharma 
LGM Pharma 
CDCA = chenodeoxycholic acid; NA = not applicable; TID = 3 times daily 
a Open-label CDCA (pediatric dose titration and treatment periods and open-label periods and open label rescue 
during the adult cohort) will be distributed in commercial product packaging for Chenodal as bottles of 100 instead 
of 30 (Section 9.1.1 ). Chenodal film-coated tablets for oral administration contain 250 mg of chenodiol, which is 
the non-proprietary name for CDCA 
8.3. 
Rescue Medication Criteria in the Adult Cohort 
Blinded or open-label 250 mg CDCA TID rescue medication will be provided during the DB 
periods, if needed, based on blinded biomarkers (blinded rescue) and/or clinical CTX-related 
symptoms (open-label rescue). Patients who require blinded and/or open-label CDCA rescue 
medication in a given period will remain on the rescue medication for the remainder of the 
respective DB period. Patients who require rescue during DB1 but otherwise remain eligible 
should continue to OL2 and then to DB2.  
Blinded CDCA will be provided to patients who meet the following criterion: increase of 
10 times the baseline value for a given period (ie, Visits 6 and 14) in urine 23S-pentol. Blinded 
CDCA will be assigned through the Interactive Voice/Web Response System (IxRS) at the next 
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scheduled in-clinic visit. Values entered in the IxRS system will be the geometric mean of the 
urine 23S-pentol results from each of the first morning void samples provided by the patient per 
visit timepoint. If the urine 23S-pentol value is below the level of quantification (BLQ), the 
lowest value in the analytical range will be used either to calculate the geometric mean or entered 
into the IxRS system. The Investigator and patient will remain blinded to biomarker data, 
treatment assignment, and if blinded rescue medication criteria are met. 
Patients receiving either blinded CDCA or blinded placebo during the DB period will be rescued 
with open-label CDCA at the discretion of the Investigator if they present with new or worsening 
CTX-related symptoms relative to their respective pretreatment assessments as defined in the 
protocol. The Investigator is responsible for evaluating patients to determine if they meet the 
criteria for rescue medication at each follow-up visit during DB1 and DB2 (Appendix 1). 
The specific reasons (see Appendix 4 and Appendix 5) contributing to the Investigator decision 
and supportive data will be collected in the database. All assessments should continue as 
indicated in the SOA (Appendix 1). 
8.4. 
Concomitant Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
If the patient is receiving anticoagulants, the patient should be well-controlled in the judgment of 
the Investigator to continue receiving study medication.  
8.5. 
Prohibited Medications 
Patients currently taking Chenodal® and/or an alternative therapy for CTX are required to stop 
their medication/therapy prior to the start of study medication in OL1 for the adult cohort or the 
titration period for the pediatric cohort. Patients may resume or start taking Chenodal® and/or an 
alternative therapy for CTX after completing the study (ie, EOS visit) or permanently 
discontinuing study medication. 
Patients should not take medications that impact bile acid absorption, such as bile acid 
sequestering agents (eg, cholestyramine, colestipol, aluminum-based antacids). Patients should 
not take cholic acid medication. 
8.6. 
Treatment Compliance 
The patient must return the container and unused study medication (if any) to the study site for 
a compliance check at the visits specified in the SOA (Appendix 1 or Appendix 2). 
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8.7. 
Randomization and Blinding for the Adult Cohort 
Adult cohort patients will be randomized on Day 1 (Visit 6) at a 1:1 ratio to 1 of 2 treatment 
sequences (AB or BA). Patients randomized to sequence AB will receive blinded CDCA TID for 
4 weeks or until open-label rescue medication criteria are triggered; 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. 
The patient’s treatment allocation will remain blinded to all parties involved with the study 
throughout its course, with the exception of the Data Monitoring Committee (DMC) (see 
Section 17.1), study medication supply, the SAE reporting contact, Unblinded Study Monitor, 
and the independent statistical team(s) supporting the DMC. The randomization schedule for 
treatment allocation will be securely maintained and will not be disclosed until after database 
lock. Doses allowed during the study are shown in Table 2, and dose modifications are not 
allowed (Section 6.5). 
For emergency unblinding only, randomization codes and corresponding treatment assignments 
will be made available to the Investigator through the interactive response technology (IRT) 
system. When possible, the Medical Monitor should be consulted if a medical emergency 
necessitates unblinding (ie, in situations where knowledge of the unblinded treatment is 
necessary for further medical management of the patient). If it is not reasonable to inform the 
Medical Monitor in advance of unblinding, the Investigator must promptly document the case in 
the patient’s study record. Subsequently, the Investigator should contact the Medical Monitor to 
explain any premature unblinding of treatment assignment (eg, accidental unblinding or 
unblinding due to an SAE). Procedures for unblinding a patient’s treatment will be provided 
separately to the Investigator. Similarly, if the Medical Monitor breaks the blind to evaluate an 
emergent safety issue or for regulatory reporting purposes, the Medical Monitor will document 
within study correspondence the rationale, circumstances, and the person(s) being informed 
about the unblinding. 
Access to randomization codes and corresponding treatment assignments will also be made 
available through the IRT system to the appropriate, named individual(s) responsible for 
unblinding suspected, unexpected serious adverse reactions (SUSARs) for reporting to 
regulatory authorities. 
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9. 
STUDY MEDICATION MATERIALS AND MANAGEMENT 
9.1. 
Chenodeoxycholic Acid  
The chemical name of CDCA (Chenodal, chenodiol, tablets 250 mg) is 3α, 7α dihydroxy-5β 
cholan-24-oic acid. 
9.1.1. 
CDCA Packaging and Labeling 
CDCA is provided as a film-coated tablets for oral administration that contain 250 mg of CDCA. 
Inactive ingredients: pregelatinized starch; silicon dioxide; microcrystalline cellulose; sodium 
starch glycolate; and magnesium stearate; the thin-film coating contains: opadry YS 2 7035 
(consisting of methylcellulose and glycerin) and sodium lauryl sulfate.  
CDCA drug substance (or Active Pharmaceutical Ingredient [API]) is synthesized under current 
Good Manufacturing Practices (GMP) by Erregierre (S.P.A.) Via Francesco Baracca, 19, 24060 
San Paolo D’argon BG, Italy. 
CDCA 250 mg (tablets) is available as white film-coated 250 mg tablets, manufactured by LGM 
Pharma, 17802 Gillette Ave., Irvine, CA 92614, imprinted “MP” on one side and “250” on the 
other. Blinded CDCA will be provided in bottles of 30. Open-label CDCA (pediatric dose 
titration and treatment periods and open-label periods and open-label rescue during the adult 
cohort) will be distributed in commercial product packaging of Chenodal as bottles of 100 
instead of 30, NDC 68974 876-40. Chenodal tablets for oral administration contain 250 mg of 
chenodiol, which is the non-proprietary name for CDCA.  
9.1.2. 
CDCA Storage 
CDCA must be stored at 20°C to 25°C (68°F to 77°F), in a secure location with limited access at 
all times. 
9.1.3. 
CDCA Preparation 
Not applicable for adult cohort. For pediatric cohort, see Section 9.4 and refer to the Pharmacy 
Manual. 
9.1.4. 
Blinded CDCA and Open-Label CDCA 
Open-label and blinded CDCA are the same drug product. Blinded CDCA study medication will 
be provided in bottles that are the same as placebo study medication. Open-label CDCA study 
medication will be provided in commercial product packaging for Chenodal, which contains 
250 mg of chenodiol (the non-proprietary name for CDCA). 
9.2. 
Placebo in Adult Cohort 
Placebo study medication is provided in the same form as blinded CDCA, as white film-coated 
250-mg tablets with no CDCA, manufactured by LGM Pharma, 17802 Gillette Ave., Irvine, CA 
92614, imprinted “MP” on one side and “250” on the other. Placebo will be provided in bottles 
of 30 and will be labeled and handled in the same manner. 
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9.3. 
Blinded CDCA and Placebo Administration in Adult Cohort 
Blinded CDCA or placebo is administered orally at home. Patients ≥16 years of age will receive 
250 mg blinded CDCA or placebo TID. On days of study site visits, patients should hold the first 
administration of study medication until on site. 
9.4. 
Open-Label CDCA Administration in Pediatric Cohort 
For pediatric cohort patients (≥1 month and <16 years of age), the CDCA tablet will be carefully 
crushed by the pharmacist and added to a sodium bicarbonate solution 8.4% (1 mmol/mL) to 
create a 10 mg/mL liquid suspension (ie, one 250-mg tablet per 25 mL) and supplied to the 
patient for oral administration (Table 2). Pediatric cohort patients who are able to take an 
equivalent weight-based dose of 750 mg/day and are capable of swallowing a tablet will have the 
option to take CDCA 250 mg tablets TID or the liquid suspension form of CDCA. 
On days of study visits, patients should hold the first administration of study medication until 
after completing visit assessments.  
Study medication may be transported directly to a patient via a traceable courier and/or shipping 
provider to ensure uninterrupted treatment, if necessary. Before doing this, sites will be 
instructed to acquire verbal agreement from the patient or caregiver, verification of correct 
shipping address, and the patient’s or caregiver’s availability to receive the shipment. 
Confirmation of receipt and the shipping process will be documented in the site source 
documentation. The patient’s identity and personal information will continue to be kept 
confidential and will not be shared with the Sponsor. Refer to the Pharmacy Manual for 
additional details. 
9.5. 
Study Medication Accountability 
Blinded and open-label CDCA and placebo will be stored at each study site pharmacy, which 
will be locked with restricted access. No additional procedures are required for the safe handling 
of the tablets. 
The storage temperature in the study site pharmacy where CDCA and placebo are stored must be 
recorded by using a minimum/maximum thermometer or electronically, 24 hours a day, with 
printouts available. Any deviation from the recommended storage conditions should be 
immediately reported to the Sponsor or Clinical Research Organization (CRO). 
Recommendations for study participants: the tablets should be kept in the original packaging 
(bottles). The bottles should be stored in the study participant’s home at room temperature (20°C 
to 25°C [68°F to 77°F]) and out of reach of children and away from direct sunlight. No study 
medication should be given to other persons. 
If necessary because an on-site visit by the patient is not feasible, CDCA or placebo bottles may 
be transported directly to a patient via courier to ensure uninterrupted treatment. It is the 
responsibility of the Investigator to document this process in the patient's source documents. 
Refer to the Pharmacy Manual for additional details.  
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9.6. 
Blinded CDCA and Placebo Handling 
Blinded CDCA and placebo will be dispensed in 30-count HDPE bottles through a validated 
randomization and study supply management system. Details are provided in the Pharmacy 
Manual. 
9.7. 
Study Medication During the Adult and Pediatric Open-Label 
Periods and Adult Open-Label Rescue Period 
During the open-label period of the adult cohort and if a patient receives open-label rescue, 
CDCA will be provided in commercial product packaging for Chenodal. All study medication in 
the pediatric cohort will be provided in commercial product packaging for Chenodal. Additional 
details are provided in Section 9.1 and the Pharmacy Manual. 
10.
STUDY PROCEDURES
•
Study procedures and their timing are summarized in the SOA (Appendix 1 or 
Appendix 2). Protocol waivers or exemptions are not allowed.
•
Immediate safety concerns should be discussed with the Investigator, Medical 
Monitor, and Sponsor immediately upon occurrence or awareness to determine if the 
patient should continue or discontinue study intervention.
•
Adherence to the study design requirements, including those specified in the SOA 
(Appendix 1 or Appendix 2), is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Study procedures related to the extension of the open-label period because of 
COVID-19 and their timing are summarized in the Schedule of Assessments
(Appendix 6).
•
If an on-site visit is not feasible, investigators may interface with patients via 
telephone or video conferencing.
10.1. 
Study Visits in the Adult Cohort 
The adult cohort will be approximately 24 to 28 weeks in duration. The adult cohort includes a 
screening period, an open-label run-in period (OL1), the first DB period (DB1) followed by an 
OL period (OL2), and then a second DB period (DB2) (Figure 1). The duration of the adult 
cohort may extend beyond 28 weeks if the start of a double-blind period is delayed due to 
COVID-19. 
The screening period is up to 28 days (4 weeks) before OL1 begins. The screening period begins 
when a patient undergoes a screening assessment after signing informed consent. OL1 lasts for 
8 weeks with biweekly study visits. Randomization occurs on Day 1, which is the first day of 
DB1. During DB1, patients will visit the study site on a weekly basis for 4 weeks. OL2 lasts 
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8 weeks and patients will visit the site biweekly. DB2 lasts 4 weeks and patients will visit the 
site on a weekly basis during this period. See Appendix 1 for visit details. See Section 11 for 
screening assessments details. 
If necessary, the extension of the open-label periods as a result of COVID-19 will incorporate 
monthly visits anchored from the last dispensation of open-label study medication during OL1 or 
OL2. If a patient completes 2 or more extension visits in 1 open-label period, the patient will 
complete a visit 2 weeks prior to the start of a double-blind period. 
A safety follow-up phone call will be conducted for all patients 30 (±7) days after last dose of 
study medication. 
10.2. 
Study Visits in the Pediatric Cohort 
The pediatric cohort will be approximately 24 to 28 weeks in duration. The pediatric cohort 
includes an up to 28-day (4-week) screening period; an 8-week, open-label, dose-titration period; 
and a 16-week, open-label treatment period at the identified safe and tolerated dose as 
maintenance. The screening period begins when a patient undergoes a screening assessment after 
signing informed consent. During the titration period, pediatric cohort patients will have weekly 
visits. During the treatment period, the pediatric cohort patients will return to the study site 
every 4 weeks. See Appendix 2 for visit details. See Section 11 for screening assessments 
details. 
A safety follow-up phone call will be conducted 30 (±7) days after last dose of study medication. 
11. 
SCREENING ASSESSMENTS
Laboratory samples required at Screening may be collected across multiple days to reduce blood 
volume drawn on a single day. Laboratory samples at Screening do not have to be collected in 
fasting conditions. Screening laboratory results must be received before OL1 Week 1 in the adult 
cohort and before Titration Start in the pediatric cohort. If screening results are not available 
prior to the end of the patient’s 28-day screening period (adult and pediatric cohorts), the 
patient’s screening may be extended up to 2 additional weeks with approval by the Medical 
Monitor. If a patient’s screening window is extended, the patient is not required to repeat 
screening assessments. 
Screening assessments for the adult and pediatric cohorts will be collected according to the 
respective SOA (Appendix 1 or Appendix 2).   
Clinical chemistry, hematology, thyroid stimulating hormone, serologic and coagulation (adult 
cohort only) tests, as well as routine urinalysis will be conducted and are listed in Appendix 3. 
For WOCBP, a serum pregnancy test will be conducted. In addition to the urinalysis conducted 
at the study site, first morning void on 3 mornings within 5 days prior to the visit will be 
collected and brought to the site visit for urine 23S-pentol analysis. Alternatively, the patient 
may bring these urine samples to the site after the Screening visit and before the first day of the 
OL1 period (adult cohort) or start of the titration period (pediatric cohort). 
Pediatric cohort patients without bladder control will have urine collected via sterile bags.  
A 12-lead ECG will be conducted. 
Patients will be trained on completing the Patient Reported Outcomes diary (Appendix 4). 
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All procedures and assessments will be conducted according to the SOA for the respective cohort 
(Appendix 1 or Appendix 2) and the Study Manual. 
12.
ASSESSMENT OF EFFICACY OR DISEASE PROGRESSION
12.1. 
Biomarker Efficacy Assessments
Laboratory assessments at each visit should be collected prior to the first daily dose of CDCA. 
12.1.1. 
Urine 23S-Pentol 
Urine 23S-pentol will be determined using first morning void urine samples and will be 
calculated as the geometric mean of 3 first morning void urine samples collected within 5 days 
prior to each visit at which urine 23S-pentol is assessed according to the SOA (Appendix 1, 
Appendix 2, or Appendix 6). Total (free and glucuronidated) 23S-pentol in urine will be 
monitored using positive mode liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
and will be conducted at a central laboratory (Van Grouw 2019). 
In the adult cohort, the baseline value for the first DB period is the measurement taken for Day 1; 
the baseline value for the second DB period is the measurement taken at Day 85 at the beginning 
of the second DB period. 
Pediatric cohort patients who do not have bladder control will have urine samples collected via 
sterile collection bags.  
If necessary because of restrictions related to COVID-19, a patient may transport the first 
morning void urine samples to the site via courier. It is the responsibility of the Investigator to 
document this process in the patient’s source documents. 
12.1.2. 
Plasma Bile Alcohols (plasma tetrol-glucuronide) 
Plasma tetrol-glucuronide will be monitored using LC-MS/MS (DeBarber 2018). Plasma 
samples will be collected at timepoints as indicated by the SOA (Appendix 1, Appendix 2, or 
Appendix 6). LC-MS/MS will be conducted at a central laboratory. In the adult cohort, the 
baseline value for the first DB period is the measurement taken for Day 1; the baseline value for 
the second DB period is the measurement taken at Day 85 at the beginning of the second DB 
period. 
12.1.3. Plasma 7αC4 and 7α12αC4 
Plasma 7αC4 and 7α12αC4 will be monitored using LC-MS/MS (Donato 2018; DeBarber 2018). 
Plasma samples will be collected at timepoints as indicated by the SOA (Appendix 1, Appendix 
2, or Appendix 6). LC-MS/MS will be conducted at a central laboratory. In the adult cohort, the 
baseline value for the first DB period is the measurement taken for Day 1; the baseline value for 
the second DB period is the measurement taken at Day 85 at the beginning of the second DB 
period.  
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12.1.4. 
Plasma Cholestanol 
Total (free and ester) cholestanol in plasma will be monitored using LC-MS/MS (Xu 2013). 
Samples will be collected at timepoints as indicated by the SOA (Appendix 1, Appendix 2 or 
Appendix 6). LC-MS/MS will be conducted at a central laboratory. In the adult cohort, the 
baseline value for the first DB period is the measurement taken for Day 1; the baseline value for 
the second DB period is the measurement taken at Day 85 at the beginning of the second DB 
period. 
12.2. 
Assessments in the Patient Diary 
All adult cohort patients (regardless of their history of CDCA use) and/or their caregivers will be 
asked to complete the daily and per-event patient-reported outcome (PRO) diaries for bowel 
function and seizures during the 7 days prior to Visit 4 (OL1), Visit 6 (DB1), and Visit 14 (DB2) 
and throughout the duration of each double-blind period. Additionally, adult cohort patients who 
are treatment-nave or have been treated with CDCA for ≤2 months prior to screening will also 
complete the daily and per-event PRO diaries for bowel function and seizures during the 7 days 
prior to Visit 3 and Visit 5 (OL1).  
Pediatric cohort patients (regardless of their history of CDCA use) and/or their parent/legal 
guardian will be asked to complete the daily and per-event PRO diaries for bowel function and 
seizures during the 7 days prior to Visits 4, 10, 14, and 18. 
Patient and/or parent/legal guardian and/or caregivers will receive periodic reminder 
notifications about completing the diary as described in the Study Manual. Diaries will be 
reviewed for compliance at study visits as indicated in the SOA (Appendix 1 or Appendix 2); 
patient and/or parent/legal guardian and/or caregivers will be retrained as needed on the 
completion of the diary. The assessments are presented in Appendix 4. Additional information 
on training and completion of the diary is in the Study Manual. 
The primary intent of these assessments is to document CTX-related symptoms including 
gastrointestinal symptoms and stool consistency (Bristol Stool Form Scale [BSFS]) (Lewis 1997; 
Lane 2011) and seizures, as well as manifestations for each patient to aid the Investigator in 
evaluating potential disease progression. A composite endpoint will also be derived from these 
assessments to aid in evaluating treatment effect at the patient level in the adult cohort.  
12.3. 
Assessments Performed at Clinic Visits 
The following assessments and instruments will be conducted at the clinic to document 
CTX-related symptoms and manifestations to aid the Investigator in evaluating potential disease 
progression in each patient. While results of these assessments are not necessarily considered 
efficacy endpoints due to the heterogenous nature of clinical manifestations across CTX patients, 
composite endpoints may be derived from these assessments or instruments in the adult cohort. 
12.3.1. 
Clinician Global Impression Scale 
The Clinician Global Impression (CGI) scale is comprised of the CGI-S (severity) and CGI-C 
(change) scales. The CGI-S measures the severity of the patient’s disease using a global, 7-point 
scale. The CGI-C is a global, 7-point scale used to assess how much the patient’s illness has 
improved or worsened relative to the patient’s condition since baseline. The score ranges from 
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1 (very much improved) to 7 (very much worse). The CGI-S and the CGI-C will be completed 
by the clinician at the timepoints indicated in the SOA (Appendix 1 or Appendix 2). Procedures 
for the CGI-S and the CGI-C are described in the Study Manuals. 
12.3.2. 
Health Status Questionnaire 
Patients will complete a visual analog scale by rating their overall health status over the past 
week from 0 to 100. The health status questionnaire will be completed at timepoints indicated 
in the SOA (Appendix 1 or Appendix 2). 
12.3.3. 
Motor Developmental Milestones (Pediatric Cohort Patients) 
Assessment of motor developmental milestones for pediatric cohort patients will be done by the 
clinician at the timepoints indicated in the SOA for the pediatric cohort (Appendix 2). The 
6 developmental milestones are based upon the World Health Organization (WHO) assessment 
from the Multicentre Growth Reference Study (Wijnhoven 2004). The clinician will assess 
whether the milestone is met, not met, or not assessed/not age appropriate. After the baseline 
assessment at Titration start, there will be a trigger question to ask if there have been any 
changes to previous milestones assessed (either new milestone met or a regression). Procedures 
for the Motor Developmental Milestones are described in the Study Manuals. 
12.4. 
Documentation of Rationale for Rescue Treatment Based Upon 
Investigator’s Clinical Judgment 
At the end of each clinic visit during the double-blind treatment period, the Investigator will 
assess if the patient needs rescue treatment to prevent potential irreversible disease progression. 
The Investigator will review relevant information, including data from the patient’s diary, 
CGI-C, and EEG (Section 12.3). If in the Investigator’s judgment, the patient needs rescue 
treatment, the Investigator will complete a questionnaire intended to document the need for 
rescue with open-label CDCA, including the specific reasons contributing to the decision 
(Appendix 5). 
13.
PHARMACOKINETIC ASSESSMENTS
13.1. 
Adult Cohort
A blood sample for plasma PK will be drawn within 1 hour prior to study medication 
administration. PK samples will be collected predose, and at 0.5, 1, 2, 3, 6, and 8 hours postdose 
at the 6-week visit during the OL1 period as indicated in the SOA (Appendix 1). Patients will 
need to hold the first dose of study medication for on-site administration.  
A standardized low-fat meal will be provided 45 to 60 minutes prior to the first dose of study 
medication at this visit. The timing of PK sample draws and the administration of study 
medication relative to the completion of this and subsequent meals are described in Table 3. 
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Table 3: 
Timing of Standardized Low-fat Meal, Pharmacokinetic Sample Draws, and 
Study Medication Administration for the Adult and Pediatric Cohorts 
Event/Collection 
Adult Cohort 
Pediatric Cohort 
Window 
Standardized Low-fat 
Meal #1 
X 
X 
Administer 45-60 minutes prior to 
dosing 
Complete meal within 30 minutes of 
starting 
Predose Collection 
X 
X 
15-30 minutes post completion of
meal
Dose #1 
X 
X 
Immediately after predose collection 
0.5 hours post dose #1 
X 
± 5 minutes 
1 hour post dose #1 
X 
X 
± 10 minutes 
2 hours post dose #1 
X 
± 10 minutes 
3 hours post dose #1 
X 
X 
± 10 minutes 
Small Snack (optional) 
X 
Complete snack within 30 minutes 
post 3-hour timepoint 
6 hours post dose #1 
X 
± 15 minutes 
Standardized Meal #2 
X 
Administer 45-60 minutes prior to 
8-hour timepoint
Complete meal within 30 minutes of 
starting 
8 hours post dose #1 
X 
15-30 minutes post completion of
meal
Dose #2 
X 
Taken after the 8-hour collection 
The PK sample will be analyzed for determination of three bile acids that include CDCA and two 
conjugated forms of CDCA, gCDCA, and tCDCA.  
The PK analysis will be the individual analysis for CDCA, gCDCA, tCDCA, and total CDCA 
(summed of CDCA, gCDCA, and tCDCA). PK will be analyzed unadjusted for baseline 
endogenous levels. 
PK assessments will include: 
•
Steady-state PK parameters of CDCA, gCDCA, and tCDCA and total CDCA via
noncompartmental PK analysis (AUCss, Cmax,ss, Cmin,ss, tmax,ss, CL/F)
•
Relationships between PK exposure parameters (AUCss, Cmax,ss, or Cmin,ss) and
changes in biomarker levels (cholestanol, bile alcohols, 7αC4 and 7α12αC4,
cholesterol)
•
Relationships between PK exposure parameters (AUCss, Cmax,ss, or Cmin,ss) and safety
endpoints
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13.2. 
Pediatric Cohort 
Patients will need to hold first dose of study medication for on-site administration. Steady-state 
PK concentrations (CDCA, gCDCA, tCDCA, and total CDCA) in pediatric cohort patients will 
be assessed via samples obtained at predose, 1 hour, and 3 hours postdose at the visits indicated 
in the SOA (Appendix 2).  
A standardized low-fat meal will be provided 45 to 60 minutes prior to the first dose of study 
medication at visits with PK assessments. The timing of PK sample draws and the administration 
of study medication relative to the completion of this and the subsequent meal are described in 
Table 3. 
14.
ASSESSMENT OF SAFETY
14.1. 
Safety Parameters
14.1.1. 
Demographic/Medical History 
During the screening period, demographic and medical history data will be collected according 
to the SOA (Appendix 1 or Appendix 2). Data collected includes age and year of birth, sex, race, 
and ethnicity; CTX diagnosis history (eg, age of onset, age of first symptoms, age of diagnosis); 
medical history; medications and therapies within 30 days of signing informed consent. 
14.1.2. 
Vital Signs 
Vital signs assessments (to be taken before blood collection for laboratory tests) will be assessed 
at study visits as indicated in the SOA (Appendix 1, Appendix 2 or Appendix 6) and include 
blood pressure (systolic and diastolic), heart rate, respiratory rate, and body temperature. 
14.1.3. 
Weight and Height 
Body weight and height will be measured and Body Mass Index (BMI) calculated and recorded 
according to the SOA (Appendix 1, Appendix 2, or Appendix 6) for adult cohort patients.  
Body weight, height, and head circumference will be measured at all visits for pediatric cohort 
patients to be able to determine Failure to Thrive (FTT). Definitions for determining FTT are 
provided in the Study Manual. BMI will also be calculated. 
14.1.4. 
Physical Examination 
A complete PE will include an assessment of the following body systems: abdomen; 
cardiovascular; ear, nose, and throat; eyes; hair and skin; lymph nodes; mental status; 
musculoskeletal; neurological; and respiratory.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Physical examination will be conducted at timepoints indicated in the SOA (Appendix 1, 
Appendix 2, or Appendix 6).  
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14.1.5. 
Electroencephalogram (EEG) 
An EEG will be administered at the timepoints indicated in the SOA (Appendix 1 or 
Appendix 2). Procedures for the EEG are described in the Study Manuals.  
14.1.6. 
Electrocardiogram (ECG) 
Triplicate 12-lead ECG will be obtained as indicated in the SOA (Appendix 1 or Appendix 2) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTcF intervals. ECG to be assessed prior to vital signs and blood sampling for laboratory 
tests. 
After a minimum of 5 minutes of rest in supine position, 3 consecutive recordings should be 
made in succession, no more than 2 minutes apart. The full set of triplicates should be completed 
in less than 4 minutes. These ECGs will be read by the Central Reader, the Investigator, or a 
designee. The Investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal ECG finding is clinically significant. 
14.1.7. 
Laboratory Assessments 
Laboratory assessments at each visit should be collected prior to the first dose of CDCA. Patients 
will need to hold the first dose of study medication for on-site administration for all visits. 
Patients will need to arrive to the study site fasted for visits that include blood collections for 
assessing lipid and PK parameters. The visits where lipid profile (including cholesterol) and PK 
parameters are assessed are indicated in the SOAs (Appendix 1, Appendix 2, or Appendix 6). A 
standardized low-fat meal will be provided 45 to 60 minutes prior to the on-site study medication 
administration at visits with PK assessments.  
Laboratory tests will be conducted at a central laboratory. During the titration period of the 
pediatric cohort, testing at a local laboratory is permitted to facilitate titration review if there are 
delays to central laboratory reporting (eg, lost or hemolyzed blood sample). In addition to the 
tests listed in Appendix 3, if the patient is a WOCBP, β-hCG urine and serum tests will be 
conducted as described in the SOA (Appendix 1, Appendix 2, or Appendix 6). Procedures are 
described in the Study Manuals. See the SOA (Appendix 1, Appendix 2, or Appendix 6) for the 
timing and frequency of clinical laboratory tests. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient’s condition. Of particular 
note, LFTs 3 times the ULN are associated with treatment withdrawal (see Section 6.6.1 and 
Section 14.2.4). 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
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•
If such values do not return to normal/baseline within a period of time judged
reasonable by the Investigator, the etiology should be identified and the Sponsor and
CRO notified.
•
All protocol-required laboratory assessments, as defined in Appendix 3, must be
conducted in accordance with the laboratory manual and the SOA (Appendix 1,
Appendix 2, or Appendix 6).
•
If laboratory values from non-protocol specified laboratory assessments performed at
the institution’s local laboratory or at the central laboratory require a change in the
patient’s management or are considered clinically significant by the Investigator (eg,
SAE or AE or dose modification), then the results must be recorded as an AE or SAE
in the eCRF and if an SAE, an SAE form should be completed as per Section 14.2.
14.2. 
Adverse Event Reporting 
14.2.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can, therefore, be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product. 
All AEs should be recorded and reported. 
AEs may include: 
•
Symptoms described by the patient
•
Clinically significant changes in the patient’s physical examination or other signs
observed by the Investigator or medical staff
•
Test abnormalities (laboratory tests, ECG, X-rays, etc.) that reflect a change from
baseline and/or that may result in changes in administration of study medication or in
an alteration in medical care (diagnostic or therapeutic)
•
Conditions present at baseline that have either worsened or recurred following
resolution
Note: 
It is anticipated that some patients will have a worsening of the underlying condition of 
the disease, such as increasing diarrhea. Any such conditions considered by the 
Investigator to be worsening of the underlying condition should be reported as AEs. 
Investigators should also report such AEs as part of the clinical rescue assessment as 
appropriate (Section 12.4). 
The patient will be evaluated for new AEs and the status of existing AEs at each study visit, 
including screening or washout periods, or at any time contact is made with the patient outside of 
a scheduled visit. The Investigator may elicit symptoms using an open-ended question, followed 
by appropriate questions that clarify the patient’s verbatim description of AEs or change in 
concomitant medications. 
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14.2.2. 
Serious Adverse Event (SAE) 
An SAE is an AE that results in any of the following: 
• Death:  The patient died as the result of the event. 
• Is life-threatening:  An AE that places the patient, in the view of the Investigator or 
the Sponsor, at immediate risk of death from the AE as it occurred, ie, does not 
include an AE that had it occurred in a more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of an existing hospitalization  
Note:  Planned or elective hospital admissions for treatment/procedures for a 
condition/disease that existed prior to signing the informed consent will be recorded 
in the patient’s screening documents and will not be captured as SAEs. If, however, 
the admission or procedure occurs other than planned due to a worsening of the 
condition, the event will be recorded as an SAE. 
• Persistent or significant disability/incapacity:  An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in 
the offspring of a patient exposed to the study medication. 
• Other medically important serious events:  An AE that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, the event may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
14.2.3. 
Evaluation of Adverse Events/Serious Adverse Events 
14.2.3.1. Causality Assessment 
Assessment of the relationship between the AE and exposure to the study medication is 
important for regulatory reporting and assists in the overall analysis of the safety information. 
For each AE/SAE the Investigator will determine whether, based on available evidence, there is 
a reasonable possibility that the study medication caused the event. Causal relationship will be 
classified according to the following criteria: 
• Not Related:  There is no suspicion of a causal relationship between exposure and the 
AE. 
• Unlikely Related:  There is no evidence for a causal relationship between exposure 
and the AE; however, such a relationship cannot be ruled out. 
• Possibly Related:  There is some evidence supporting the possibility of a causal 
relationship between exposure and the AE. 
• Related: There is strong evidence that there is a causal relationship between exposure 
and the AE. 
A causality assessment will be provided for each AE/SAE recorded, even if there is only limited 
information at the time. 
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Upon receipt of follow-up information, the Investigator may change his/her assessment of 
causality and amend the AE/SAE report accordingly. 
14.2.3.2. Severity 
Severity indicates the intensity of the event and should not be confused with seriousness (ie, 
Section 14.2.2), which is an event outcome applied for the purpose of event classification and 
regulatory reporting. 
The Investigator will assess the severity of all AEs/SAEs as mild, moderate, or severe, based on 
the following definitions:  
• Mild:  A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• Moderate:  A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
• Severe:  A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
14.2.3.3. Outcome 
Outcome describes the status of the AE. The Investigator will provide information regarding the 
patient outcome of each AE. Definitions for possible results of an AE outcome include: 
• Recovered/Resolved:  the event has improved or the patient recuperated 
• Recovering/Resolving:  the event is improving 
• Not Recovered/Not Resolved:  the event has not improved or the patient has not 
recuperated 
• Recovered/Resolved with sequelae:  the patient recuperated but retained pathological 
conditions directly resulting from the disease or injury 
• Fatal:  termination of life as a result of an AE. There should be only one AE marked 
with this outcome 
• Unknown:  not known, not observed, not recorded, or refused 
14.2.3.4. Action Taken Regarding the Study Medication 
The action taken with regard to the study medication in response to the AE will be provided at 
the time the event is reported. Options for action taken include the following: 
• Drug Withdrawn:  medication schedule was modified by permanently terminating a 
prescribed regimen of medication 
• Dose Reduced:  medication schedule was modified by subtraction, either by changing 
the frequency, strength, or amount 
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• Dose Not Changed:  medication schedule was maintained 
• Drug Interrupted:  medication schedule was modified by temporarily terminating a 
prescribed regimen of medication 
• Unknown:  not known, not observed, not recorded, or refused 
• Not Applicable:  determination of a value is not relevant in the current context, for 
example, if the AE began and ended prior to treatment or after discontinuation of 
treatment 
14.2.3.5. Assessment of Expectedness 
The expectedness of an SAE will be determined by the Sponsor in accordance with the 
Reference Safety Information (which is contained in the IB). 
14.2.4. 
Adverse Events of Interest  
An AEOI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is required. 
All AEOIs must be reported to the Sponsor’s Medical Monitor within 24 hours of the 
Investigator’s first knowledge of the event, regardless of causal relationship. 
Abnormalities in ALT, AST, and total bilirubin are considered AEOIs and must be reported to 
the Sponsor’s Medical Monitor within 24 hours of awareness if one of the following conditions 
are met: 
• The abnormality represents a new elevation in ALT or AST >3 times the ULN, with 
or without an elevation of total serum bilirubin >2 times ULN; or 
• The abnormality represents a 2-fold increase in ALT or AST above the baseline value 
in patients who had elevated values prior to starting study medication. 
In such instances, the following steps should be taken: 
• Temporarily discontinue study medication. 
• Repeat testing of ALT, AST, liver-specific alkaline phosphatase (ALP), and total 
bilirubin; to be completed within 48 to 72 hours to confirm the abnormalities. 
• If the abnormality is confirmed by repeat results or after consulting with the 
Sponsor’s Medical Monitor: 
− Complete an AEOI Report Form that documents both the liver function test 
findings and any associated signs or symptoms, and report by email to the SAE 
contact on the Study Contact Information page of this protocol. 
− Monitor liver enzymes and serum bilirubin 2 or 3 times weekly. The frequency of 
re-testing can decrease to once weekly or less if the abnormalities stabilize and 
the patient is asymptomatic. 
− Perform additional testing to evaluate liver function, as appropriate (eg, 
international normalized ratio [INR] and direct bilirubin). 
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• Do not resume study medication until monitoring indicates abnormalities have 
resolved or stabilized. 
Patients are not allowed to resume study medication, unless approved by the Medical Monitor, if 
they have: 
• ALT or AST >8 times ULN 
• ALT or AST >5 times ULN for more than 2 weeks 
• ALT or AST >3 times ULN and total bilirubin >2 times ULN or INR >1.5 
• ALT or AST >3 times ULN with symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5% eosinophils) 
Management of such patients should be closely coordinated with the Sponsor’s Medical Monitor. 
In addition to monitoring liver function tests, the Investigator should perform other relevant 
clinical and laboratory measurements to identify potential causes of the abnormalities (eg, acute 
viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic 
steatohepatitis; biliary tract disease or exposure to hepatotoxic medications or environmental 
chemical agents). 
Cases of increased liver function tests will always be considered serious (ie, medically 
important) if they meet both the following criteria: 
• Study medication is suspected to have caused hepatocellular injury, generally shown 
by a confirmed elevation of 3-fold or greater above ULN in ALT or AST; and, 
• The ALT or AST elevations are accompanied by a total bilirubin >2 times the ULN 
or INR >1.5, without initial findings of cholestasis (elevated serum liver-specific 
ALP) 
14.2.5. 
Reporting Adverse Events and Serious Adverse Events and Adverse Events of 
Interest 
14.2.5.1. Reporting Adverse Events  
AEs (including SAEs) will be captured from the time informed consent is signed to the patient’s 
final visit. In addition, AEs (including SAEs) will 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. 
• AEs will be recorded using appropriate medical terminology. When recording, it is 
preferable to provide a diagnosis. In the absence of a diagnosis, each sign and 
symptom will be captured as a unique AE. Sufficient information should be sought to 
assist the Investigator both in determining the diagnosis and in making a causality 
assessment.  
• Reporting should not be delayed pending receipt of all required information. If 
information is unavailable at the time of the initial report, the Investigator is expected 
to follow up until the required information has been obtained. 
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14.2.5.2. Reporting Serious Adverse Events 
The necessity and time requirements for reporting of SAEs to the Sponsor or its designee and/or 
regulatory agencies are as follows: 
•
All SAEs will be reported by email to the SAE contact on the Study Contact page of 
this protocol or by fax to the number in the Investigator Site File within 24 hours of 
the Investigator’s first knowledge of the event, regardless of causal relationship.
•
A completed SAE Report Form containing a detailed written description of the event 
along with available supporting documents (eg, discharge summary, autopsy report, 
diagnostic test results, etc.) will be provided by email to the SAE contact on the 
Study Contact page or by fax to the number in the Investigator Site File.
•
Additional information that is not available at the time the initial SAE Report Form 
was completed will be promptly reviewed and provided by email to the SAE contact 
on the Study Contact page or by fax to the number in the Investigator Site File within 
48 hours of receipt. Full supporting documentation should be solicited by the study 
site even if the SAE occurred at another institution. Such documentation may include 
copies of relevant patient/hospital records, discharge summaries, laboratory/test 
results, or autopsy reports.
•
If at any time after the patient has completed participation in the study and for
30 days post end of study (EOS), the Investigator or study staff becomes aware of an 
SAE that they suspect is related to the study medication (see Section 14.2.3.1), the 
event and any known details will be reported promptly by email to the SAE contact 
on the Study Contact page or by fax to the number in the Investigator Site File, 
following the reporting instructions in this section.
•
For medical emergencies, the IxRS can be used at any time by the Investigator to 
notify the Sponsor for unblinding permissions, if deemed necessary to manage the 
event. For SUSARs, the Sponsor’s Pharmacovigilance designee responsible for 
managing SAEs will access the IxRS to obtain the patient’s treatment assignment for 
the purpose of regulatory reporting. Refer to the study manuals for unblinding 
procedures.
14.2.5.2.1. Follow-up of Adverse Events and Serious Adverse Events 
All AEs will be followed until resolution, until the condition stabilizes, or until completion of the 
patient’s participation or study termination, whichever occurs first.  
Serious AEs will be followed until resolution, until the condition stabilizes, or until the 
Investigator and the Sponsor agree that follow-up is no longer necessary.  
All AEs/SAEs documented at a previous visit/contact where event outcome is designated as not 
recovered/not resolved, recovering/resolving, or unknown will be reviewed by the Investigator at 
subsequent visits/contacts. SAEs that are ongoing after completion of the last scheduled visit will 
continue to be followed to determine the final outcome.  
Rules for AE/SAE follow-up apply to all patients, to the extent allowed by the patient’s consent. 
The Investigator will ensure that follow up includes further investigations consistent with 
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appropriate medical management to understand the nature and/or causality of the AE/SAE. The 
Sponsor, its designee, or regulatory authorities may also request additional information regarding 
an SAE at any time. 
All follow-up information will be promptly reviewed by the Investigator and provided by email 
to the SAE contact on the Study Contacts page of this protocol or by fax to the number in the 
Investigator Site File within the specified timelines. Additional AEs/SAEs may be identified 
during the review of follow-up information and will be processed in accordance with 
requirements defined throughout Section 14.2. 
14.2.5.2.2. Reporting to Regulatory Authorities, Investigators and Institutional Review 
Boards/Independent Ethics Committees 
The Sponsor will ensure that processes are in place for provision of SAEs and Expedited SAE 
reports (SUSARs) to Regulatory Authorities, Investigators, and IRBs/IECs, as required, within 
the specified timelines.  
The Sponsor will submit SAE and/or SUSAR reports to regulatory authorities and the 
Investigator as required. In the US, Investigators will report SAEs and SUSARs to their IRB in 
accordance with applicable Standard Operating Procedures (SOPs) and/or local reporting 
requirements. In the European Union (EU), the Sponsor or its designee will notify the IEC of any 
SUSARs. 
Investigators will forward copies of the IRB/IEC notification to the Sponsor or its designee, 
when applicable. 
14.2.6. 
Pregnancy Reporting 
Although not an AE in itself, exposure to study medication during pregnancy must be reported; 
therefore, all pregnancies will be reported via an initial Pregnancy Notification Form. If a patient 
becomes pregnant during the study, study medication will be immediately discontinued, and 
pregnancy will be documented as the reason for study medication discontinuation. If a urine 
pregnancy test is positive, study medication will be immediately discontinued until a serum 
pregnancy test confirms the result. 
If the Investigator suspects that a pregnancy was the result of an interaction between the study 
medication and the contraceptive method, in addition to the pregnancy, the study medication 
interaction will also be captured as a separate AE.  
The Investigator will report any pregnancy associated with exposure to study medication 
throughout the study period. When a site becomes aware that a patient is pregnant, they are to 
contact the Medical Monitor immediately (within 24 hours of the site becoming aware of the 
event), complete an initial Pregnancy Notification Form, and send the form by email to the SAE 
contact on the Study Contacts page of this protocol or by fax to the number in the Investigator 
Site File. 
Female patients will be instructed to notify the Investigator immediately if they discover they are 
pregnant. Male patients will be instructed to notify the Investigator immediately if they discover 
that their sexual partner is pregnant. In the latter instance, the partner must provide written 
consent before pregnancy information can be collected.  
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If the Investigator learns of a report of pregnancy after signing informed consent, the Investigator 
will complete the Pregnancy forms and submit them to the study contact on the Study Contacts 
page of this protocol or by fax to the number in the Investigator Site File. 
All pregnancies will be followed to outcome (ie, delivery, elective termination, spontaneous 
abortion). The Investigator will inform the patient that the Sponsor or its designee is required to 
gather information regarding the course and outcome of the pregnancy after exposure to the 
study medication. All study-related visits/contacts involving a known pregnancy will include 
pregnancy status assessment until pregnancy outcome is known. The Investigator should further 
obtain follow-up information no later than 1 month after the gestational period to obtain 
maternal/fetal/neonatal outcome and any other relevant information. Upon obtaining pregnancy 
outcome, the Investigator will complete the Pregnancy Outcome form and submit it to the study 
contact on the Study Contacts page of this protocol or by fax to the number in the Investigator 
Site File.  
All information related to the pregnancy and its outcome will be assessed for the occurrence of 
an AE or SAE. Should an AE or SAE occur in the mother or the child, it will be processed per 
study guidelines. Spontaneous abortions and stillbirths will always be reported as SAEs. If the 
pregnancy results in the birth of a child, the neonate should be followed for a minimum of 
4 weeks postdelivery. In certain cases, it may be necessary to follow up on the long-term 
outcome of an AE using the Pregnancy Follow-up Form. If needed, an SAE report form will be 
completed and provided by email to the SAE contact on the Study Contacts page of this protocol 
or by fax to the number in the Investigator Site File. 
15.
DATA COLLECTION, QUALITY ASSURANCE, AND
MANAGEMENT
15.1. 
Recording of Data 
The study will use eCRFs for data collection wherever possible. Data collection points identified 
for data entry by the site will be performed by trained site personnel only. The Investigator is 
responsible for ensuring that all sections of each eCRF are completed promptly and correctly and 
that the data can be verified against source data. Additional data may be collected directly from 
contracted organizations as described in the data management plan and/or data transfer plans. 
AEs and medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Similarly, prior and concomitant medications and concomitant therapies will be 
coded using the World Health Organization Drug Dictionary (WHO-DD).  
15.2. 
Data Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
designee may conduct a quality assurance audit.  
15.3. 
Data Management 
Data management will be performed by a qualified vendor under their SOPs. The Sponsor will 
provide oversight. 
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16.
STATISTICS
16.1. 
Sample Size Justification and Power Analysis for Adult Cohort
The hypothesis to be tested is H0: Δ = 0 against Ha: Δ ≠ 0, where Δ is the true paired treatment 
difference between CDCA and placebo for the change from baseline in loge-transformed urine 
23S-pentol. The planned sample size is expected to provide at least 90% power at the final 
analysis (approximately 12 patients; two sided nominal α = 0.0436). For the sample size 
calculation, it is assumed that the true average paired treatment difference between CDCA and 
placebo in change from baseline in the loge-transformed urine 23S-pentol is -2.4 with a standard 
deviation no higher than 1.15. In a meta-analysis of the literature data from eleven CTX patients 
receiving CDCA treatment, the mean reduction from baseline in loge-transformed urine 
23S-pentol was 3.1 with a 1.15 SD. The assumed 2.4 difference between CDCA and placebo is 2 
standard errors (SEs) less than the observed 3.1 reduction. 
For the proportion of patients requiring rescue treatment (secondary endpoint), the planned 
sample size of approximately 12 patients at the final analysis is expected to provide at least 85% 
power with two sided nominal α = 0.0436. This assumes that 85% of patients (approximately 
10/12) on placebo and 15% of patients (approximately 2/12) on CDCA will need rescue 
treatment, with a discordance of 80%, based on McNemar’s test. 
16.2. 
Analysis Sets 
16.2.1. 
Adult Cohort 
Enrolled Analysis Set (EAS): All adult cohort patients who signed informed consent and take at 
least one dose in the open-label run-in period. This will be used to assess patient characteristics, 
disposition during the run-in period, and overall safety presentation during the study. 
Full Analysis Set (FAS): All adult cohort patients who are randomized and take at least one 
dose of randomized study medication will be included in the FAS. Patients in the FAS will be 
analyzed according to randomized treatment assignment. All efficacy analyses will be based on 
the FAS. 
•
Treatment-Experienced Full Analysis Set (TEFAS): All adult cohort patients in the
FAS who had been on CDCA for at least 2 months prior to the OL run-in period.
•
Newly-Initiated Full Analysis Set (NIFAS): All adult cohort patients in the FAS
who are either treatment-naïve or had been on CDCA for less than 2 months prior to
the OL run-in period.
Per Protocol Analysis Set (PPAS): The PPAS is a subset of the FAS containing adult cohort 
patients who meet study eligibility requirements, have at least one efficacy measurement in the 
DB2 treatment period, and have no protocol deviations that might impact the assessment of 
efficacy measurements. Patients will be analyzed according to randomized treatment sequence 
assignment. The PPAS will be used for sensitivity analyses relating to efficacy. The type of 
protocol deviations governing exclusion from the PPAS will be determined prior to breaking the 
blind and will be detailed in the SAP. 
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Safety Analysis Set (SAS): All adult cohort patients who are randomized and take at least one 
dose of randomized therapy will be included in the SAS. The SAS will be used for safety 
analyses during the double-blind period and will be based upon randomized study medication 
actually received. 
Pharmacokinetic Analysis Set (PKAS): All adult cohort patients in the EAS with evaluable PK 
samples will be included in the PKAS. The PKAS will be used for summaries of PK 
concentration and assessment of PK parameters. 
16.2.2. 
Pediatric Cohort 
Pediatric Safety Analysis Set (PSAS): All pediatric cohort patients whose parent/legal guardian 
signed informed consent and received at least one dose of study medication. This will be used to 
assess patient characteristics, disposition, biomarkers, health status, and overall safety 
presentation for pediatric cohort patients. 
16.3. 
Demographics and Baseline Characteristics 
Demographic and relevant baseline characteristics will be presented and summarized for the 
EAS, FAS, and PSAS. 
16.4. 
Analysis of Efficacy Endpoints 
Efficacy endpoints will first be summarized by descriptive statistics. Continuous variables will 
be summarized by mean, SD, SE, confidence intervals (CIs), median, quartiles, minimum, and 
maximum. For parameters analyzed in the loge-scale such as urine 23S-pentol, geometric mean 
and % coefficient of variation (CV) will also be presented.  
Categorical variables will be summarized by count, percentage, or shift tables (if applicable). 
Descriptive statistics will be produced separately for adult cohort and pediatric cohort patients. 
The following sections describe inferential statistical testing procedures for efficacy endpoints 
collected during the double-blind period among adult cohort patients.  
16.4.1. 
Analysis of Primary Efficacy Endpoint of Urine 23S-Pentol 
The primary analysis of the primary endpoint of change from baseline in loge-transformed urine 
23S-pentol at the end of each DB treatment period will be conducted via a paired t-test 
comparing CDCA with placebo using the FAS (adult cohort). Log-transformation is performed 
due to the anticipated wide range of urine 23S-pentol levels among CTX patients. Urine 
23S-pentol will be determined using first morning void urine samples and will be calculated as 
the geometric mean of 3 first morning void urine samples collected within 5 days prior to each 
visit at which urine 23S-pentol is assessed. The baseline value for the first double-blind period is 
the measurement taken for Day 1; the baseline value for the second double-blind period is the 
measurement taken at Day 85 at the beginning of the second DB period. Measurements obtained 
after initiation of rescue medication will be considered “missing” for purposes of the primary 
analysis. An appropriate multiple imputation (MI) method will be used to impute missing values 
and the values after initiating rescue medication, under the assumption of missing at random 
(MAR). The imputed values, not the actual values obtained after the initiation of the rescue 
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medication, will be used in the analysis. Further information on imputation of missing data 
methods and sensitivity analyses will be described in the SAP. 
The primary endpoint of change from baseline in loge-transformed urine 23S-pentol at the end of 
each DB treatment period will also be analyzed via a mixed effects model. The loge-transformed 
urine 23S-pentol measurements during the DB treatment periods prior to initiating rescue 
medication will serve as the dependent variable. Fixed effects for randomized treatment, 
sequence, period, baseline value, nominal time (in days within period; categorical), and 
randomized treatment-by-time interaction will be included. Random effects for patients will be 
included, for which an unstructured covariance matrix will be assumed. If convergence issues 
arise, a first order auto-regressive structure will be used. The REPEATED statement will be used 
to specify the covariance structure associated with the repeated measures. The primary treatment 
effect estimate will be the contrast between CDCA and placebo randomized treatment-by-time 
evaluated at 4 weeks.  
16.4.2. 
Analysis of Key Secondary Efficacy Endpoints 
The proportion of patients requiring rescue treatment and the corresponding exact 95% CI will 
be presented for each treatment. Patients who require blinded and/or open-label CDCA during 
the DB periods will be considered to have met the event (ie, received rescue medication) for the 
primary analysis. The difference in proportions, the corresponding exact CI, and exact p-values 
will be calculated and presented using Prescott's method (Prescott 1981). This analysis will be 
performed on the FAS.  
Percent change from baseline in plasma cholestanol levels, and plasma 7αC4 and 7α12αC4 
levels at the end of each DB treatment period will be analyzed in a similar way as for the primary 
endpoint. Since cholestanol is expected to require longer treatment with CDCA to show 
meaningful changes, the primary analysis for cholestanol will be conducted on the TEFAS to 
mitigate against the potential impact of the shorter treatment duration prior to the DB period. For 
plasma 7αC4, the analysis will be based on the FAS. 
16.4.3. 
Analysis of Other Secondary Endpoints 
Other continuous efficacy endpoints (such as plasma cholestanol to cholesterol ratio and plasma 
7α12αC4) will be analyzed using the same approach described for percent change in urine 
23S-pentol. Other binary efficacy endpoints (such as incidence of new or worsening CTX-related 
clinical manifestations) will be analyzed using the same approach described for the proportion of 
patients requiring rescue medication. 
The proportion of patients with negative net change in symptoms or manifestations (described 
below) reported in the diary during the double-blind period is a composite endpoint and will be 
analyzed as a binary efficacy endpoint using the same approach described for the proportion of 
patients requiring rescue medication. For each symptom or manifestation, the value for each 
planned visit (ie, Day 1 [baseline], Weeks 1, 2, 3, and 4, for DB1; Day 85 [baseline], Weeks 13, 
14, 15, and 16 for DB2) will be based on the results reported in the diary during the 7 days 
preceding the visit. Data obtained after initiation of rescue treatment will be excluded from the 
calculations. The following parameters will contribute to the composite endpoint calculated at 
the planned visits for each patient: 
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•
Bowel function:  the proportion of bowel movements with the BSFS scores of 1
(severe constipation), 2 (mild constipation), 6 (mild diarrhea), or 7 (severe diarrhea);
the average BSFS score of all reported bowel movements
•
Seizures:  the rate of seizure per day (ie, total number of seizures/total days with diary
data); the average duration of seizures; the average severity of seizures
•
Tremors:  the proportion of days with tremors (ie, number of days with tremors/total
days with diary data); the average number of body parts with tremors; the average
severity of all tremors reported
•
Individual manifestations:  the proportion of days with the specific manifestation
(ie, number of days with manifestation/total days with diary data); the weighted (2 for
most bothersome manifestations, 1 for other manifestations) average impact or
discomfort/distress score (0 to 4, ranging from no impact or discomfort/distress to
very severe impact or discomfort/distress)
For each parameter above, the change from baseline score will be calculated as the difference 
between the value for a specific visit during the double-blind period and the corresponding 
baseline visit (ie, baseline – postbaseline visit). The sign of the change will be noted as -1, 0, or 
+1 if it is less than 0, equal to 0, or greater than 0, respectively. Patients are considered to have a 
negative net change if there are more negative changes than positive changes. Additional details 
will be described in the SAP.
16.5. 
Control of Type 1 Error 
Multiple comparison procedures will be implemented to strongly control the family-wise type 1 
errors across the primary endpoint and the key secondary efficacy endpoints. The first family of 
hypotheses consists of the analysis of urine 23S-pentol. The second family of hypotheses consist 
of the key secondary efficacy endpoints of proportion requiring rescue medication, percent 
change from baseline plasma cholestanol, and percent change from baseline plasma 7αC4 (in no 
particular order). The schematic of the multiple comparison procedure is presented in Figure 4. 
Figure 4: 
The Multiple Comparison Procedure for Type 1 Error Control 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The primary endpoint of urine 23S-pentol will be tested at the final analysis at an α = 0.05. If the 
test is significant, the Family One is rejected and the entire α = 0.05 is preserved and then passed 
onto Family Two of hypotheses (ie, key secondary endpoints) for testing at the final analysis. 
Otherwise, there is no remaining α to be passed onto Family Two, and therefore, the key 
secondary endpoints will not be formally tested, and nominal p-values will be reported instead. 
The Bonferroni-Holms procedure will be used to control the Type 1 errors for Family Two of 
hypotheses at an overall α = 0.05. 
All other secondary efficacy endpoints will be analyzed at the nominal 0.05 significance level.  
16.6. 
Analysis of Safety Endpoints 
Descriptive statistics will be used to summarize the safety data by randomized treatment group 
among adult cohort patients based on the SAS and by administered dose among pediatric cohort 
patients based on the PSAS. 
Clinical laboratory parameters will be measured at baseline and postbaseline visits. Each 
continuous laboratory variable will be summarized in terms of changes from baseline by 
treatment group. Laboratory data will also be classified as low, normal, or high relative to the 
parameter’s reference range. Laboratory abnormalities for each treatment will also be 
summarized using shift tables.  
AEs will be coded using the MedDRA by System Organ Class and Preferred Term. AEs that 
begin after the first administration of study medication, or existing AEs that worsen after the first 
dose of study medication, are considered TEAEs. The number and percentage of patients 
reporting TEAEs will be summarized for each treatment group by MedDRA System Organ Class 
and Preferred Term, by severity, and by relationship to study medication. The number and 
percentage of patients reporting serious TEAEs, TEAEs leading to treatment discontinuation, 
and TEAEs of interest (see Section 14.2.4) will also be summarized for each treatment group by 
MedDRA System Organ Class and Preferred Term. 
16.7. 
Analysis of Pharmacokinetics Endpoints 
PK concentration and estimated parameters will be summarized using descriptive statistics.  
The PK analysis will be the individual analysis for CDCA, gCDCA, tCDCA, and total CDCA 
(summed of CDCA, gCDCA, and tCDCA). PK will be analyzed unadjusted for baseline 
endogenous levels. 
16.8. 
Interim Analysis 
No interim analysis will be conducted for this study. 
 
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17. 
SPECIAL REQUIREMENTS AND PROCEDURES 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 1996; ICH Guidelines for 
Safety Data Management, 1994; the US Code of Federal Regulations (CFR 21 Parts 50, 56, and 
312); and the EU Clinical Trials Directive, 2001/20/EC. The protocol meets legal and regulatory 
requirements according to the country of conduct. 
Institutional and Ethics Review 
This protocol and associated Informed Consent Form (ICF), participant information sheet, any 
information provided to the patient, the Investigator’s Brochure, and any proposed advertising 
material, will be submitted to an appropriate IRB/IEC, applicable regulatory authorities, and host 
institution(s) for written approval (where applicable). These documents will also be submitted to, 
and approved by, the above parties for all amendments to the original approved documents 
(where applicable). Documentation of any applicable approval(s) and the approved ICF will be 
received by the Sponsor or its designee prior to enrollment of patients and release of study 
medication. 
17.1. 
Unblinded Data Monitoring Committee 
An unblinded DMC, including physicians with experience treating patients with CTX, 
physicians trained in neurology, internal medicine, and/or pharmacovigilance, as well as 
statistician(s), will monitor accumulating data, including biomarkers (urine and plasma bile 
alcohols, plasma cholestanol, plasma 7αC4, and plasma 7α12αC4). The DMC will review 
efficacy, clinical outcomes, and safety results to potentially stop the study early based on the 
overall benefit-risk assessment, including the risk of irreversible disease progression among 
those receiving placebo. The scope of the DMC’s review will be further defined within the DMC 
Charter. 
DMC members will not be involved in the study as Investigators or consultants. The DMC will 
have study conduct oversight as defined by the DMC Charter. All members will have 
considerable experience with clinical study conduct and DMCs. Any candidate found to have a 
financial, intellectual, or personal conflict of interest, or whose name is listed on the FDA 
debarment list, will not be offered membership. Conflicts of interest will be assessed regularly, 
and if members are found to have a new conflict of interest they will be replaced. 
The DMC will meet approximately every 6 months at scheduled meetings but may agree to 
adjust meeting frequency based upon actual and projected data availability. In addition, ad hoc 
meetings may be convened, as appropriate, to review safety data.   
Based on review of available data, the DMC will advise the Sponsor on the validity and 
scientific merit of continuing the study.  
Written minutes of both open and closed DMC sessions will be prepared. The minutes of closed 
sessions will be made available to the appointed Sponsor designees only after the database is 
locked and all data are unblinded. 
The DMC may request unblinded individual patient data as appropriate. Data reviewed during 
the meetings will include, at a minimum, disposition, demographics, exposure, clinical 
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laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of study 
medication. At each meeting, detailed narratives of interval SAEs (including events resulting in 
death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to patient safety that alter the 
conduct of this study. The Investigators will inform patients of such actions, and the protocol and 
ICF will be revised, as appropriate. 
17.2. 
Changes to the Conduct of the Study or Protocol 
Any changes to the study protocol, such as changes in the study design, objectives or endpoints, 
inclusion and exclusion criteria, and/or procedures (except to eliminate an immediate hazard) 
will be implemented only after approval by the Sponsor or its designee. All protocol changes will 
be documented in protocol amendment(s). Protocol amendment(s) (excluding urgent safety 
amendments) will be signed by the Investigator and approved by the IRB/IEC and regulatory 
agencies (where required) prior to implementation. Any changes in study conduct that result 
from a pending amendment will be considered protocol deviations and should be reported to the 
IRB/IEC. Documentation of IRB/IEC approval will be returned to the Sponsor or its designee. 
17.3. 
Investigator’s Responsibilities 
The Investigator agrees to: 
 Conduct the study in accordance with the protocol and make changes only after 
receiving written approval from the Sponsor or its designee, except to protect the 
safety, rights, or welfare of patients. 
 Personally conduct or supervise the study. 
 Ensure that requirements related to obtaining informed consent and IRB/IEC review 
and approval comply with ICH E6, CFR 21 Parts 50 and 56, and local laws. 
 Report to the Sponsor or its designee any AEs that occur during the study in 
accordance with ICH E6, CFR 21 Part 312.64, and local laws. 
 Read and understand the Investigator’s Brochure, including potential risks and side 
effects of the study medication. 
 Ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed of their obligations in meeting the above commitments. 
 Maintain adequate records in accordance with ICH E6, 21 CFR Part 312.62, and local 
laws, and have records available for inspection by the Sponsor, FDA, or other 
authorized agency. 
 Ensure that the IRB/IEC complies with requirements of ICH E6, 21 CFR Part 56, and 
local laws and will be responsible for initial and continuing review and approval of 
the clinical study. 
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 Promptly report to the IRB/IEC and the Sponsor or its designee all changes in 
research activity and unanticipated problems involving risks to patients or others 
(including amendments and expedited safety reports). 
 Comply with all other requirements regarding obligations of Investigators and all 
other pertinent requirements listed in ICH E6, 21 CFR Part 312, and local laws. 
 Provide progress reports and notifications of SAEs to the IRB/IEC according to local 
regulations and guidelines. 
17.3.1. 
Patient Informed Consent 
Investigators agree to adhere to GCP, which includes ethical principles that have their origin in 
the Declaration of Helsinki, when developing the patient informed consent and assent (where 
applicable) forms and when obtaining consent and assent from the patient, parent, or legal 
guardian. Written informed consent is required prior to enrollment in the study. It is the 
responsibility of the Investigator to document the consent process within the source documents 
and obtain consent using an IRB/IEC-approved consent form. 
If necessary because of restrictions related to COVID-19, a patient may provide informed 
consent remotely (ie, via telephone, email, etc.). It is the responsibility of the Investigator to 
document this consent process within the source documents.  
The Investigator will ensure that each patient or parent or legal guardians (as appropriate) is 
given full and adequate oral and written information about the nature, purpose, possible risks, 
and benefits of the study as well as potential treatment alternatives. Investigators will ensure that 
consent/assent is obtained with the appropriate age range form. For developmentally delayed or 
cognitively impaired patients, Investigators will determine which age range assent will be 
appropriate based on the patient's physical and cognitive ability and will document the process of 
determination. Patients or parents or legal guardians (as appropriate) will be notified that they are 
free to discontinue participation in the study at any time and will be given the opportunity to ask 
questions and allowed time to consider the information provided.  
17.3.2. 
Case Report Forms 
Copies of pertinent records in connection with the study, including all source documents, will be 
made available to the Sponsor or its designee upon request with due precaution toward protecting 
the privacy of the patient. 
Data will be entered by the site onto the eCRFs in the Electronic Data Capture system or 
downloaded from a device, as in the case of patient-reported outcomes, or imported into the 
electronic database as described in the data management plan and/or data transfer plans. Unless 
explicitly directed, blank data fields are not acceptable. Any erroneous entries made on the 
eCRFs will be corrected by the site. Changes made to the data after initial entry into the eCRF 
will be captured via an electronic audit trail and include the reason for change. Incomplete 
entries or entries needing additional explanation will be queried to the site for clarification. 
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17.3.3. 
Record Retention 
The Investigator is responsible for oversight and maintenance of the study records and patient 
source documents. These records will be readily available for audit or inspection. 
The Investigator will retain study records for at least 2 years after the last marketing approval has 
been granted and there are no pending marketing applications in an ICH region, or until at least 
2 years have elapsed since the formal discontinuation of the clinical program. However, these 
documents should be retained for a longer period, if required by other applicable requirements 
(eg, applicable local regulatory requirement) or by an agreement with the Sponsor or its 
designee. The Investigator will contact the Sponsor or its designee prior to any record 
destruction. 
Patient records or other source data will be kept for the maximum period of time mandated by 
the hospital, institution, or private practice, but not less than 15 years. 
If off-site archiving is used, all records will be retrieved and made available for review at the 
time of an audit or regulatory authority inspection. 
17.3.4. 
Monitoring 
A representative of the Sponsor or its designee will visit the Investigator periodically for the 
purpose of monitoring the progress of this study in accordance with the protocol, GCP, and local 
regulations. If necessary, because of restrictions related to COVID-19, monitoring activities may 
be performed remotely. Further details regarding the scope and timing of these remote and 
on-site monitoring activities are included in the Clinical Monitoring Plan. Non-compliance with 
the protocol, GCP, and local regulations will be documented and corrective actions implemented, 
if necessary. It is the responsibility of the Investigator to be present or available for consultation 
during monitoring visits. During these routine visits, all data pertaining to a patient’s 
participation in this clinical investigation will be made available to the Study Monitor. The 
Investigator will comply with applicable privacy and security laws for use and disclosure of 
information. Study Monitors will perform source document verification according to the Clinical 
Monitoring Plan to ensure consistency between the eCRFs and source documents. Discrepancies 
will be resolved in accordance with the principles of GCP. 
At any time prior to, during, or after completion of the clinical study, an audit may be performed 
on a study site by the Sponsor or its designee, an IRB/IEC, or a representative of a national 
regulatory agency. Investigators will notify the Sponsor or its designee upon notification of 
inspection by a representative of a national regulatory agency. A Sponsor or designee 
representative will be available to assist in the preparation for study site inspections. All 
pertinent study data will be made available for verification, audit, or inspection purposes. 
An Unblinded Study Monitor will be assigned to the study to perform source data verification of 
biomarker data entered by central laboratory personnel into the IxRS system (ie, blinded rescue 
medication calculation) and a standalone biomarker database. Non-compliance with the testing 
protocols, GCP, and local regulations will be documented and corrective actions implemented, if 
necessary. The Unblinded Study Monitor will have no other role on the study. Further details 
regarding the Unblinded Study Monitor are included in the Unblinded Monitoring Plan. 
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17.3.5. 
Study or Site Termination 
If the Sponsor or its designee, the Investigator, or regulatory authorities discover any conditions 
during the study that indicate that the study or study site should be terminated, this action may be 
taken after appropriate consultation between the Sponsor, its designee, and the Investigator. The 
Sponsor has the right to terminate the participation of either an individual site or the study at any 
time, for any reason which may include the following: 
 The incidence and severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
 Patient enrollment is unsatisfactory. 
 Data recording is inaccurate or incomplete. 
 Investigator(s) do(es) not adhere to the protocol or applicable regulatory guidelines in 
conducting this study. 
 Knowingly false information from the study site is submitted to the Sponsor, its 
designee, or regulatory authorities. 
In the event that the study is terminated early, the Sponsor or its designee will provide specific 
guidance to study sites regarding the end-of-study procedures. 
17.3.6. 
Study Medication Control 
The Investigator will acknowledge that study medication supplies are investigational, and as 
such must be used strictly in accordance with the protocol and only under the supervision of the 
Investigator or Sub-Investigator(s) listed on Form FDA 1572 (or regional equivalent). Study 
medication must be stored in a safe and secure place with limited access and according to 
Sponsor instructions. 
The Investigator must maintain adequate records documenting the receipt and disposition of all 
study medication supplies. The Sponsor or its designee will supply forms on which to record the 
date study medication was received and a dispensing record in which to record each patient’s 
use. It is the Investigator's responsibility to ensure that patients return their unused study 
medication. 
17.3.6.1. Receipt of Study Medication 
A proof of receipt, which details the quantity and description of the study medication, will 
accompany the shipment from the Sponsor or its designee to the Investigator. The Investigator 
will provide the Sponsor or its designee with a signed and dated copy of this receipt (or an 
electronic equivalent) within 48 hours after receipt of study medication, while retaining the 
original within the site pharmacy files. The Investigator is responsible for ensuring that the study 
medication is maintained in a controlled location, with limited access, and under adequate 
storage conditions. 
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17.3.6.2. Disposition of Unused Study Medication 
All unused study medication will be maintained under adequate storage conditions in a limited 
access area. If any unused material is remaining upon completion of the study, the material will 
be returned to the Sponsor or its designee or destroyed only after the following has been 
completed: 
 Accountability has been performed by a representative of the Sponsor or its designee. 
 Appropriate study medication return/destruction documentation has been completed 
by the study site pharmacist or his/her designee. 
17.3.7. 
Product Handling and Complaints Reporting 
If any issues arise during the course of the study related to the quality of the study medication, 
the study site pharmacist or pharmacy designee will contact the product handling/complaints 
group listed on the Study Contact page of this protocol. 
17.3.8. 
Insurance 
The Sponsor will maintain a liability insurance policy covering all clinical studies under its 
sponsorship, and that policy will comply with local laws and requirements. The Sponsor or its 
designee will provide a certificate of insurance to any IRB/IEC, National Competent Authority, 
or regional Health Authority that may require such a document. Note that this Sponsor insurance 
coverage does not relieve the Investigator, the Institution, and their collaborators from each 
maintaining their own liability insurance policy for their clinical research activity. 
17.3.9. 
Data Confidentiality 
All patient information obtained during the conduct of the study will be regarded as confidential. 
Study Monitors, auditors, and inspectors who require access to a patient’s medical notes for 
source document verification will maintain patient confidentiality at all times. An agreement for 
disclosure of any such information will be obtained in writing and is included in the ICF. No 
study data will be disclosed to a third party (with the exception of auditors and/or regulatory 
authorities) without the written consent of the Sponsor. All data shall be secured against 
unauthorized access. 
The Investigator will maintain a list of patient names and identifying information (eg, patient 
hospital number, unique patient number). This list will not be collected by the Sponsor. 
The written participant information sheet will explain that study data will be stored in a computer 
database, maintaining confidentiality in accordance with national data protection laws. All data 
that is computer processed by the Sponsor or designee will be identified only by unique patient 
number/randomization code/patient initials/site number. 
When personal patient data are stored in or processed by computer, the data must be protected to 
prevent their disclosure to unauthorized third parties. Pertinent sections of national data 
protection laws will be complied with in full, according to the country of conduct. 
The ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including patient medical history. 
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A description of this study will be available on http://www.clinicaltrials.gov, as required by US 
law. However, no personal patient information will be included on this website. 
17.3.10. 
Clinical Study Report 
The Sponsor or its designee is responsible for preparing a clinical study report. If requested, a 
study summary may be provided to the Investigator. 
18.
PUBLICATION POLICY
Publication policy is addressed separately in the Clinical Study Agreement.  
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19.
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MS/MS quantification of 4β-hydroxycholesterol and cholesterol in plasma samples of limited 
volume. J Pharm Biomed Anal. 2013 Nov;85:145-54. 
Yahalom G, Tsabari R, Molshatzki N, Ephraty L, Cohen H, Hassin-Baer S. Neurological 
outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus 
late diagnosis. Clin Neuropharmacol. 2013;36(3):78–83.
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20.
APPENDICES
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a Assessments for Visits 3, 4, 11, 12, and 13 may be conducted by a home health vendor at an alternative site than the Investigator’s site. 
b PK blood draws will be collected at Visit 5. PK samples will be collected predose and at 0.5, 1, 2, 3, 6, and 8 hours postdose. Patients will need to hold the first 
dose of study medication for on-site administration to facilitate the correct timing of the blood draw for the PK analysis. PK samples will only be obtained from 
patients who are on 750 mg (250 mg TID). A standardized low-fat meal will be provided 45-60 minutes prior to the first study medication dose and should be 
completed within 30 minutes of starting the meal. Predose blood sample for plasma PK will be drawn within 15-30 minutes post completion of the meal. After 
the first study medication dose, the 0.5 hours post dose draw has a ±5-minute window. The 1, 2, and 3-hour post dose draws have a ±10-minute window. An 
optional small snack may be offered and completed within 30 minutes of the post 3-hour timepoint. The 6-hour post dose draw has a ±15-minute window. A 
second standardized low-fat meal is provided 45 to 60 minutes prior to the 8-hour timepoint and the meal will be completed within 30 minutes of starting the 
meal. The 8-hour PK draw will be taken 15-30 minutes after the completion of the meal. 
c If open-label rescue medication criteria are triggered prior to Visits 10 or 18, all assessments must be conducted prior to administration of open-label treatment. 
d If prior genetic confirmation of CTX is not available, blood will be drawn at Visit 1 for gene sequencing. No patient with negative genetic sequencing will be 
randomized. 
e CTX medical history should include a complete list of CTX-related symptoms present at the time of Screening. 
f Serum pregnancy tests will be performed at Screening for WOCBP. Urine pregnancy tests will be performed at all other visits. A positive urine pregnancy test 
will be confirmed by a serum test. All WOCBP must have a negative pregnancy test (urine, with positive results confirmed by serum) at every visit. 
g The CGI-C needs to be completed at this visit if a patient leaves the study early during DB1 or DB2. 
h Ophthalmology exam includes BCVA and cataracts. The ophthalmology exam has a window of ±1 day to accommodate being conducted by a separate 
specialist. 
i At Screening, the physical examination is a full physical examination; at subsequent visits, the physical examination can be an abbreviated exam. Height will 
be measured at Screening, baseline (Visit 6/Day 1), and EOS for adult cohort patients. Physical examinations will include assessment of the following body 
systems: abdomen; cardiovascular; ear, nose, and throat; eyes; hair and skin; lymph nodes; mental status; musculoskeletal; neurological; and respiratory. 
j The Investigator will assess if a patient requires OL rescue medication at each visit of a DB period including Visits 10 and 18 when OL medication is dispensed 
per protocol. If OL rescue medication is required, the Investigator must complete and submit a Clinical Progression Requiring Rescue Form (Appendix 5). If 
OL rescue medication is not required, the rescue form must be submitted at the completion of each DB period (ie, Visit 10 and Visit 18). 
k Vital signs will always be measured prior to having blood drawn for laboratory evaluations. 
l All adult cohort patients (regardless of their history of CDCA use) and/or their parent/legal guardian will be asked to complete the daily and per-event PRO 
diaries for bowel function and seizures during the 7 days prior to Visit 4 (OL1), Visit 6 (DB1), Visit 14 (DB2), and throughout the duration of each double-
blind period. Reminders regarding the completion of the PRO diary will be sent to patients and/or patient’s parent/legal guardian at times specified in the Study 
Manual. Diaries will be reviewed for compliance at each visit that it is required. If the review of the PRO diary indicates that the patient or the patient’s 
parent/legal guardian is not sufficiently compliant with completion of the diary as described in the Study Manual, the patient or the patient’s parent/legal 
guardian will be retrained on how to complete the diary. 
m Distribution and training on use of diary only. 
n Patients who are treatment-naïve or have been treated with CDCA for ≤2 months prior to Screening will also complete the daily and per-event PRO diaries for 
bowel function and seizures during the 7 days prior to Visit 3 and Visit 5 (OL1).  Diaries will also be reviewed for compliance at these visits. 
o First morning void on 3 mornings within 5 days prior to the visit will be collected and brought to the site visit. For the Screening visit, the patient may bring 
these urine samples to the site after the Screening visit and before the first day of the OL1 period. 
p Collected only from patients on anticoagulants at all visits, except Visits 7, 9, 15, and 17. 
q A list of clinical laboratory assessments is provided in Appendix 3. 
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r Blood draw for thyroid stimulating hormone will only be collected at Screening. 
s Fasting blood draws for the assessment of lipid parameters will be collected at Visits 2, 6, 10 (EOT1), 14, and 18 (EOT2/EOS/ET). 
t It is anticipated that some patients will have a worsening of the underlying condition of the disease, such as increasing diarrhea. Any such conditions 
considered by the Investigator to be worsening of the underlying condition should be reported as AEs. Investigators should also report such AEs as part of the 
clinical rescue assessment as appropriate (Section 12.4). 
u EEG has a window of ±1 day to accommodate being conducted by a separate specialist. 
v Patients will need to hold the first dose of study medication for on-site administration. 
w In OL1 and OL2, open-label study medication is dispensed at Visit 4 and Visit 12, respectively. 
 
 
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Note 1: Laboratory samples required at Screening may be collected across multiple days to reduce blood volume drawn on a single day. Screening laboratory 
results must be received before Titration Period W1. If genetic results are still pending after 28 days, the screening window may be extended up to 2 additional 
weeks, with approval by the Medical Monitor. If a patient’s screening window is extended, the patient is not required to repeat screening assessments. Laboratory 
assessments for all other visits should be collected prior to the first daily dose of CDCA. 
Note 2: Patients will be contacted (via telephone call) 30 (±7) days after the last dose of study medication to ascertain patient safety (see Section 6.6.2 and 
Section 6.8 for details). 
a Assessments for Visits 3, 5, 7, 9, 12, 14, and 16 may be conducted by a home health vendor at an alternative site than the Investigator’s site. However, the EEG 
assessment at Visit 14 must be conducted on site. 
b Patients will need to hold the first dose of study medication for on-site administration. 
c If prior genetic confirmation of CTX is not available, blood will be drawn at Visit 1 for gene sequencing. No patient with negative genetic sequencing will be 
enrolled. 
d CTX medical history should include a complete list of CTX-related symptoms present at the time of Screening. 
e Serum pregnancy tests will be performed at Screening for WOCBP. Urine pregnancy tests will be performed at all other visits. A positive urine pregnancy test 
will be confirmed by a serum test. All WOCBP must have a negative pregnancy test (urine, with positive results confirmed by serum) at every visit. 
f The CGI-C needs to be completed at this visit if a patient leaves the study early during the treatment period. 
g Note that after the baseline assessment at Titration start, there will be a trigger question to ask if there have been any changes to previous milestones assessed 
(either new milestone met or a regression). 
h Ophthalmology exam includes BCVA and cataracts. The ophthalmology exam has a window of ±1 day to accommodate being conducted by a separate 
specialist. 
i At Screening, the physical examination is a full physical examination; at subsequent visits, the physical examination can be an abbreviated exam. Height, 
weight, and head circumference will be measured at all visits for pediatric cohort patients to be able to determine Failure to Thrive. Physical examinations will 
include assessment of the following body systems: abdomen; cardiovascular; ear, nose, and throat; eyes; hair and skin; lymph nodes; mental status; 
musculoskeletal; neurological; and respiratory. 
j Vital signs will always be measured prior to having blood drawn for laboratory evaluations. 
k All pediatric cohort patients (regardless of their history of CDCA use) and/or their parent/legal guardian will be asked to complete the daily and per-event PRO 
diaries for bowel function and seizures during the 7 days prior to Visits 4, 10, 14, and 18. Reminders regarding the completion of the PRO diary will be sent to 
patients and/or patient’s parent/legal guardian at times specified in the Study Manual. Diaries will be reviewed for compliance at Visits 4, 10, 14, and 18. If the 
review of the PRO diary indicates that the patient or the patient’s parent/legal guardian is not sufficiently compliant with completion of the diary as described in 
the Study Manual, the patient or the patient’s parent/legal guardian will be retrained on how to complete the diary. 
l Distribution and training on diary only. 
m First morning void on 3 mornings within 5 days prior to the visit will be collected and brought to the site visit. For the Screening visit, the patient may bring 
these urine samples to the site after the Screening visit and before the first day of the Titration period. 
n Laboratory tests will be conducted at a central laboratory. During the titration period of the pediatric cohort, testing at a local laboratory is permitted to 
facilitate titration review if there are delays to central laboratory reporting (eg, lost or hemolyzed blood sample). A list of clinical laboratory assessments is 
provided in Appendix 3. 
o Fasting blood draws for the assessment of lipid parameters will be collected at Visits 2 (Titration Start), 8 (Titration Week 6), 12 (Week 4), 16 (Week 12), 18 
(Week 16/EOT/EOS/ET). 
p Blood draw for thyroid stimulating hormone will only be collected at Screening. 
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q Blood sample for plasma PK will be drawn within 1 hour prior to study medication administration. PK samples will be collected predose (t0), and at 1 and 3 
hours postdose at Visit 2 (Titration Start). PK samples will be collected at Visits 4, 6, or 8 only if there is a dose change. Additional PK samples will be 
collected at Visit 12 if a steady dose has been maintained for ≥1 month prior to the visit. If a steady dose was not maintained for ≥1 month prior to Visit 12, PK 
sample collection may be delayed to Visit 14. If a steady dose was not maintained for ≥1 month prior to Visit 14, PK sample collection may be delayed and will 
occur at Visit 16. Patients will need to hold first daily dose of study medication for on-site administration to facilitate the correct timing of the blood draw for 
the PK analysis. A standardized low-fat meal will be provided 45-60 minutes prior to dosing and should be completed within 30 minutes of starting the meal. 
Predose blood sample for plasma PK will be drawn within 15-30 minutes post completion of the meal. After the first study medication dose, the 0.5 hours post 
dose draw has a ±5-minute window. The 1, 2, and 3 hour post dose draws have a ±10-minute window. 
r Adverse event information should be collected by Investigators throughout the study, regardless of where the visit takes place (ie, on-site or homecare). 
s EEG has a window of ±1 day to accommodate being conducted by a separate specialist. 
t EEG will be performed only at Visit 14. 
u Treatment Day 1 occurs one week after Visit 9 (Titration Week 7). 
v Study medication may be shipped directly to the patient or made available for dispensation at the site. 
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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Blood Urea Nitrogen 
Creatinine 
Total bilirubin 
Direct bilirubin 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Lactate dehydrogenase 
Alkaline phosphatase 
Creatine kinase 
 
Thyroid stimulating hormone 
 
Serologic Testing 
Hep B 
Hep C 
HIV 
 
Biomarkers 
Cholestanol 
7αC4 
7α12αC4 
Urine 23S-pentol  
Plasma tetrol-glucuronide (plasma 
bile alcohol) 
Hematology  
Red blood cell count 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC 
RBC distribution width 
Platelet count 
White blood cell count 
WBC differential (% and 
absolute) 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Monocytes 
Routine Urinalysis 
Color 
Appearance 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Urobilinogen 
Nitrates 
Leukocyte esterase 
Microscopic examination 
(performed if blood, protein, 
or leukocyte esterase is 
abnormal in urine) 
 
For WOCBP, pregnancy 
test (confirmed with serum 
test if positive)  
 
Coagulation (adult cohort only) 
Prothrombin time 
INR 
Lipid Profile 
Total cholesterol 
Triglycerides 
HDL 
LDL 
Abbreviations: 7αC4 = 7 alpha hydroxy 4 cholesten-3 one; 7α12αC4 = 7-alpha,12-alpha-dihydroxy-4-cholesten-3-
one; HDL = high-density lipoprotein; Hep = hepatitis; HIV = Human immunodeficiency virus; INR = international 
normalized ratio; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; WBC = white 
blood cell; WOCBP = women of childbearing potential. 
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APPENDIX 4. PATIENT/CAREGIVER ASSESSMENT OF DISEASE-
RELATED SYMPTOMS OR MANIFESTATIONS  
For consistency, please enter data as close to the end of each event (ie, bowel movement and 
seizure) or before bedtime for symptoms or manifestations collected daily. The actual questions 
will reflect who fills out the questionnaire, either the patient or the caregiver. 
Are you the Patient (___) or the Caregiver (___)? 
Symptoms 
1. Collected for each bowel movement or at the end of the day if no bowel movement 
occurred during the day:  
Did you/the patient in your care have a bowel movement (BM)? Yes [ ] No [ ] 
If YES, please fill out the BSFS reflecting the most recent bowel movement. 
If YES, please indicate if there was any discomfort in the stomach or rectal area during 
the most recent bowel movement:  
 
No discomfort [ ] Mild [ ] Moderate [ ] Severe [ ] Very severe [ ] 
2. Collected for each seizure or at the end of the day if no seizure occurred during the day:  
Did you/the patient in your care have any seizures? Yes [ ] No [ ] 
If YES, please contact the study doctor and record the 
 
Duration of the seizure (seconds or minutes): _________  
 
Severity of seizure: Mild [ ] Moderate [ ] Severe [ ] Very severe [ ] 
3. Collected at the end of the day: 
Did you/the patient in your care have any tremors today? Yes [ ] No [ ] 
If YES, please fill out the tremor questionnaire indicating the area(s) affected and the 
severity. 
 
Area Affected 
If YES 
Mild 
Moderate 
Severe 
Very Severe 
Head 
Yes [ ]  No [ ] 
 
 
 
 
Face 
Yes [ ]  No [ ] 
 
 
 
 
Tongue 
Yes [ ]  No [ ] 
 
 
 
 
Neck 
Yes [ ]  No [ ] 
 
 
 
 
Arms/hands 
Yes [ ]  No [ ] 
 
 
 
 
Trunk 
Yes [ ]  No [ ] 
 
 
 
 
Legs/feet 
Yes [ ]  No [ ] 
 
 
 
 
Voice 
Yes [ ]  No [ ] 
 
 
 
 
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Manifestations: Impact on Daily Activities 
Rate the impact on performing daily activities today for you/the patient in your care due to 
difficulty. 
 
Did you/ 
patient in 
your care 
have 
difficulty 
(Yes/No) 
If YES 
No 
Impact 
Slight impact, 
able to 
perform most 
typical daily 
tasks 
Moderate 
impact, unable 
to perform 
some typical 
daily tasks 
Severe impact, 
unable to 
perform most 
typical daily 
tasks 
Very severe 
impact, unable 
to perform any 
typical daily 
task  
Walking 
 
 
 
 
 
 
With weakness 
 
 
 
 
 
 
Speaking 
 
 
 
 
 
 
Using hands 
 
 
 
 
 
 
Seeing 
 
 
 
 
 
 
Thinking/ 
mentally focusing 
 
 
 
 
 
 
Sleeping 
 
 
 
 
 
 
Other (specify) 
 
 
 
 
 
 
Manifestations: Discomfort or Distress 
Rate the discomfort or distress for you/the patient in your care due to  
 
Did you/the 
patient in your 
care have 
(Yes/No) 
If YES 
No 
discomfort 
or distress 
Slight 
discomfort 
or distress 
Moderate 
discomfort 
or distress 
Severe 
discomfort 
or distress 
Very severe 
discomfort 
or distress  
Difficulty eating 
or swallowing 
 
 
 
 
 
 
Difficulty 
dressing 
 
 
 
 
 
 
Difficulty with 
hygiene 
 
 
 
 
 
 
Mood changes 
 
 
 
 
 
 
Difficulty 
urinating 
 
 
 
 
 
 
Headaches 
 
 
 
 
 
 
Pain other than 
headache 
 
 
 
 
 
 
Dystonia 
 
 
 
 
 
 
Other (specify) 
 
 
 
 
 
 
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Most Bothersome Symptoms or Manifestations 
Among the SYMPTOMS or MANIFESTATIONS that you/the patient in your care had today 
(those will be listed), indicate the three that bothered you/the patient in your care most today. Is 
there another symptom or symptoms that has/have not been captured? 
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APPENDIX 5. CLINICAL PROGRESSION REQUIRING RESCUE FORM 
Clinical Progression Requiring Rescue 
In the Investigator’s clinical judgment, does the patient require rescue with open-label CDCA, 
based on the available information? Yes [ ] No [ ]  
If yes, please indicate the specific reason(s) contributing to this decision. 
Changes relative to the baseline (open-label 
period) preceding each double-blind period 
If YES 
 
Mild 
Moderate 
Severe 
Very Severe 
Increased frequency or worsening of 
diarrhea? 
Yes [ ]  
No [ ] 
 
 
 
 
Increased frequency or severity of 
tremors? 
Yes [ ]  
No [ ] 
 
 
 
 
Increased frequency or severity of 
seizures? 
Yes [ ]  
No [ ] 
 
 
 
 
New or worsening neurological 
symptoms or manifestations? 
Yes [ ]  
No [ ] 
 
 
 
 
Loss or deterioration in motor skills? 
Yes [ ]  
No [ ] 
 
 
 
 
Reduction or deterioration of 
cognitive function? 
Yes [ ]  
No [ ] 
 
 
 
 
Reduction or deterioration of visual 
acuity? 
Yes [ ]  
No [ ] 
 
 
 
 
New or worsening EEG abnormality? 
Yes [ ]  
No [ ] 
 
 
 
 
Demonstrated Failure to Thrive? 
Yes [ ]  
No [ ] 
 
 
 
 
Decline in overall health status? 
Yes [ ]  
No [ ] 
 
 
 
 
Additional Details 
 
 
 
 
 
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i It is anticipated that some patients will have a worsening of the underlying condition of the disease, such as increasing diarrhea. Any such conditions 
considered by the Investigator to be worsening of the underlying condition should be reported as adverse events. Investigators should also report such adverse 
events as part of the clinical rescue assessment as appropriate (Section 12.4). 
j Patients will need to hold the first dose of study medication for on-site administration. 
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SAP_001.pdf: 
 
A PHASE 3 STUDY TO EVALUATE THE EFFECTS OF 
CHENODEOXYCHOLIC ACID IN ADULT AND 
PEDIATRIC PATIENTS WITH CEREBROTENDINOUS 
XANTHOMATOSIS (RESTORE) 
 
Investigational Medicinal Product: 
Chenodeoxycholic Acid (CDCA) 
Protocol Number: 
Cheno-CTX-301 
IND Number: 
IND 124960 
NCT Number: 
NCT04270682 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is the property of Travere Therapeutics, Inc. and contains information that is of 
a confidential, trade secret, and/or proprietary nature. It is intended for use by Travere 
Therapeutics, Inc. and its designees, and no portion may be photocopied, disclosed, or 
transmitted to any unauthorized person without the written approval of 
Travere Therapeutics, Inc. 


Statistical Analysis Plan - Version 2.0
Statistical Analysis Plan
Protocol Number: Cheno-CTX-301
A PHASE 3 STUDY TO EVAULATE THE EFFECTS OF CHENODEOXYCHOLIC 
ACID IN ADULT AND PEDIATRIC PATIENTS WITH CEREBROTENDINOUS 
XANTHOMATOSIS (RESTORE)
Original Protocol:
13 November 2018
Amendment 1:
19 December 2018
Amendment 2:
05 April 2019
Amendment 3:
22 July 2019
Amendment 4:
15 April 2020
Amendment 5:
23 August 2021 
Administrative Letter 2: 28 September 2022
Amendment 6:
04 April 2023
Prepared by:
Manager, Statistics
Pharmapace, Inc.
Version:
2.0 
Date:
17 July 2023
 
 
 
2


Statistical Analysis Plan - Version 2.0
Page 2 of 50
Statistical Analysis Plan
Protocol Number: Cheno-CTX-301
A PHASE 3 STUDY TO EVAULATE THE EFFECTS OF CHENODEOXYCHOLIC 
ACID IN ADULT AND PEDIATRIC PATIENTS WITH CEREBROTENDINOUS 
XANTHOMATOSIS (RESTORE)
Original Protocol:
13 November 2018
Amendment 1:
19 December 2018
Amendment 2:
05 April 2019
Amendment 3:
22 July 2019
Amendment 4:
15 April 2020
Amendment 5:
23 August 2021
Administrative Letter 2: 28 September 2022
Amendment 6:
04 April 2023
This Statistical Analysis Plan has been reviewed and approved by:
Date
Associate Director, Biostatistics
Travere Therapeutics, Inc. 
Date
Vice President, Biometrics
Travere Therapeutics, Inc. 
Date
Medical Monitor
Travere Therapeutics, Inc. 
 
 
  
 
 
 
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Statistical Analysis Plan - Version 2.0
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TABLE OF CONTENTS
1
INTRODUCTION...........................................................................................................................................9
2
STUDY OBJECTIVES ...................................................................................................................................9
2.1
Efficacy Objective ................................................................................................................................9
2.2
Safety Objective....................................................................................................................................9
2.3
Exploratory Objectives .........................................................................................................................9
3
STUDY OVERVIEW ...................................................................................................................................10
3.1
Overall Study Design..........................................................................................................................10
3.1.1
Adult Cohort.........................................................................................................................10
3.1.2
Extension of an Open-Label Period as a Result of COVID-19 ............................................11
3.1.3
Pediatric Cohort....................................................................................................................12
3.2
Study Procedures ................................................................................................................................14
3.2.1
Rescue Medication Criteria in the Adult Cohort ..................................................................14
3.2.2
Randomization and Blinding for the Adult Cohort...............................................................14
3.2.3
Replacement .........................................................................................................................15
3.2.4
Unblinded DMC ...................................................................................................................15
3.3
Study Enrollment and Duration ..........................................................................................................15
3.3.1
Number of Patients ...............................................................................................................15
3.3.2
Duration of Study .................................................................................................................15
4
STUDY ENDPOINTS...................................................................................................................................16
4.1
Primary Efficacy Endpoint for the Adult Cohort................................................................................16
4.2
Key Secondary Efficacy Endpoints for the Adult Cohort...................................................................16
4.3
Other Secondary Efficacy Endpoints for the Adult Cohort ................................................................16
4.4
Safety Endpoints for Both Adult and Pediatric Cohorts .....................................................................16
4.5
Exploratory Endpoints for both Adult and Pediatric Cohorts .............................................................17
4.5.1
Adult Cohort.........................................................................................................................17
4.5.2
Pediatric Cohort....................................................................................................................17
5
STATISTICAL ANALYSIS CONSIDERATIONS......................................................................................18
5.1
Sample Size Justification and Power Analysis for Adult Cohort........................................................18
5.2
Analysis Sets.......................................................................................................................................18
5.2.1
Adult Cohort.........................................................................................................................18
5.2.2
Pediatric Cohort....................................................................................................................19
5.2.3
Adult and Pediatric Cohorts..................................................................................................19
5.3
Data Handling.....................................................................................................................................20
5.3.1
Reference Date and Study Day.............................................................................................20
5.3.2
Handling of Multiple Observations (For both Cohorts)........................................................20
5.3.3
Baseline and Change from Baseline .....................................................................................21
5.3.3.1
Adult Cohort.......................................................................................................21
5.3.3.2
Pediatric Cohort..................................................................................................21
5.3.4
Handling of Safety Results beyond the Limit of Quantification (For both Cohorts)............21
5.3.5
Handling of Biomarker Results Above or Below the Limit of Quantification (For both 
Cohorts) ................................................................................................................................21
5.3.6
Imputation of Incomplete Dates (For both Cohorts).............................................................22
5.3.7
PK Parameters Calculation (For Adult Cohort)....................................................................22
5.4
Statistical Methods..............................................................................................................................22
5.4.1
Statistical Notation and Presentation ....................................................................................22
5.4.2
Statistical Hypothesis ...........................................................................................................23
5.4.3
Multiple Comparison............................................................................................................23
5.4.4
Interim Analysis ...................................................................................................................24
6
STATISTICAL ANALYSIS .........................................................................................................................24
6.1
Study Patients .....................................................................................................................................24
6.1.1
Analysis Population..............................................................................................................24
6.1.2
Patient Eligibility..................................................................................................................25
  
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Statistical Analysis Plan - Version 2.0
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6.1.3
Patient Disposition................................................................................................................25
6.1.4
Demographic Characteristics................................................................................................25
6.1.5
Medical History....................................................................................................................25
6.1.6
Study Treatment Administration ..........................................................................................25
6.1.7
Protocol Deviations ..............................................................................................................26
6.1.8
Concomitant Medications.....................................................................................................26
6.1.8.1
Adult Cohort.......................................................................................................26
6.1.8.2
Pediatric Cohort..................................................................................................27
6.2
Analysis of Efficacy ...........................................................................................................................27
6.2.1
Analysis of Primary Efficacy Endpoint of Urine 23S-Pentol ...............................................27
6.2.2
Analysis of Key Secondary Efficacy Endpoints...................................................................28
6.2.2.1
Proportion of Patients requiring Rescue Medication ..........................................28
6.2.2.2
Percent Change from baseline in Plasma Cholestanol........................................30
6.2.2.3
Percent Change from baseline in Plasma 7 C4..................................................30
6.2.3
Analysis of Other Secondary Efficacy Endpoints.................................................................31
6.2.3.1
Change from baseline in Plasma Cholestanol to Cholesterol Ratio....................31
6.2.3.2
Percent Change from baseline in Plasma 7 12 C4............................................31
6.2.3.3
Proportion of Patients with Negative Net Change in Symptoms and 
Manifestations reported in the Diary..................................................................31
6.3
Analysis of Safety Endpoints..............................................................................................................32
6.3.1
Extent of Exposure ...............................................................................................................32
6.3.2
AEs .......................................................................................................................................32
6.3.2.1
Adult Cohort.......................................................................................................33
6.3.2.2
Pediatric Cohort..................................................................................................33
6.3.2.3
Adult and Pediatric Cohort .................................................................................34
6.3.3
Laboratory Evaluations.........................................................................................................34
6.3.3.1
Adult Cohort.......................................................................................................34
6.3.3.2
Pediatric Cohort..................................................................................................35
6.3.4
Vital Signs and Body Weight ...............................................................................................35
6.3.5
EEG and 12-Lead ECG ........................................................................................................35
6.3.6
Physical Examination ...........................................................................................................35
6.4
Analysis of Exploratory Endpoints.....................................................................................................36
6.4.1
Adult Cohort.........................................................................................................................36
6.4.2
Pediatric Cohort....................................................................................................................36
6.5
Handling of Missing Data (For both Cohorts)....................................................................................37
6.5.1
Imputation Rules for Analysis Sets ......................................................................................37
6.5.2
MI under MAR assumption..................................................................................................37
6.6
Statistical Software .............................................................................................................................39
7
REFERENCES..............................................................................................................................................39
8
APPENDIX ...................................................................................................................................................39
LIST OF TABLES
Table 1: Schedule of Assessments for Adult Cohort............................................................................................40
Table 2: Schedule of Assessments for Pediatric Cohort.......................................................................................45
Table 3: Schedule of Assessments during the Extension of the Open-label Periods in the Adult Cohort............49
LIST OF FIGURES
Figure 1: Study Design Diagram for Adult Cohort ..............................................................................................13
Figure 2: Study Design Diagram for Extension of Open-Label Period in the Adult Cohort ................................13
Figure 3: Study Design Diagram for Pediatric Cohort .........................................................................................13
Figure 4 : The Multiple Comparison Procedure ...................................................................................................24
 
 
  
 
 
 
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Figure 5: The Algorithm and Notations by Anna Pictor.......................................................................................29
  
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FCS
Fully Conditional Specification
gCDCA
GlycoChenodeoxycholic acid
IRT
Interactive response technology
IxRS
Interactive voice/Web response system
LLOQ
Lower limit of quantification
LS
Least squares
MAR
Missing at random
MAX
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MIN
Minimum
NIFAS
Newly-Initiated Full Analysis Set
OL
Open-label
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PPAS
Per Protocol Analysis Set
PPKAS
Pediatric Pharmacokinetic Analysis Set
PSAS
Pediatric Safety Analysis Set
PTAS
Pooled TEAE Analysis Set
Q1
First quartile
Q3
Third quartile
RI
Run-in
SAE(s)
Serious adverse event(s)
SAP
Statistical analysis plan
SAS
Safety Analysis Set
SD
Standard deviation
SE(s)
Standard error(s)
tCDCA
TauroChenodeoxycholic acid
TEAE(s)
Treatment emergent adverse event(s)
TEFAS
Treatment-Experienced Full Analysis Set
TID
Three times daily
 
 
  
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tmax,ss
Time to reach maximum (peak) plasma concentration following drug 
administration at steady state
ULN
Upper limit of normal
ULOQ
Upper limit of quantification
W
Week
WHO-DD
World Health Organization Drug Dictionary
 
 
  
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1
INTRODUCTION
This document describes the statistical methods and data presentations to be used in the summary 
and analysis of efficacy and safety of chenodeoxycholic acid (CDCA) in patients with 
cerebrotendinous xanthomatosis (CTX).  Background information is provided for the overall 
study design and objectives.  The reader is referred to the study protocol Cheno-CTX-301 
Amendment 6 (04 April 2023) and case report forms (CRFs) for details of study conduct and 
data collection.
The proposed methods and approaches to the data analysis should be viewed as flexible.  If the 
data suggest and warrant it, deviations from this statistical analysis plan (SAP) will be 
considered.  However, any deviations from this SAP must be substantiated by sound and 
convincing statistical rationale and documented in the clinical study report. 
Where appropriate, this document will provide sample computer (SAS®) codes to aid 
understanding of the statistical methods and help statistical analysts (programmers) to implement 
the statistical methods.  However, the actual computer codes may be slightly different to reflect 
the actual dataset structure.  
2
STUDY OBJECTIVES
The purpose of this study is to investigate the efficacy and safety of CDCA in patients with CTX 
in comparison with placebo. 
2.1
Efficacy Objective
Determine the effects of CDCA, compared with placebo, on biomarkers and clinical 
symptoms of CTX in adult patients with CTX.
2.2
Safety Objective
Assess the safety and tolerability of CDCA in adult and pediatric patients.
2.3
Exploratory Objectives
Characterize the relationship among biomarkers in adult and pediatric patients. 
Characterize steady-state pharmacokinetics (PK) of CDCA and 2 conjugated forms of 
CDCA, GlycoChenodeoxycholic Acid (gCDCA) and TauroChenodeoxycholic Acid 
(tCDCA) in adult patients.
Characterize the relationship between dose and PK concentration among pediatric 
patients.
Assess biomarkers and health status among pediatric patients treated with CDCA. 
 
 
  
 
 
 
 
 
 
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3
STUDY OVERVIEW
3.1
Overall Study Design
This study is made up of 2 designs: 1) a randomized, double-blind (DB), crossover study design 
-label (OL), dose-
at Screening (pediatric cohort).
3.1.1
Adult Cohort
Patients in the adult cohort will participate in a randomized, double-blind, placebo-controlled, 
2-period × 2-treatment crossover study with rescue medication to assess the efficacy and safety 
of CDCA in the treatment of CTX.  Approximately 12 male and/or female CDCA-naïve or 
CDCA-
sion criteria and 
none of the exclusion criteria and whose clinical symptoms are stable during the open-label run-
in period (OL1) are planned to be randomized in the study. 
At least 6 of the patients randomized in the study will be treatment-experienced (i.e. those who 
have been on a stable dose of CDCA for at least 2 months prior to the run-in period).  Patients 
who are either CDCA-naïve or those with less than 2 months of treatment prior to the run-in 
period are considered newly-initiated patients.
The study design is summarized in Figure 1.
Patients will be screened at Visit 1 and those who satisfy all the inclusion and none of the 
exclusion criteria will participate in the 8-week OL1 to establish reliable baseline measurements 
for biomarkers and other efficacy assessments.  Patients who fail screening may be rescreened as 
needed. 
Adult cohort patients will receive 250 mg open-label CDCA three times daily (TID) during the 
OL periods of the study (OL1 and OL2).  During the double-blind periods (DB1 and DB2), adult 
cohort patients will receive either blinded CDCA 250 mg TID or matching placebo TID. 
Following the OL1 period, patients will be reassessed for eligibility before randomization 
(Day 1).  To be randomized, patients are required to have tolerated CDCA and not have 
developed any condition that, in the judgment of the Investigator, warranted discontinuation of 
CDCA treatment.  Adult cohort patients will be randomized on Day 1 at a 1:1 ratio to one of two 
treatment sequences (AB or BA) to enter a 4-week DB period (DB1), an 8-week OL period 
(OL2), and then a second 4-week DB period (DB2).  
Blinded- or open-label 250 mg CDCA TID rescue medication will be provided during the DB 
periods, if needed, based on blinded biomarkers (blinded rescue) and/or clinical CTX-related 
symptoms (open-label rescue).  Patients who require blinded and/or open-label CDCA rescue 
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respective DB period.  Patients who require rescue medication during DB1 but otherwise remain 
eligible should continue to OL2 and then to DB2. 
After the last dose of study medication, patients may transition to treatment for CTX per the 
guidance of the Investigator or prescribing physician.  A safety follow-up phone call will be 
conducted for all patients 30 (±7) days after last dose of study medication. 
4-Week DB1: On Day 1, patients will be randomized to treatment sequence AB or BA.  Patients 
randomized to sequence AB will receive blinded 250 mg CDCA TID for 4 weeks or until rescue 
medication criteria are triggered; patients randomized to sequence BA will receive placebo TID 
for 4 weeks or until rescue medication criteria are triggered.  Should rescue medication criteria 
be met, patients will receive 250 mg CDCA TID until the end of DB1.  Patients will return to the 
clinic on Day 8, and weekly thereafter for the remaining 3 weeks. 
8-Week OL2: Upon completion of DB1, patients will receive open-label 250 mg CDCA TID for 
8 weeks and return to the clinic for bi-weekly scheduled visits.
4-Week DB2: At Week 12, patients who were randomized to sequence AB will crossover into 
DB2 and receive placebo treatment TID for 4 weeks or until rescue medication criteria are 
triggered; patients who were randomized to sequence BA will receive blinded 250 mg CDCA 
TID treatment for 4 weeks or until rescue medication criteria are triggered.  Should rescue 
medication criteria be met, patients will receive 250 mg CDCA TID until the end of DB2.  
Patients will return to the clinic on Day 92 (7 days after first day of DB2 period), and weekly 
thereafter for the remaining 3 weeks. 
3.1.2
Extension of an Open-Label Period as a Result of COVID-19
An adul
the start of a DB withdrawal period (DB1 or DB2) if study and/or site operations are disrupted as 
a result of the COVID-19 pandemic.  The decision to postpone the start of a DB period will be at 
the discretion of both the Investigator and Medical Monitor.  If it is decided to extend an OL 
period, the patient will return to the study site once a month from the Visit 4 (OL1) or Visit 12 
(OL2) date or last dispensation of OL study medication during the respective OL period.  During 
these extension visits, the Investigator will ensure patient safety monitoring and dispensation of 
additional OL study medication is performed.  Efficacy assessments during the extension visits 
are optional.  See Table 3 for the Schedule of Assessments. 
Patients will continue to receive 250 mg open-label CDCA TID during the extension periods.  
Details within the clinical study protocol regarding study medication in the OL1 and OL2 
extend beyond 24 weeks if an extension visit is required because of COVID-19.
A patient may proceed with the start of a DB withdrawal period when the Investigator and 
Medical Monitor agree that the impact to site and/or study operations because of COVID-19 has 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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visits without interruption and the timely reporting of necessary study results.  A patient will 
resume the patient schedule as detailed in Table 1 when starting a DB period.
If a patient completes 2 or more extension visits in 1 OL period, the patient must complete a 
study visit 2 weeks prior to the start of a DB period to complete all safety and efficacy 
assessments that were otherwise required during a visit in the OL period.
The modified study design is summarized in Figure 2.
3.1.3
Pediatric Cohort
-week, 
open-label cohort with an 8-week titration period to identify a safe and tolerable dose, and a 
16-week treatment period at the safe and tolerated dose as maintenance.  Patients will be 
screened at Visit 1 and those who satisfy all the inclusion criteria and none of the exclusion 
criteria will be eligible to participate in this cohort to evaluate safety, PK, and biomarkers in this 
population.  Patients will have visits every week during the titration period and every 4 weeks 
during the treatment period.  A safety follow-up phone call will be conducted for all patients 30 
(±7) days after the last dose of study medication. 
During the dose titration period, dose escalation decisions will be based on safety and 
tolerability.  Dosing will be as follows:
Treatment-naïve pediatric cohort patients will receive doses of 5 mg/kg/day (TID), 
10 mg/kg/day (TID), or 15 mg/kg/day (TID), titrated up every 2 weeks based on safety 
and tolerability over a period of 8 weeks.
Treatment-
CDCA will start at their current dose and titrate up every 2 weeks to the next dose level 
up to 15 mg/kg/day based on safety and tolerability over a period of 8 weeks.  Patients 
with a history demonstrating intolerance at higher doses will not be required to dose 
escalate.
Pediatric cohort dosing of CDCA will not exceed an equivalent dose of 750 mg/day.
Pediatric cohort patients who are able to take an equivalent weight-based dose of 
750 mg/day and are capable of swallowing a tablet will have the option to dose with 
CDCA 250 mg tablets TID or the liquid suspension form of CDCA. 
During the treatment period, dosing will be maintained at the dose tolerated during the titration 
period.  After the last dose of study medication, patients may transition to treatment for CTX per 
the guidance of the Investigator or prescribing physician.  The study design is summarized in 
Figure 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Figure 1: Study Design Diagram for Adult Cohort
Figure 2: Study Design Diagram for Extension of Open-Label Period in the Adult Cohort
Figure 3: Study Design Diagram for Pediatric Cohort
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
 
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3.2
Study Procedures
Study procedures and their timing are summarized in Table 1 (for the adult cohort) and Table 2
(for the pediatric cohort).  Protocol waivers or exemptions are not allowed. 
Study procedures related to the extension of the open-label period because of COVID-19 and 
their timing are summarized in Table 3.
3.2.1
Rescue Medication Criteria in the Adult Cohort
Blinded- or open-label 250 mg CDCA TID rescue medication will be provided during the DB 
periods, if needed, based on blinded biomarkers (blinded rescue) and/or clinical CTX-related 
symptoms (open-label rescue).  Patients who require blinded and/or open-label CDCA rescue 
medication in a given period will remain on the rescue medication for the remainder of the 
respective DB period.  Patients who require rescue during DB1 but otherwise remain eligible 
should continue to OL2 and then to DB2. 
Blinded CDCA will be provided to patients who meet the following criterion: increase of 10 
times the baseline value for a given period (i.e., Visit 6 and 14) in urine 23S-pentol.  Blinded 
CDCA will be assigned through the Interactive Voice/Web Response System (IxRS) at the next 
scheduled in-clinic visit.  Values entered in the IxRS system will be the geometric mean of the 
urine 23S-pentol results from each of the first morning void samples provided by the patient per 
visit time point.  If the urine 23S-pentol value is below the level of quantification (BLQ), the 
lowest value in the analytical range (i.e., the lower limit of quantification [LLOQ]) will be used 
either to calculate the geometric mean or entered into the IxRS system.  The Investigator and 
patient will remain blinded to biomarker data, treatment assignment, and if blinded rescue 
medication criteria are met.
Patients receiving either blinded CDCA or blinded placebo during the DB period will be rescued 
with open-label CDCA at the discretion of the Investigator if they present with new or worsening 
CTX-related symptoms relative to their respective pre-treatment assessments as defined in the 
protocol.  The Investigator is responsible for evaluating patients to determine if they meet the 
criteria for rescue medication at each follow-up visit during DB1 and DB2.
The specific reasons contributing to the Investigator decision and supportive data will be 
collected in the database.  All assessments should continue as indicated in Table 1.
3.2.2
Randomization and Blinding for the Adult Cohort
Adult cohort patients will be randomized on Day 1 (Visit 6) at a 1:1 ratio to 1 of 2 treatment 
sequences (AB or BA).  Patients randomized to sequence AB will receive blinded CDCA TID 
for 4 weeks or until open-label rescue medication criteria are triggered; 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. 
  
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throughout its course, with the exception of the Data Monitoring Committee (DMC) (refer to 
3.2.4), study medication supply, the serious adverse event (SAE) reporting contact, unblinded 
study monitor and the independent statistical team(s) supporting the DMC.  The randomization 
schedule for treatment allocation will be securely maintained and will not be disclosed until after 
database lock.  Only for emergency unblinding, randomization codes and corresponding 
treatment assignments will be made available to the Investigator through the interactive response 
technology (IRT) system. 
3.2.3
Replacement
In general, patients are encouraged to remain in the study until they complete the study.  A 
patient who permanently discontinues from the study will complete the Early Termination (ET) 
assessments listed in Table 1 or Table 2
medication or as soon as possible for those patients who had previously completed an end of 
treatment (EOT) visit.  The visit data, including the primary reason for premature discontinuation 
from the study, will be recorded on the ET electronic CRF.
Patients discontinuing from the study will not be replaced.
3.2.4
Unblinded DMC
An unblinded DMC will monitor accumulating data, including biomarkers (urine and plasma bile 
efficacy, clinical outcomes, and safety results to potentially stop the study early based on the 
overall benefit-risk assessment, including the risk of irreversible disease progression among 
DMC Charter.  
3.3
Study Enrollment and Duration
3.3.1
Number of Patients
separately 
in the pediatric cohort. 
3.3.2
Duration of Study
The adult cohort will be approximately 24 to 28 weeks in duration, including an up to 4-week 
screening period; an 8-week OL run-in period (OL1); two 4-week DB treatment periods (DB1 
and DB2); and an 8-week OL treatment period (OL2) in between DB1 and DB2.  The duration of 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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the adult cohort may extend beyond 28 weeks if the start of a DB period is delayed due to 
COVID-19. 
The pediatric cohort will be approximately 24 to 28 weeks in duration, including an up to 4-week 
screening period; an 8-week, OL dose titration period; and a 16-week, OL treatment period at the 
identified safe and tolerated dose as maintenance.
If genetic results are still pending after 28 days, the screening window for both cohorts may be 
extended up to 2 additional weeks, with approval by the Medical Monitor, which will bring the 
maximum total duration of the study to 30 weeks.
For both cohorts, a safety follow-up phone call will be conducted 30 (±7) days after the last dose 
of study medication. 
4
STUDY ENDPOINTS
4.1
Primary Efficacy Endpoint for the Adult Cohort
Change from baseline in loge-transformed urine 23S-pentol at the end of each DB 
treatment period
4.2
Key Secondary Efficacy Endpoints for the Adult Cohort
Proportion of patients requiring rescue medication during the DB periods
Percent change from baseline in plasma cholestanol levels at the end of each DB 
treatment period
4.3
Other Secondary Efficacy Endpoints for the Adult Cohort
Change from baseline in plasma cholestanol to cholesterol ratio during the DB periods
Proportion of patients with negative net change in symptoms and manifestations reported 
in the diary during the DB periods
4.4
Safety Endpoints for Both Adult and Pediatric Cohorts
Change from baseline in body weight, vital signs, physical examinations, 
electroencephalogram (EEG), 12-lead electrocardiogram (ECG), clinical laboratory 
parameters (hematology, chemistry, coagulation [adult cohort only], lipid profile 
[including cholesterol]) and urinalysis laboratory parameters at each visit where 
parameters are collected
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
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Incidence of treatment-emergent adverse events (TEAEs), including SAEs, adverse 
events (AEs) leading to discontinuation of study medication, and AEs of interest (AEOI)
4.5
Exploratory Endpoints for both Adult and Pediatric Cohorts
4.5.1
Adult Cohort
Percent change from baseline in plasma bile alcohol at the end of each DB treatment
period
Steady-state PK parameters (AUCss, Cmax,ss, Cmin,ss, tmax,ss, CL/F) of 3 bile acids that 
include CDCA, gCDCA, tCDCA and total CDCA (summed CDCA, gCDCA, and 
tCDCA)  
Relationships among biomarkers (urine and plasma bile alcohols, plasma cholestanol,
Relationships between PK exposure parameters (AUCss, Cmax,ss or Cmin,ss) and changes in 
Relationships between PK exposure parameters (AUCss, Cmax,ss or Cmin,ss) and safety 
endpoints
Change in disease severity as assessed by the Clinician Global Impression of Change 
(CGI-C) during each DB treatment period
Change in health status questionnaire
4.5.2
Pediatric Cohort
Relationships among biomarkers (urine and plasma bile alcohols, plasma cholestanol, 
Steady-state PK concentration of CDCA, gCDCA, tCDCA and total CDCA (summed 
CDCA, gCDCA and tCDCA)
Mean biomarker levels (urine and plasma bile alcohols, pla
Change in disease severity as assessed by the CGI-C during the treatment period
Change in health status questionnaire
Change in developmental milestones
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
   
 
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5
STATISTICAL ANALYSIS CONSIDERATIONS
5.1
Sample Size Justification and Power Analysis for Adult Cohort
Sample size calculations were performed assuming an interim analysis (when approximately ½ 
of adult patients completed the study) and a final analysis (when all adult patients completed the 
study) using a group sequential design. Therefore, sample size and power calculations assumed 
2-
interim analysis and 2-
at the final 
analysis. Subsequent to the sample size calculations, the interim analysis was removed from the 
design and only one (final) analysis will be performed when all adult patients complete the study. 
The single final analysis will be performed using 2-
. The references to 
= 0.0436 in the sample size and power calculations reported below are retained to reflect the 
assumption at the time of study design. The power at the planned study size (approximately 
12 patients) using 2-
2-
The hypothesis to be tested is H0
a
difference between CDCA and placebo for the change from baseline in loge-transformed urine 
23S-pentol.  The planned sample size is expected to provide at least 90% power at the final 
For the sample size calculation, it is assumed that the true average paired treatment difference 
between CDCA and placebo in change from baseline in the loge-transformed urine 23S-pentol is 
-2.4 with a standard deviation no higher than 1.15.  In a meta-analysis of the literature data from 
eleven CTX patients receiving CDCA treatment, the mean reduction from baseline in loge-
transformed urine 23S-pentol was 3.1 with a 1.15 SD.  The assumed 2.4 difference between 
CDCA and placebo is 2 standard errors (SEs) less than the observed 3.1 reduction. 
For the proportion of patients requiring rescue treatment (secondary endpoint), the planned 
sample size of approximately 12 patients at the final analysis is expected to provide at least 85% 
power with 2-
10/12) on placebo and 15% of patients (approximately 2/12) on CDCA will need rescue 
treatment, with a di
5.2
Analysis Sets
The following analysis sets will be defined for the study. 
5.2.1
Adult Cohort
Enrolled Analysis Set (EAS): All adult cohort patients who signed informed consent and take at 
least one dose in the open-label run-in period.  This will be used to assess patient characteristics, 
disposition during the run-in period, and overall safety presentation during the study.
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Full Analysis Set (FAS): All adult cohort patients who are randomized and take at least one 
dose of randomized study medication will be included in the FAS.  Patients in the FAS will be 
analyzed according to randomized treatment assignment.  All efficacy analyses during the DB 
treatment periods will be based on the FAS.
Treatment-Experienced Full Analysis Set (TEFAS): All adult cohort patients in the 
FAS who had been on CDCA for at least 2 months prior to the OL run-in period.
Newly-Initiated Full Analysis Set (NIFAS): All adult cohort patients in the FAS who 
are either treatment-naïve or had been on CDCA for less than 2 months prior to the OL 
run-in period. 
Per Protocol Analysis Set (PPAS): The PPAS is a subset of the FAS containing adult cohort 
patients who meet study eligibility requirements, have at least one efficacy measurement in the 
DB2 treatment period, and have no protocol deviations that might impact the assessment of 
efficacy measurements.  Patients will be analyzed according to randomized treatment sequence 
assignment.  The PPAS will be used for sensitivity analyses relating to efficacy.  The type of 
protocol deviations governing exclusion from the PPAS will be determined prior to breaking the 
blind and are detailed in this SAP.
Safety Analysis Set (SAS): All adult cohort patients who are randomized and take at least one 
dose of randomized therapy will be included in the SAS.  The SAS will be used for safety 
analyses during the DB periods and will be based upon actual study medication received.
Pharmacokinetic Analysis Set (PKAS): All adult cohort patients in the EAS with evaluable PK 
samples will be included in the PKAS.  The PKAS will be used for summaries of PK 
concentration and assessment of PK parameters. 
5.2.2
Pediatric Cohort
Pediatric Safety Analysis Set (PSAS): All pediatric cohort patients whose parent/legal guardian 
signed informed consent and received at least one dose of study medication.  This will be used to 
assess patient characteristics, disposition, biomarkers, health status, and overall safety 
presentation for pediatric cohort patients. 
Pediatric Pharmacokinetic Analysis Set (PPKAS): All pediatric cohort patients in the PSAS 
with evaluable PK samples will be included in the PPKAS.  The PPKAS will be used for 
summaries of PK concentration.
5.2.3
Adult and Pediatric Cohorts
Pooled TEAE Analysis Set (PTAS): All adult cohort patients in the EAS and all pediatric 
cohort patients in the PSAS. This analysis set will be used to summarize AEs pooled from both 
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5.3
Data Handling
5.3.1
Reference Date and Study Day 
Visit day within the protocol schedule of assessments is described based on the date of first dose 
in DB1 for adult patients and date of first dose in treatment period for pediatric patients
(Figure 1, Figure 2, and Figure 3). For all summaries by visit specified in this SAP, the protocol 
specified visit label and visit day will be used (Appendix Table 1). The mapping of unscheduled 
assessments to scheduled visits is discussed in 5.3.2.  
However, not all adult patients may reach DB1 and/or not all pediatric patients may reach the 
treatment period. In order to support study datasets and listings, a study day must be derived
based on a single reference date that will be consistently available for all patients as follows:
Adult cohort: the first dose date in OL1
Pediatric cohort: the first dose date in Titration Period  
Thus, study day used in listings and study datasets presents the day of study events relative to the 
first dose in the study, not relative to the date of first dose in DB1 for adult patients or date of 
first dose in treatment period for pediatric patients as presented in the protocol schedule of 
assessments.
Study day 1 in listings and study datasets is defined as the reference date. 
Subsequent Study Days (i.e. when the date of event is on or after the reference date) are 
defined as = [(date of event reference date) + 1].
Preceding Study Days (i.e. when the date of event is before the reference date) are 
defined as = [(date of event reference date)].
Thus, by definition, there is no Study Day = 0.
5.3.2
Handling of Multiple Observations (For both Cohorts)
A patient may have multiple scheduled or unscheduled visits that are associated with a protocol 
defined visit (nominal visit).  Each unscheduled visit will be assigned a nominal visit number 
following the visit number of the associated scheduled visit (e.g., unscheduled visit number 2.1 is 
assigned to an unscheduled visit associated with protocol scheduled visit 2).  If a patient has a 
scheduled visit, the assessment obtained at the scheduled visit will be used for data summary and 
analysis.  Otherwise, if no scheduled visit assessment exists but at least one unscheduled visit 
assessment is available within a visit window of ±3 days (e.g., unscheduled visit 2.1 and 2.2 exist 
but not the scheduled visit 2), then the data at the latest unscheduled visit within the protocol
visit window will be used for data summary and analysis. 
Any unscheduled visits that cannot be attributed to a scheduled visit will not be included in 
statistical summary or analysis but will be presented in data listings.  Since all visits during 
 
 
  
 
 
 
 
 
 
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extension of OL period in the adult cohort are planned as unscheduled, results from extension 
visits will be listed only.   
For biomarker and lab data, if multiple measurements are recorded for the same time point (e.g. 
if the same blood sample is analyzed twice and recorded in the clinical database as two 
distinguished entries), the re-assayed data (the repeated one) will be included in data summary 
and analysis.  All measurements will be presented in data listings.  
5.3.3
Baseline and Change from Baseline
In general, the baseline values are defined as in 5.3.3.1 and 5.3.3.2 unless specified otherwise.  
The change from baseline value is defined as post-baseline value minus baseline value.  The 
percent change from baseline value is defined as (post-baseline value minus baseline value) / 
baseline value × 100. 
5.3.3.1
Adult Cohort
Efficacy Endpoints: The baseline values for DB1 are the last measurements prior to dose on 
Day 1.  The baseline values for DB2 are the last measurements prior to dose on Day 85 (the 
beginning of DB2 period). 
measurements prior to dose on Day -56 (the beginning of OL1 period), will also be applied when 
analyzing the efficacy endpoints.
Safety Endpoints: The baseline values will be defined separately for the two sets of analyses 
described in 6.3.3.1
prior to dose on Day -56 (the beginning of OL1 period).
5.3.3.2
Pediatric Cohort
All Endpoints: The baseline values for the study are the last measurements prior to dose on 
Visit 2 (the beginning of Titration period).
5.3.4
Handling of Safety Results beyond the Limit of Quantification (For both Cohorts)
Any safety laboratory tes
with the absolute value of the number without the sign (e.g., < 2.5 will be imputed as 2.5) for 
statistical summary and analysis. 
5.3.5
Handling of Biomarker Results Above or Below the Limit of Quantification (For 
both Cohorts)
Any biomarker results (urine 23S-
and plasma tetrol glucuronide) reported as BLQ in the database will be imputed with the LLOQ 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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for statistical summary and analysis. Any biomarker results reported as above the upper limit of 
quantification (ULOQ) in the database will be imputed with the upper limit of quantification for 
statistical summary and analysis. 
5.3.6
Imputation of Incomplete Dates (For both Cohorts)
In cases of incomplete dates for AEs or non-study medications, the missing component(s) will be 
assumed as the most conservative value(s) possible.  For example, the imputation rule is to 
conservatively capture AEs with missing start dates as TEAEs:
of the non-missing month.
-missing year.
assumed to occur on the same day as the first dose date. 
In addition, the imputation rule is to conservatively assign TEAEs with partial dates for adult 
patients to a DB
DB period or open-label 
period.
Non-study medications with missing or partial dates will be imputed similarly.
Dates imputation will only be used for computational purposes (e.g., treatment-emergent status 
or identifying concomitant medications).  Actual data values as they appear in the clinical 
database will be shown in data listings. 
5.3.7
PK Parameters Calculation (For Adult Cohort)
Steady-state PK parameters (AUCss, Cmax,ss, Cmin,ss, tmax,ss, CL/F) of CDCA, gCDCA, tCDCA and 
total CDCA will be estimated using non-compartmental analysis if feasible.  The calculation will 
be performed by LabCorp, Inc. Summary of PK concentration and PK parameters is outside the 
scope of this SAP. A separate analysis plan will be generated to describe the summary 
methodology for these endpoints.  
5.4
Statistical Methods
5.4.1
Statistical Notation and Presentation
For descriptive statistical summaries, mean, sample size (n), standard deviation (SD), SE, 
median, the first quartile (Q1), the third quartile (Q3), minimum (MIN) and maximum (MAX) 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
   
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will be calculated for continuous variables.  For parameters analyzed in the loge-scale such as 
urine 23S-pentol, geometric mean, SE and %CV will also be presented.  
Categorical variables will be summarized by count, percentage, or shift tables (if applicable).
Min, max, Q1 and Q3 values will be presented to the precision of the original value.  Means and 
medians will be rounded to one decimal place greater than the precision of the original value.  
SDs/SEs and 95% confidence intervals (CIs) will be rounded to two decimal places greater than 
the precision of the original value.  Percentages for summarizing categorical data will be rounded 
to one decimal place and will be based on nonmissing data, unless otherwise specified.  
-values will be 
presented with four decimal places and values less than 0.0001 will be presented as <0.0001. 
The by-patient listings, including data at scheduled and unscheduled visits, will be sorted by 
treatment sequence, patient number, study visit, and then by date/time of the records. 
5.4.2
Statistical Hypothesis
The null (H0) hypothesis and the alternative (Ha) hypothesis to be tested for the primary efficacy 
endpoint are that 
H0
a
CDCA and placebo for the change from 
baseline in loge-transformed urine 23S-pentol in the adult cohort. 
5.4.3
Multiple Comparison
Multiple comparison procedure will be implemented to strongly control the family-wise type 1 
errors across the primary endpoint and the key secondary efficacy endpoints.  The first family of 
hypotheses consists of urine 23S-pentol primary endpoint. The second family of hypotheses 
consist of the key secondary efficacy endpoints of proportion requiring rescue medication, 
percent change from baseline plasma cholestanol, and percent change from baseline plasma 
The schematic of the multiple comparison procedure is presented 
in Figure 4.
The primary endpoint of urine 23S-
the Family 
Two of hypotheses (i.e. key secondary endpoints) for testing at the final analysis.  Otherwise, 
endpoints will not be formally tested, and nominal p-values will be reported instead.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
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Figure 4 : The Multiple Comparison Procedure 
The Bonferroni-Holms procedure will be used to control the Type 1 errors for the Family Two of 
(1) 
(2) 
(3) 
denote the ordered unadjusted p-values with associated null hypotheses H(1), H(2), H(3) for the 
three key secondary efficacy endpoints described in 4.2 and 6.2.2. Then we have the following 
stepwise procedure:
If P(1)
(1) and continue; else stop
If P(2) 
(2) and continue; else stop
If P(3) 
(3)
All other secondary efficacy endpoints will be analyzed at the nominal 0.05 significance level. 
5.4.4
Interim Analysis 
No interim analysis will be conducted for this study.
6
STATISTICAL ANALYSIS
6.1
Study Patients
6.1.1
Analysis Population
Counts and percentages of patients in each analysis population will be summarized by treatment 
sequence and overall for the adult cohort and overall for the pediatric cohort. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
 
 
 
   
  
 
    
  
 
 
  
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6.1.2
Patient Eligibility
Patient eligibility (inclusion and exclusion criteria failures) for adults and pediatric patients will 
be provided in separate data listings for the EAS and the PSAS. 
6.1.3
Patient Disposition
Patient disposition will be presented for adults and pediatric patients.  Counts and percentages of 
patients who are randomized, completed, or discontinued from the study or study treatment, as 
well as the discontinuation reasons, will be summarized by treatment sequence and overall for 
the EAS and overall for the PSAS.  Counts and percentages of patients completing key study 
milestones (OL1, DB1, OL2, DB2 for the adult cohort; titration and treatment periods for the 
pediatric cohort) will also be presented. 
6.1.4
Demographic Characteristics
Demographics and baseline characteristics including age, sex, race, ethnicity, height, weight, 
BMI, CTX diagnosis history and ophthalmology exam results will be summarized descriptively 
by treatment sequence and overall for the EAS, FAS, TEFAS, NIFAS and overall for the PSAS.
6.1.5
Medical History
Medical History will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 22.0 or later and will be summarized descriptively by treatment sequence, 
System Organ Class and Preferred Term for the EAS.  CTX Medical History will be summarized 
descriptively by treatment sequence and categories provided on CRF for the EAS.
Medical History for pediatric patients will be listed for the PSAS.
6.1.6
Study Treatment Administration
Study drug administration and dosing information will be presented in a listing for the EAS and 
PSAS.  
Treatment compliance (e.g. percent of planned tablets received) will be summarized by treatment 
group and treatment period (separately for on-study and DB) for the EAS.  Percent of planned 
tablets received is calculated as the total number of tablets received in a treatment period divided 
by the planned tablets the patient should have received during the same treatment period 
(excluding dose interruption period) while still actively enrolled.  The total number of tablets 
received will be calculated from the total number of tablets dispensed minus the total number of 
tablets returned for each patient. 
  
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6.1.7
Protocol Deviations
Protocol deviations will be listed for the EAS and PSAS.  All protocol deviations will be 
reviewed by clinical and statistical personnel prior to database lock. The type of protocol 
deviations governing exclusion from the PPAS will be determined prior to breaking the blind and 
are detailed here.
Evaluation of patient
Compliance of study entry criteria (inclusion and exclusion)
Receipt of the randomized treatment 
Adequate study medication exposure (no extended dosing interruptions)
Adequate treatment compliance based on prescribed dose level (within 80% to 120%)
No prohibited concomitant medications or therapies during the study
No accidental or intentional un-blinding at the investigational site
No other major protocol deviations that may affect efficacy or safety conclusions, may 
include:
Non-withdrawal though at least one withdrawal criterion was met
Extensive visit window violations
Extensive missing visits
Non-adherence to study procedures
Inadequate handling of study medication 
6.1.8
Concomitant Medications
The World Health Organization Drug Dictionary (WHO-DD) (B3 March 2019 or later) will be 
used to categorize verbatim descriptions of non-study medications into the Anatomic 
Therapeutic Chemical (ATC) Classification System.  Each verbatim name will be classified by 
anatomical main group (ATC level 1), therapeutic subgroup (ATC level 2), pharmacological 
subgroup (ATC level 3), chemical subgroup (ATC level 4), and trade name. 
6.1.8.1
Adult Cohort
Concomitant medications are non-study medications that have been used starting from OL1 
throughout the study.  Prior concomitant medications are medications that start prior to dose on 
Day -56 (the beginning of OL1) and continue after the first dose on Day -56.  New concomitant 
medications are medications that start after receiving the first dose on Day -56.
The number and percentage of patients receiving any concomitant medications will be 
summarized by treatment group, treatment period (separately for on-study and DB), and ATC 
classification (ATC level 2 and level 4) for the EAS.  A concomitant medication will be 
attributed to a specific treatment period that the medication starts or is still ongoing. 
Pre-treatment medications that start and stop prior to receiving the first dose on Day -56 will be 
provided in data listing. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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6.1.8.2
Pediatric Cohort
All non-study medications data that are collected will be provided in a listing.
6.2
Analysis of Efficacy 
The efficacy endpoints will be analyzed primarily on the FAS and on the PPAS which will serve 
as sensitivity analyses. 
6.2.1
Analysis of Primary Efficacy Endpoint of Urine 23S-Pentol
Urine 23S-pentol will be determined using first morning void urine samples and will be 
calculated as the geometric mean of 3 first morning void urine samples collected within 5 days 
prior to each visit at which urine 23S-pentol is assessed.  The baseline value for DB1 is the 
calculated geometric mean of samples for Day 1.  The baseline value for DB2 is the calculated 
geometric mean of samples for Day 85.  Measurements obtained after initiation of rescue 
only 
1 sample or 2 samples are collected within 5 days prior to an assessment visit, the value of the 
sample or the geometric mean of 2 samples will be used instead, respectively.  In the event when 
the value of a sample is BLQ, the value will be set to the LLOQ.
The paired t-test comparing CDCA with placebo will be conducted on the change from baseline 
to the last non-missing observation in loge-transformed urine 23S-pentol of each DB period.  
Specifically, the paired difference will be calculated between CDCA and placebo in the change 
from baseline to the last non-missing observation in loge-transformed urine 23S-pentol for each 
patient, ignoring the randomized order of receiving the treatment.  Log-transformation is 
performed due to the anticipated wide range of urine 23S-pentol levels among CTX patients.  A 
sensitivity analysis using paired t-test on FAS with missing 23S-pentol values imputed will also 
be performed; refer to 6.5 for details. 
Additionally, the changes from baseline in loge-transformed urine 23S-pentol during the DB 
treatment periods will be analyzed via a mixed effects model with treatment, sequence, period, 
period baseline value, nominal time (in days within period; categorical), and treatment-by-time 
interaction as fixed effects, and patients as random effect.  The model will be fitted with an 
unstructured covariance matrix.  If convergence issues arise, a heterogeneous first order auto-
regressive structure will be used. If convergence issues still arise, a first order auto-regressive 
structure will be used.  The least squares (LS) means difference between CDCA and placebo 
randomized treatment-by-time evaluated at 4 weeks, its confidence interval (two-sided 95%) and 
the p-value will be calculated.  P-values of the other fixed effects will also be provided. 
Estimates and CIs will also be converted to percentages via the following transformation:
[exp(least squares mean change from baseline in loge-transformed urine 23S-pentol) 1 ] x 100
The analysis results using the mixed effects model will be considered supportive. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The actual values and changes from baseline in urine 23S-pentol for each DB treatment period 
will also be summarized descriptively by treatment.  Similar descriptive analysis using the study 
baseline (i.e. the calculated geometric mean of samples for Day -56) instead of the DB period 
baseline will be performed on urine 23S-pentol collected during OL and DB periods. Figures of 
actual values and changes from baseline will also be presented.
The SAS® sample code for the mixed effects model:
proc mixed data = bile;
class trtp (ref="Placebo") trtseqpn aperiodc days usubjid;
model chg = trtp trtseqpn aperiodc base days trtp*days;
repeated days / subject = usubjid type = UN;
lsmeans trtp*days /cl alpha = 0.05 pdiff;
run;
6.2.2
Analysis of Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints will be tested using the Bonferroni-Holms procedure 
described in 5.4.3.
6.2.2.1
Proportion of Patients requiring Rescue Medication 
The proportion of patients requiring rescue treatment and the corresponding exact 95% CI will 
be calculated and presented using Clopper-Pearson method for each treatment.  Patients who 
require blinded and/or open-label CDCA rescue during the DB periods will be considered to 
have met the event (i.e. require rescue medication) for the primary analysis.  
SAS® sample code for the Clopper-Pearson method:
data clop_ci;
set rescue;
p=round ((x/n),.001);
if p=0 then CI_LOW=0;
if p=1 then CI_HIGH=1;
if p ne 0 then CI_LOW=round((1-betainv(.975,(n-x+1),x)),.00001);
if p ne 1 then CI_HIGH=round((1-betainv(.025,(n-x),x+1)),.00001);
run;
The probability of observing contingency tables of rescue data with equal or more extreme 
values (exact p-values) will be calculated 
Prescott, 1981).  The method 
will be implemented in SAS® using the algorithm and notations (Figure 5
Outcome Data from a Crossover Design Study using the SAS
Figure 5 is defined as those who require rescue in both periods or 
those who do not require rescue in either period.  Rejection of the null hypothesis for no 
association suggests there is a difference between two treatments. 
 
 
 
 
 
  
  
 
 
  
 
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Figure 5: The Algorithm and Notations by Anna Pictor  
Sequence 
Prefer First 
Period 
No Preference
Prefer Second 
Period 
Total for all 
Preferences
CDCA - Placebo
d
e
f
r1
Placebo - CDCA
g
h
k
r2
Total for both 
Sequences
s1
s2
s3
N
SAS®
data tab;
d = 0; 
f = 0; 
r1 = 20;
r2 = 20;
s1 = 9;
s2 = 21;
s3 = 10;
n = 40;
diff = 5;
e = r1-d-f;
g = s1-d;
h = s2-e;
k = s3-f;
do while (e ge 0 and g ge 0 and h ge 0 and k ge 0);
do while (e ge 0 and g ge 0 and h ge 0 and k ge 0);
if d-f ge diff or d-f le -diff then output;
f+1;
e = r1-d-f;
g = s1-d;
h = s2-e;
k = s3-f;
end;
f=0;
d+1;
e = r1-d-f;
g = s1-d;
h = s2-e;
k = s3-f;
end;
run;
data ppres;
set tab;
c_d = comb(s1,d);
c_e = comb(s2,e);
 
 
  
 
 
 
 
 
 
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c_f = comb(s3,f);
c_r1 = comb(n,r1);
product = c_d*c_e*c_f;
sum_p + product;
p_two_sided = sum_p/c_r1;
run;
6.2.2.2
Percent Change from baseline in Plasma Cholestanol 
Since cholestanol is expected to require longer treatment with CDCA to show meaningful 
changes, the primary analysis (as described below) for cholestanol will be conducted on the 
TEFAS to mitigate against the potential impact of the short duration of the treatment run-in 
period prior to the DB period.  The baseline values and measurements obtained after initiation of 
rescue medication will be handled in the same manner as for the primary efficacy endpoint.
The paired t-test comparing CDCA with placebo will be conducted on the percent change from 
baseline to the last non-missing measurement of each DB period in the same manner as for the 
analysis of the primary endpoint.  A sensitivity analysis using paired t-test on TEFAS with 
missing cholestanol levels imputed will also be performed; refer to 6.5 for details.
Additionally, the percent change from baseline in plasma cholestanol levels during the DB 
treatment periods will be analyzed in the same manner as for the analysis of the primary endpoint 
via a mixed effects model with treatment, sequence, period, period baseline value, nominal time 
(in days within period; categorical), and treatment-by-time interaction as fixed effects, and 
patients as random effect.  The model will be fitted with an unstructured covariance matrix.  If 
convergence issues arise, a heterogeneous first order auto-regressive structure will be used. If 
convergence issues still arise, a first order auto-regressive structure will be used.  The LS means 
difference between CDCA and placebo randomized treatment-by-time evaluated at 4 weeks, its 
p-value will be calculated.  P-values of the other fixed effects will also be provided. Estimates 
and CIs will also be converted to percentages via the following transformation:
[exp(least squares mean change from baseline in loge-transformed plasma cholestanol) 1 ] x 
100
The analysis results using the mixed effects model will be considered supportive.
The actual values, actual change, and percent change from baseline in plasma cholestanol levels 
for each DB treatment period will also be summarized descriptively by treatment.  Similar 
descriptive analysis using the study baseline (i.e. the last measurement prior to dose on Day -56) 
instead of the DB period baseline will be conducted on plasma cholestanol collected during OL 
and DB periods. Figures of actual values and changes from baseline will also be presented.
6.2.2.3
Percent Change from baseline in Plasma 7 C4
6.2.2.2.  The primary analysis will be based on the FAS.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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6.2.3
Analysis of Other Secondary Efficacy Endpoints
All other secondary efficacy endpoints will be analyzed at the nominal 0.05 significance level at 
the final analysis. 
6.2.3.1
Change from baseline in Plasma Cholestanol to Cholesterol Ratio
Change from baseline in plasma cholestanol to cholesterol ratio will be analyzed in a similar way 
as in 6.2.2.3.
6.2.3.2
Percent Change from baseline in Plasma 7 12 C4
Percent change from baseline in plasma 7 12 C4 will be analyzed in a similar way as in 6.2.2.3.
6.2.3.3
Proportion of Patients with Negative Net Change in Symptoms and 
Manifestations reported in the Diary
The proportion of patients with negative net change in symptoms (described below) or  
manifestations reported in the diary during the DB period is a composite endpoint and will be 
analyzed as a binary efficacy endpoint using the same approach described for the proportion of 
patients requiring rescue medication.  
For each symptom, the value for each planned visit (i.e. Day 1 [baseline], Weeks 1, 2, 3, and 4, 
for DB1; Day 85 [baseline], Weeks 13, 14, 15, and 16, for DB2) will be based on the results 
reported in the diary during the 7 days preceding the visit.  Data obtained after initiation of 
rescue treatment will be excluded from the calculations.  The following parameters will 
contribute to the composite endpoints (i.e. bowel function, seizures, tremors, and manifestations) 
calculated at the planned visits for each patient:
Bowel function: 
o
the proportion of bowel movements with Bristol Stool Form Scale (BSFS) scores 
of 1 (severe constipation), 2 (mild constipation), 6 (mild diarrhea), or 7 (severe 
diarrhea); 
o
the average BSFS score of all reported bowel movements
Seizures: 
o
the rate of seizure per day (i.e. total number of seizures / total days with diary 
data); 
o
the average duration of seizures; 
o
the average severity of seizures (1 for mild; 2 for moderate; 3 for severe; 4 for 
very severe)
Tremors: 
 
 
  
 
 
 
 
 
 
 
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o
the proportion of days with tremors (i.e. number of days with tremors / total days 
with diary data); 
o
the average number of body parts with tremors; 
o
the average severity of all tremors reported (1 for mild; 2 for moderate; 3 for 
severe; 4 for very severe)
Manifestations: 
o
the proportion of days with the specific manifestation (i.e. number of days with 
the manifestation / total days with diary data); 
o
the weighted (2 for most bothersome manifestations, 1 for other manifestations) 
average impact or discomfort/distress score (0 to 4, ranging from no impact or 
discomfort/distress to very severe impact or discomfort/distress)
For each parameter above, the change from baseline score will be calculated as the difference 
between the value for a specific visit during the DB period and the corresponding baseline visit 
(i.e. post-baseline baseline visit).  The sign of the change will be noted as -1, 0, or +1 if it is 
greater than 0, equal to 0, or less than 0, respectively.  Patients are considered to have a negative
net change in a symptom or manifestations if there are more negative changes than positive 
changes across the contributed parameters and visits. 
The count and proportion of patients with negative net change in each composite endpoint will 
be summarized by treatment and visit; and by treatment at the end of double-blind period (DB1 
or DB2).
6.3
Analysis of Safety Endpoints
Descriptive statistics will be used to summarize the safety data by treatment group or sequence
among adult patients and by overall among pediatric patients.  For the adult cohort, EAS will be 
used for on-study summary, and SAS will be used for DB periods summary.  PSAS will be used 
for the pediatric cohort summary. For DB periods summary, measurements obtained after 
initiation of rescue medi
6.3.1
Extent of Exposure
Total number of days on CDCA per patient will be summarized descriptively for the EAS and 
PSAS.  Additionally, the number of days on CDCA and placebo during the DB period will be 
summarized for the SAS.
6.3.2
AEs
An AE is any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a study medication, whether or not considered 
 
 
  
 
 
 
 
 
 
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related to the study medication.  The patient will be evaluated for new AEs and the status of 
existing AEs at each study visit, including screening or washout periods, or at any time contact is 
made with the patient outside of a scheduled visit. 
6.3.2.1
Adult Cohort
TEAEs will be defined as those that start from OL1 throughout the study, or existing AEs that 
worsen during or after OL1.  AEs prior to OL1 will be classified as pre-treatment.  An AE will 
be attributed to a specific treatment period that the event occurs.  All AEs will be coded using the 
MedDRA (Version 22.0 or later) by System Organ Class and Preferred Term. 
Number and percentage of patients with TEAEs during the DB periods and on-study will be 
summarized separately by treatment group, system organ classification, and preferred term.
TEAEs leading to discontinuation of study medication, TEAEs related to study medication 
(possibly related will be grouped together with related for summary), serious TEAEs, TEAEs by 
severity, and TEAEs of interest during the DB periods and on-study will also be summarized 
separately by treatment group, system organ class, and preferred term.  For each system organ 
class and preferred term, patients with multiple events (different severities or relationships) will 
be counted only once at the worst grade.  TEAEs with missing severity or missing relationship 
Abnormal liver function tests that meet the below criteria will be considered TEAEs of interest:
The abnormality represents a new elevation in alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN), with or 
without an elevation of total serum bilirubin >2 times ULN; or
The abnormality represents a 2-fold increase in ALT or AST above the baseline value in 
patients who had elevated values prior to starting any medication. 
Death and pre-treatment AEs will be listed if any. 
6.3.2.2
Pediatric Cohort
TEAEs will be defined as those that start from Titration period throughout the study, or existing 
AEs that worsen during or after Titration period.  AEs prior to Titration period will be classified 
as pre-treatment.  All AEs will be coded using the MedDRA (Version 22.0 or later) by System 
Organ Class and Preferred Term. 
Number and percentage of patients with TEAEs during the study will be summarized by overall, 
system organ classification, and preferred term.
TEAEs leading to discontinuation of study medication, TEAEs related to study medication, 
serious TEAEs, TEAEs by severity, and TEAEs of interest during the study will also be 
summarized  overall, by system organ class and preferred term. 
 
 
 
 
 
  
 
 
 
 
 
  
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Death and pre-treatment AEs will be listed if any. 
6.3.2.3
Adult and Pediatric Cohort
Targeted pooled analyses of TEAEs for the PTAS (adult patients in the EAS and pediatric 
patients in the PSAS) will be performed. 
Number and percentage of patients with TEAEs while on-study will be summarized separately 
by treatment group (CDCA and overall), system organ classification, and preferred term.
TEAEs leading to discontinuation of study medication, TEAEs related to study medication 
(possibly related will be grouped together with related for summary), serious TEAEs, and 
TEAEs of interest while on-study will also be summarized separately by treatment group (CDCA 
and overall), system organ class, and preferred term.  
6.3.3
Laboratory Evaluations
All hematology, chemistry, coagulation, lipid profile and urinalysis results will be listed.  
Laboratory assessments that are outside of normal ranges and/or with clinical significance will 
be flagged in the listings.
6.3.3.1
Adult Cohort
For central lab results, the following descriptive analyses will be performed separately on 2 sets 
with different baseline values: during the study and during the DB periods.  
Baseline values (refer to 5.3.3.1), values at post-baseline visits, and changes from the 
baseline values will be summarized for quantitative laboratory assessments by treatment 
group.  
Count and percentage will be summarized for laboratory assessments with categorical 
results (including pregnancy test) by treatment group and visit.  
Shift tables of laboratory data will be generated to summarize the normal and abnormal 
(abnormal high and abnormal low if applicable) status changes from baseline to the worst 
post-baseline during the treatment period.  
Tables that summarize the count and percentage of values outside of normal ranges for 
hematology, chemistry and urinalysis will also be provided. 
Additionally, the count and percentage of each category as defined below will be summarized by 
treatment group and visit on the 2 sets.  
ALT and AST: >1 x ULN; >2 x ULN; >3 x ULN; >5 x ULN; >8 x ULN
Alkaline phosphatase (ALP): >1 x ULN; >1.5 x ULN; >2.5 x ULN; >5 x ULN
Total Bilirubin: >1 x ULN; >1.5 x ULN; >2 x ULN; >3 x ULN
 
 
  
 
 
 
 
 
 
 
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6.3.3.2
Pediatric Cohort
For central lab results, the following descriptive analyses will be performed on the set: during the 
study:  
Baseline values (refer to 5.3.3.2), values at post-baseline visits, and changes from the 
baseline values will be summarized descriptively for quantitative laboratory assessments 
by overall.  
Count and percentage will be summarized for laboratory assessments with categorical 
results (including pregnancy test) by overall and visit.  
Shift tables of laboratory data will be generated to summarize the normal and abnormal 
(abnormal high and abnormal low if applicable) status changes from baseline to the worst 
post-baseline.  
Tables that summarize the count and percentage of values outside of normal ranges for 
hematology, chemistry and urinalysis will also be provided. 
Additionally, the count and percentage of each category as defined below will be summarized by 
overall and visit.  
ALT and AST: >1 x ULN; >2 x ULN; >3 x ULN; >5 x ULN; >8 x ULN
ALP: >1 x ULN; >1.5 x ULN; >2.5 x ULN; >5 x ULN
Total Bilirubin: >1 x ULN; >1.5 x ULN; >2 x ULN; >3 x ULN
6.3.4
Vital Signs and Body Weight
For vital signs (blood pressure, heart rate, respiratory rate and oral temperature) and body 
weight, baseline values, post-baseline values, and changes from baseline values will be 
summarized descriptively by treatment group for the adult cohort, and by overall for the pediatric 
cohort.  For each cohort, the analysis will be performed on the sets as for the lab analysis. 
6.3.5
EEG and 12-Lead ECG
Shift tables of EEG and ECG data will be generated to summarize the assessment interpretation 
changes from baseline to the worst post-baseline during the treatment period by treatment group 
for the adult cohort, and by overall for the pediatric cohort.  For each cohort, the analysis will be 
performed on the same sets as for the lab analysis.
6.3.6
Physical Examination
Physical examination results will be listed for both cohorts. 
 
 
  
 
 
 
 
 
 
 
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6.4
Analysis of Exploratory Endpoints
6.4.1
Adult Cohort
Percent change from baseline in plasma bile alcohol (tetrol glucuronide) will be analyzed in a 
similar way as in 6.2.2.3. 
For each pair of biomarkers (e.g. urine 23S-pentol vs. plasma cholestanol), pooled changes from 
DB period baseline to each post-baseline nominal visit (in days within period) grouped by 
in the 
original and loge scales.  Pooled changes from DB period baseline to the worst post-baseline 
during the period (either DB1 or DB2) grouped by treatment will be plotted the same. 
Changes from baseline in biomarker (urine and plasma bile alcohols, plasma cholestanol, plasma 
un-In Week 6 (RIW6; Visit 5) vs. PK exposure parameter 
(AUCss, Cmax,ss or Cmin,ss) of CDCA, gCDCA, tCDCA and total CDCA at RIW6 per patient will 
The event count of TEAEs in OL1 vs. PK exposure parameter of CDCA at RIW6 per patient will 
also 
The event count of TEAEs of interest in OL1 vs. PK exposure parameter of CDCA at RIW6 per 
patient will be plotted the same.     
The Clinician Global Impression of Severity (CGI-S) measures the severity 
disease using a global, 7-point scale.  The CGI-C is a global, 7-point scale used to assess how 
baseline.  The score ranges from 1 (very much improved) to 7 (very much worse).  The number 
and percentage of patients for each CGI-S score and each CGI-C score during DB treatment 
periods will be summarized by treatment group and visit. 
Patients will complete a visual analog scale by rating their overall health status over the past 
week from 0 to 100.  The actual values and changes from baseline in health status scores during 
DB treatment periods will be summarized descriptively by treatment group and visit. 
6.4.2
Pediatric Cohort 
Biomarker levels (urine an
visit. 
For each pair of biomarkers (e.g. urine 23S-pentol vs. plasma cholestanol), changes from 
baseline to the worst post-baseline during the study will be presented by scatter plot along with 
in the original and loge scales. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan - Version 2.0
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The number and percentage of patients for each CGI-S score and each CGI-C score collected 
during Treatment Period will be summarized by overall and visit. 
The actual values and changes from baseline in health status scores will be summarized 
descriptively by overall and visit. 
Assessment of motor developmental milestones will be done at Titration Start (baseline) and 
W16/EOT/EOS/ET (Table 2).  The count and percentage of patients with any post-baseline 
changes to previous milestones assessed will be summarized by overall and visit.  
6.5
Handling of Missing Data (For both Cohorts)
6.5.1
Imputation Rules for Analysis Sets
FAS (or TEFAS if applicable): Measurements of urine 23S-pentol, cholestanol, pl
-
will be performed using a multiple imputation (MI) method under the assumption of missing at 
random (MAR) separately for each treatment group.  The efficacy endpoints analyses using the 
imputed values will serve as sensitivity analyses, whereas the efficacy endpoints analyses 
without using the imputation will be treated as the primary analyses; refer to 6.2 for details. 
PPAS: No imputation of missing data will be performed for the efficacy endpoints.
SAS: No imputation of missing data will be performed for the safety endpoints.
PKAS: No imputation of missing data will be performed for the PK endpoints.
PSAS: No imputation of missing data will be performed for any endpoints. 
PPKAS: No imputation of missing data will be performed for the PK endpoints.
6.5.2
MI under MAR assumption
MI is a general approach to the problem of missing data that aims to account for uncertainty 
associated with imputing the missing data by creating several different plausible imputed data 
sets and appropriately combining results obtained from each of them.  MAR approach assumes 
that any systematic difference between the missing values and the observed values can be 
explained by differences in observed data.  The use of MI under MAR assumption provides 
estimation due to the presence of missing data. 
Fully Conditional Specification (FCS) regression methods will be used to impute missing 
biomarker values for the efficacy endpoints.  The imputation will be performed on the scale in 
which the variables are analyzed (eg, natural log scale for urine bile alcohol). The imputed data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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Statistical Analysis Plan - Version 2.0
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sets will then be analyzed according to 6.2, and analysis results will be synthesized using the 
MIANALYZE procedure of SAS®.  In order to prevent a power falloff due to choosing the 
number of imputations too small, 25 imputations will be performed (Graham, John W. et al. 
2007). Imputation will be performed separately by treatment. If imputation by treatment is not 
possible (due to, for example, insufficient observations to fit the regression models), then 
treatment may be added as a class variable in the regression model. SAS® sample code for the 
whole process is given as below:
*Create a Sample dataset;
data temp;
do trt = 'Placebo', 'Cheno';
do subject = 1 to 12;
bile1 = rannor(1);
bile2 = rannor(2);
bile3 = rannor(3);
bile4 = rannor(4);
bile5 = rannor(5);
missing1 = ranuni(1);
missing2 = ranuni(2);
missing3 = ranuni(3);
missing4 = ranuni(4);
missing5 = ranuni(5);
output;
end;
end;
run;
data temp (drop=missing1 missing2 missing3 missing4 missing5);
set temp;
if missing1 > 0.95 then bile1 =.;
if missing2 > 0.9 then bile2 =.;
if missing3 > 0.85 then bile3 =.;
if missing4 > 0.8 then bile4 =.;
if missing5 > 0.75 then bile5 =.;
run;
*Multiple Imputation using PROC MI;
proc sort data=temp;
by trt;
run;
proc mi data=temp nimpute=25 seed=123 out=bile;
by trt;
fcs reg(bile5/details);
var bile1 bile2 bile3 bile4 bile5;
run;
data bile_pl (keep=_imputation_ subject chg rename=(chg=chg_pl)) bile_cheno 
(keep=_imputation_ subject chg rename=(chg=chg_cheno));
set bile;
chg = bile5 - bile1;
if trt = 'Placebo' then output bile_pl;
else output bile_cheno;
run;
 
 
  
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Statistical Analysis Plan - Version 2.0
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data bile_new;
merge bile_pl bile_cheno;
by _imputation_ subject;
run;
*Analysis of completed data sets;
ods trace on;
proc ttest data=bile_new plots=none;
by _imputation_;
paired chg_pl*chg_cheno;
ods output Statistics = stats;
run;
ods trace off;
*Synthesize analysis results;
proc mianalyze data = stats;
modeleffects mean;
stderr stderr;
ods output parameterestimates = stats_syn;
run;
6.6
Statistical Software
All statistical analyses will be performed using SAS
7
REFERENCES
Graham, John W., Allison E. Olchowski, and Tamika D. Gilreath. "How many imputations are 
really needed? Some practical clarifications of multiple imputation theory." Prevention 
science 8.3 (2007): 206-213.
Prescott, R. J. "The comparison of success rates in cross over trials in the presence of an order 
effect." Journal of the Royal Statistical Society: Series C (Applied Statistics) 30.1 (1981): 9-15.
Pictor, Anna. "Analyzing Binary Outcome Date from a Crossover Design Study using the SAS
System." SAS VIEWS 2003. https://www.lexjansen.com/views/2003/statpharm/st02.pdf.
8
APPENDIX
 
 
  
 
 
 
 
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