Clinical trial NCT03041116
Conditions: Pantothenate Kinase-Associated Neurodegeneration
Keywords: PKAN
Sponsor: Travere Therapeutics, Inc.
Start date: 2017-07-17; Completion date: 2019-12-30
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study investigated whether fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy, was safe and effective in treating participants with PKAN.

Detailed description:

Arms: arm 1: Administered as powder for reconstitution. arm 2: Administered as powder for reconstitution.
Interventions: intervention 1: Fosmetpantotenate intervention 2: Placebo
Intervention descriptions: intervention 1: Daily dosing intervention 2: Daily dosing

Protocol documents:
Prot_000.pdf: 
Efficacy, Safety, and Tolerability of Fosmetpantotenate 
(RE-024), a Phosphopantothenate Replacement Therapy, in 
Patients with Pantothenate Kinase-Associated 
Neurodegeneration (PKAN): A Randomized, Double-Blind, 
Placebo-Controlled Study With an Open-Label Extension 
 
Unique Protocol ID: 
024PKAN15004 
NCT Number: 
NCT03041116 
EudraCT Number:  
2016-001955-29 
Date of Protocol:  
23 May 2019 
 


 
 
Retrophin, Inc. 
Version 4 Final: 23 May 2019 
Proprietary and Confidential 
 
 
CLINICAL STUDY PROTOCOL 
EFFICACY, SAFETY, AND TOLERABILITY OF 
FOSMETPANTOTENATE (RE-024), A PHOSPHOPANTOTHENATE 
REPLACEMENT THERAPY, IN PATIENTS WITH PANTOTHENATE 
KINASE-ASSOCIATED NEURODEGENERATION (PKAN): A 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
WITH AN OPEN-LABEL EXTENSION 
PROTOCOL NUMBER: 024PKAN15004 
IND #: 121943 
EudraCT #: 2016-001955-29 
 
Version 1 
13 September 2016 
Version 2 
10 April 2018 
Version 3 
Version 4 
06 February 2019 (United States Amendment Only) 
23 May 2019 (includes United States v3 and United 
States Administrative Letter 4)  
 
Sponsor: 
Retrophin, Inc. 
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
 
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.  This document contains proprietary and confidential 
information of Retrophin, Inc.  Acceptance of this document constitutes agreement by the recipient that no 
previously unpublished information contained herein will be published or disclosed without the prior written 
approval of Retrophin, Inc. with the exception that this document may be disclosed to study personnel under 
your supervision who need to know the contents for conducting the study and appropriate Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs) under the condition that the personnel have 
agreed to keep this information confidential.  The foregoing shall not apply to disclosure required by 
governmental regulations or laws; however, Retrophin, Inc. shall be promptly notified of any such 
disclosure. 
I have read and agree to abide by the requirements of this protocol. 
Investigator Signature 
Date 
Investigator Name (please print or type) 


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Study Contact Information 
 
Medical Monitor(s): 
North America:  
 
Email:  
 
Europe: 
 
Email: 
 
Serious Adverse Event 
Reporting: 
ProPharma Group 
Email: 
 
Fax: 
See study manual 
Product 
Handling/Complaints 
Tel:  
 
Email:  
 
Medical Director 
 
 
Retrophin, Inc. 
Tel:   
 
Email:   
  
Clinical Project 
Manager: 
  
 
Retrophin, Inc. 
Tel:   
 
Email:   
  
Global Safety Officer: 
 
 
Retrophin, Inc. 
Tel:   
 
Email:   
  
 
 
 
 
 
 
 
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Clinical Protocol Number 024PKAN 15004 
Signature Page for Sponsor's Representative 
I have reviewed and approved the protocol entitled, "Efficacy, Safety, and Tolerability of 
Fosmetpantotenate (RE-024), a Phosphopantothenate Replacement Therapy, in Patients with 
Pantothenate Kinase-associated Neurodegeneration (PK.AN): A Randomized, Double-blind, 
Placebo-controlled Study with an Open-label Extension" 
Retrophin, Inc. 
Retrophin, Inc. 
Proprietary and Confidential 
tt:z £5J/._ 20!/ 
Dae 
Version 4 Final: 23 May 2019 
PPD


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1. 
SYNOPSIS 
NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
TITLE:  
Efficacy, Safety, and Tolerability of Fosmetpantotenate (RE-024), a Phosphopantothenate Replacement 
Therapy, in Patients with Pantothenate Kinase-associated Neurodegeneration (PKAN):  A Randomized, 
Double-blind, Placebo-controlled Study with an Open-label Extension 
PROTOCOL NO.:  024PKAN15004 
INVESTIGATOR STUDY SITES: 
Approximately 20 sites in the North America, Europe, and other regions will participate in this study. 
OBJECTIVES:  
Efficacy Objective:  To evaluate the efficacy of fosmetpantotenate over 24 weeks in patients with pantothenate 
kinase-associated neurodegeneration (PKAN) 
Safety Objective:  To assess the safety and tolerability of fosmetpantotenate in patients with PKAN 
Other Objectives: 
• 
To determine the pharmacokinetics (PK) following multiple doses of fosmetpantotenate in patients 
with PKAN 
• 
To explore potential biomarkers of disease, along with their potential response to treatment in patients 
with PKAN 
Endpoints associated with these objectives are listed in the ENDPOINTS section. 
METHODOLOGY:  
This is a pivotal, randomized, double-blind, placebo-controlled, multi-center, 2-arm study evaluating 24 weeks 
of treatment with fosmetpantotenate or placebo in patients with PKAN aged 6 to 65 years, with a 278-week 
open label extension period. If the product becomes commercially available during the extension period, 
patients may transition to commercial product before the end of the open-label extension period. 
Following screening, patients meeting all eligibility criteria will be enrolled in the study.  Patients will be 
randomized in a 1:1 ratio to receive either fosmetpantotenate or placebo for a 24-week double-blind period.  
Treatment in the double-blind period will begin with dose escalation for Days 1 through 3, followed by the full 
dose 3 times daily (TID) starting on Day 4.  Matching placebo will be given according to the same dose 
escalation sequence as active investigational product. 
After completing the 24-week double-blind period, patients will be eligible to receive open-label 
fosmetpantotenate in the study for up to 278 weeks followed by a phone safety review 4 weeks later.  The total 
study duration will be approximately 310 weeks. 
 


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Retrophin, Inc. 
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NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
Data Monitoring Committee 
After 8 patients aged 18 to 65 years complete 3 weeks of study treatment in the double-blind period, the 
independent Data Monitoring Committee (DMC) will review safety data to determine whether the study can 
continue as planned, including initiating enrollment of patients aged 6 to <18 years.  Enrollment of patients 
18 to 65 years of age (only) will continue while this review is occurring.  If the DMC determines it is safe to 
continue the study, enrollment of patients 6 to <18 years of age will begin, and enrollment of patients 18 to 
65 years of age will continue. 
Similarly, after the first 8 patients aged 6 to <18 years complete 3 weeks of study treatment in the double-blind 
period, the DMC will review the safety data from all patients to date and determine whether the study can 
continue as planned.  Enrollment of patients 18 to 65 years of age and up to 8 additional patients aged 6 to 
<18 years of age may continue while this review occurs.  If the DMC determines it is safe to continue the study, 
enrollment of patients 6 to 65 years of age will continue. 
The DMC will also review safety data periodically throughout the study as described in the DMC charter. 
NUMBER OF PATIENTS: 
Approximately 82 patients aged 6 to 65 years will be enrolled in the study to achieve a target sample size of at 
least 74 patients completing the double-blind period of the study.  Patients will be randomized in a 1:1 ratio to 
receive either fosmetpantotenate or placebo in the double-blind period, followed by open-label treatment with 
fosmetpantotenate.  Randomization will be stratified by weight (≥40 kg, ≥20 kg but <40 kg, or <20 kg) and by 
age group (pediatric [ages 6 to <18 years] or adult [ages 18 to 65 years, inclusive]). 
INCLUSION/EXCLUSION CRITERIA:  
Inclusion Criteria: 
A patient will meet all of the following criteria to be eligible for this study. 
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. 
2. The patient has a diagnosis of PKAN as indicated by confirmed mutations in the pantothenate kinase 2 
(PANK2) gene (if available, the specific mutation will be recorded). 
3. The patient has a score of ≥6 on the Pantothenate Kinase-associated Neurodegeneration Activities of 
Daily Living (PKAN-ADL) scale. 
4. The patient is male or female aged 6 to 65 years, inclusive. 
5. If sexually active with male partners, the female patient of childbearing potential agrees to use a 
medically acceptable method of contraception for the duration of the study and for at least 30 days 
after the last dose of investigational product.  Females are considered of childbearing potential if they 
are post-menarchal, have not been surgically sterile for at least 6 weeks (ie, total hysterectomy, 
bilateral salpingo-oophorectomy, or tubal ligation) and are pre-menopausal (menopause is defined as 
cessation of menstruation for at least 1 year).  Acceptable methods of contraception include: 


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NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
A. the simultaneous use of stable combined (estrogen and progestogen containing) or progestogen-
only hormonal contraception (eg, oral, transdermal or intravaginal) associated with inhibition of 
ovulation in conjunction with a double-barrier method (eg, condom with spermicide or diaphragm 
with spermicide), or; 
B. the use of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) in place for 
at least 3 months or; 
C. vasectomized partner, (vasectomy at least 3 months prior to screening), or;  
D. sexual abstinence 
6. If sexually active with female partners, the sexually mature, nonsterile male patient agrees to use a 
medically acceptable method of contraception for the duration of the study and for at least 90 days 
after the last dose of investigational product.  Males are considered surgically sterile if they have 
undergone bilateral orchiectomy or vasectomy at least 3 months prior to screening.  Acceptable 
methods of contraception include: 
A. the simultaneous use of stable combined (estrogen and progestogen containing) or progestogen-
only hormonal contraception (eg, oral, transdermal or intravaginal) associated with inhibition of 
ovulation by the female partner in conjunction with a double barrier method (eg, condom with 
spermicide or diaphragm with spermicide), or; 
B. the female partner’s use of an IUD or IUS in place for at least 3 months, or; 
C. the female partner is surgically sterile for at least 6 weeks or is at least 1 year postmenopausal. 
7. The male patient agrees to not donate sperm for at least 90 days after the last dose of investigational 
product. 
Exclusion Criteria: 
A patient who meets any of the following criteria will be excluded from this study. 
1. The patient has required regular or intermittent invasive ventilatory support to maintain vital signs 
within 24 weeks prior to randomization. 
2. The patient has been (or is currently) enrolled in a clinical trial involving an investigational product or 
non-indicated use of a drug or device within 30 days prior to randomization. 
3. The patient has a positive serologic test for Hepatitis B virus surface antigen (HBsAg), Hepatitis C 
virus (HCV) antibody, or human immunodeficiency virus (HIV) at screening. 
4. The patient has a history of metastasized or ongoing malignancy, regardless of whether or not it has 
been or is being treated. 
5. The patient has a serious, unstable medical or psychiatric condition not related to PKAN that, in the 
opinion of the Investigator, could interfere with the patient’s ability to participate in the study safely or 
to complete the scheduled study assessments, or that would confound the assessment of safety or 
efficacy. 
6. The patient has a history of drug or alcohol use disorder within the past 1 year. 


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NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
7. The patient has a history of suicide attempts within the past 1 year or is considered by the Investigator 
to be at imminent risk of suicide. 
8. The patient has had a major surgical procedure within 30 days prior to screening. 
9. The patient has had a deep brain stimulation (DBS) device implanted within 6 months prior to 
screening. 
10. The patient has abnormal laboratory values at screening that, in the opinion of the Investigator, are 
clinically significant, and would compromise the safety of the patient during study participation. 
11. The patient is a female who is pregnant or lactating, or who presents with a positive serum pregnancy 
test at screening, or a positive urine pregnancy test at Baseline. 
12. The patient is unwilling or, in the opinion of the Investigator, is unable to adhere to the requirements of 
the study, including study procedures and the visit schedule. 
13. The patient is unable or unwilling to remain on their pre-study dose(s) of allowed concomitant PKAN 
maintenance medications and therapies (including DBS settings) for the double-blind period of the 
study. (See Section 8.3 of the protocol for discussion of concomitant medication/treatment use during 
the study, and Section 15.2.1 for a list of allowed concomitant medications and therapies.) 
14. The patient has taken deferiprone within 30 days prior to screening. 
Patients who do not meet eligibility criteria may be re-screened twice. 
DOSE/ROUTE/REGIMEN (TEST ARTICLE):  
Fosmetpantotenate will be supplied in dried powder form for reconstitution and oral administration, packaged in 
a dose strength of 75 mg capsules, and, after receipt of regulatory approval, 75 mg and 300 mg sachets. In all 
patients, the 24-week double-blind period will begin with dose escalation on Days 1 through 3 (described 
below), followed by the full dose starting on Day 4.  The full dose for patients aged 18 to 65 years will be 
300 mg TID for a total daily dose of 900 mg.  The full dose for patients aged 6 to <18 years will be determined 
by weight at screening: patients weighing ≥40 kg will receive 300 mg TID for a total daily dose of 900 mg (ie, 
the same as patients aged 18 to 65 years); patients weighing ≥20 kg but <40 kg will receive 150 mg TID for a 
total daily dose of 450 mg; and patients weighing <20 kg will receive 75 mg TID, for a total daily dose of 225 
mg. All doses of investigational product will be taken with food. 
Dose escalation on Days 1 through 3 will proceed as follows, based on age and weight at screening: 
Patients aged 18 to 65 years and patients aged 6 to <18 years weighing ≥40 kg:  On Day 1, patients will 
receive one 300 mg dose (in the morning); on Days 2 and 3, they will receive 300 mg twice daily (BID, at least 
8 hours apart) for a total daily dose of 600 mg; and on Day 4, they will receive the full dosage of 300 mg TID 
(given at approximately 8 hour intervals) for a total daily dose of 900 mg. 
Patients aged 6 to <18 years weighing ≥20 kg but <40 kg:  On Day 1, patients will receive one 150 mg dose (in 
the morning); on Days 2 and 3, they will receive 150 mg BID (at least 8 hours apart) for a total daily dose of 
300 mg; and on Day 4, they will receive the full dosage of 150 mg TID (given at approximately 8 hour 
intervals) for a total daily dose of 450 mg. 


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NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
Patients aged 6 to <18 years weighing <20 kg:  On Day 1, patients will receive one 75 mg dose (in the 
morning); on Days 2 and 3, they will receive 75 mg BID (at least 8 hours apart) for a total daily dose of 150 mg; 
and on Day 4, they will receive the full dosage of 75 mg TID (given at approximately 8 hour intervals) for a 
total daily dose of 225 mg. 
Elective dose reductions for safety or tolerability reasons only are allowed throughout the first 6 weeks of the 
double-blind period of the study.  Dose reductions may only occur one time, according to the schedule in 
Section 6.5.3.  Patients who are unable to tolerate the reduced dose will be discontinued from the study.  The 
Investigator should attempt to increase the dose back to the patient’s assigned fixed dose as safety and 
tolerability allow. 
Once patients have been treated in the open-label period for at least 24 weeks, and after the second DMC review 
has occurred, dose increases of 1 level will be allowed for perceived lack of efficacy.  Dose increases will only 
be allowed following consultation between the Investigator, the Medical Monitor, and the Sponsor, and only to 
the maximum dosage of 300 mg TID. 
REFERENCE TREATMENT:  
The matching placebo treatment will be administered orally. 
ENDPOINTS: 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the change in the score from the PKAN-ADL, from Baseline to the end 
of the 24-week double-blind period. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint will be the change in the score from Part III of the Unified Parkinson’s Disease 
Rating Scale (UPDRS) from Baseline to the end of the 24-week double-blind period. 
Safety Endpoints 
The safety and tolerability of fosmetpantotenate will be assessed throughout the study by monitoring: 
• 
Occurrence of adverse events (AEs).  AEs will be classified according to their intensity (ie, mild, moderate, 
severe) and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) classification 
dictionary. 
• 
Serial vital signs, weight, and physical examinations 
• 
Serial clinical laboratory testing (chemistry, hematology, coagulation, and urinalysis) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) Assessments 
• 
Serial 12-lead electrocardiogram (ECG) 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will include change from Baseline to the end of the 24-week double-blind period 
in the following: 
• 
Clinical Global Impression of Improvement (CGI-I) 
• 
Barry Albright Dystonia (BAD) scale 


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NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
• 
Quality of Life (QoL): 
o 
Neuro-QoL, upper and lower extremity modules (adult and pediatric versions) 
o 
EuroQol 5-dimension, 3-level QoL instrument (EQ-5D-3L)/EuroQol-5D Youth Version (EQ-5D-Y) 
• 
Functional independence:  Functional Independence Measure (FIM)/Functional Independence Measure for 
Children (WeeFIM) 
• 
Function measures: 
o 
Ambulation:  25-foot walk test (in appropriate patients) 
o 
Speech:  Diadochokinetic (DDK) assessments (ie, alternating motion rate [AMR] and sequential 
motion rate [SMR]) 
Pharmacokinetics 
Multiple dose PK of fosmetpantotenate in whole blood will be evaluated using a sparse sampling design.  Blood 
samples may also be used for metabolite quantitation and/or identification. 
Biomarkers 
Exploratory biomarkers will be assessed in plasma. 
Pharmacogenomics 
Pharmacogenomic assessment may be performed on for drug metabolizing enzymes, transporters, or indicators 
of therapeutic response or safety.  These assessments will only be performed where local regulations permit and 
where approved by the site’s Institutional Review Board/Independent Ethics Committee (IRB/IEC), and will be 
subject to separate consent/assent by the patient/parent/legal guardian as appropriate. 
STATISTICAL METHODS: 
Power and Sample Size: 
A total of 74 patients will provide approximately 80% power to detect a 3-point difference between treatment 
groups in the average change from Baseline scores from the PKAN-ADL, based on Student’s t-test with 
alpha=0.05 (2-sided); this calculation assumes a standard deviation of 4.5 points for the change from Baseline 
scores.  Additional patients will be randomized to ensure that at least 74 patients complete the double-blind 
period with evaluable data (ie, having assessments at Baseline and Week 24 for the PKAN-ADL). 
Analysis Sets: 
Safety Population: 
Double-blind:  The safety population will consist of all randomized patients who receive at least 1 dose of 
blinded investigational product.  This population will be used for all summaries of patient accountability, 
demographic and Baseline data, and safety information, including AE incidence, for the double-blind period of 
the study. 
Open-label:  The safety population will consist of all patients who receive at least 1 dose of investigational 
product after entering the open-label period of the study.  This population will be used for all summaries of 
patient accountability, demographic and Baseline data, and safety information, including AE incidence, for the 
open-label period of the study. 


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Full Analysis Set (FAS): 
Double-blind:  The FAS will consist of all randomized patients with at least 1 post-Baseline efficacy 
assessment.  This population will serve as the basis for efficacy analyses from the double-blind period. 
Open-label:  The FAS will consist of all patients with at least 1 post-Baseline efficacy assessment in the 
open-label period of the study.  This population will serve as the basis for efficacy analyses from the open-label 
period of the study. 
Demographics and Baseline Characteristics: 
Demographic data (including age, race, ethnicity, gender, height, and weight), PKAN-specific and other 
medical history, prior treatments, and pre-treatment clinical characteristics will be summarized by treatment 
group for the safety population. 
Safety: 
Safety analyses will be performed using data from the safety population.  Safety will be evaluated on the basis 
of treatment-emergent AEs (TEAEs), vital signs, physical examinations, clinical laboratory assessments, 
C-SSRS assessments (in assessable patients), and ECG findings.  Changes from Baseline in vital signs, weight, 
clinical laboratory values, and ECGs will be summarized by treatment group using descriptive statistics.  All 
AEs will be coded by Preferred Term using the MedDRA classification dictionary.  The incidence of TEAEs 
will be summarized by treatment group, and by severity and relationship to investigational product.  Serious 
AEs (SAEs) and AEs leading to withdrawal from the study will be tabulated. 
Pharmacokinetics: 
Multiple-dose blood concentrations of fosmetpantotenate will be tabulated and summarized by dose cohort and 
sample time.  Concentration measures may also be analyzed by nonlinear mixed-effects modeling, either alone 
or in conjunction with data from other studies.  Available metabolite concentrations will be analyzed similarly.  
Summarizations will include appropriate descriptive statistics (eg, n, geometric mean, coefficient of variation, 
minimum, median, maximum). 
Efficacy: 
The primary efficacy analysis will be based on the FAS population defined for the double-blind period.  For 
each patient, the change from Baseline in the PKAN-ADL score at Weeks 3, 6, 12, 18, and 24 of the 
double-blind period will be used for analysis.  The treatment effect will be evaluated on the basis of mixed 
model repeated measures (MMRM) analysis using the restricted maximum likelihood method (REML).  The 
model will be implemented using PROC MIXED in SAS, and will include fixed effects for treatment, age 
(pediatric/adult), visit and treatment-by-visit interaction, a random effect for patient, and Baseline PKAN-ADL 
score as a covariate.  The PKAN-ADL measurement obtained prior to the first dose of investigational product 
will serve as each patient’s Baseline value.  Least-squares adjusted means and the adjusted mean difference 
between treatment groups will be reported at each study visit, along with 2 sided 95% confidence intervals (CIs) 
and the p-value for the treatment comparison.  Additional sensitivity analyses will be performed to support the 
primary efficacy analysis. 
Secondary and exploratory efficacy endpoints that are continuous measures will be evaluated using a similar 
mixed model for repeated measures or fixed-effect analysis of covariance, as appropriate.  Summary statistics 
for efficacy measures will include graphical plots of means and mean change from Baseline values at each study 
visit, by treatment group.  Treatment effects on categorical outcomes will be examined using frequency tables 
and tested via chi-square methods. 
Biomarkers: 
Biomarker assessments will be listed and summarized by time point using descriptive statistics (mean, median, 
standard deviation, standard error of the mean, coefficient of variation, minimum, and maximum) and graphical 
displays. 


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NAME OF COMPANY 
Retrophin, Inc.  
3721 Valley Centre Drive, Suite 200 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT 
fosmetpantotenate (RE-024) 
NAME OF ACTIVE INGREDIENT 
Methyl 3-((2R)-2-hydroxy-4-(((((S)-l-methoxy-1-oxopropan-2-yl)amino) 
(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido) propanoate 
Mean or mean change from Baseline (whichever is considered more relevant) plasma concentration-time 
profiles will be plotted on either or both linear and semi logarithmic scales.  Inclusion/exclusion of the data in 
the calculations will be determined using an outliers test. 
Interim Analysis: 
The efficacy and safety analyses of the double-blind period of the study will be performed after all patients have 
completed the double-blind period and reported in an interim clinical study report.  In addition, the interim 
report will include all available data from patients in the open-label period as of the data cutoff date. 
 


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2.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
TABLE OF CONTENTS 
1.
SYNOPSIS ...................................................................................................................4 
2.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
4.
INTRODUCTION ......................................................................................................19
4.1. 
Summary of Potential Risks .......................................................................................20 
4.1.1. 
Fosmetpantotenate (RE-024) Non-Clinical Studies ...................................................20 
4.1.2. 
Fosmetpantotenate (RE-024) Clinical Studies and Other Use ...................................21 
4.2. 
Summary of Potential Benefits ...................................................................................22 
5.
STUDY OBJECTIVES ..............................................................................................23 
5.1. 
Efficacy Objective ......................................................................................................23 
5.2. 
Safety Objective ..........................................................................................................23 
5.3. 
Other Objectives .........................................................................................................23 
6.
INVESTIGATIONAL PLAN .....................................................................................24 
6.1. 
Endpoints ....................................................................................................................24 
6.1.1. 
Primary Efficacy Endpoint .........................................................................................24 
6.1.2. 
Secondary Efficacy Endpoints ....................................................................................24 
6.1.3. 
Safety Endpoints .........................................................................................................24 
6.1.4. 
Exploratory Efficacy Endpoints .................................................................................24 
6.1.5. 
Pharmacokinetic Endpoint ..........................................................................................25 
6.1.6. 
Biomarkers ..................................................................................................................25 
6.1.7. 
Pharmacogenomics .....................................................................................................25 
6.2. 
Study Design ...............................................................................................................25 
6.3. 
Completion of a Patient’s Participation in the Study and Overall Study 
Completion .................................................................................................................29 
6.3.1. 
Completion of a Patient’s Participation in the Study ..................................................29 
6.3.2. 
Overall Study Completion ..........................................................................................30 
6.3.3. 
Premature Discontinuation from the Study ................................................................30 
6.4. 
Discussion of Study Design, Including Choice of Control Group .............................30 
6.5. 
Dosing Considerations ................................................................................................31 


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6.5.1. 
Dose Selection Rationale ............................................................................................31 
6.5.2. 
Dose Initiation ............................................................................................................32 
6.5.2.1. 
Double-Blind Period ...................................................................................................32 
6.5.2.2. 
Open-Label Period ......................................................................................................33 
6.5.3. 
Dose Modification ......................................................................................................33 
6.5.4. 
Interruption and Discontinuation of Study Medication ..............................................33 
6.5.4.1. 
Temporary Interruption of Study Medication .............................................................33 
6.5.4.2. 
Permanent Discontinuation of Study Medication .......................................................34 
7. 
PATIENT POPULATION AND SELECTION .........................................................35 
7.1. 
Inclusion Criteria ........................................................................................................35 
7.2. 
Exclusion Criteria .......................................................................................................36 
8. 
TREATMENTS ..........................................................................................................37 
8.1. 
Treatments Administered ............................................................................................37 
8.2. 
Investigational Product(s) ...........................................................................................37 
8.2.1. 
Packaging and Labeling, Storage, and Preparation and Administration of 
Investigational Product ...............................................................................................37 
8.2.1.1. 
Study Drug Administration.........................................................................................37 
8.2.1.2. 
Packaging, Labeling, and Storage ..............................................................................38 
8.2.1.3. 
Study Drug Storage at Study Centers .........................................................................38 
8.2.1.4. 
Study Drug Storage Instructions for Patients .............................................................38 
8.3. 
Prior and Concomitant Medications and Therapeutic Procedures .............................39 
8.4. 
Method of Assigning Patients to Treatment ...............................................................39 
8.5. 
Randomization ............................................................................................................39 
8.5.1. 
Blinding and Breaking the Blind ................................................................................40 
8.5.1.1. 
Breaking the Blind in Medical Emergency ................................................................40 
8.5.1.2. 
Breaking the Blind for Regulatory Requirement ........................................................40 
8.6. 
Treatment Compliance ................................................................................................40 
9. 
STUDY ASSESSMENTS ..........................................................................................42 
9.1. 
Study Schedule of Events ...........................................................................................42 
9.2. 
Demographic and Screening Assessments .................................................................42 
9.3. 
Safety Assessments .....................................................................................................42 
9.3.1. 
Physical Examination .................................................................................................42 


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9.3.2. 
Vital Signs ..................................................................................................................42 
9.3.3. 
Clinical Laboratory Tests ...........................................................................................43 
9.3.4. 
Electrocardiograms .....................................................................................................43 
9.3.5. 
Columbia Suicide Severity Rating Scale ....................................................................43 
9.4. 
Pharmacokinetic Assessments ....................................................................................44 
9.5. 
Efficacy Assessments .................................................................................................44 
9.5.1. 
Pantothenate Kinase-associated Neurodegeneration Activities of Daily 
Living and Unified Parkinson’s Disease Rating Scale Part III...................................44 
9.5.2. 
Clinician’s Global Impression of Improvement .........................................................44 
9.5.3. 
Barry Albright Dystonia (BAD) Scale .......................................................................45 
9.5.4. 
Quality of Life ............................................................................................................45 
9.5.5. 
Functional Independence Measure (FIM) ..................................................................45 
9.5.6. 
Function Measures ......................................................................................................46 
9.6. 
Exploratory Measures .................................................................................................46 
9.6.1. 
Biomarkers ..................................................................................................................46 
9.6.2. 
Pharmacogenomics .....................................................................................................47 
9.6.3. 
Additional Exploratory Assessment for Research ......................................................47 
9.7. 
Unscheduled Visits .....................................................................................................47 
9.8. 
Home Care ..................................................................................................................47 
9.9. 
Travel and Reimbursement .........................................................................................47 
10. 
ADVERSE EVENT REPORTING ............................................................................49 
10.1. 
Adverse Event (AE) ....................................................................................................49 
10.2. 
Serious Adverse Event (SAE) ....................................................................................49 
10.3. 
Adverse Events of Interest (AEOI) .............................................................................50 
10.4. 
Evaluation of Adverse Events/Serious Adverse Events .............................................51 
10.4.1. 
Causality Assessment .................................................................................................51 
10.4.2. 
Severity Assessment ...................................................................................................52 
10.4.3. 
Outcome ......................................................................................................................52 
10.4.4. 
Action Taken Regarding the Investigational Product .................................................52 
10.4.5. 
Assessment of Expectedness ......................................................................................53 
10.5. 
Reporting Adverse and Serious Adverse Events ........................................................53 
10.5.1. 
Reporting Adverse Events ..........................................................................................53 


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10.5.2. 
Reporting Serious Adverse Events .............................................................................53 
10.5.3. 
Follow-Up of Adverse Events/Serious Adverse Events .............................................54 
10.5.4. 
Reporting to Regulatory Authorities, Investigators and Institutional Review 
Boards/Independent Ethics Committees .....................................................................55 
10.6. 
Pregnancy Reporting ..................................................................................................55 
11. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ..........57 
11.1. 
Recording of Data .......................................................................................................57 
11.2. 
Data Quality Assurance ..............................................................................................57 
11.3. 
Data Management .......................................................................................................57 
11.4. 
Audits and Inspections ................................................................................................57 
12. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................58 
12.1. 
General Considerations ...............................................................................................58 
12.2. 
Determination of Sample Size ....................................................................................58 
12.3. 
Analysis Sets ...............................................................................................................58 
12.4. 
Demographics and Baseline Characteristics ...............................................................59 
12.5. 
Patient Accountability ................................................................................................59 
12.6. 
Study Treatment Usage and Compliance ...................................................................59 
12.7. 
Safety Analyses ..........................................................................................................59 
12.7.1. 
Physical Examination and Vital Signs ........................................................................59 
12.7.2. 
Clinical Laboratory Tests and Electrocardiograms ....................................................59 
12.7.3. 
Adverse Events ...........................................................................................................60 
12.7.4. 
Open-Label Period ......................................................................................................60 
12.8. 
Pharmacokinetic Analyses ..........................................................................................60 
12.9. 
Efficacy .......................................................................................................................60 
12.9.1. 
Double-Blind Period ...................................................................................................60 
12.9.2. 
Open-Label Period ......................................................................................................61 
12.10. 
Biomarkers ..................................................................................................................61 
12.11. 
Missing or Invalid Data ..............................................................................................62 
12.12. 
Interim Analysis ..........................................................................................................62 
13. 
SPECIAL REQUIREMENTS AND PROCEDURES................................................63 
13.1. 
Institutional and Ethics Review ..................................................................................63 
13.2. 
Data Monitoring Committee .......................................................................................63 


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13.3. 
Changes to the Conduct of the Study or Protocol .......................................................63 
13.4. 
Investigator’s Responsibilities ....................................................................................64 
13.4.1. 
Patient Informed Consent ...........................................................................................64 
13.4.2. 
Case Report Form .......................................................................................................64 
13.4.3. 
Record Retention ........................................................................................................64 
13.4.4. 
Monitoring ..................................................................................................................65 
13.4.5. 
Study or Site Termination ...........................................................................................65 
13.4.6. 
Investigational Product Control ..................................................................................65 
13.4.6.1. 
Receipt of Investigational Product ..............................................................................66 
13.4.6.2. 
Disposition of Unused Investigational Product ..........................................................66 
13.4.6.3. 
Product Handling and Complaints Reporting .............................................................66 
13.4.7. 
Insurance .....................................................................................................................66 
13.4.8. 
Confidentiality ............................................................................................................66 
13.4.9. 
Clinical Study Report .................................................................................................67 
14. 
REFERENCES ...........................................................................................................68 
15. 
APPENDICES ............................................................................................................71 
15.1. 
Appendix A:  Schedules of Study Events ...................................................................72 
15.2. 
Appendix B:  Supplemental Study Information: ........................................................79 
15.2.1. 
Allowed PKAN Maintenance Treatments ..................................................................79 
15.2.2. 
Study Blood Assessments ...........................................................................................80 
 
LIST OF TABLES 
Table 1: 
Study Drug Administration by Dose (Capsule) ..........................................................38 
Table 2: 
Pharmacokinetic Sampling Schemes ..........................................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study 024PKAN15004 Overview Flow Chart ...........................................................28 
Figure 2: 
Study 024PKAN15004 Study Visits in Double-Blind  and Open-Label 
Periods ........................................................................................................................29 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations used throughout the protocol should not be used by the site when documenting 
AEs, medical history, etc. on source documents. 
Abbreviation 
Definition 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AMR 
Alternating motion rate 
ANCOVA 
Analysis of covariance 
BAD 
Barry Albright Dystonia scale 
BID 
Twice daily 
CDISC 
Clinical Data Interchange Standards Consortium 
CGI-I 
Clinician’s Global Impression of Improvement 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CoA 
Coenzyme A 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBS 
Deep brain stimulation 
DDK 
Diadochokinetic(s) 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ-5D-3L 
EuroQol, 5-dimension, 3-level QoL instrument 
EQ-5D-Y 
EuroQol-5D Youth Version 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FIM 
Functional Independence Measure 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus antibody 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 


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Abbreviation 
Definition 
IWRS 
Integrated web response system 
LOCF 
Last observation carried forward 
MDS 
Movement Disorder Society 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
NINDS 
National Institute of Neurological Disorders and Stroke 
NBIA 
Neurodegeneration of the Brain with Iron Accumulation 
OC 
Observed case 
PA 
Pantothenate (vitamin B5) 
PanK 
Pantothenate kinase enzyme 
PanK1 
Pantothenate kinase 1 enzyme 
PanK2 
Pantothenate kinase 2 enzyme 
PANK2 
Pantothenate kinase 2 gene 
PBMCs 
Peripheral blood mononuclear cells 
PGx 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PKAN 
Pantothenate kinase-associated neurodegeneration 
PKAN-ADL 
Pantothenate Kinase-associated Neurodegeneration Activities of Daily Living (scale) 
PPA 
Phosphopantothenic acid 
QoL 
Quality of life 
REML 
Restricted maximum likelihood (statistical method) 
RTSM 
Randomization and trial supply management 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SMR 
Sequential motion rate 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
TID 
Three times daily 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US 
United States 
WeeFIM 
Functional Independence Measure for Children 


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4. 
INTRODUCTION 
Pantothenate kinase associated neurodegeneration (PKAN), the most common form of 
Neurodegeneration with Brain Iron Accumulation (NBIA), is a progressive, often fatal, 
neurodegenerative disease estimated to affect 1 to 3 individuals per million people 
(Freeman, 2007).  PKAN is an autosomal recessive genetic disorder caused by mutations in the 
pantothenate kinase2 gene (PANK2), resulting in defective pantothenate (PA, vitamin B5) 
metabolism.  PANK2 encodes pantothenate kinase 2 (PanK2), a regulatory enzyme that 
phosphorylates pantothenate as a key step in coenzyme A (CoA) biosynthesis.  Defective PanK2 
enzymes, which are localized primarily in mitochondria (Alfonso-Peccio, 2012; Balibar, 2011; 
Hörtnagel, 2003; McGuigan, 1996) in humans, are postulated to result in decreased 
concentrations of CoA in selectively vulnerable human tissues including brain.  The majority of 
PKAN patients are diagnosed in the first 10 years of life, and affected children usually lose the 
ability to walk within 10 to 15 years after disease onset (Gregory, 2009).  Early mortality is 
typically caused by disease-associated sequelae such as malnutrition or aspiration/pneumonia 
(Gregory, 2009).  Clinical manifestations of PKAN include developmental delay in children, 
parkinsonism with Parkinson’s-like freezing and bradykinesia, dystonia sometimes causing 
intractable pain, choreoathetosis, status dystonicus, dysarthria, spasticity, rigidity, and dysphagia 
often leading to feeding tube placement (Gregory, 2009; Gregory, 2004; Klopstock, 2005; 
Kruer, 2015).  Age of onset does not seem to correlate with rate of progression; some patients 
progress rapidly to death within a few years, and others may live into their 30s to 50s with more 
slowly progressive symptoms of neurodegeneration (Gregory, 2009).  All patients with PKAN 
experience significant morbidity and, eventually, severe functional impairment.  The initial 
diagnosis of PKAN is often suggested by magnetic resonance imaging of the brain showing the 
near pathognomonic “eye-of-the-tiger” sign produced by disease-associated iron accumulation 
(Gregory, 2013), and confirmed by genetic testing (Gregory, 2009; Kruer, 2015).  The diagnosis 
must be confirmed through genetic testing and identification of a PANK2 mutation. 
There are currently no approved disease-modifying treatments for patients with PKAN.  A range 
of treatments are used to manage the dystonia and parkinsonism, as well as neuropsychiatric 
symptoms of PKAN, which are described in the literature as transiently effective (Kruer, 2015).  
These treatments include oral medications, injectables, and surgical interventions.  Exploratory 
trials have been conducted with mixed results to date with Deep Brain Stimulation (DBS), 
baclofen (given orally or intrathecally), and deferiprone, an iron chelating agent.  Deferiprone is 
currently being studied in a Phase 3 clinical trial.   
Fosmetpantotenate (RE-024) is a phosphopantothenic acid (PPA) precursor designed to deliver 
PPA, the product of pantothenate kinase (PanK), to cells.  Systemic administration of the product 
of PanK, 4’ phosphopantothenic acid, is not effective since it does not cross cell membranes 
(Balibar, 2011).  Fosmetpantotenate is designed to be metabolized intracellularly to PPA, 
becoming a substrate to downstream enzymes in the same manner as endogenously produced 
PPA, thus restoring CoA levels. 
Retrophin (the Sponsor) is developing fosmetpantotenate as a potential phosphopantothenate 
replacement therapy for the treatment of PKAN.  Primary pharmacodynamic studies indicate that 
fosmetpantotenate effectively delivers PPA to enzymes downstream of PanK2, the defective 
enzyme in PKAN.  In vitro, CoA concentrations were increased in pantothenate kinase 1 


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knockout (Pank1-/-) mouse embryonic fibroblasts incubated with fosmetpantotenate at 200 µM.  
In vivo, single intraperitoneal or oral doses of fosmetpantotenate at 1.2 µmole/g increased CoA 
concentrations in the liver of Pank1-/- mice to levels comparable to or higher than that in wild-
type mice.  In contrast, neither PA nor PPA increased CoA in these in vitro and in vivo models.  
This result was expected due to the lack of pantothenate kinase 1 (PanK1) enzyme in Pank1-/- 
mice to convert PA to PPA intracellularly and the fact that PPA is not expected to cross the cell 
membrane.  These data support evaluation of fosmetpantotenate for treatment of PKAN. 
This clinical study will evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of 
fosmetpantotenate in patients with PKAN. 
4.1. 
Summary of Potential Risks 
This section discusses data available at the time of this protocol revision.  For further information 
and details concerning warnings, precautions, and contraindications, the Investigator should refer 
to the appropriate section of the fosmetpantotenate Investigator’s Brochure (IB). 
4.1.1. 
Fosmetpantotenate (RE-024) Non-Clinical Studies 
A pivotal 28-day repeat-dose toxicity study was conducted in rats given twice daily oral doses of 
neat fosmetpantotenate at 125, 375, 1000 mg/kg/dose (250, 750, or 2000 mg/kg/day).  
Fosmetpantotenate-related adverse effects consisted of decreased body weight gain and increased 
alanine aminotransferase (ALT) in males and hepatocellular necrosis in both sexes at 2000 
mg/kg/day, and squamous epithelium hyperplasia with occasional associated erosion/ulceration, 
hyperkeratosis, and/or inflammation in the stomach at 750 and 2000 mg/kg/day.  All other 
fosmetpantotenate-related changes, including infiltrates of macrophages (often vacuolated) in 
various tissues, were not considered adverse or secondary to adverse gastric lesions. 
A 90-day repeat-dose toxicity study was conducted in rats given twice daily oral doses of 
fosmetpantotenate at 125, 300, 625 mg/kg/dose (250, 600, or 1250 mg/kg/day).  
Fosmetpantotenate-related adverse effects consisted of panlobular hepatocellular hypertrophy, 
individual hepatocellular necrosis, hepatocellular vacuolation, bile duct hypertrophy, and/or 
vacuolated macrophages coupled with increased ALT in both sexes at ≥1250 mg/kg/day. 
Two pivotal 7-day repeat dose oral toxicity studies were conducted in monkeys.  Gastrointestinal 
disturbances evidenced by emesis, inappetence, soft/watery feces, and body weight loss were 
observed in both control and fosmetpantotenate-treated animals in both studies.  In the second 
study, generalized lymphoid depletion in thymus was observed in both sexes, and thymus 
weights were decreased in males.  Infiltrates of macrophages, frequently vacuolated, and 
occasionally accompanied by minimal to mild subacute/chronic inflammation, were observed in 
various tissues in monkeys at 700 mg/kg/day. 
A pivotal 28-day repeat dose toxicity study was conducted in monkeys given twice daily oral 
doses of neat fosmetpantotenate at 100, 200, 350 or 1000 mg/kg/dose (200, 400, 700, or 2000 
mg/kg/day).  Two females at the 2000 mg/kg/day dose became moribund after the first dose on 
Day 2 and were euthanized.  Adverse changes in albumin (18% decrease), sodium (2.6% 
decrease), and globulin (15% increase) at 1250 mg/kg were considered secondary to 
inflammatory or gastrointestinal effects.  Fosmetpantotenate-related adverse pathologic changes 


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were limited to stomach ulceration at 1250 mg/kg/day, and red focus/foci and stomach ulceration 
at 2000 mg/kg/day in the animals that were moribund and euthanized. 
For further details, refer to the fosmetpantotenate IB, which contains comprehensive information 
on non-clinical studies. 
4.1.2. 
Fosmetpantotenate (RE-024) Clinical Studies and Other Use 
In 2 Phase 1 studies of fosmetpantotenate (Study 024HVOL14004 and Study 024HVOL15008), 
single oral doses up to 3600 mg were safe and well tolerated in healthy adult volunteers, and no 
serious adverse events (SAEs) were reported.  In the first study, which included 
fosmetpantotenate doses from 75 mg to 1800 mg (024HVOL14004), all AEs were mild in 
severity.  Of the subjects who received fosmetpantotenate, 11/30 (36.7%) experienced 15 AEs, 
10 of which were considered to be possibly related to the investigational product.  Of these 
10 AEs, 7 were related to taste (product taste abnormal); the remaining 3 AEs considered 
possibly related to investigational product included 1 event each of hiccups, throat irritation, and 
diarrhea.  One AE of increased creatinine level uncertain etiology possibly dehydration 
(preferred term ‘dehydration’), was initially considered possibly related.  The safety review 
committee concluded that this AE was likely explained by dehydration due to reduced fluid 
intake.  The sponsor assessed this AE as unlikely related to study drug. 
In the second study (Study 024HVOL15008), which included fosmetpantotenate doses of 
1800 mg and 3600 mg, 6 of 14 subjects (43%) receiving fosmetpantotenate experienced 14 AEs.  
One subject who received 1800 mg fosmetpantotenate reported 1 AE (abdominal discomfort) 
that was mild in severity and considered possibly related/related to investigational product.  The 
remaining 13 AEs were reported in 4/8 (50%) subjects who received 3600 mg 
fosmetpantotenate.  Of these 13 AEs, 11 were considered possibly related/related to the 
investigational product.  These AEs included nausea (3 events); vomiting, dizziness, and 
headache (2 events each); and tremor and chills (1 event each).  One event of vomiting was 
considered moderate in severity, and the remaining AEs were considered mild in severity.  Thus, 
3600 mg, which resulted in 1 moderate AE of vomiting and additional mild AEs in 3 other 
subjects, is considered the maximum tolerated dose. 
In a Phase 1 food effect study (024HVOL15007) of the proposed clinical dose of 300 mg 
fosmetpantotenate in 29 adult subjects, the dose was safe and well-tolerated when given under 
either fasted or fed conditions; there were no SAEs, all AEs were mild in severity, and all AEs 
resolved by the end of the study.  The 3 AEs considered possibly or probably related to drug 
included 1 AE (nausea) in the fed state, and 2 AEs (dizziness and headache) in the fasted state. 
Across these 3 studies, no clinically meaningful findings were seen in the safety parameters 
evaluated. 
In an uncontrolled, compassionate-use setting, transient, reversible transaminase elevations were 
reported by the treating physician in one patient receiving 240 mg/day but have not recurred to 
date in this patient upon gradual re challenge up to 210 mg/day.  In the current study, patients 
undergo a medical evaluation (including an abdominal examination) at each visit.  Signs or 
symptoms of gastrointestinal-related adverse effects will be evaluated medically as appropriate, 
which may, for example, include gastroscopy to evaluate for evidence of gastric erosion. 


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Other potential risks include lack of improvement while taking investigational product and/or 
worsening of PKAN signs and symptoms throughout the study. 
4.2. 
Summary of Potential Benefits 
It is hypothesized that treatment with fosmetpantotenate may improve signs and symptoms of 
PKAN and stabilize disease progression; however, it is unknown whether patients will see 
improvements in signs and symptoms of PKAN as a result of participating in this study. 


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5. 
STUDY OBJECTIVES  
5.1. 
Efficacy Objective 
The efficacy objective of this study is to evaluate the efficacy of fosmetpantotenate over 
24 weeks in patients with PKAN. 
5.2. 
Safety Objective 
The safety objective of the study is to assess the safety and tolerability of fosmetpantotenate in 
patients with PKAN. 
5.3. 
Other Objectives 
Other objectives are: 
• To determine the PK following multiple doses of fosmetpantotenate in patients with 
PKAN 
• To explore potential biomarkers of disease, along with their potential response to 
treatment in patients with PKAN 
 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Endpoints 
6.1.1. 
Primary Efficacy Endpoint 
The Unified Parkinson’s Disease Rating Scale (UPDRS) is a comprehensive assessment of the 
burden and severity of signs and symptoms of parkinsonism captured via systematic interview 
and neurological examination.  It has established clinimetric properties, with high internal 
consistency, very high correlation between the original UPDRS and the modified version (ie, the 
Movement Disorder Society- [MDS] UPDRS) (0.96), and a reliable factor structure 
(Goetz, 2008; Martinez-Martin, 2013).  The UPDRS also correlates with other widely accepted 
measures of disability (Goetz, 2012).  The UPDRS consists of 4 parts that can be used as 
individual scales or summed for a total score (Goetz, 2008). 
Part II of the UPDRS is an in-depth health outcomes assessment of motor activities of daily 
living that are impaired by a wide range of neurological diseases, including PKAN.  For this 
study, Part II of the UPDRS has been adapted to be optimally relevant to PKAN through a 
systematic revision involving experts, patient advocacy leaders, and regulatory interaction; it will 
serve as the primary efficacy endpoint and will be referred to in this protocol as the 
“Pantothenate Kinase-associated Neurodegeneration Activities of Daily Living” scale, 
abbreviated as PKAN-ADL. 
Thus, the primary efficacy endpoint for this study will be the change in the score from the 
PKAN-ADL, from Baseline to the end of the 24-week double-blind period. 
6.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoint will be the change in the score from Part III of the UPDRS 
from Baseline to the end of the 24-week double-blind period. 
6.1.3. 
Safety Endpoints 
The safety and tolerability of fosmetpantotenate will be assessed throughout the study by 
monitoring the occurrence of AEs and by serial vital signs, physical examinations, clinical 
laboratory parameters (chemistry, hematology, coagulation, and urinalysis), Columbia Suicide 
Severity Rating Scale (C-SSRS) assessments (in assessable patients), and 12-lead 
electrocardiograms (ECG). 
AEs will be classified as mild, moderate, or severe.  The definitions of mild, moderate, and 
severe were developed from Clinical Data Interchange Standards Consortium (CDISC) Study 
Data Tabulation Model (SDTM) standard terminology v3.1.1.  See Section 10.4.2 for definitions. 
6.1.4. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will include change from Baseline to the end of the 24-week 
double-blind period in the following: 
• Clinician Global Impression of Improvement (CGI-I) 
• Barry Albright Dystonia (BAD) scale 


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• Quality of life (QoL): 
o Neuro-QoL, upper and lower extremity modules (adult and pediatric versions) 
o EuroQol 5-dimension, 3 level QoL instrument (EQ-5D-3L)/EuroQol-5D Youth Version 
(EQ-5D-Y) 
• Functional independence: Functional Independence Measure (FIM)/Functional Independence 
Measure for Children (WeeFIM) 
• Function measures: 
o Ambulation: 25-foot walk test (in appropriate patients) 
o Speech: Diadochokinetic (DDK) assessments (ie, alternating motion rate [AMR] and 
sequential motion rate [SMR]) 
6.1.5. 
Pharmacokinetic Endpoint 
Multiple dose PK of fosmetpantotenate in whole blood will be evaluated using a sparse sampling 
design.  Blood samples may also be used for metabolite quantification and/or identification. 
6.1.6. 
Biomarkers 
Exploratory biomarkers will be assessed in plasma.  Potential biomarkers assessed may include 
succinate, lactate, maleate, pyruvate, alanine, acetone, acetoacetic acid, 3-hydroxybutyric acid, 
2-hydroxybutyric acid, and acetylCoA.  Although other biomarkers may be assessed, the samples 
will not be used for genetic testing. 
6.1.7. 
Pharmacogenomics 
Pharmacogenomic assessment may be performed on for drug metabolizing enzymes, 
transporters, or indicators of therapeutic response or safety.  These assessments will only be 
performed where local regulations permit and where approved by the site’s Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), and will be subject to separate consent/assent 
by the patient/parent/legal guardian as appropriate. 
Samples intended for pharmacogenomic (PGx) analyses will be collected at study sites.  PGx 
sample analyses will be limited to variations that affect drug absorption, distribution, 
metabolism, and excretion (ADME), therapeutic response, or drug safety.  Upon completion of 
the clinical phase of the study, pharmacokinetic (PK) data will be assessed.  Pursuant to that 
assessment, PGx analyses will be performed, guided by, and as indicated by the PK analyses, 
and as informed by pre-clinical data.  If PK analyses do not indicate the need for PGx, samples 
will be destroyed without analyses. 
6.2. 
Study Design 
This is a pivotal, randomized, double-blind, placebo-controlled, multi-center, 2-arm study 
evaluating 24 weeks of treatment with fosmetpantotenate or placebo in patients with PKAN aged 
6 to 65 years, with a 278-week open-label extension. 
Following screening, patients meeting all eligibility criteria will be enrolled in the study.  
Patients will be randomized in a 1:1 ratio to receive either fosmetpantotenate or placebo for a 
24-week double-blind period.  Treatment in the double-blind period will begin with dose 


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escalation for Days 1 through 3, followed by the full dose 3 times daily (TID) starting on Day 4.  
Matching placebo will be given according to the same dose escalation sequence as active 
investigational product (see Section 6.5.2).  For patients 6 to <18 years, the daily dose patients 
receive will be based on their weight at the Screening visit and will not be changed due to 
changes in patient weight during the double-blind period. 
After completing the double-blind period, patients will be eligible to receive open-label 
fosmetpantotenate in the study for up to 278 weeks followed by a phone safety review 4 weeks 
later.  The total study duration will be approximately 310 weeks.  If the product becomes 
commercially available during the extension period, patients may transition to commercial 
product before the end of the extension period. 
After 8 patients aged 18 to 65 years complete 3 weeks of study treatment in the double-blind 
period, the independent Data Monitoring Committee (DMC) will review safety data to determine 
whether the study can continue as planned, including initiating enrollment of patients aged 6 to 
<18 years.  Enrollment of patients 18 to 65 years of age (only) will continue while this review is 
occurring.  If the DMC determines it is safe to continue the study, enrollment of patients 6 to 
<18 years of age will begin, and enrollment of patients 18 to 65 years of age will continue.  
Similarly, after the first 8 patients aged 6 to <18 years complete 3 weeks of study treatment in 
the double-blind period, the DMC will review the safety data from all patients to date and 
determine whether the study can continue as planned.  Enrollment of patients 18 to 65 years of 
age and up to 8 additional patients aged 6 to <18 years of age may continue while this review is 
occurring.  If the DMC determines it is safe to continue the study, enrollment of patients 6 to 
65 years of age will continue. 
Screening will take place within 29 days prior to the start of the double-blind period.  Patients 
who fail screening for any reason may be re-screened up to 2 times.  The protocol allows PKAN 
patients to be considered for participation three times (1 screening + 2 re-screening).  If a given 
patient fails to qualify based on eligibility criteria, but the Investigator believes that this reason 
for non-qualification is a temporary situation, the patient can be screened a second time and a 
third time to determine whether he or she qualifies.  Examples of such a situation include but are 
not limited to: 
1. Abnormal labs suggestive of treatable, temporary abnormalities such as infection, 
anemia, dehydration, etc. 
2. The patient had a major surgery within 30 days of screening, or DBS implantation within 
6 months. 
3. The patient has taken deferiprone within 30 days of screening. 
4. The patient’s symptoms are too mild to qualify with a PKAN-ADL Score < 6, but 
unfortunately it is possible that the disease will progress during the course of the trial 
enrollment such that the patient might qualify at a later date. 
Assessment visits will occur at Baseline (Day -1), Days 1 through 4, and Weeks 3, 6, 12, 18, and 
24.  Patients may be admitted to an inpatient facility for safety monitoring from Baseline through 
completion of the Day 4 assessments for the double-blind period, or may be followed closely in a 
nearby outpatient setting.  In order to provide training in proper administration, investigational 
product will be prepared and administered by site personnel, together with the patient and/or 


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family/caregiver, during in-clinic patient visits.  Following adequate training, doses may be 
self-administered by the patient or caregiver at the site’s discretion. 
After the 24-week double-blind period, patients will receive fosmetpantotenate open-label for an 
additional 278 weeks.  During the open-label period, assessment visits will occur at Weeks 27, 
30, 36, 48, 60, 72, 84, 96, 108, and 120 and every 26 weeks thereafter (W146, W172, W198, 
W224, W250, W276, and W302). If the investigator determines that more frequent visits should 
occur after W120, additional unscheduled visits can be performed.  Three-month (every 
13 weeks) safety phone calls will be made in between each 6-month onsite visit following 
Week 120. 
Flow charts depicting the study are presented in Figure 1 and Figure 2. 
 


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Figure 1: 
Study 024PKAN15004 Overview Flow Chart 
 
 
 
AE = adverse event; PKAN-ADL = Pantothenate Kinase-associated Neurodegeneration Activities of Daily Living (scale) 
Note: Three-month (every 13 weeks) safety phone calls will be to assess PKAN-ADL, AEs, and Concomitant Medications in between each 6-month onsite visit 
following W120. 


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Figure 2: 
Study 024PKAN15004 Study Visits in Double-Blind  
and Open-Label Periods 
A. Double-Blind Period 
 
Pre-
Screening1 Screening 
Baseline 
Inpatient Blinded 
Treatment2 
Blinded Treatment 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study 
Day/
Week 
 
Days 
-29 to -2 
Day -1  
(Randomization) 
D1 
D2 
D3 
D4 
W3 
± 
3D 
W6 
± 
3D 
W12 
± 
3D 
W18 
± 
3D 
W24 
± 
3D 
1 For patients who are taking deferiprone or who require a PANK2 genetic mutation confirmation test.  This visit 
will be accomplished at least 30 days prior to the Screening visit for washout of deferiprone or PANK2 genetic 
mutation confirmation test. 
2 Alternatively, patients may be followed closely in a nearby outpatient setting. 
B. Open-Label Period 
Visit 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22-
V281 
Study 
Week 
W27 
± 7D 
W30 
± 7D 
W36 
± 7D 
W48 
± 7D 
W60 
± 7D 
W72 
± 7D 
W84 
± 7D 
W96 
± 7D 
W108 
± 7D 
W120 
± 7D 
W146, 
W172, 
W198, 
W224, 
W250, 
W276, 
W302 
± 7D 
AE = adverse event; PKAN-ADL = Pantothenate Kinase-associated Neurodegeneration Activities of Daily Living 
(scale) 
1 Three-month (every 13 weeks) safety phone calls will be to assess PKAN-ADL, AEs, and Concomitant 
Medications in between each 6-month onsite visit following W120. 
 
6.3. 
Completion of a Patient’s Participation in the Study and Overall 
Study Completion 
6.3.1. 
Completion of a Patient’s Participation in the Study 
Each patient will participate in the study for approximately 4 weeks during the screening phase, 
followed by 24 weeks of double-blind treatment and 278 weeks of open-label treatment.  At the 
end of the open-label treatment period, study medication will be discontinued, and patients will 
be contacted by phone for a safety review 4 weeks later.  Thus, patients will participate for a total 
of approximately 310 weeks. 
A patient will be considered as having completed the study, regardless of whether the patient is 
on or off study medication, if the patient is followed until Week 302 or if rolled off early onto 
commercial product, whichever happens first.  Patients who successfully complete the study will 
complete the Week 302 assessments listed in the schedule of events (Section 15.1).  The visit 


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data, including final disposition of the patient, will be recorded on the End of Treatment /Early 
Termination electronic case report form (eCRF). 
6.3.2. 
Overall Study Completion 
The study will be considered complete when the last patient completes his/her final visit. 
6.3.3. 
Premature Discontinuation from the Study 
In general, patients should be encouraged to both stay on study medication and remain in the 
study until study termination/completion.  However, patients or their parents/guardians are free 
to withdraw consent/assent and/or discontinue the patient’s 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 the Sponsor. 
Reasons for premature discontinuation from the study may include: 
• Death 
• Voluntary withdrawal of patient/guardian assent/consent (complete withdrawal of 
consent requires a patient’s/parent’s/guardian’s refusal of ALL methods of follow-up 
noted in the informed consent form:  procedures, participation in reduced 
procedures/study visits, telephone/alternative contact only, source document or 
designated alternative contact, or access to medical records from alternative sources) 
• Termination of the study by the Sponsor, or any regulatory authorities (see 
Section 13.4.5) 
• Lost to follow-up 
o 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.” 
o Patients will be considered “lost to follow-up” only after reasonable, documented 
attempts to reach the patient prove unsuccessful.  “Reasonable” is defined as at 
least 3 phone calls and a certified letter.  This information and dates of attempted 
contact must be recorded in the patient’s source documents. 
A patient who chooses to not continue regularly scheduled study visits (ie, withdraws consent) 
will complete the Early Termination assessments listed in the schedule of events (Section 15.1) 
as close as possible to the patient’s last dose of study medication.  The visit data, including the 
primary reason for premature discontinuation from the study, will be recorded on the Early 
Termination eCRF.  Post-study SAEs will be reported according to Section 10.5.2. 
Decisions to prematurely discontinue patients from the study will be reviewed by the 
Investigator, the Medical Monitor, and the Sponsor. 
6.4. 
Discussion of Study Design, Including Choice of Control Group 
The heterogeneity of signs, symptoms, and key phenotypic features (eg, age at onset, rate of 
progression, and survival duration) in patients with PKAN is a critical consideration in designing 
a clinical study for this disease.  Placebo-control is necessary to control for variability in disease 


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severity and rate of progression.  A randomized, placebo-controlled, parallel design study allows 
for a balanced distribution of uncontrolled variables across randomized groups, and a rigorous 
assessment of true drug effects on the outcome variables, controlling for nonspecific effects. 
Demonstration of a clinically meaningful treatment effect over a 24-week period is sufficient to 
establish fosmetpantotenate as safe and efficacious for the treatment of PKAN, as there are no 
effective treatments available to date for this debilitating disease.  The double-blind period of the 
trial will evaluate the efficacy of fosmetpantotenate in improving signs, symptoms, and 
functioning in patients with PKAN, and the safety extension will evaluate whether these 
improvements are generally maintained during an open-label treatment period that aims to 
simulate more real-world therapeutic conditions (eg, concomitant medications, which are fixed 
during the 24-week double-blind period, may be adjusted during the open-label extension based 
on medical judgment). 
6.5. 
Dosing Considerations 
Investigational product will be prepared and administered by site personnel, together with the 
patient and/or family, during in-clinic patient visits in order to provide training in proper 
administration.  Following adequate training, doses may be self-administered by the patient or 
caregiver at the site’s discretion. 
All investigational product should be taken with food.  If necessary, investigational product may 
be given through a feeding tube. 
Details regarding dosing can be found in the study manuals. 
6.5.1. 
Dose Selection Rationale 
A dose of 900 mg fosmetpantotenate daily, administered as 300 mg TID with food, will be used 
in this study for adult patients (18 and older) and pediatric patients weighing 40 kg or more. 
Two lower dose strengths will be used for pediatric patients weighing less than 40 kg.  For 
pediatric patients weighing at least 20 kg but less than 40 kg, a dose of 450 mg daily, 
administered in 3 equally divided doses of 150 mg (TID) with food, will be used.  For pediatric 
patients weighing less than 20 kg, a dose of 225 mg daily, administered in 3 equally divided 
doses of 75 mg (TID) with food, will be used. 
In the Phase 1 healthy adult volunteer studies (Studies 024HVOL14004, 024HVOL15007, and 
024HVOL15008), fosmetpantotenate was safe and well tolerated at single oral doses up to 
1800 mg, with no identifiable dose-related safety findings (see also Section 4.1).  A dose of 
3600 mg was associated with mostly mild gastrointestinal AEs.  Administration of 300 mg 
fosmetpantotenate with a high-fat meal resulted in greater exposure and longer overall exposure 
time, without an increase in maximum fosmetpantotenate concentration (Cmax). 
PKAN is characterized by a large number of genotypic mutations of the PANK2 gene that have 
an unclear relationship with phenotypic manifestations.  Earlier-onset, rapidly progressive PKAN 
may be associated with decreased functionality of the PanK2 enzyme (Hartig, 2006); thus, higher 
doses than those used to date in patients with PKAN may be required in some patients to produce 
a treatment effect.  A dose of 300 mg TID with food (900 mg daily), is therefore being used in 


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this study.  The 300 mg dose was safe and well tolerated in both fed and fasted states in a 
Phase 1 food effect study. 
Single-dose data from the Phase 1 studies also showed the absence of a relationship between 
blood exposure and any safety related signal until a dose of 3600 mg was used; additionally, no 
SAEs were reported in the studies.  Therefore, of primary practical importance for this pivotal 
study was the selection of a dose that will be safe in pediatric patients, while showing efficacy 
for as many of these patients as possible. 
The overall safety profile of fosmetpantotenate to date suggests that a weight-based pediatric 
dosing strategy, which facilitates ease of use for patients and their caregivers, is medically 
reasonable. 
The mean weight for a normal 11 ½- to 12-year-old in the United States (US) is approximately 
40 kg (Kuczmarski, 2002).  However, patients under the age of 12 years, as well as adolescent 
patients who are underweight due to developmental delay or other nutritional and metabolic 
effects of PKAN, are likely to weigh less than 40 kg.  In addition, patients ages 6 or older will be 
enrolled in this trial, who will likely also weigh less than 40 kg.  Thus, for pediatric patients 
weighing less than 40 kg but at least 20 kg, the 900 mg daily dose (300 mg TID) will be reduced 
by 50% to 450 mg daily (150 mg TID).  For the few pediatric patients weighing <20 kg, the dose 
will be reduced by an additional by 50% to 225 mg daily (75 mg TID).  The conservative dosing 
approach outlined here reduces the daily fosmetpantotenate dose by approximately 2-fold 
relative to adults in children weighing less than 40 kg, and an additional 2-fold in children 
weighing less than 20 kg. 
6.5.2. 
Dose Initiation 
6.5.2.1. 
Double-Blind Period 
The double-blind period will begin with dose escalation for Days 1 through 3, followed by the 
full dose (TID) starting on Day 4.  Dose escalation on Days 1 through 3 will proceed as follows, 
based on the patient’s age and weight at screening: 
Patients aged 18 to 65 years and patients aged 6 to <18 years weighing ≥40 kg:  On Day 1, 
patients will receive one 300 mg dose (in the morning); on Days 2 and 3, they will receive 
300 mg twice daily (BID, at least 8 hours apart) for a total daily dose of 600 mg; and on Day 4, 
they will receive the full dosage of 300 mg TID (given at approximately 8 hour intervals) for a 
total daily dose of 900 mg. 
Patients aged 6 to <18 years weighing ≥20 kg but <40 kg:  On Day 1, patients will receive one 
150 mg dose (in the morning); on Days 2 and 3, they will receive 150 mg BID (at least 8 hours 
apart) for a total daily dose of 300 mg; and on Day 4, they will receive the full dosage of 150 mg 
TID (given at approximately 8 hour intervals) for a total daily dose of 450 mg. 
Patients aged 6 to <18 years weighing <20 kg:  On Day 1, patients will receive one 75 mg dose 
(in the morning); on Days 2 and 3, they will receive 75 mg BID (at least 8 hours apart) for a total 
daily dose of 150 mg; and on Day 4, they will receive the full dosage of 75 mg TID (given at 
approximately 8 hour intervals) for a total daily dose of 225 mg. 


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6.5.2.2. 
Open-Label Period 
Patients will receive open-label fosmetpantotenate after they complete the double-blind period of 
the study.  No dose escalation is required for the open-label period.  All patients (regardless of 
randomization assignment for the double-blind period) will initiate treatment with 
fosmetpantotenate in the open-label period according to the dose of study medication they were 
receiving at the end of the double-blind period; for patients 6 to <18 years of age, the initial dose 
may be adjusted, if needed, based on the patient’s weight at the end of the double-blind period. 
For patients 6 to <18 years of age, the dose will be adjusted as needed during the open-label 
period based on their weight taken at study visits every 24 weeks. 
6.5.3. 
Dose Modification 
Elective dose reductions for safety or tolerability reasons only are allowed, and only 1 time, 
throughout the first 6 weeks of the double-blind period of the study, according to the following 
schedule: 
• Patients 18 to 65 years of age or 6 to <18 years of age and weighing ≥40 kg: the 300 mg 
TID dose may be reduced to 150 mg TID 
• Patients 6 to <18 years of age and weighing ≥20 kg but <40 kg: the 150 mg TID dose 
may be reduced to 75 mg TID 
• Patients 6 to <18 years of age and weighing <20 kg: the 75 mg TID dose may be reduced 
to 75 mg once daily 
Patients who are unable to tolerate the reduced dose will be discontinued from treatment.  The 
Investigator should attempt to increase the dose back to the patient’s assigned fixed dose as 
safety and tolerability allow. 
Once patients have been treated in the open-label period for at least 24 weeks, and after the 
second DMC review has occurred, dose increases of 1 level will be allowed for perceived lack of 
efficacy.  Dose increases will only be allowed following consultation between the Investigator, 
the Medical Monitor, and the Sponsor, and only to the maximum dosage of 300 mg TID.  
Elective dose reductions for safety or tolerability reasons only are allowed, and only 1 time, 
throughout the first 6 weeks of the open-label period of the study. 
Fosmetpantotenate will not in any case be used as a rescue medication. 
6.5.4. 
Interruption and Discontinuation of Study Medication 
6.5.4.1. 
Temporary Interruption of Study Medication 
Patients who temporarily interrupt prior to completion of the study, will continue with study 
visits and assessments according to the schedule of study events (Section 15.1).  Unless 
contraindicated, treatment should be resumed whenever possible (including between visits), and 
treatment resumption should be considered at every visit following study medication 
interruption.  If the patient’s dose was reduced prior to the temporary interruption, the study 
medication should be resumed at the reduced dose and the Investigator should attempt to 
increase the dose back to the patient’s assigned fixed dose as safety and tolerability allow. 


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6.5.4.2. 
Permanent Discontinuation of Study Medication 
A patient’s investigational product may be discontinued at any time at the patient’s/parent’s/legal 
guardian’s request or at the discretion of the Investigator, the Medical Monitor, or the Sponsor.  
Justifiable reasons for the Investigator or the Sponsor to discontinue a patient from treatment 
may include, but are not limited to: 
• The patient experiences any AE, clinically significant laboratory abnormality, or 
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 (adverse event). 
• A significant protocol violation (ie, patient failed to meet entry criteria or did not comply 
with protocol requirements resulting in an unacceptable risk to the patient’s health) 
(protocol deviation). 
•  Noncompliance with study medication (non-compliance with study drug). 
• Patient or parent/legal guardian decision to stop study medication (withdrawal by 
parent/guardian). 
• Investigator discretion (physician decision). 
• The patient participates in another investigational study without the prior written 
authorization of the Sponsor or its designee (protocol deviation). 
• The patient becomes pregnant (pregnancy); study medication must be discontinued 
immediately once the patient becomes aware of the pregnancy and the investigator must 
be notified of the pregnancy (pregnancy) (see also Section 10.6, Pregnancy Reporting). 
• The patient’s concomitant PKAN maintenance medications/therapies are adjusted during 
the double-blind period (protocol deviation). 
• Patient is lost to follow-up (lost to follow-up). 
Decisions to prematurely discontinue patients from study medication should be reviewed by the 
Investigator, the Medical Monitor, and the Sponsor. 
Patients who permanently discontinue study medication early should be encouraged to continue 
study visits through Week 120 for continued collection of safety and efficacy data despite 
stopping study medication, but may withdraw consent at any time (see Section 6.3.3).  Patients 
who agree to continue regularly scheduled study visits will complete the End of Treatment 
assessments listed in the schedule of events (Section 15.1) 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 End of Treatment eCRF.  Subsequent study visit data 
will be recorded on the visit-specific eCRF, and the patient’s final study visit will be recorded on 
the End of Treatment/Early Termination eCRF. 
For patients who permanently discontinue study medication, the Investigator should resume 
standard of care treatment, including treatment with appropriate medications, as deemed 
necessary. 


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7. 
PATIENT POPULATION AND SELECTION  
7.1. 
Inclusion Criteria 
A patient will meet all of the following criteria to be eligible for this study. 
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. 
2. The patient has a diagnosis of PKAN as indicated by a confirmed mutation in the PANK2 
gene (if available, the specific mutation will be recorded). 
3. The patient has a score of ≥6 on the PKAN-ADL scale. 
4. The patient is male or female aged 6 to 65 years, inclusive. 
5. If sexually active with male partners, the female patient of childbearing potential agrees 
to use a medically acceptable method of contraception for the duration of the study and 
for at least 30 days after the last dose of investigational product.  Females are considered 
of childbearing potential if they are post-menarchal, have not been surgically sterile for at 
least 6 weeks (ie, total hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation) 
and are pre-menopausal (menopause is defined as cessation of menstruation for at least 
1 year).  Acceptable methods of contraception include: 
A. the simultaneous use of stable combined (estrogen and progestogen containing) or 
progestogen-only hormonal contraception (eg, oral, transdermal or intravaginal) 
associated with inhibition of ovulation in conjunction with a double-barrier method 
(eg, condom with spermicide or diaphragm with spermicide), or; 
B. the use of an intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS) in place for at least 3 months or; 
C. vasectomised partner (vasectomy at least 3 months prior to screening), or; 
D. sexual abstinence 
6. If sexually active with female partners, the sexually mature, nonsterile male patient 
agrees to use a medically acceptable method of contraception for the duration of the study 
and for at least 90 days after the last dose of investigational product.  Males are 
considered surgically sterile if they have undergone bilateral orchiectomy or vasectomy 
at least 3 months prior to screening.  Acceptable methods of contraception include: 
A. the simultaneous use of stable combined (estrogen and progestogen containing) or 
progestogen-only hormonal contraception (eg, oral, transdermal or intravaginal) 
associated with inhibition of ovulation by the female partner in conjunction with a 
double-barrier method (eg, condom with spermicide or diaphragm with spermicide), 
or; 
B. the female partner’s use of an IUD or IUS in place for at least 3 months, or; 
C. the female partner is surgically sterile for at least 6 weeks or is at least 1 year 
postmenopausal. 


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7. The male patient agrees to not donate sperm for at least 90 days after the last dose of 
investigational product. 
7.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study. 
1. The patient has required regular or intermittent invasive ventilatory support to maintain 
vital signs within 24 weeks prior to randomization. 
2. The patient has been (or is currently) enrolled in a clinical trial involving an 
investigational product or non-indicated use of a drug or device within 30 days prior to 
randomization. 
3. The patient has a positive serologic test for Hepatitis B virus surface antigen (HBsAg), 
Hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) at screening. 
4. The patient has a history of metastasized or ongoing malignancy regardless of whether or 
not it has been or is being treated. 
5. The patient has a serious, unstable medical or psychiatric condition not related to PKAN 
that, in the opinion of the Investigator, could interfere with the patient’s ability to 
participate in the study safely or to complete the scheduled study assessments, or that 
would confound the assessment of safety or efficacy. 
6. The patient has a history of drug or alcohol use disorder within the past 1 year. 
7. The patient has a history of suicide attempts within the past 1 year or is considered by the 
Investigator to be at imminent risk of suicide. 
8. The patient has had a major surgical procedure within 30 days prior to screening. 
9. The patient has had a deep brain stimulation (DBS) device implanted within 6 months 
prior to screening. 
10. The patient has abnormal laboratory values at screening that, in the opinion of the 
Investigator, are clinically significant, and would compromise the safety of the patient 
during study participation. 
11. The patient is a female who is pregnant or lactating, or who presents with a positive 
serum pregnancy test at screening, or a positive urine pregnancy test at Baseline. 
12. The patient is unwilling or, in the opinion of the Investigator, is unable to adhere to the 
requirements of the study, including study procedures and the visit schedule. 
13. The patient is unable or unwilling to remain on their pre-study dose(s) of allowed 
concomitant PKAN maintenance medications and therapies (including DBS settings) for 
the double-blind period of the study.  (See Section 8.3 of the protocol for discussion of 
concomitant medication/treatment use during the study, and Section 15.2.1 for a list of 
allowed concomitant medications and therapies.) 
14. The patient has taken deferiprone within 30 days prior to screening. 
Patients who do not meet eligibility criteria may be re-screened twice. 


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8. 
TREATMENTS  
8.1. 
Treatments Administered 
The investigational product administered in this study is fosmetpantotenate, a 
phosphopantothenate replacement therapy. 
8.2. 
Investigational Product(s) 
Fosmetpantotenate active pharmaceutical ingredient is a yellowish oil. 
The chemical name of fosmetpantotenate is methyl 3-((2R)-2-hydroxy-4-(((((S)-1-methoxy-1-
oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)-3,3-dimethylbutanamido)propanoate. 
Fosmetpantotenate contains 2 chiral carbon atoms with known absolute stereochemistry.  The 
amino acid portion of the molecule is prepared from naturally occurring L-alanine.  The 
secondary alcohol (OH) functionality is part of naturally occurring vitamin B5, and has 
R-stereochemistry.  The phosphorus atom is also a chiral center, and is racemic; thus, 
fosmetpantotenate exists as a mixture of diastereomers. 
Fosmetpantotenate will be supplied in dried powder form for reconstitution and oral 
administration, packaged in a dose strength of 75 mg capsules, and after receipt of regulatory 
approval, 75 mg and 300 mg sachets. 
The placebo for the study will be representative of, and physically identical to, active 
fosmetpantotenate. 
Details regarding blinding for fosmetpantotenate and placebo can be found in the study manuals. 
8.2.1. 
Packaging and Labeling, Storage, and Preparation and Administration of 
Investigational Product 
8.2.1.1. 
Study Drug Administration 
Patients will be instructed to take the study drug 3 times daily (approximately 8-hour intervals) 
with food.  The Investigator/designee will provide instructions on study drug preparation when 
patients have to take their dose of the study drug at home.  If vomiting occurs, patients will be 
instructed not to take another dose of study drug and continue the study drug with their usual 
dosing schedule and inform the Investigator.  In case the patients miss any dose of the study 
drug, they will be instructed not to take the missed dose immediately but follow their next 
scheduled dosing. 
Study drug administration is outlined in Table 1. 


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Table 1: 
Study Drug Administration by Dose (Capsule) 
Total 
Daily Dose 
Each Dose 
Number of Capsules  
Total Number of Bottles 
(84 capsules/bottle) 
Double-Blind Period 
(24 weeks) 
Total Number of Bottles 
(84 capsules/bottle)  
Open-Label Period 
(278 weeks) 
Per Day 
Per Dose 
225 mg 
75 mg 
3 
1 
9 
70 
450 mg 
150 mg 
6 
2 
17 
139 
900 mg 
300 mg 
12 
4 
30 
278 
Table 2:  
Study Drug Administration by Dose (Sachet – Open Label Only) 
Total 
Daily 
Dose 
Each 
Dose 
Number of Sachets  
Total Number of 
Boxes  
(30 sachets/box)  
Open-Label Period 
(278 weeks) 
75 mg 
Sachet 
Per Day 
75 mg 
Sachet 
Per Dose 
300 mg 
Sachet 
Per Day 
300 mg 
Sachet 
Per Dose 
225 mg 
75 mg 
3 
1 
NA 
NA 
128 
450 mg 
150 mg 
6 
2 
NA 
NA 
255 
900 mg 
300 mg 
NA 
NA 
3 
1 
128 
8.2.1.2. 
Packaging, Labeling, and Storage 
Study drug will be packaged by the Sponsor according to all local legal requirements.  The study 
drug will be labeled in accordance with applicable regulatory requirements. 
8.2.1.3. 
Study Drug Storage at Study Centers 
The fosmetpantotenate powder for oral suspension in a dose strength of 75 mg and 300 mg and 
placebo to match fosmetpantotenate powder for oral suspension in a dose strength of 75 mg must 
be stored frozen (-20 ± 5°C), in a secure location with limited access.  The fosmetpantotenate 
and placebo suspensions are to be kept at room temperature and should be used within 8 hours of 
preparation. 
8.2.1.4. 
Study Drug Storage Instructions for Patients 
Investigator/designee will provide the following instructions to the patients on the study drug 
storage. 
• Keep the study drug in the freezer (- 20°C ± 5°C) OR (5°F to -13°F). Alternatively, 
patients can store the study drug in the refrigerator at 2°C – 8°C (36°F - 46°F) for up to 
14 days.  Patients/caregivers should be instructed to write the date it went into the 
refrigerator on the bottle to ensure they do not go past 14 days. 
• Patients will be instructed to keep the prepared mixture of study drug and water at room 
temperature (15°C – 25°C) or (59°F - 77°F) and should be administered within 8 hours of 
preparation. 


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• While travelling, patients are instructed to use the freezer bags provided to them and 
make sure the study drug is stored per instructions once they reach destination. 
• Patients are instructed to save and bring all empty study drug bottles and unused study 
drug to their next visit. 
Patient and/or caregiver must take care to prevent the accidental ingestion of or exposure to this 
medication by anyone other than the intended recipient (patient). 
Details on the packaging, labeling, preparation and administration of the fosmetpantotenate 
active pharmaceutical ingredient and placebo can be found in the study manuals. 
8.3. 
Prior and Concomitant Medications and Therapeutic Procedures 
Deferiprone is prohibited within 30 days prior to screening for the study and throughout the 
patient's participation in the study. 
Double-blind Period:  The PKAN maintenance treatments listed in Section 15.2.1 are allowed 
during the study.  However, no changes or modifications to any of these treatments are allowed 
for 30 days prior to randomization until the completion of the double-blind period of the study, 
unless medically necessary and after consultation between the Investigator, the Medical Monitor, 
and the Sponsor (except in cases of medical emergency). 
Open-Label Period:  Dose adjustments of allowed concomitant treatments are permitted for 
optimal effect in the open-label period of the study. 
Both Periods:  Based on the Investigator’s judgment, medical management of patients from 
screening through study completion may also include administering or modifying treatments 
(excluding deferiprone) for AEs, symptoms, or disease states unrelated to managing the 
symptoms of PKAN. 
8.4. 
Method of Assigning Patients to Treatment 
Patients will be assigned to a treatment group at Baseline by an integrated web response system 
(IWRS). 
8.5. 
Randomization 
Following screening, patients meeting all eligibility criteria will be enrolled in the study.  
Patients will be randomized via IWRS in a 1:1 ratio to receive either fosmetpantotenate or 
placebo during the 24-week double-blind period, followed by open-label treatment with 
fosmetpantotenate.  Randomization will be stratified by weight (≥40 kg, ≥20 kg but <40 kg, or 
<20 kg) and age group (pediatric: ages 6 to <18 years, or adult: ages 18 to 65 years, inclusive) as 
measured at the Screening visit. 
For the open-label period, all patients will receive fosmetpantotenate open-label. 
The IWRS will also randomize patients to one of the sampling schemes for PK sampling as 
described in Section 9.4. 


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8.5.1. 
Blinding and Breaking the Blind 
The first 24 weeks of treatment will be administered in a double-blind manner.  The identity of 
the treatments will be concealed by the use of study drugs that are identical in packaging, 
labeling, and schedule of administration, appearance, taste, and odor.  During the open-label 
extension, patients (including parents or legal guardians of patients <18 years of age) and site 
personnel will remain blinded to the patient’s randomized treatment assignment. 
The study blind should not be broken except in a medical emergency (where knowledge of the 
study drug received would affect the treatment of the emergency) or regulatory requirement (e.g., 
for SAEs or death).  The patient’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded. 
8.5.1.1. 
Breaking the Blind in Medical Emergency 
Before breaking the blind of an individual patient’s treatment, the Investigator should determine 
that the unblinded information is necessary, i.e., it will alter the patient’s immediate 
management.  In many cases, particularly when the emergency is clearly not related to the study 
drug, the problem may be properly managed by assuming that the patient is receiving active 
product.  It is highly desirable that the decision to unblind treatment assignment be discussed 
with the Medical Monitor/Sponsor.  Emergency code breaks will be performed using the IWRS.  
Only the Investigator and Medical Monitor will have access to unblinding through IWRS in case 
of emergency.  Emergency unblinding should be performed only after the decision to discontinue 
the patient from treatment has been made.  The unblinding procedure is described in the 
Randomization and Trial Supply Management (RTSM) User Guide.  In cases of accidental 
unblinding, within 24 hours, the Investigator should immediately contact the Medical Monitor 
and ensure that every attempt is made to preserve the blind. 
If the blind is broken, the date and time must be recorded in the IWRS and the reason must be 
recorded in the patient’s source documentation. 
8.5.1.2. 
Breaking the Blind for Regulatory Requirement 
For Suspected, Unexpected, Serious Adverse Reactions (SUSARs), the Sponsor’s 
Pharmacovigilance designee responsible for managing SAEs, will access the IWRS to obtain the 
patient’s treatment assignment for the purpose of regulatory reporting. 
Details of randomization and unblinding will be documented in the RTSM User Guide. 
8.6. 
Treatment Compliance 
Records of investigational product used, dosages administered, and intervals between visits will 
be kept during the study.  Drug compliance will be performed by a count of investigational 
product units returned at each visit.  Drug compliance is calculated as the number of actual 
investigational product units taken (based on product units returned at each visit) divided by the 
number of investigational product units that should have been taken during the dosing period 
multiplied by 100%.  Patients will be asked to return all used and unused investigational product 
and packaging at each visit. 


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Compliance with treatment will be defined as having taken between 80% and 120% (inclusive) 
of the doses that should have been taken during the study. 


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9. 
STUDY ASSESSMENTS 
9.1. 
Study Schedule of Events 
The schedule of study assessments is in Section 15.1.  Table 15.1-1 shows assessments for the 
double-blind period, and Table 15.1-2 shows assessments for the open-label period. 
Additional guidance on the completion of the assessments can be found in the study manuals. 
9.2. 
Demographic and Screening Assessments 
Approximately 82 patients will be enrolled in the study.  The nature of this study and the 
potential risks associated with participation in the study will be explained to all potential study 
patients and their parent/legal guardian as appropriate.  Written informed consent/assent will be 
obtained before any screening procedures are performed. 
Demographic data will include age, race, ethnicity, and gender.  Complete medical history, 
including a detailed history of PKAN on the PKAN-specific Medical History form, will be 
obtained, along with concomitant medications/therapies at enrollment. 
Patients who are re-screened due to initial screening failure will undergo confirmation of 
inclusion and exclusion criteria, assessment of PKAN-ADL, UPDRS Part III, and any other 
necessary assessments (see Section 6.2). 
9.3. 
Safety Assessments 
The safety and tolerability of fosmetpantotenate will be evaluated by AEs and by serial vital 
signs, weight, physical examinations, clinical laboratory parameters, C-SSRS assessments (in 
assessable patients), and ECGs.  See Section 10 for AE reporting requirements. 
9.3.1. 
Physical Examination 
Physical examinations will be performed according to the schedule of study assessments in 
Section 15.1.  Complete physical examinations will evaluate the following body systems/organs: 
general appearance; dermatological; head and eyes; ears, nose, mouth and throat; pulmonary; 
cardiovascular; abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and 
neurological.  Abbreviated physical examinations will evaluate the following body 
systems/organs: general appearance; dermatological; pulmonary; cardiovascular; abdominal; and 
neurological.  Height will be recorded at Baseline for all patients; for patients who are <18 years 
of age at enrollment, height will also be measured at additional visits according to the schedule 
of study assessments.  Weight will be collected according to the schedule of study assessment in 
Section 15.1 and recorded in kilograms. 
9.3.2. 
Vital Signs 
Vital sign measurements will be performed according to the schedule of study assessments in 
Section 15.1, and will include blood pressure, heart rate, respiration rate, and temperature. 


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9.3.3. 
Clinical Laboratory Tests 
The clinical laboratory tests listed in Section 15.2.2 will be performed according to the schedule 
of study assessments in Section 15.1. 
Investigators will evaluate the clinical significance of all abnormal laboratory values.  All 
abnormal laboratory values considered clinically significant by the Investigator will be recorded 
as AEs in the eCRF and will be followed up until resolution or, if unresolved, until the final visit. 
9.3.4. 
Electrocardiograms 
Standard 12-lead ECGs will be performed at the time points specified in the schedule of 
assessments in Section 15.1. 
 
Patients who have a DBS may experience interference with the ECG machine resulting in an 
inaccurate readout.  In the best interest of the patient, the DBS device should not be turned off in 
an effort to collect the ECG, rather, using clinical judgement and following consultation with the 
Sponsor Medical Monitor, ECG assessments may be waived for these patients. 
 
Complete details for performing ECG assessments are contained in the study manuals. 
9.3.5. 
Columbia Suicide Severity Rating Scale 
The C-SSRS will be administered at the time points specified in the schedule of assessments in 
Section 15.1.  Patients will be administered the Screening/Baseline version of the C-SSRS at 
Screening.  This assessment will serve as the baseline measurement of suicidality for each 
patient.  At subsequent visits, patients will be administered the Since Last Visit version of the 
C-SSRS to assess changes in suicidality since Screening. 
The C-SSRS will be administered to patients who are determined by the Investigator to be 
assessable.  Assessable patients are defined as: 
a) adults who are verbal and cognitively intact, such that questions can be understood and 
responded to in an understandable manner, or; 
b) children who are verbal (ie, can respond to questions and be understood) and not 
cognitively impaired. 
The pediatric version of the C-SSRS will be used for patients 6 to <12 years of age, and the adult 
version will be used for patients ≥12 years of age.  Patients who are administered the pediatric 
version of the C-SSRS at Baseline will continue assessment with this scale throughout the study. 
Patients who at any point in the evaluation or study process report the presence or emergence of 
serious suicidal ideation (ie, with some intent to act or a plan to act) will be evaluated 
immediately and then managed as medically appropriate (eg, referred immediately for treatment 
and/or hospitalized).  The same will apply for any evaluation that reveals a potential medical 
emergency detected at any point through the course of the study. 
Poland Only: Using clinical judgment, the Investigator may decide not to administer the C-SSRS 
for reasons other than lack of ability to assess the patient. Such a decision is to be documented in 
the CRF. 


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9.4. 
Pharmacokinetic Assessments 
Whole blood samples for PK analyses will be obtained at visits specified in the schedule of 
assessments in Section 15.1.  All patients will have a pre-dose blood draw at Baseline.  For 
subsequent visits at which PK samples are obtained following the first dose of the day, patients 
will undergo 2 blood draws according to randomization to one of the sampling schemes in 
Table 2.  Within each treatment group (ie, fosmetpantotenate and placebo), the number of 
patients assigned to each sampling scheme will be approximately equal, and the assignment will 
remain the same for all visits at which PK samples are obtained.  The actual time of in-clinic 
administration of investigational product, and the exact time of each blood draw for PK analysis 
will be recorded to the nearest minute on the eCRF. 
Table 2: 
Pharmacokinetic Sampling Schemes 
Scheme 
Number 
Blood Draw 1  
(Minutes Post Dose) 
Blood Draw 2  
(Minutes Post Dose) 
1 
10 ± 5 
60 ± 10 
2 
10 ± 5 
210 ± 15 
3 
10 ± 5 
420 ± 15 
4 
20 ± 5 
60 ± 10 
5 
20 ± 5 
210 ± 15 
6 
20 ± 5 
420 ± 15 
7 
45 ± 5 
60 ± 10 
8 
45 ± 5 
210 ± 15 
9 
45 ± 5 
420 ± 15 
9.5. 
Efficacy Assessments 
9.5.1. 
Pantothenate Kinase-associated Neurodegeneration Activities of Daily Living 
and Unified Parkinson’s Disease Rating Scale Part III 
The PKAN-ADL and Part III of the UPDRS will be administered to the patient at the time points 
specified in the schedule of assessments in Section 15.1.  See Section 6.1.1 for further 
description of both scales. 
9.5.2. 
Clinician’s Global Impression of Improvement 
The CGI-I will be administered to the patient at the time points specified in the schedule of 
assessments in Section 15.1. 
The CGI-I is a global, 7-point scale used to assess the amount of improvement or worsening in a 
patient’s illness relative to their condition prior to starting therapy.  The score ranges from 
1  (very much improved) to 7 (very much worse). 


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9.5.3. 
Barry Albright Dystonia (BAD) Scale 
The BAD scale will be administered to the patient at the time points specified in the schedule of 
assessments in Section 15.1. 
The BAD scale assesses dystonia in 8 domains on a 5-point ordinal scale, allowing systematic 
evaluation of secondary generalized dystonia.  It generates a total score and ratings of individual 
body regions (Barry, 1999; Montbaliu, 2010). 
9.5.4. 
Quality of Life 
The Neuro-QoL (upper and lower extremity modules; adult version for patients ≥18 years of age 
and pediatric version for patients <18 years of age) and EQ-5D-3L/EQ-5D-Y quality of life 
instruments will be administered to the patient at the time points specified in the schedule of 
assessments in Section 15.1. 
The Neuro-QoL is a domain-specific instrument that was developed by the National Institute of 
Neurologic Disorders and Stroke (NINDS) for adults and children with neurologic disorders 
(Cella, 2012).  The upper (fine motor and activities of daily living) and lower (mobility) 
extremity modules assess a range of practical tasks and activities that are relevant to patients 
with neurodegenerative motor disease and are designed to be sensitive to clinically meaningful 
improvement in a neurology patient with relatively severe motor impairment.  The upper 
extremity function module includes 20 items that assess the ability to carry out various activities 
involving digital, manual, and reach-related functions, ranging from fine motor to self-care 
activities.  The lower extremity function module includes 19 items that assess the ability to carry 
out various activities involving the trunk region and increasing degrees of bodily movement, 
ambulation, balance, or endurance. 
The EQ-5D-3L (administered to patients ≥18 years of age) is a widely used self-report scale that 
assesses 5 domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) 
across 3 levels (from “no problems” to “extreme problems”) (EuroQol Group, 1990).  The scale 
also records the patient’s self-rated health on a vertical, visual analogue scale with endpoints 
labelled ‘the best health you can imagine’ and ‘the worst health you can imagine’.  The 
EQ-5D-Y (administered to patients <18 years of age) is a youth friendly version of the 
EQ-5D-3L.  The EQ-5D-Y contains the same 5 dimensions and 3 levels as the EQ-5D-3L, but 
using child friendly wording; it also uses the same visual analogue scale for the patient to 
self-rate health (van Reenen, 2014).  Patients who are administered the EQ-5D-Y at Baseline will 
continue assessment with this scale throughout the study. 
9.5.5. 
Functional Independence Measure (FIM) 
The FIM (patients ≥18 years of age) or WeeFIM (patients <18 years of age) will be administered 
to the patient at the time points specified in the schedule of assessments in Section 15.1. 
The FIM is a measure of patient functioning that is widely used in rehabilitation medicine to 
assess the basic quality of daily living activities in persons with physical impairments.  It has 
established reliability, validity, and responsiveness to change, and captures clinically meaningful 
gradations of functional independence (Ottenbacher, 1996).  The FIM contains 18 items that 
assess motor and cognitive tasks on a 7-point ordinal scale.  The score ranges from 18 (total 


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assistance) to 126 (complete independence).  The WeeFIM is a direct derivative of the FIM, 
assessing self-care, mobility, and cognition in children, as well as in patients with motor, 
communicative, and neurodevelopmental disabilities up to 21 years of age.  Patients who are 
administered the WeeFIM at Baseline will continue assessment with this scale throughout the 
study. 
9.5.6. 
Function Measures 
The 25-foot walk test will be administered to patients who can safely walk independently, with 
assistive devices, or with the support of another person at the time points specified in the 
schedule of assessments in Section 15.1.  Evaluation at the Screening Visit will determine 
whether the patient can be evaluated safely during the study. 
The timed 25-foot walk test is a widely used quantitative measure of lower extremity function 
and ambulation.  The patient is timed while walking 25 feet as quickly and safely as possible; the 
task is then immediately repeated with the patient walking back to the starting point.  Patients 
may use assistive devices or the support of another person.  The same assistive device or method 
of support should be used for each assessment throughout the double-blind period.  A maximum 
time limit of 3 minutes per trial is allowed for completion of the task (Cutter, 1999; 
Fischer, 2001).  If the patient’s gait improves during the study such that the walk test can be 
completed with less assistance than at Baseline (eg, changes from needing a cane to walking 
independently or from needing a walker to needing only a cane), the assessment should be 
repeated (ie, a second set of walking from and to the starting point). 
DDK assessments (AMR and SMR) will be administered at the time points specified in the 
schedule of assessments in Section 15.1.  These assessments will test oral motor function (lip, 
jaw, and tongue).  Sites will video record the assessments, which will be rated by a central rater. 
DDK is a common component of the cranial nerve examination used by neurologists and speech 
language pathologist to assess oral motor function.  Both the AMR and SMR assessments require 
the participant to produce a target syllable (eg, puh-puh-puh) or syllable sequence (eg, puh-tuh-
kuh) as fast and accurately as possible within one breath.  Because the syllables are produced at a 
rapid rate, the task is intended to be physiologically demanding, thus testing the physiologic 
capacity of the oral motor system.  Performance is quantified using 2 scores: repetition rate in 
seconds (also called DDK rate), and repetition count (ie, the number of repetitions produced in 
one breath).  Normative data for DDK is widely published (Kent, 1987), and DDK has been 
shown to be a strong indicator of oromotor impairments due to amyotrophic lateral sclerosis 
(Dworkin, 1980; Rong, 2016) and other neurologic conditions including ataxia (Sidtis, 2010), 
Parkinson’s disease (Tjaden, 2003), multiple sclerosis (Tjaden, 2003) and traumatic brain injury 
(Wang, 2004). 
9.6. 
Exploratory Measures 
9.6.1. 
Biomarkers 
Blood samples for assessment of the potential biomarkers listed in Section 6.1.6 will be obtained 
at the time points specified in the schedule of assessments in Section 15.1.  The actual time of 


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in-clinic administration of investigational product, and the exact time of blood sampling for 
biomarker analysis will be recorded to the nearest minute on the eCRF. 
9.6.2. 
Pharmacogenomics 
Blood samples for potential pharmacogenomic assessment will be drawn in patients who sign 
separate consent/assent.  Blood samples for pharmacogenomic assessment should be drawn at 
the Screening visit, if possible; however, samples may be drawn at any visit through Visit 6, if 
needed.  Potential assessments may include drug metabolizing enzymes, transporters, or 
indicators of therapeutic response or safety. 
9.6.3. 
Additional Exploratory Assessment for Research 
A blood sample will be collected at 2-3 different sites from up to a total of 8 eligible patients 
(half adult, half pediatric) with different confirmed mutations in PANK2 to generate peripheral 
blood mononuclear cells (PBMCs). 
To be eligible to participate, patients must have negative serologic tests for all tests outlined in 
Section 15.2.2.  Patients will be required to sign a separate consent to participate in this 
exploratory substudy. If a patient discontinues participation in the substudy, their participation in 
the main study will not be affected. 
9.7. 
Unscheduled Visits 
If a patient requires an unscheduled visit, the following assessments (at a minimum) should be 
performed: 
• Assessments related to the purpose of the unscheduled visit 
• AEs 
• Concomitant medications 
9.8. 
Home Care 
Patients may be offered an opportunity to have some study visits performed in their home.  If an 
Investigator agrees with the patient to utilize home care services, a licensed nurse will contact the 
patient to schedule the visits.  In order to conduct the home visits, the home care nurse, the home 
care agency, and the home care services provider may have access to the patient’s personal data 
including their individually identifiable protected health information, such as the patient’s name, 
address, or phone number.  This type of information will only be used as necessary to schedule 
and conduct the home visits and will not be provided to the Sponsor of this study. 
9.9. 
Travel and Reimbursement 
In order to support patient’s participation in the study and improve adherence to study 
assessment schedules, travel and reimbursement vendors have been arranged for use at the 
patient’s discretion.  In order to provide travel and/or reimbursement services, the provider may 
have access to the patient’s personal data including their individually identifiable protected 
health information, such as the patient’s name, date of birth, address, phone number, and email.  


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This type of information, in accordance with local regulations, will only be used in relation to 
travel and/or reimbursement and will not be provided to the Sponsor of this study. 


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10. 
ADVERSE EVENT REPORTING 
10.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of the investigational product 
(active or placebo) in a clinical investigation patient, which does not necessarily have a causal 
relationship with the investigational product.  An AE can, therefore, be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of an investigational product, whether or not considered related to the 
investigational product. 
Adverse events 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 investigational product or 
in an alteration in medical care (diagnostic or therapeutic) 
• Conditions present at Baseline that have either worsened or recurred following resolution 
The patient will be evaluated for new AEs and the status of existing AEs at each study visit, 
including the screening period, 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. 
Of note, bitter taste of study medication will not be captured on the AE eCRF.  Any symptoms 
caused by the taste of study medication (eg vomiting, gagging) must be reported as an AE. 
10.2. 
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:  The 
patient may be hospitalized as part of the clinical use and monitoring of the 
investigational product as outlined in the protocol or by the judgment of the Investigator; 
in this case, the hospitalization would not meet serious criteria.  However, if medically 
significant changes in the patient’s condition develop during hospital monitoring that 
meet AE criteria and prolong the patient’s hospitalization, these events should be 
recorded as serious AEs. 


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Note:  Planned or elective hospital admissions for treatment/procedures for a 
condition/disease that existed prior to signing the informed consent should be recorded 
during the patient’s screening visit 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 should 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 investigational product. 
• Other medically important serious medical 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. 
10.3. 
Adverse Events of Interest (AEOI) 
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 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 study medication. 
In such instances, the following steps will be taken: 
1. Temporarily discontinue study medication. 
2. Repeat testing of ALT, AST, alkaline phosphatase and total bilirubin, to be completed 
within 48 to 72 hours (if possible) to confirm the abnormalities. 
3. If the abnormality is confirmed by repeat results or after consulting with Sponsor Medical 
Monitor: 
a. 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. 
b. 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. 
c. Perform additional testing to evaluate liver function, as appropriate (eg, international 
normalized ratio [INR], direct bilirubin). 
4. Do not resume study medication until monitoring indicates abnormalities have resolved 
or stabilized. 
 


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Patients would not typically be allowed to resume study medication 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 alkaline phosphatase) 
10.4. 
Evaluation of Adverse Events/Serious Adverse Events 
10.4.1. 
Causality Assessment 
Assessment of the relationship between the AE and exposure to the investigational product 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 investigational product 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.  Upon receipt of follow-up information, the Investigator may change 
his/her assessment of causality and amend the AE/SAE report accordingly. 


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10.4.2. 
Severity Assessment 
Severity indicates the intensity of the event and should not be confused with seriousness (see 
Section 10.2), which is an event outcome applied for the purpose of event classification and 
regulatory reporting. 
Severity Grading 
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. 
10.4.3. 
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: 
• 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 
10.4.4. 
Action Taken Regarding the Investigational Product 
The action taken with regard to the investigational product in response to the AE should be 
provided at the time the event is reported. 
Options for action taken include the following: 
• Drug Withdrawn:   medication schedule was modified through termination of a 
prescribed regimen of medication 


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• Dose Reduced:  medication schedule was modified by subtraction, either by changing the 
frequency, strength, or amount 
• Dose Increased:  medication schedule was modified by addition; either by changing the 
frequency, strength, or amount 
• 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 
10.4.5. 
Assessment of Expectedness 
The expectedness of an AE/SAE will be determined by the Sponsor in accordance with the 
fosmetpantotenate IB. 
10.5. 
Reporting Adverse and Serious Adverse Events 
10.5.1. 
Reporting Adverse Events 
AEs will be captured from the time the main study informed consent is signed to 30 days after 
the patient’s last dose of investigational product or the patient’s last scheduled visit, whichever 
occurs last.  
• AEs should 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 
should 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 or until 30 days after the 
patient’s last dose or last scheduled visit. 
10.5.2. 
Reporting Serious Adverse Events 
The necessity and time requirements for reporting of SAEs to the Sponsor or its designee are as 
follows: 
• All SAEs will be reported by email to the SAE contact on the Study Contact Information 
page of this protocol or by fax to the number in the study manual within 24 hours of the 
Investigator’s first knowledge of the event, regardless of causal relationship. 
• A completed Clinical Study 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.) should be provided by email to the SAE contact on the 
Study Contact Information page or by fax to the number in the study manual. 


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• 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 Information page or by fax to the number in the study manual within 48 
hours of receipt.  Full supporting documentation should be solicited by the investigative 
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 (as defined in 
Section 6.3.1), the Investigator or study staff becomes aware of an SAE that they suspect 
is related to the investigational product (see Section 10.4.1), the event and any known 
details will be reported promptly by email to the SAE contact on the Study Contact 
Information page or by fax to the number in the study manual, following the reporting 
instructions above (Section 10.5.2). 
• For medical emergencies, the IWRS can be used at any time by the Investigator to 
unblind the patient’s treatment assignment, if deemed necessary to manage the event.  
For SUSARs, the Sponsor’s Pharmacovigilance designee responsible for managing SAEs 
will access the IWRS to obtain the patient’s treatment assignment for the purpose of 
regulatory reporting.  Refer to the study manuals for unblinding procedures. 
10.5.3. 
Follow-Up of Adverse Events/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 should 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 
appropriate medical management to understand the nature and/or causality of the AE/SAE.  The 
Sponsor 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 contact on the Study Contact Information page of this protocol or by fax to the number in 
the study manual within the specified timelines.  Additional AEs/SAEs may be identified during 
the review of follow-up information and should be processed in accordance with requirements 
defined throughout Section 10. 


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10.5.4. 
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 local 
IRBs and the Contract Research Organization (CRO) will report SAEs and SUSARs to the 
central IRB in accordance with applicable standard operating procedures and/or local reporting 
requirements.  In the European Union (EU) or Canada, 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. 
10.6. 
Pregnancy Reporting 
Although not an AE in itself, exposure to the investigational product during pregnancy must be 
reported, therefore all pregnancies will be recorded on the AE eCRF.  If the Investigator suspects 
that a pregnancy was the result of an interaction between the investigational product and the 
contraceptive method, in addition to the pregnancy, the drug interaction should also be captured 
as a separate AE. 
The Investigator will report any pregnancy associated with exposure to investigational product, 
including at least 30 days after final investigational product administration.  When a site 
becomes aware that a patient or a male patient’s partner is pregnant, they are to contact the 
Medical Monitor within 24 hours of the site staff becoming aware of the event, as well as 
complete an initial Pregnancy Notification Form and send by email it to the SAE contact on the 
Study Contact Information page of this protocol or by fax to the number in the study manual. 
Female patients will be instructed to notify the Investigator and to stop taking study medication 
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. 
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 
investigational product.  All study related visits/contacts involving a known pregnancy should 
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. 
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, 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, and an AE/SAE occurs in the child, the data should be documented and, if 


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needed, an SAE report form should be completed and provided by email to the SAE contact on 
the Study Contact Information page of this protocol or by fax to the number in the study manual. 
When investigational product is discontinued because of pregnancy, pregnancy will be 
documented as the reason for treatment discontinuation. 


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11. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT 
11.1. 
Recording of Data 
The study will use eCRFs for data collection.  The data will be entered 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 any source data. 
Adverse events and medical history will be coded with the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA) available at study initiation.  Similarly, prior 
and concomitant medications and concomitant therapies will be coded using the latest version of 
World Health Organization Drug Dictionary available at study initiation.  The versions employed 
at study start will be maintained throughout the project. 
11.2. 
Data Quality Assurance 
To ensure compliance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements, the Sponsor may conduct a quality assurance audit.  See Section 11.4 for more 
details regarding this process. 
11.3. 
Data Management 
Data management will be performed by a qualified vendor under their standard operating 
procedures.  The Sponsor will provide oversight. 
11.4. 
Audits and Inspections 
At any time prior to, during, or after completion of the clinical study, an audit or inspection may 
be performed by the Sponsor or designated representative, a regulatory authority, an IRB, or an 
IEC.  The purpose of the audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, GCP guidelines 
of the International Council for Harmonisation (ICH), and any applicable regulatory 
requirements.  The Investigator should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection.  The Sponsor or a designated representative will be 
available to assist in the preparation of the study site for inspections.  All pertinent study data 
will be made available for verification, audit, or inspection purposes. 


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12. 
STATISTICAL METHODS AND PLANNED ANALYSES 
12.1. 
General Considerations 
A Statistical Analysis Plan (SAP), specifying further details of the planned analyses, will be 
prepared and approved prior to lock of the database.  This section presents a highlight of the 
approaches to be taken in performing the planned analyses. 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS® Software (Version 9.2 or higher).  Descriptive statistics include mean, 
standard deviation (SD), median, minimum, and maximum for continuous variables, and 
frequency tables with counts and percentages for discrete variables. 
Unless otherwise stated, “Baseline” will be defined as the last measurement obtained prior to the 
first dose of investigational product (pre-dose on Day 1).  Hypothesis-testing will be performed 
at the 2-sided 5% significance level. 
12.2. 
Determination of Sample Size 
A total of 74 patients will provide approximately 80% power to detect a 3-point difference 
between treatment groups in the average change from Baseline scores from the PKAN-ADL, 
based on Student’s t-test with alpha = 0.05 (2-sided); this calculation assumes a standard 
deviation of 4.5 points for the change from Baseline scores.  Additional patients will be 
randomized to ensure that at least 74 patients complete the double-blind period with evaluable 
data (ie, having assessments at Baseline and Week 24 for the PKAN-ADL). 
12.3. 
Analysis Sets 
Double-Blind Period 
Safety Population:  The safety population will consist of all randomized patients who receive at 
least 1 dose of blinded investigational product.  This population will be used for all summaries of 
patient accountability, demographic and Baseline data, and safety information, including AE 
incidence, for the double-blind period of the study. 
Full Analysis Set (FAS):  The FAS will consist of all randomized patients with at least 1 post 
Baseline efficacy assessment.  This population will serve as the basis for all efficacy analyses for 
the double-blind period of the study. 
Open-Label Period 
Safety Population:  The safety population will consist of all patients who receive at least 1 dose 
of investigational product after entering the open-label period of the study.  This population will 
be used for all summaries of patient accountability, demographic and Baseline data, and safety 
information, including AE incidence, for the open-label period of the study. 
Full Analysis Set (FAS):  The FAS will consist of all patients with at least 1 post-Baseline 
efficacy assessment in the open-label period of the study.  This population will serve as the basis 
for efficacy analyses from the open-label period of the study. 


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12.4. 
Demographics and Baseline Characteristics 
Demographic data (including age, race, ethnicity, gender, height, and weight), medical history 
(including PKAN-specific medical history), prior treatments, and pre-treatment clinical 
characteristics will be summarized by treatment group for the safety population using descriptive 
statistics. 
12.5. 
Patient Accountability 
All patients who meet all inclusion criteria and no exclusion criteria for the study, sign the 
informed consent form, and are enrolled and exposed to the investigational product will be 
accounted for in the safety analyses.  Screen failures will not be accounted for in the data 
presentation. 
Accountability tables will summarize the following information by treatment group:  the number 
of patients randomized, the number included in each analysis population, the number evaluated 
at each study visit, the number discontinued from treatment by reason for treatment 
discontinuation, and the number discontinued from the study by reason for study discontinuation.  
A by-patient data listing of study completion information, including the timing and reason(s) for 
premature treatment discontinuation or study withdrawal, if applicable, will be presented. 
12.6. 
Study Treatment Usage and Compliance 
Compliance information collected via dispensed/returned investigational product unit counts will 
be summarized descriptively for each treatment group, including frequency tables to indicate the 
number of patients at least 80% compliant with the dosing regimen during the double-blind and 
open-label periods of the study. 
12.7. 
Safety Analyses 
Safety analyses will be performed using data from the safety population.  Safety will be 
evaluated on the basis of treatment-emergent AEs (TEAEs), vital signs, weight, physical 
examinations, clinical laboratory assessments, C-SSRS, and ECG findings. 
12.7.1. 
Physical Examination and Vital Signs 
Vital signs and body weight will be summarized by treatment group using descriptive statistics.  
Summary statistics will be calculated for both the actual value and the change from Baseline 
value at each scheduled visit. 
Pre-study physical examination abnormalities and physical examination abnormalities reported 
at the end of study will be tabulated by body system. 
12.7.2. 
Clinical Laboratory Tests and Electrocardiograms 
Clinical laboratory and ECG data will be summarized by treatment group using descriptive 
statistics based on the observed values and change from Baseline values at each scheduled visit.  
In addition, the number and percentage of patients with laboratory values that shift categories (ie, 
below/within/above normal range) will be tabulated at each study visit.  Patients with clinically 


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significant changes from Baseline in laboratory values will be summarized and flagged in data 
listings. 
12.7.3. 
Adverse Events 
All AEs will be coded by Preferred Term and System Organ Class using the most recent version 
of MedDRA available at study initiation.  By-patient listings of deaths, SAEs, and AEs leading 
to treatment discontinuation will be provided.  The by-patient AE data listings will include onset 
and resolution dates, verbatim term, System Organ Class, Preferred Term, treatment, severity, 
relationship to treatment, action taken for the event, and outcome. 
TEAEs in the double-blind period are defined as AEs that are new or are a worsening of an 
existing condition that begins from the day of first dose of investigational product until the day 
after the last dose for the double-blind treatment period.  The incidence of TEAEs will be 
summarized for each treatment group by Preferred Term within body system, overall and by 
severity and relationship to treatment.  Incidence calculations will be based on the numbers and 
percentages of patients with AEs.  Although a MedDRA term may be reported more than once 
for a patient, that patient will be counted only once for that MedDRA term. 
12.7.4. 
Open-Label Period 
Safety data collected for the safety population during the open-label period of the study will be 
summarized using descriptive statistics, including summary tables of AEs, summary tables and 
graphical plots of mean values over time for continuous measurements (eg, vital signs, weight, 
laboratory evaluations), and frequency tables for categorical data obtained at each study visit.  
The last measurement obtained prior to the first dose of open-label investigational product will 
serve as the Baseline value for assessing change from Baseline during the open-label period of 
the study. 
12.8. 
Pharmacokinetic Analyses 
Multiple-dose blood concentrations of fosmetpantotenate will be tabulated and summarized by 
dose cohort and sample time.  Concentration measures may also be analyzed by nonlinear 
mixed-effects modeling, either alone or in conjunction with data from other studies.  Available 
metabolite concentrations will be analyzed similarly.  Summarizations will include appropriate 
descriptive statistics (eg, n, geometric mean, coefficient of variation, minimum, median, 
maximum). 
12.9. 
Efficacy 
12.9.1. 
Double-Blind Period 
The primary efficacy analysis will be based on the FAS population defined for the double-blind 
period of the study (see Section 12.3).  For each patient, the change from Baseline in 
PKAN-ADL scores at Weeks 3, 6, 12, 18, and 24 of the double-blind period will be used for 
analysis.  The treatment effect will be evaluated on the basis of mixed model for repeated 
measures (MMRM) analysis to assess data from all visits simultaneously.  The model will 
include fixed effects for treatment, age stratum (6 to <18 or 18 to 65 years), visit and treatment 
by-visit interaction, a random effect for patient within treatment group, and Baseline 


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PKAN-ADL score as a covariate.  The PKAN-ADL measurement obtained prior to the first dose 
of investigational product will serve as each patient’s Baseline value.  Least-squares adjusted 
means and the adjusted mean difference between treatment groups will be reported at each study 
visit, along with 2-sided 95% confidence intervals (CIs) and the p-value for the treatment 
comparison. 
The mixed-effect linear model will be implemented using PROC MIXED in SAS with the 
restricted maximum likelihood (REML) estimation method and Kenward-Roger degrees of 
freedom algorithm for the F-test.  Significance tests will be based on least squares means using 
Type III sum of squares. 
To support the primary efficacy analysis, analysis of covariance (ANCOVA) models will be 
applied to change from Baseline in PKAN-ADL scores assessed after 3, 6, 12, 18, and 24 weeks 
of treatment.  For each week analyzed, the model will include treatment and age stratum (6 to 
<18 or 18 to 65 years) as fixed effects and Baseline PKAN-ADL score as a covariate.  Estimates 
of the adjusted mean treatment differences and the 2-sided 95% CIs at each time point will be 
obtained from the model. 
Secondary and exploratory efficacy endpoints that are continuous measures recorded at each 
study visit will be evaluated using the MMRM approach described above for the primary 
efficacy endpoint.  Summary statistics for efficacy measures will include graphical plots of mean 
and mean change from Baseline values at each study visit, by treatment group. 
Treatment effects on categorical outcomes will be examined using frequency tables and tested 
using Cochran-Mantel-Haenszel chi-square methods with stratification by age group (6 to <18 or 
18 to 65 years). 
12.9.2. 
Open-Label Period 
Long-term treatment effects will be examined using data from the FAS defined for the 
open-label period (see Section 12.3).  Efficacy measures will be summarized using descriptive 
statistics, including tabulations and graphical plots of mean values and mean change from 
Baseline values at each study visit.  For this purpose, Baseline is defined as the last assessment 
prior to the first dose in the open-label period.  Hypothesis testing will be applied in exploratory 
analyses to primary and secondary efficacy variables on data collected during the open-label 
period, as appropriate, to assess changes from Baseline, both overall and in the groups to which 
patients were initially randomized for the double-blind period (ie, fosmetpantotenate or placebo).  
Between-group t tests will be used to explore whether improvement is greater for patients who 
convert to fosmetpantotenate from placebo, compared to those maintained on active 
investigational product for the open-label period.  Mixed-effect linear models may also be used 
to explore differences in the pattern of change over time between groups. 
12.10. 
Biomarkers 
Biomarker assessments will be listed and summarized by time point using descriptive statistics 
and, where appropriate, graphical displays. 


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Mean or mean change from Baseline (whichever is considered more relevant) plasma 
concentration time profiles will be plotted on either or both linear and semi-logarithmic scales.  
Inclusion/exclusion of the data in the calculations will be determined using an outliers test. 
12.11. 
Missing or Invalid Data 
The MMRM approach used for the primary efficacy analysis adjusts for missing data through a 
variance covariance structure.  ANCOVA models will be used with both observed-case (OC) and 
last-observation-carried-forward (LOCF) procedures to account for drop-outs and ensure that the 
treatment effect is robust.  No other data imputation procedures are planned. 
12.12. 
Interim Analysis 
The efficacy and safety analyses of the double-blind period of the study will be performed after 
all patients have completed the double-blind period and reported in an interim clinical study 
report.  In addition, the interim report will include available data from patients in the open-label 
period as of a data cutoff date. 


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13. 
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; ICH Guidelines for Safety 
Data Management, 1994; the Code of Federal Regulations (CFR 21 Parts 50, 56, and 312); and 
the European Union Clinical Trials Directive, 2001/20/EC. 
13.1. 
Institutional and Ethics Review 
This protocol and associated informed consent form, participant information sheet, any 
information provided to the patient, the IB, 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 consent form will be received by 
the Sponsor or its designee prior to enrollment of patients and release of investigational product. 
13.2. 
Data Monitoring Committee 
During the conduct of the study, responsibilities of the DMC will be to periodically review safety 
study results, evaluate treatment groups for excess AEs, determine whether the basic study 
assumptions remain valid, evaluate whether the overall integrity, scientific merit and conduct of 
the study remain acceptable, and make recommendations to the Sponsor.  Per the DMC charter, 
the DMC may request unblinded (unmasked) data for individual patients or in aggregate in the 
case of a safety concern that could potentially lead to a major study action. 
DMC members are expected to have no substantive conflict of interest with the study.  DMC 
members should not be directly involved with the conceptual design of the study, participate in 
any other study of this development program as Principal Investigator, Co-Investigator, or as 
physician caring for a study patient during the conduct of the study. In addition, DMC members 
are obligated to disclose concurrent participation in any DMCs of the same, related, or 
competing products.  All DMC activities will be managed independently of the Sponsor by the 
Sponsor’s CRO DMC Core Team, a two-member team that acts separately from the general 
project and trial management teams within the Sponsor and the CRO.  The CRO’s DMC Core 
Team is comprised of an Independent Statistician and a Medical Board Manager, who both 
serves as a central point of contact or firewall between the DMC members, the Sponsor and the 
CRO trial management teams. 
The specific responsibilities of the DMC are described in the DMC charter, which is maintained 
as a separate document. 
13.3. 
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 the mutual agreement of the Investigator and the Sponsor or its 
designee.  All protocol changes will be documented in protocol amendment(s).  Protocol 
amendment(s) will be signed by the Investigator and approved by the IRB/IEC prior to 
implementation.  Any changes in study conduct that result from a pending amendment will be 


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considered protocol deviations until IRB/IEC approval is granted.  Documentation of IRB/IEC 
approval will be returned to the Sponsor or its designee. 
13.4. 
Investigator’s Responsibilities 
Refer to the study manuals for further details regarding the Investigator’s responsibilities as 
outlined in the sections below. 
The Investigator will provide progress reports and notifications of SAEs to the IRB/IEC 
according to local regulations and guidelines. 
13.4.1. 
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. 
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. 
13.4.2. 
Case Report Form 
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.  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 onto 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. 
13.4.3. 
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, 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 


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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. 
13.4.4. 
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.  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 Monitor. 
Study Monitors will perform source document verification according to the clinical monitoring 
plan to ensure there are no inconsistencies between the eCRFs and source documents.  
Discrepancies will be resolved in accordance with the principles of GCP. 
13.4.5. 
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 or its designee and the Investigator.  
The Sponsor or its designee or regulatory authorities have 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 investigational sites regarding the end-of-study procedures. 
13.4.6. 
Investigational Product Control 
Control of investigational product is further detailed in the study manuals. 


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13.4.6.1. Receipt of Investigational Product 
A proof of receipt, which details the quantity and description of the investigational product, 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 investigational product, while retaining the 
original within the site pharmacy files.  The Investigator is responsible for ensuring that the 
investigational product is maintained in a controlled location, with limited access, and under 
adequate storage conditions. 
13.4.6.2. Disposition of Unused Investigational Product 
All unused investigational products 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 investigational product return/destruction documentation has been completed 
by the pharmacist or his/her designee  
Investigational product return/destruction documentation will be retained within the site 
pharmacy files. 
13.4.6.3. Product Handling and Complaints Reporting 
If any issues arise during the course of the study related to the quality of the investigational 
product, the clinical site pharmacist or pharmacy designee will contact the product 
handling/complaints group listed on the Study Contact Information page of this protocol. 
13.4.7. 
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 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. 
13.4.8. 
Confidentiality 
All study findings and documents will be regarded as confidential.  The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor.  The anonymity of participating subjects must be maintained.  
Subjects will be identified in the eCRF system and other documents submitted to the CRO by 
their subject number and/or year of birth, not by name or initials.  Documents not to be submitted 
to the CRO that identify the subject (e.g., the signed informed consent) must be maintained in 
confidence by the Investigator. 


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All details related to the disclosure and publication of study data will be addressed in the 
Investigator’s study contract. 
13.4.9. 
Clinical Study Report 
The Sponsor or its designee is responsible for preparing a clinical study report.  Study results 
will be provided to the Investigator. 
 


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14. 
REFERENCES 
1. Alfonso-Peccio A, Garcia M, Lonardi R, Jackowski S. Compartmentalization of 
mammalian pantothenate kinases. PLoS One 2012;7:e49509. 
2. Balibar C, Hollis-Symynkywicz M, Tao J. Pantethine rescues 
phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine 
decarboxylase deficiency in Escherichia coli but not in Pseudomonas aeruginosa. 
J Bacteriol 2011 Jul;193(13):3304-12. 
3. Barry MJ, VanSwearingen JM, Albright AL. Reliability and responsiveness of the Barry 
Albright Dystonia Scale. Dev Med Child Neurol 1999 Jun;41(6):404-11. 
4. Cella D, Lai JS, Nowinski C, Victorson D, Peterman A, Miller D, et al. Neuro-QoL: brief 
measures of health-related quality of life for clinical research in neurology. Neurology 
2012 Jun 5;78(23):1860-7. 
5. Cutter GR, Baier ML, Rudick RA, Fischer JS, Petkau J, Syndulko K, et al. Development 
of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 
1999 May;122(Pt 5):871-82. 
6. Dworkin JP, Aronson AE, Mulder DW.  Tongue force in normals and in dysarthric 
patients with amyotrophic lateral sclerosis. J Speech Hear Res 1980 Dec;23(4):828-37. 
7. EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of 
life. Health Policy 1990 Dec;16(3):199-208. 
8. Fischer JS, Jak AJ, Kniker JE, Rudick RA, Cutter G. Multiple Sclerosis Functional 
Composite: administration and scoring manual. 2nd ed. National Multiple Sclerosis 
Society;2001. 
9. Freeman K, Gregory A, Turner A, Blasco P, Hogarth P, Hayflick S. Intellectual and 
adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration. 
J Intellect Disabil Res 2007;51(Pt 6):417-26. 
10. Goetz CG, Stebbins GT, Tiley BC. Calibration of unified Parkinson’s disease rating scale 
scores to Movement Disorder Society-unified Parkinson’s disease rating scale scores.  
Mov Disord 2012 Sep 1;27(10):1239-42. 
11. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. 
Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. 
Mov Disord 2008 Nov 15;23(15):2129–70. 
12. Gregory A, Hayflick S. Neurodegeneration with Brain Iron Accumulation. In: Brice A, 
editor. Orphanet Encyclopedia;2004. 
13. Gregory A, Hayflick S. Neurodegeneration with brain iron accumulation disorders 
overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, 
et al., editors. GeneReviews® [Internet]. Seattle:University of Washington, 
Seattle;2013 Feb 28. 


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14. Gregory A, Polster BJ, Hayflick S. Clinical and genetic delineation of neurodegeneration 
with brain iron accumulation. J Med Genet 2009 Feb;46(2):73-80. 
15. Hartig MB, Hörtnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, et al. Genotypic 
and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with 
brain iron accumulation. Ann Neurol 2006 Feb;59(2):248-56. 
16. Hörtnagel K, Prokisch H, Meitinger T.  An isoform of hPANK2, deficient in 
pantothenate kinase associated neurodegeneration, localizes to mitochondria. Hum Mol 
Genet 2003 Feb 1;12(3):321-7. 
17. Kent RD, Kent JF, Rosenbek JC.  Maximum performance tests of speech production. 
J Speech Hear Disord 1987 Nov;52(4):367-87. 
18. Klopstock T, Elstner M, Lücking C, Müller-Myhsok B, Gasser T, Botz E, et al. 
Mutations in the pantothenate kinase gene PANK2 are not associated with Parkinson 
disease. Neurosci Lett 2005 May 13;379(3):195-8. 
19. Kruer M. Pantothenate kinase-associated neurodegeneration. In: Rosenberg R, Pascual J, 
editors. Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric 
Disease. 5th ed:London:Academic Press, 2015;473-81. 
20. Kuczmarski RJ, Ogden CL, Guo SS, et al.  2000 CDC growth charts for the United 
States: methods and development.  National Center for Health Statistics. Vital Health Stat 
11(246):2002. 
21. Martinez-Martin P, Rodriguez-Blazquez C, Alvarez-Sanchez M, Arkaki T, 
Bergareche-Yarza A, Chade A, et al. Expanded and independent validation of the 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). 
J  Neurol 2013 Jan;260(1):228-36. 
22. McGuigan C, Cahard D, Sheeka H, De Clercq E, Balzarini J. Aryl phosphoramidate 
derivatives of d4T have improved anti HIV efficacy in tissue culture and may act by the 
generation of a novel intracellular metabolite. J Med Chem 1996 Apr 12;39(8):1748-53. 
23. Montbaliu E, Ortibus E, Roelens F, Desloovere K, Deklerck J, Prinzie P, et al. Rating 
scales for dystonia in cerebral palsy: reliability and validity. Devel Med Child Neurol 
2010 Jun;52(6):570-5. 
24. Ottenbacher KJ, Hsu Y, Granger CV, Fiedler RC.  The reliability of the functional 
independence measure: a quantitative review. Arch Phys Med Rehabil 1996 
Dec;77(12):1226-32. 
25. Rong P, Yunusova Y, Wang J, Zinman L, Pattee GL, Berry JD, et al.  Predicting speech 
intelligibility decline in amyotrophic lateral sclerosis based on the deterioration of 
individual speech subsystems. PLoS One 2016 May 5;11(5):e0154971. 
26. Sidtis JJ, Strother SC, Groshong A, Rottenberg DA, Gomez C.  Longitudinal cerebral 
blood flow changes during speech in hereditary ataxia. Brain Lang 2010 
Jul;114(1):43-51. 


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27. Tjaden K, Watling E.  Characteristics of diadochokinesis in multiple sclerosis and 
Parkinson’s disease. Folia Phoniatr Logop 2003 Sep-Oct;55(5):241-59. 
28. van Reenen M, Janssen B, Oppe M, Kreimeier S, Greiner W.  EQ-5D-Y user guide: basic 
information on how to use the EQ-5D-Y instrument.  The EuroQol Group 2014.  
Accessed at:  
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
Y_User_Guide_v1.0_2014.pdf. 
29. Wang YT, Kent RD, Duffy JR, Thomas JE, Weismer G.  Alternating motion rate as an 
index of speech motor disorder in traumatic brain injury. Clin Linguist Phon 2004 
Jan-Feb;18(1):57-84. 
 


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15. 
APPENDICES 


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15.1. 
Appendix A:  Schedules of Study Events 
Written informed consent will be obtained prior to any protocol-required procedure. 
Table 15.1-1. Double-Blind Period: Screening and Treatment 
Visit 
Pre-
Screening1 
Screening 
V12 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Unsched 
Visit3 
End of 
Treatment/ 
Early 
Termination 
Visit/Final 
Contact4 
Study Day/Week 
 
Days 
-29 to -2 
Day -1 
D1 
D2 
D3 
D4 
W3 
± 3D 
W6 
± 3D 
 
W12 
± 3D  
W18 
±3D  
W24 
± 3D  
Patient registration / 
Obtain informed 
consent/assent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility review 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
characteristics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS6 
 
X7 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Physical Examination/ 
Abbreviated Physical 
examination8 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Vital signs9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead ECG9 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Genetic testing for 
confirmation of PKAN  
X10 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomic 
testing (as applicable) 
 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology12 
 
X 
 
X13 
 
 
X13 
X 
X 
X 
X 
X 
 
X 
Chemistry12 
 
X 
 
X13 
 
 
X13 
X 
X 
X 
X 
X 
 
X 
Serology12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit 
Pre-
Screening1 
Screening 
V12 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Unsched 
Visit3 
End of 
Treatment/ 
Early 
Termination 
Visit/Final 
Contact4 
Study Day/Week 
 
Days 
-29 to -2 
Day -1 
D1 
D2 
D3 
D4 
W3 
± 3D 
W6 
± 3D 
 
W12 
± 3D  
W18 
±3D  
W24 
± 3D  
Coagulation12 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Serum pregnancy14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis12 
 
X 
 
X13 
 
 
 
X 
X 
X 
X 
X 
 
X 
Urine drug/alcohol 
screen15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy14 
 
 
X* 
 
 
 
 
* 
* 
X* 
* 
X* 
 
X 
PKAN-ADL 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
UPDRS Part III 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
BAD scale 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
CGI-I 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
25-foot walk test16 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Neuro-QoL 
Adult/Pediatric (upper 
and lower extremity) 17 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
EQ-5D-3L/EQ-5D-Y17 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
FIM/WeeFIM17 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Diadochokinetic 
assessments18 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
PK sampling19 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Biomarkers 
 
 
X20 
 
 
 
X21 
 
X21 
 
X21 
X22 
 
X22 
Blinded investigational 
product dispensing 
/accountability23 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X24 
 
X24 
Open-label 
investigational product 
dispensing 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AE assessment 
Continuous Monitoring   
Conmeds/therapies 
Continuous Monitoring   


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Abbreviations:  BAD = Barry Albright Dystonia; CGI-I = Clinician Global Impression of Improvement; Con meds = concomitant medications; C-SSRS = Columbia Suicide 
Severity Rating Scale; D = Day; EQ-5D-3L/EQ-5D-Y = EuroQol 5-dimension, 3-level quality of life instrument/EuroQol-5D Youth Version; FIM/WeeFIM = Functional 
Independence Measure/Functional Independence Measure for Children; IRB/IEC = Institutional Review Board/Independent Ethics Committee; Neuro-QoL = quality of life 
measure for adults/children with neurological disorders; PK = pharmacokinetic; PKAN-ADL = Pantothenate Kinase-associated Neurodegeneration Activities of Daily Living; 
Unsched = unscheduled; UPDRS = Unified Parkinson’s Disease Rating Scale; V = Visit; W = Week 
1 For patients who are taking deferiprone or who require confirmation of mutation in the PANK2 gene.  This visit will be accomplished at least 30 days prior to the Screening visit for 
washout of deferiprone. 
2 Patients who fail screening for any reason may be re-screened up to 2 times.  Re-screening will consist of confirmation of inclusion and exclusion criteria, for re-screening criteria, 
refer to the Section 6.2 and Section 9.2. 
3 If a patient requires an unscheduled visit, assessments related to the purpose of the visit should be performed (see Section 9.7). 
4 For patients who are prematurely withdrawn from treatment (End of Treatment) or from the study (Early Termination) during the double-blind period. Patients who agree to 
continue regularly scheduled study visits will complete the End of Treatment as close as possible to the patient’s last dose of study medication. In addition to the Early Termination 
Visit, patients who prematurely discontinue from the study will be contacted (via telephone call) 30 days (±7 days) after the last dose of investigational product to ascertain patient 
safety.  If a patient who has prematurely discontinued study medication, decides to withdraw consent/assent and discontinue from the study within 6 weeks of completing the End of 
Treatment, the End of Treatment Visit conducted at the time of study medication withdrawal may serve as the patient’s final site visit.   
5 Includes the PKAN-specific Medical History Form. 
6 The C-SSRS will be completed in patients who are determined by the Investigator to be assessable.  See Section 9.3.5 for definition of assessable patients and assessments.  
7 Patients will be administered the Screening/Baseline version of the C-SSRS at Screening. 
8 A complete physical examination will be performed at Screening (see Section 9.3.1 for assessments); an abbreviated physical examination will be performed at Baseline (Day -1); 
the Week 3, 6, 12, 18, and 24 visits, and the Early Termination visit, if applicable (see Section 9.3.1 for assessments).  
9 Vital signs and 12-lead electrocardiograms will be assessed 2 hours (± 30 minutes) after the first dose of the day at all visits.  (Patients who have a DBS may experience interference 
with the ECG machine resulting in an inaccurate readout.  In the best interest of the patient, the DBS device should not be turned off in an effort to collect the ECG, rather, using 
clinical judgement and following consultation with the Sponsor Medical Monitor, ECG assessments may be waived for these patients.) 
10 Genetic test (if required to determine eligibility) can be done at Screening if not performed during Pre-screening period. If available, the specific mutation will be recorded.  
11 Pharmacogenomic testing samples will be collected in patients who sign separate IRB/IEC-approved informed consent. Samples should ideally be collected at the Screening visit; 
however, if limitations present at this visit, the samples may be collected at any visit through Visit 6. See Section 9.6.2 
12 Clinical laboratory parameters to be measured are listed in Section 15.2.2. 
13 Samples will be taken within 2 hours (± 30 minutes) prior to the first dose of the day at these visits. 
14 To be assessed in women of childbearing potential only.  Any positive urine pregnancy results will be confirmed by a serum pregnancy test.  (*Norway and Poland specific procedure: 
Sexually active women of childbearing potential to conduct pregnancy testing at home between study visits.  Site will provide the patient enough tests to conduct pregnancy testing 
once per month until the next scheduled study visit.  A positive urine pregnancy test will be confirmed by a serum test).  
15 To be conducted in patients 12 years of age and older. The Investigator should use clinical judgment to determine whether or not a patient with a positive test result should be 
admitted to the study (eg, if the Investigator believes that the result may be indicative of a drug or alcohol disorder, that the patient may not be able to comply with the protocol, or 
that participating in the study may put the patient at undue risk, the patient should be excluded per the exclusion criteria). 
16 To be administered to patients who can safely walk independently or with assistance.  Screening evaluation will determine whether the patient can be evaluated during the study. 
17 See Section 9.5.4 and Section 9.5.5 for age-based administration guidelines.   
18 Diadochokinetic assessments will include alternating motion rate and sequential motion rate.  Sites will video record the assessments, which will be rated by a central rater. 
19 All patients will have a pre-dose blood draw at Baseline.  For subsequent visits, patients will be randomly assigned to a sampling scheme according to Table 2; assignment will remain 
the same for all visits.  The actual time of administration of investigational product, and the exact time of blood sampling for PK analysis will be recorded to the nearest minute on the 
eCRF. 
20 At Baseline, 3 samples will be collected for biomarkers; the first will be collected prior to any assessments, and all 3 will be collected at least 3 hours apart.   


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21 At the Week 1 Day 4, Week 6, and Week 18 visits, 2 samples will be collected for biomarkers, at the times of PK sample collection.   
22 At the Week 24 visit, 2 samples will be collected for biomarkers at least 3 hours apart. If the patient prematurely discontinues study medication, but does not withdraw from the 
study, 2 samples should be collected at least 3 hours apart at the End of Treatment visit. 
23 In order to provide training in proper administration, investigational product will be prepared and administered by site personnel, together with the patient and/or family/caregiver, 
during in-clinic patient visits. Following adequate training, doses may be self-administered by the patient or caregiver at the site’s discretion. 
24 Blinded investigational product dispensation is not performed at the Week 24, End of Treatment Early Termination visits. 
 


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Table 15.1-2 Open-Label Period 
Visit 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22-
V2813 
Unsched 
Visit1 
End of 
Treatment/
Early 
Termination 
Visit/Final 
Contact2 
Study Week 
W27 
± 7D 
W30 
± 7D 
W36 
± 7D 
W48 
± 7D 
W60 
± 7D 
W72 
± 7D 
W84 
± 7D 
W96 
± 7D 
W108 
± 7D 
W120 
± 7D 
W146, 
W172, 
W198, 
W224, 
W250, 
W276, 
W302 
± 7D 
Weight 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Height (if <18 years of age at 
enrollment) 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
C-SSRS3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Abbreviated physical 
examination4 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead electrocardiogram5 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Hematology6 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Chemistry6 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Coagulation6 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Urinalysis6 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Urine pregnancy7 
 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
 
X 
PKAN-ADL 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
UPDRS Part III 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
BAD scale 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
CGI-I 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
25-foot walk test8 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Neuro-QoL Adult/Pediatric 
(upper and lower extremity)9 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
EQ-5D-3L/EQ-5D-Y9 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
FIM/WeeFIM9 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 


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Visit 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22-
V2813 
Unsched 
Visit1 
End of 
Treatment/
Early 
Termination 
Visit/Final 
Contact2 
Study Week 
W27 
± 7D 
W30 
± 7D 
W36 
± 7D 
W48 
± 7D 
W60 
± 7D 
W72 
± 7D 
W84 
± 7D 
W96 
± 7D 
W108 
± 7D 
W120 
± 7D 
W146, 
W172, 
W198, 
W224, 
W250, 
W276, 
W302 
± 7D 
Diadochokinetic Assessments10 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Pharmacokinetic sampling11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample collection14 
At Selected Sites Only: 1 Blood sample15 
 
 
Investigational product 
dispensing/accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
X12 
 
X12 
AE Assessment 
 
Continuous Monitoring   
Conmeds/therapies 
 
Continuous Monitoring   
Abbreviations:  AE = adverse event; BAD = Barry Albright Dystonia; CGI-I = Clinician Global Impression of Improvement; Con meds = concomitant 
medications; C-SSRS = Columbia Suicide Severity Rating Scale; D = Day; EQ-5D-3L/ EQ-5D-Y = EuroQol 5-dimension, 3-level quality of life 
instrument/EuroQol-5D Youth Version; FIM/WeeFIM = Functional Independence Measure/Functional Independence Measure for Children; Neuro-QoL = 
quality of life measure for adults/children with neurological disorders; PK = pharmacokinetic; PKAN-ADL = Pantothenate Kinase-associated Neurodegeneration 
Activities of Daily Living; Unsched = unscheduled UPDRS = Unified Parkinson’s Disease Rating Scale; V = Visit; W = Week 
1 If a patient requires an unscheduled visit, assessments related to the purpose of the visit should be performed (see Section 9.7). 
2 For patients who are prematurely withdrawn from treatment (End of Treatment) or from the study (Early Termination) during the open-label period.  If a 
patient who has prematurely discontinued study medication, decides to withdraw consent/assent and discontinue from the study within 6 weeks of completing 
the End of Treatment Visit, the End of Treatment Visit conducted at the time of study medication withdrawal may serve as the patient’s final site visit.  If the 
study withdrawal occurs within 30 days of the patient’s last dose of investigational product, the patient will be contacted (via telephone call) 30 days 
(±7 days) after the last dose of investigational product to ascertain patient safety.  Patients who complete the study will be contacted (via telephone call) 
30  days (±7 days) after the last dose of investigational product to ascertain patient safety. 
3 See Section 9.3.5. 
4 See Section 9.3.1 for abbreviated physical examination assessments. 
5 Vital signs and 12-lead electrocardiograms will be assessed 2 hours (± 30 minutes) after the first dose of the day at all visits.  See Section 9.3.2 and Section 9.3.4. 
(Patients who have a DBS may experience interference with the ECG machine resulting in an inaccurate readout.  In the best interest of the patient, the DBS 
device should not be turned off in an effort to collect the ECG, rather, using clinical judgement and following consultation with the Sponsor Medical Monitor, 
ECG assessments may be waived for these patients.) 


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6 Clinical laboratory parameters to be measured are listed in Section 15.2.2.  Laboratory assessments for coagulation factors to be collected once yearly during 
the open-label extension period. 
7 To be assessed in women of childbearing potential only.  Any positive urine pregnancy results will be confirmed by a serum pregnancy test. (*Norway and 
Poland specific procedure:  Sexually active women of childbearing potential to conduct pregnancy testing at home between study visits.  Site will provide the 
patient enough tests to conduct pregnancy testing once per month until the next scheduled study visit.  A positive urine pregnancy test will be confirmed by a 
serum test). 
8 See Section 9.5.6. 
9 See Sections 9.5.4 and Section 9.5.5 for age-based administration guidelines. 
10 See Section 9.5.6. 
11 See Section 9.4. 
12 Investigational product dispensation is not performed at the Week 302 or Early Termination visit. 
13 Three-month (every 13 weeks) safety phone calls will be performed to assess PKAN-ADL, AEs, and Concomitant Medications in between each 6-month 
onsite visit following W120. 
 
At selected sites only: 
14  A blood sample will be collected at 2-3 different sites from up to a total of 8 eligible patients with different confirmed mutations in PANK2 to generate 
PBMCs. 
15 Blood sample collection for substudy can occur at any point after collection of substudy consent.  To be eligible to participate, patients must have negative 
serologic tests at screening for all tests outlined in Section  15.2.2. 
 


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15.2. 
Appendix B:  Supplemental Study Information: 
15.2.1. 
Allowed PKAN Maintenance Treatments 
The PKAN maintenance treatments listed below are allowed during the study; however, dosage 
changes or adjustments including DBS can only be made during the double-blind period of the 
study following consultation between the Investigator, the Medical Monitor, and the Sponsor 
(except in cases of medical emergency such as dystonic crisis).  Based on the Investigator’s 
judgment, concomitant medications (excluding deferiprone) may be administered or modified at 
any time during the course of the study to treat AEs, symptoms, or disease states unrelated to 
managing the symptoms of PKAN. 
Trihexyfenidyl 
Benzodiazepines 
Anticholinergics 
Pain medications 
L-dopa 
Other treatments for Parkinsonism 
Antipsychotics 
Antidepressants 
Treatments for attention deficit/hyperactivity disorder 
Baclofen (oral or intrathecal pump) 
Deep brain stimulation (DBS; if implanted ≥ 6 months before screening, modifications to the 
settings are allowed; however, patients are not allowed to have a DBS implanted during the 
course of the study [double-blind and open-label]) 
Botulinum toxin; most recent injection must have occurred between 1 to 2 months prior to 
Baseline, and injections will continue on a regular schedule throughout the double-blind period. 
 
 


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15.2.2. 
Study Blood Assessments 
 
 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Blood Urea Nitrogen 
Creatinine 
Total bilirubin 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Lactate dehydrogenase 
Alkaline phosphatase 
Creatine kinase 
Total cholesterol 
Triglycerides 
 
Serology/Screening Tests 
Hepatitis B surface antigen 
Hepatitis C antibody 
HIV antibody 
Serum/Urine Pregnancy test 
Drug/Alcohol screen 
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 
 
 
 
 
 
 
 
Coagulation 
Prothrombin Time, INR 
aPTT 
 
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) 
 
 
Potential Biomarkersa 
Succinate 
Lactate 
Maleate 
Pyruvate 
Alanine 
Acetone 
Acetoacetic acid 
3-hydroxybutyric acid 
2-hydroxybutyric acid 
AcetylCoA 
Abbreviations:  aPTT= activated partial thromboplastin time; HIV=human immunodeficiency virus; 
INR=International Normalized Ratio; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; WBC=white blood cells 
a Additional potential biomarkers may be assessed, but the samples will not be used for genetic testing. 
 


Signature Page for VV-CLIN-001743 v1.0
Signature Page for VV-CLIN-001743 v1.0
Approval
29-May-2019 02:02:48 GMT+0000
Approval
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Approval
30-May-2019 02:43:57 GMT+0000
Approval
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SAP_001.pdf: 
Efficacy, Safety, and Tolerability of Fosmetpantotenate 
(RE-024), a Phosphopantothenate Replacement Therapy, in 
Patients with Pantothenate Kinase-Associated 
Neurodegeneration (PKAN): A Randomized, Double-Blind, 
Placebo-Controlled Study With an Open-Label Extension 
 
Unique Protocol ID: 
024PKAN15004 
NCT Number: 
NCT03041116 
EudraCT Number:  
2016-001955-29 
Date of SAP:  
22 April 2019 
 


FOSMETPANTOTENATE (Phosphopantothenate Replacement Therapy)
Page 1
Statistical Analysis Plan:  Protocol 024PKAN15004
Statistical Analysis Plan
EFFICACY, SAFETY, AND TOLERABILITY OF FOSMETPANTOTENATE 
(RE-024), A PHOSPHOPANTOTHENATE REPLACEMENT THERAPY, IN 
PATIENTS WITH PANTOTHENATE KINASE-ASSOCIATED 
NEURODEGENERATION (PKAN): A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY WITH AN OPEN-LABEL EXTENSION
Protocol Number: 024PKAN15004
IND #: 121943
EudraCT #: 2016-001955-29
Version 2.0
Date:  22 April 2019
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations. Persons to whom the information is disclosed must be informed that the information is 
privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will 
apply equally to all future information supplied.


FOSMETPANTOTENA’I‘E
Plan: Protocol 024PKANI
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FOSMETPANTOTENA TE (Phosphopantothenate Replacement Therapy) 
Statistical Analysis Plan: Protocol 024PKAN15004 
SPONSOR SIGNATURE PAGE 
Approved by: 
CONFIDENTIAL 
Retrophin, Inc. 
Retrophin, Inc. 
Retrophin, Inc. 
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Date 
Date 
02~2019 
Date 
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PAREXEL SIGNATURE PAGE
This document has been signed electronically on the final page by the following:
Signatory
Author
Project Role: 
Biostatistics Reviewer
Project Role: 
Statistical Programming 
Reviewer
Project Role: 
Medical Writing Reviewer
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Statistical Analysis Plan:  Protocol 024PKAN15004
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Table of Contents
List of Abbreviations........................................................................................................... 6
1
Introduction................................................................................................................... 8
2
Study Objectives and Endpoints................................................................................... 8
2.1
Primary Efficacy Endpoint ............................................................................. 8
2.2
Secondary Efficacy Endpoint ......................................................................... 9
2.3
Exploratory Efficacy Endpoints...................................................................... 9
2.4
Safety Endpoints ............................................................................................ 9
2.5
Pharmacokinetic Endpoints .......................................................................... 10
2.6
Biomarkers................................................................................................... 10
2.7
Pharmacogenomics....................................................................................... 10
3
Overall Study Design................................................................................................... 10
4
Statistical Methodology ............................................................................................... 11
4.1
General Statistical Considerations ................................................................ 11
4.2
Determination of Sample Size ...................................................................... 12
4.3
Planned Analysis Schedule........................................................................... 12
4.4
Data Sets Analyzed ...................................................................................... 12
4.5
Disposition of Patients.................................................................................. 13
4.6
Demographics and Baseline Characteristics.................................................. 15
4.7
Medical History............................................................................................ 15
4.8
Prior/Concomitant Medications.................................................................... 16
4.8.1
Prior and Concomitant Medications.............................................................. 16
4.9
Study Treatment Usage and Compliance ...................................................... 17
4.10
Efficacy Analysis ......................................................................................... 17
4.10.1
Primary Efficacy Endpoint ........................................................................... 17
4.10.1.1
Sensitivity Analysis...................................................................................... 21
4.10.1.2
Handling of Dropouts and/or Missing Data................................................... 22
4.10.1.3
Exploratory Subgroup Analysis.................................................................... 23
4.10.2
Secondary Efficacy Endpoint ....................................................................... 24
4.10.3
Exploratory Efficacy Endpoints.................................................................... 25
4.10.3.1
Clinician Global Impression of Improvement (CGI-I) .................................. 26
4.10.3.2
Barry Albright Dystonia (BAD) scale........................................................... 26


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4.10.3.3
Quality of Life (QoL)................................................................................... 27
4.10.3.4
Functional Independence Measure................................................................ 29
4.10.3.5
Function Measures ....................................................................................... 30
4.10.4
Adjustment for Multiple Hypothesis Testing ................................................ 32
4.10.5
Safety Data Monitoring ................................................................................ 32
4.11
Safety Analysis ............................................................................................ 32
4.11.1
Adverse Events (AEs) .................................................................................. 33
4.11.2
Clinical Laboratory Tests and Electrocardiogram ......................................... 35
4.11.3
Physical Examination and Vital Signs .......................................................... 37
4.11.4
C-SSRS Scale .............................................................................................. 37
4.12
Open-Label Extension.................................................................................. 38
4.12.1
Open-Label Efficacy Analysis...................................................................... 38
4.12.2
Open-Label Safety Analysis ......................................................................... 39
4.13
Pharmacokinetic Analysis ............................................................................ 39
4.14
Biomarkers................................................................................................... 40
5
References.................................................................................................................... 40
6
Programming Considerations ..................................................................................... 41
6.1
Table, Listing, and Figure Format ................................................................ 41
6.1.1
General ........................................................................................................ 41
6.1.2
Headers........................................................................................................ 42
6.1.3
Display Titles............................................................................................... 42
6.1.4
Column Headers........................................................................................... 43
6.1.5
Body of the Data Display ............................................................................. 43
6.1.6
Footnotes ..................................................................................................... 44
6.2
Data-Handling Rules .................................................................................... 45
6.2.1
Unit Conversion to Months/Years ................................................................ 45
6.2.2
Visits............................................................................................................ 45
6.2.3
Demographics and Baseline Characteristics.................................................. 45
6.2.4
Prior and Concomitant Medications.............................................................. 46
6.2.5
Adverse Events ............................................................................................ 47


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List of Abbreviations
AE
Adverse Event
AEOI
Adverse Event of Interest
AMR
Alternating Motion Rate
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical
BAD
Barry Albright Dystonia
BMI
Body Mass Index
BSA
Body Surface Area
CGI-I
Clinician Global Impression of Improvement
CI
Confidence Interval
CSR
Clinical Study Report
C-SSRS
Columbia- Suicide Severity Rating Scale
DDK
Diadochokinetic(s)
eCRF
Electronic Case Report Form
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EQ-5D-3L
EuroQol 5-dimension, 3-level quality of life instrument
EQ-5D-Y
EuroQol-5D Youth Version
EU
European Union
FAS
Full Analysis Set
FIM
Functional Independence Measure
GLM
General Linear Model
ICF
Informed Consent Form
ICH
International Council for Harmonisation
INR
international normalized ratio
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LOCF
Last Observation Carry Forward
LSM
Least-Squares Mean
MAR
Missing at Random
max
Maximum
MCAR
Missing Completely at Random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
min
Minimum
MMRM
Mixed Model for Repeated Measures
MNAR
Missing Not at Random
Neuro-
Quality of life measure for adults/children with neurological disorders


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QoL
OL
Open Label
PK
Pharmacokinetic(s)
PKAN
Pantothenate Kinase Associated Neurodegeneration
PKAN-
ADL
Pantothenate Kinase Associated Neurodegeneration Activities of Daily 
Living Scale
PT
Preferred Term
REML
Restricted maximum likelihood
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SE
Standard Error
SMR
Sequential Motion Rate
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-Emergent AE
TID
ter in die (three times a day)
TLFs
Tables, Listings and Figures
UPDRS
Unified Parkinson’s Disease Rating Scale
US
United States
WeeFIM
Functional Independence Measure for Children
WHO
World Health Organization


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1
Introduction
This document summarizes key elements of the statistical analysis plan (SAP) for 
Protocol 024PKAN15004.  The main purpose of this document is to describe the 
statistical methods to be used for the primary analysis of efficacy and safety endpoints 
collected during the double-blind portion of the study in support of an interim Clinical 
Study Report (CSR) for submission to regulatory authorities.  This SAP also specifies the 
scope of analysis for available data collected in the open label portion of the study at the 
time of the database cut-off for the interim CSR. The plan for analysis of 
pharmacokinetics (PK) and pharmacogenomics data collected during this study is outside 
the scope of this SAP.
The SAP is being written in consideration of recommendations outlined in the 
International Council for Harmonisation (ICH) E91 Guideline entitled “Guidance for 
Industry: Statistical Principles for Clinical Trials” and the most recent ICH E32 Guideline, 
entitled “Guidance for Industry: Structure and Content of Clinical Study Reports.”
This SAP is based upon the following study documents:

Study Protocol, Version 3.0 (February 6, 2019)

electronic Case Report Form (eCRF), Version 9.0 (March 4, 
2019) 
2
Study Objectives and Endpoints
The primary objective of this study is to evaluate the efficacy of fosmetpantotenate over 
24 weeks in patients with Pantothenate Kinase Associated Neurodegeneration (PKAN). 
The secondary objective is to assess the safety and tolerability of fosmetpantotenate in 
patients with PKAN.  
Other objectives are:

To determine the pharmacokinetics (PK) following multiple doses of
fosmetpantotenate in patients with PKAN

To explore biomarkers of disease, along with their potential response to treatment in
patients with PKAN
2.1
Primary Efficacy Endpoint
The Unified Parkinson’s Disease Rating Scale (UPDRS) is a comprehensive assessment 
of the burden and severity of signs and symptoms of parkinsonism captured via 
systematic interview and neurological examination.  It consists of 4 parts that can be used 
as individual scales or summed for a total score.  
Part II of the UPDRS is an in-depth health outcome assessment of motor activities of 
daily living that are impaired by a wide range of neurological diseases, including PKAN.  
For this study, Part II of the UPDRS has been adapted and validated for use in PKAN 


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patients through a systematic, iterative process involving experts and patient advocacy 
leaders; it is the basis of the primary efficacy endpoint and will be referred to in this SAP 
as the “PKAN Activities of Daily Living” scale, abbreviated as “PKAN-ADL”.  
The primary efficacy endpoint is the change in PKAN-ADL total score, from baseline to 
the end of the 24-week double-blind period.
2.2
Secondary Efficacy Endpoint
The secondary efficacy endpoint is the change in the total score for Part III (motor 
examination) of the UPDRS from baseline to the end of the 24-week double-blind period.
2.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints will include change from baseline to the end of the 24-
week double-blind period in the following:

Clinician Global Impression of Improvement (CGI-I)

Barry Albright Dystonia (BAD) scale

Quality of life (QoL):
o
NeuroQoL, upper and lower extremity modules (adult and pediatric versions)
o
EuroQol 5-dimension, 3 level QoL instrument (EQ-5D-3L)/EuroQol-5D Youth
Version (EQ-5D-Y)

Functional independence: Functional Independence Measure (FIM)/Functional
Independence Measure for Children (WeeFIM)

Function measures:
o
Ambulation: 25-foot walk test (in appropriate patients)
o
Speech: Diadochokinetic (DDK) assessments (i.e., alternating motion rate [AMR]
and sequential motion rate [SMR])
2.4
Safety Endpoints
The safety and tolerability of fosmetpantotenate will be assessed based on the occurrence 
of adverse events (AEs) and by serial vital signs including weight, physical examinations, 
clinical laboratory parameters (chemistry, hematology, coagulation, and urinalysis), the 
Columbia Suicide Severity Rating Scale (C-SSRS) (in assessable patients), and 12-lead 
electrocardiograms (ECG).


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2.5 
Pharmacokinetic Endpoints
Multiple dose PK of fosmetpantotenate in whole blood will be evaluated using a sparse 
sampling design. Blood samples may also be used for metabolite quantification and/or 
identification.
2.6 
Biomarkers
Exploratory biomarkers will be assessed in plasma. Potential biomarkers assessed may 
include succinate, lactate, maleate, pyruvate, alanine, acetone, acetoacetic acid, 3-
hydroxybutyric acid, 2-hydroxybutyric acid, and acetylCoA. Although other biomarkers 
may be assessed, the samples will not be used for genetic testing.
2.7 
Pharmacogenomics
Pharmacogenomic assessment may be performed on blood samples drawn at screening 
for drug metabolizing enzymes, transporters, or indicators of therapeutic response or 
safety. These assessments will only be performed where local regulations permit and 
where approved by the site’s Institutional Review Board/Independent Ethics Committee 
(IRB/IEC), and will be subject to separate consent/assent by the patient/parent/legal 
guardian as appropriate.
3 
Overall Study Design
This is a pivotal, randomized, double-blind, placebo-controlled, multi-center, 2-arm study 
evaluating 24 weeks of treatment with fosmetpantotenate or placebo in patients with 
PKAN aged 6 to 65 years, with a 278 week open-label extension.  
Eligible patients will be randomized in a 1:1 ratio to receive either fosmetpantotenate or 
placebo for a 24-week double-blind period; randomization will be stratified by screening 
weight and age group (pediatric, adult), as reported by Interactive Web Response System 
(IWRS). In Protocol Version 1, Pediatric is defined as ‘<19’ and Adult is defined as 
‘≥19.’ In subsequent versions of the Protocol, Pediatric is defined as ‘<18’ and Adult is 
defined as ‘≥18.’
Treatment in the double-blind period will begin with dose escalation for Days 1-3, 
followed by the full dose 3 times daily (TID) starting on Day 4.  Matching placebo will 
be given according to the same dose escalation sequence as active investigational product.  
Study visits during the double-blind period are scheduled at baseline (within 1 to 2 days 
prior to the start of the double-blind treatment), Days 1 through 4, and Weeks 3, 6, 12, 
18, and 24.  See Protocol Appendix A (Table 15.1-1) for the schedule of assessments 
performed during the double-blind period.


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After completing the double-blind period, patients will be eligible to receive open-label 
fosmetpantotenate for up to 278 weeks.  During the open-label period, study visits are 
scheduled at Weeks 27, 30, 36, 48, 60, 72, 84, 96, 108, 120, 146, 172, 198, 224, 250, 276, 
and 302.  See Protocol Appendix A (Table 15.1-2) for the schedule of assessments 
performed during the open-label period.  
In total, patients will be in the study for approximately 302 weeks, with 24 weeks in the 
randomized, double-blind treatment period and 278 weeks in the open-label period.
4 
Statistical Methodology
This section describes the planned methods of analysis for all efficacy and safety 
endpoints collected during the double-blind and open-label extension periods.      
4.1 
General Statistical Considerations
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS® Version 9.3 or higher.  All data collected will be summarized 
using descriptive statistics, including mean, standard deviation (SD), median, minimum, 
and maximum for continuous variables, and frequency tables with counts and percentages 
for categorical variables. Age group categorization will be consistent with the Protocol 
Version that was applicable at time of patient randomization. 
Unless otherwise stated, the “baseline” assessment for the double-blind period will be 
defined as the last measurement obtained prior to the first dose of blinded investigational 
product (pre-dose on Day 1).  For patients who enter the open-label extension period, the 
baseline value will be re-defined for the open-label period as the last observation prior to 
start of open-label fosmetpantotenate, unless otherwise specified. 
As appropriate, the scales used as efficacy endpoints to measure neurological impairment, 
dystonia, motor function, and quality of life will be scored and/or normalized in 
accordance with user manuals and published scoring procedures for each instrument.  For 
each scale, the prescribed rules for deriving the total score in the presence of 1 or more 
missing items will be followed.  
Unless otherwise noted, if at least 80% of the items for a scale (i.e., PKAN-ADL, 
UPDRS Part III, BAD, Neuro-QOL) are non-missing, then the prorated total score for the 
scale is obtained by summing the non-missing item responses, multiplying by the total 
number of items in the scale, and then dividing by the number of non-missing items. 
There are two patients who had a question (item) on the PKAN-ADL mistranslated for 
screening and baseline visits. In analyses using the Double-Blind Full Analysis Set, the 
values for this item will be rendered invalid, set to missing, and the PKAN-ADL total 
score will be prorated as described above. The invalid values will be presented and 
flagged in the data listing, as originally recorded.


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For by-visit summaries, the last non-missing assessment (including repeat assessments, if 
any) recorded at each visit will be used for summarization. For across visit summaries 
(e.g. maximum post-baseline value), scheduled, unscheduled (if any) and repeat 
assessments will all be considered for the value to be analyzed; all observations will be 
presented in data listings.
Hypothesis-testing will be performed at the two-sided 5% significance level, unless 
otherwise stated. 
4.2
Determination of Sample Size
It is estimated that a total of 74 patients (37 in each treatment group) will provide 
approximately 80% power to detect a 3-point difference between groups in the average 
change from baseline score for the PKAN-ADL, based on Student’s t-test with 
alpha=0.05 (two-sided); this calculation assumes a standard deviation of 4.5 points for the 
change from baseline scores.  Allowing for 10% attrition, a total of 82 patients will be 
randomized to achieve the target sample size of at least 74 patients completing the 
double-blind period of the study.    
4.3
Planned Analysis Schedule
The primary analysis of this study will be performed after all randomized patients have 
either been assessed at the final visit of the 24-week double-blind treatment period or 
discontinued treatment and study prior to the final visit of the 24-week double-blind 
treatment period, and the database is locked/unblinded.  The results of the double-blind 
treatment period, together with available long-term follow-up information in the open-
label extension period at the time of the database cut-off, will form the basis of an interim 
CSR for submission to regulatory authorities. 
4.4
Data Sets Analyzed
The following analysis sets will be defined for this study:
Double-Blind Period
Double-Blind Safety Population:  The Double-Blind Safety Population will consist of all 
patients who receive at least 1 dose of blinded investigational product.  Patients will be 
analyzed according to the treatment received. This population will be used for all 
summaries of patient accountability, demographic and baseline data, and safety 
information, including AE incidence, for the double-blind period of the study.
Double-Blind Full Analysis Set (FAS):  The Double-Blind FAS will consist of all 
randomized patients with a baseline assessment and at least 1 post-baseline assessment of 
the primary efficacy endpoint.  Patients will be analyzed in the treatment group to which 


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they were randomized, regardless of treatment actually received. This population will 
serve as the basis for all efficacy analyses for the double-blind period of the study.  
Double-Blind Per-Protocol Set (PPS):  The PPS will consist of all FAS patients who 
complete the double-blind study without any major protocol violations that could impact 
the interpretation of efficacy. Patients will be analyzed as randomized. This population 
will be used for sensitivity analyses of the primary and secondary efficacy endpoints 
(based on PKAN-ADL and UPDRS Part III scores).  Specific protocol deviations used to 
define this analysis set will be finalized prior to database lock.   
Open-Label Period
Open-Label Safety Population:  The Open-Label Safety Population will consist of all 
patients who receive at least 1 dose of investigational product after entering the open-
label period of the study.  This population will be used for all summaries of patient 
accountability, demographic and Baseline data, and safety information, including AE 
incidence, for the open-label period of the study.
Open-Label Full Analysis Set (OL-FAS):  The OL-FAS will consist of all patients with a 
baseline assessment and at least 1 post-baseline assessment of the PKAN-ADL in the 
open-label period of the study.  This population will serve as the basis for efficacy 
analyses from the open-label period of the study.
Fosmetpantotenate Safety Population: The Fosmetpantotenate Safety population will 
consist of patients who received at least 1 dose of fosmetpantotenate product at any 
period of the study (double-blind or open-label).
The number of patients in each double-blind analysis set (Safety, FAS, and PPS) will be 
summarized by treatment group for the double-blind period of the study. For the open-
label extension, patients in the Open-Label Safety, OL-FAS, and Fosmetpantotenate 
Safety Population will be summarized overall and by treatment received in the prior 
double-blind period.  Patients excluded from any analysis set will be listed by reason.
4.5
Disposition of Patients
All patients who meet the inclusion criteria for the study and sign the informed consent 
form will be accounted for in the disposition table.  
The disposition table will present the total number of patients screened for enrollment 
and the number of patients in each treatment group (fosmetpantotenate and placebo) 
categorized as follows:  

Randomized

Evaluated at each study visit

Completing the double-blind treatment period


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
Discontinued from treatment (by reason) for each treatment period

Discontinued from the study (by reason) for each treatment period
A by-patient data listing of study completion information, including the timing and 
reason(s) for premature study withdrawal, will be presented.
Protocol deviations will be identified on an ongoing basis by the clinical study team 
based on the protocol deviation specification document (PDS) and assessed as “minor” or 
“major” in consultation with the Sponsor. This assessment will be done during the 
Protocol Deviation Review Meeting, which will take place when pre-determined accrual 
targets are met and before disclosure of randomization codes. Major deviations from the 
protocol that may lead to confounding of efficacy results will result in the exclusion of a 
patient from the per protocol set. The final determination of major protocol deviations 
and the exclusion of patients from each of the analysis populations will be made prior to 
database lock.  
Unless decided otherwise during the Protocol Deviation Review Meeting, the following 
will be major protocol deviations:

Major deviations of inclusion/exclusion criteria;

Use of prohibited medication or device adjustments post-randomization that may
influence the outcome of the study for the patient;

Participation in another investigational study post-randomization without the prior
written authorization of Sponsor or its designee;

Randomization error (use of wrong medication kit or violation from randomization
procedure) during the study;

<80% or >120% compliance with study drug during the double-blind treatment
period;

Patient met withdrawal criteria but not withdrawn from treatment;

Unblinding of study medication to blinded staff or patients;

PKAN-ADL administration error (e.g., administration performed but due to error in
translation, the instrument could not be read to the patient at Screening/Baseline
Visit; unqualified rater performed the administration of the instrument)


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
Failure to report Suspected Unexpected Serious Adverse Reaction (SUSAR) or
Serious Adverse Event (SAE) or pregnancy; and

Informed consent deviation (e.g., improper administration or timing).
Other possible major deviations may be identified during the protocol deviation review 
meetings. 
Protocol deviations will be provided in a listing, sorted by treatment group, site and 
patient. Major protocol deviations that occur throughout the study will also be 
summarized by protocol deviation category and treatment group.  
4.6
Demographics and Baseline Characteristics
Demographic data (including age, race, ethnicity, sex, height, weight, Body Mass Index 
(BMI), and Body Surface Area (BSA), pre-treatment clinical characteristics, and baseline 
disease assessment scores will be summarized by treatment group for the Double-Blind 
FAS as well as the Double-Blind Safety Population.  Descriptive statistics (n, mean, SD, 
median, minimum, and maximum) will be presented for continuous variables.  Frequency 
distributions (counts and percentages) will be presented for categorical variables. This 
table will be repeated, stratified by age group (pediatric, adult).
Similar tables summarizing demographic and baseline data will be prepared for patients 
in the PPS, OL-FAS as well as the Open-Label Safety Population, grouped by prior 
double-blind treatment assignment and overall. In the event that the FAS and Safety 
Population are identical for either the double-blind or open-label periods, then the tables 
will only be produced for the Safety Population.
A by-patient listing will be provided, presenting data collected for demographics and 
baseline characteristics at Screening, for patients in the Double-Blind Safety Population.
4.7
Medical History
Medical history data obtained at screening will be summarized by MedDRA System 
Organ Class (SOC), using Version 20.0 of the coding dictionary.  These tables will be 
presented by treatment group for the Double-Blind Safety Population only.  
PKAN-Specific Medical History will also be summarized by treatment group using the 
Double-Blind FAS and the Double-Blind Safety Population. This table will include age 
of onset, duration of illness (age at screening - age at first symptom), as well as other 
variables related to the disease history. This table will be repeated for patients in the 
Open-Label Safety Population.


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By-patient listings will be provided, presenting medical history as well as PKAN-specific 
medical history collected at Screening for all patients in the Double-Blind Safety 
Population.
4.8
Prior/Concomitant Medications
Prior and concomitant medications, as well as non-drug therapies, will be coded using the 
World Health Organization (WHO) Drug Dictionary Sep 2018 B3 Format.
4.8.1
Prior and Concomitant Medications
Medications that start and stop prior to the date of first dose of blinded investigational 
product (placebo or fosmetpantotenate) medication will be classified as Prior only for the 
double-blind period. If a medication starts before the date of first dose of blinded 
investigational product and stops on or after the date of first dose of blinded 
investigational product, then the medication will be classified as both Prior and 
Concomitant for the double-blind period. Medications that were started or taken after first 
dose of the double-blinded investigational product and before the first dose of open-label 
fosmetpantotenate will be classified as Concomitant Only for the double-blind period.  
Medications will be classified for the open label period of the study in analogous manner. 
Medications will be summarized as Prior, Concomitant, and Concomitant only, by 
treatment group using frequency counts and percentages within anatomical therapeutic 
chemical (ATC, level 2) and preferred term (PT).  Medications that are specifically for 
PKAN maintenance will also be summarized separately. These summaries will be based 
on the Double-Blind Safety Population only.
Patients on chronic medications may be counted in a medication category for all periods: 
prior and concomitant medication for the double-blind period, and prior and concomitant 
medication for the open-label extension phase. 
Although a patient may take more than one medication within the same ATC 
classification/PT, the patient will be counted only once within an ATC classification/PT 
for a given study phase. The same patient may contribute to two or more preferred terms 
in the same classification. 
Non-drug therapies will be summarized in a separate table by treatment group using 
frequency counts and percentages within anatomical therapeutic chemical (ATC, level 2) 
and preferred term (PT), with no prior/concomitant classification. This summary will be 
based on the Double-Blind Safety Population.
A by-patient listing will be provided, which presents all medications taken by patients in 
the randomized population, with flags indicating if the medication is prior, concomitant, 
etc. for the double-blind or open-label periods. Non-drug therapies will be presented as 
well, in a separate listing.


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4.9
Study Treatment Usage and Compliance
Duration of treatment in weeks [(date of last dose – date of first dose + 1)/7] during the 
double-blind period and the open-label period will be summarized for the Double-Blind 
and Open-Label Safety Populations, respectively. For patients in the Fostmetpantotenate 
Safety Population, duration of treatment following initiation of fosmetpantotenate 
(double-blind or open-label) will be summarized. The number and percentage of patients 
with dose changes or interruptions will also be presented.   
Compliance is calculated as the number of actual investigational product units (capsules) 
administered (based on product units returned at each visit) divided by the number of 
expected investigational product units to be taken during the given treatment period, 
multiplied by 100%. The number of expected capsules for a given patient is computed by 
multiplying the patient’s daily dosage, in 75mg powder/capsules (for oral suspension), by 
the daily frequency (e.g. TID) and number of days in the specified dosing period (end 
date - start date + 1), and then summing these values across all dosing periods within the 
given treatment period. In the event of a dose interruption, the expected dosage for the 
given interruption period would be 0 capsules. Compliance will be summarized 
descriptively for each treatment group, including frequency tables to indicate the number 
of patients who took between 80% and 120% of the doses prescribed for each treatment 
period.
A by-patient listing will be provided, which will present total drug accountability, along 
with information on compliance and dose modifications by treatment period.
4.10 Efficacy Analysis
Analysis of the efficacy endpoints for the Interim Analysis will be limited to data 
collected during the double-blind period. Open-Label efficacy data will be included in the 
listings only. Following the Interim Analysis, additional analyses including open-label 
efficacy data will be described in a later version of the SAP, for presentation as part of 
the Final Analysis.
4.10.1
Primary Efficacy Endpoint 
The PKAN-ADL consists of 12 items related to activities of daily living, including 
eating, dressing, and walking. Each item has responses ranging from 0-4, with a higher 
value indicating greater disability in the given activity. To compute the total score, 
responses are summed across the 12 items.
For analysis purposes, data from the pediatric and adult age groups will be pooled. All 
descriptive summary tables will be repeated using age group as a subgroup.
Descriptive statistics will be presented for the PKAN-ADL total score, with absolute and 
percent change from baseline, by treatment group for each visit of the double-blind 


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period. For post-baseline assessments, categories for change from baseline total score 
(e.g., >0, =0, <0, ≤ -1, ≤ -2, ≤ -3, ≤ -4), categories for percent improvement (i.e., 
decrease) in total score from baseline (i.e., <0%, =0% >0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%), and categories for total score status (improvement, no change, or worsening) will 
be presented. These categories may be adjusted in a way that ensures that the categories 
contain at least 10% of patients. This will be run using the Double-Blind FAS, and 
repeated using the PPS, as a sensitivity analysis. 
Change from baseline will be calculated by subtracting the baseline total score from the 
post baseline total score. Percent change from baseline will be calculated as: 
100*(Observed Score at Post-Baseline Visit – Observed Score at Baseline) / Observed 
Score at Baseline 
Furthermore, a chi-squared test will be performed at each post-baseline visit to determine 
treatment differences between the percentages of patients who had a total score indicating 
improvement, no change, or worsening. Proportions, with estimated 95% CI, will be 
reported for each treatment group, along with a p-value corresponding to the treatment 
comparison.
Frequency tables will display change from baseline for each of the 12 items, as well as 
shift from baseline, by treatment group for each post-baseline assessment of the double-
blind period. In addition, categories for change from baseline item score (i.e., >0, =0, <0, 
≤ -1, ≤ -2, ≤ -3), and categories for item score status (improvement, no change, or 
worsening) will be presented. These summaries will be run using the Double-Blind FAS 
and repeated using the PPS, as a sensitivity analysis.
Figures will be presented which show the PKAN-ADL total score for each visit during 
the double-blind period, as well as change from baseline score, by treatment group. This 
will be run using the Double-Blind FAS and repeated using the PPS.
In addition, a by-patient listing will be provided, which presents PKAN-ADL scores 
(total and for each item) across all assessments in the double-blind and open-label periods 
for patients in the Double-Blind FAS.
The change from baseline in PKAN-ADL total scores will be used to test the following 
hypotheses:
Null hypothesis:
There is no difference between the fosmetpantotenate and placebo groups, as measured 
by the change in PKAN-ADL total score from baseline to the end of the 24-week double-
blind treatment period, with adjustment for age group and baseline PKAN-ADL total 
score.  


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Alternate hypothesis:
There is a difference between the fosmetpantotenate and placebo groups, as measured by 
the change in PKAN-ADL total score from baseline to the end of the 24 week double-
blind treatment period, with adjustment for age group and baseline PKAN-ADL total 
score.
That is:
H0: Change from baseline PKAN-ADL Total Score at Week 24 (fosmetpantotenate) = 
Change from baseline PKAN-ADL Total Score at Week 24 (Placebo) estimated via 
repeated measure analysis, with adjustment for age group and baseline score
H1: Change from baseline PKAN-ADL Total Score at Week 24 (fosmetpantotenate) ≠ 
Change from baseline PKAN-ADL Total Score at Week 24 (Placebo) estimated via 
repeated measure analysis, with adjustment for age group and baseline score
The primary efficacy analysis will be based on the FAS population in the double-blind 
period of the study.  For each patient, the change from baseline in PKAN-ADL total 
scores at Weeks 3, 6, 12, 18, and 24 of the double-blind period will be used for analysis.  
The treatment effect will be evaluated on the basis of a mixed model for repeated 
measures (MMRM) analysis to assess data from all visits simultaneously.  The model 
will include fixed effects for treatment, age group (pediatric, adult), visit and treatment 
by-visit interaction, with visit as the repeating factor and patient as a random effect, and 
baseline PKAN-ADL total score as a covariate.  The PKAN-ADL total score obtained 
prior to the first dose of investigational product will serve as each patient’s baseline value.
Patients with PKAN-ADL administration errors will be included in the Double-Blind 
FAS, but excluded from the PPS, as per Section 4.5. Imputation rules for the data 
affected by the translation issue can be found in Section 4.1.
The linear mixed-effect model will be implemented using PROC MIXED in SAS with 
the restricted maximum likelihood (REML) estimation method.  An unstructured 
variance-covariance matrix will be used to model the within-patient errors.  [Note:  In the 
unlikely event that the computational algorithm fails to converge, the following structures 
will be executed in the order specified (essentially in decreasing order of complexity) 
until convergence is achieved:  Toeplitz with heterogeneity, autoregressive with 
heterogeneity by Week, compound symmetry with heterogeneous variances by Week, 
autoregressive, Toeplitz, and compound symmetry without heterogeneous variances by 
Week.] 
Significance tests will be based on least squares means (LSMs) using Type III sum of 
squares. The Kenward and Roger method will be used for calculating the denominator 
degrees of freedom for tests of fixed effects. 


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The PROC MIXED SAS coding is as follows:
proc mixed data=DATA;
   class TRT WEEK PATIENT;
   model C_score = BASE_score AGE TRT WEEK TRT*WEEK / solution 
ddfm=kr;
   repeated WEEK / subject=PATIENT type=un;
   
run;
where:
TRT = treatment group (0 = placebo, 1 = fosmetpantotenate)
WEEK = week 3, 6, 12, 18, 24
AGE = age group (0=Pediatric, 1= Adult)
C_score = change in score from baseline
BASE_score = baseline score
The LSMs for each treatment, the difference between the LSMs, and the standard error 
(SE) and 95% confidence interval (CI) associated with the difference will be reported at 
each study visit.  The primary treatment comparison will be based on the test of contrast 
between treatment effects using the LSM estimate at Week 24, adjusted for baseline score 
and age group from the Type III analysis.
To estimate the mean change from baseline for PKAN-ADL total scores in each 
treatment group (placebo or fosmetpantotenate) at Week i (i = 3, 6, 12, 18, and 24), the 
following estimate statement (as an example) will be utilized:
estimate 'Placebo Group at Week 24'
    intercept   1 
    AGE         <proportion in age group=0   proportion in age group=1>
    BASE_score  <mean of BASE_score>
    TRT         1 0
    WEEK        0 0 0 0 1
    TRT*WEEK    0 0 0 0 1
                0 0 0 0 0 / cl;
estimate 'FOSMETPANTOTENATE   Group at Week 24'
    intercept   1 
    Age         <proportion in age group=0   proportion in age group=1>
    BASE_score  <mean of BASE_score>
    TRT         0 1
    WEEK        0 0 0 0 1
    TRT*WEEK    0 0 0 0 0
                0 0 0 0 1  / cl;
To estimate the treatment effect (i.e., the difference between fosmetpantotenate and 
placebo) at Week i (i = 3, 6, 8, 12, and 24), the following estimate statement (as an 


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example) will be utilized:
estimate 'Treatment Effect at Week 24'
    TRT         -1 1
    TRT*WEEK     0 0 0 0 -1
                 0 0 0 0 1  / cl;
The point estimates and corresponding 95% CIs for the treatment effect at each week will 
be presented for the FAS (double-blind period).
4.10.1.1
Sensitivity Analysis
To check that primary efficacy findings are robust, sensitivity analyses will be performed, 
as follows:

The MMRM described in section 4.10.1 will be repeated using the PPS, and 
presented in a similar manner. Of note, patients who had a PKAN-ADL 
administration error will be excluded from the PPS.

In addition, analysis of covariance (ANCOVA) models will be applied to change 
from baseline in PKAN-ADL total scores assessed after 3, 6, 12, 18, and 24 
weeks of treatment.  For each week analyzed, the model will include treatment 
and age group (pediatric, adult) as fixed effects, and baseline PKAN-ADL total 
score as a covariate.  
The ANCOVA analysis will be performed for the Double-Blind FAS using 
PROC GLM in SAS.  The models will be run using the observed case (OC) and 
last-observation-carried-forward (LOCF) procedure to account for incomplete 
data.  In each case, estimates of adjusted treatment means and the adjusted mean 
difference between treatment groups will be presented at each time point, along 
with the two-sided 95% CIs and p-values for treatment comparisons.  
The LOCF procedure will be applied for post-baseline observations of the PKAN-
ADL total score in which more than 20% of the items are missing and cannot be 
imputed in the manner described in Section 4.1. The last observed post-baseline 
PKAN-ADL total score, including those from unscheduled visits, will be imputed 
to replace the missing value of PKAN-ADL total score.
The PROC GLM SAS coding, to be run for each visit and each OC/LOCF 
procedure, is as follows:
proc glm data=DATA;
class TRT AGE;
model week_x_total=base_score TRT AGE / solution;
lsmeans TRT/ pdiff stderr;


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run;
4.10.1.2
Handling of Dropouts and/or Missing Data
The MMRM approach used for the primary efficacy analysis accounts for data “missing 
at random” through a variance covariance structure.  The ANCOVA models (described 
above) employ both the OC and LOCF methods to explore the impact of drop-outs and 
missing data.  However, mixed models have been shown to be less biased under Missing 
at Random (MAR) and Missing Completely at Random (MCAR) conditions compared 
with LOCF or Completer analyses (Prakash, 2008).    
To assess the appropriateness of the MAR assumption, additional sensitivity analyses 
using a tipping point approach will be used to assess how extreme and detrimental 
outcomes among patients with missing data must be to overwhelm the treatment effect 
attained in those patients who had complete data. In these analyses, the same basic 
analytic model will be used as in the primary analysis, but a multiple imputation 
approach will be implemented to allow for varying impact of missing data by 
incorporating a shift parameter in the imputation model. The range of values for the shift 
parameter will explore the varying missing data assumptions, from MAR to Missing Not 
at Random (MNAR), including the scenario where the imputation model is completely 
based on the control group (i.e., control-based imputation). 
Following the approach described in Ouyang (2017), the following imputation 
procedures will be implemented: 
1. Intermittent missing values before a discontinuation event (i.e., discontinuation of 
randomized therapy or early permanent dropout): The MAR assumption is reasonable for 
intermittent missing values before a discontinuation event since the values of the 
endpoint before and after the intermittent missing value are known. Imputation of 
intermittent missing data will be accomplished using the Markov Chain Montel Carlo 
(MCMC) option in SAS PROC MI by treatment group to impute intermittent missing 
data without a monotone missing pattern, prior to performing imputation of values 
following the discontinuation event. 
2. Missing data following a discontinuation event (i.e., discontinuation of randomized 
therapy or early permanent dropout): Imputation of the post-discontinuation missing data 
by treatment group under the assumption of MAR using the regression option from the 
monotone statement of SAS PROC MI. Baseline and post-baseline scheduled visits will 
be used in the regression option to impute the missing values. 
3. Steps 1 and 2 will be repeated to generate 30 multiply-imputed datasets.


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4. For the fosmetpantotenate-treated patients, the post-discontinuation imputed values 
from step 3 will be made worse by subtracting a delta defined as k=100% times the 
treatment differences (means) obtained for the post-discontinuation visits obtained from 
the specified mixed model analysis (i.e., the analytic model) of the endpoint. No 
adjustment from the MAR assumption will be implemented for the placebo-treated 
patients (i.e., k = 0%). 
5. The mixed model (i.e., the analytic model) analysis described for the endpoint will be 
performed on each set of the newly “complete” data (observed data plus imputed values). 
6. Using Rubin’s approach (Rubin 1987), the estimated treatment effects are combined 
across imputations. This will be accomplished using SAS PROC MIANALYZE. 
7. Repeat steps 4 through 6 with increasing values of k (e.g., 120%, 140%…200%…) 
until the significance of the pre-specified analysis assuming MAR is overturned (e.g., 
from p-value <0.05 to p-value ≥0.05). The worsening by k times the treatment differences 
is applied to all the post discontinuation imputed values for each set of “complete” data 
from step 3. As an example, if a fosmetpantotenate patient had 2 post-discontinuation 
visits imputed, the values of both of these 2 imputed visits would be made worse by 
subtracting k times the fosmetpantotenate versus placebo treatment differences at these 2 
visits. 
The iterations for each value of delta will be summarized in a table where the estimated 
treatment differences for the treatment comparisons will be presented together with 95% 
confidence intervals for the differences and p-values for the treatment comparisons.
4.10.1.3
Exploratory Subgroup Analysis
The influence of potential prognostic factors on the primary efficacy endpoint will be 
assessed via the mixed model described for the primary analysis, using the Double-Blind 
FAS.  That is, the mixed model will include baseline PKAN-ADL total score and 
additional prognostic factors (each considered univariately) as covariates, with treatment 
group, Week, treatment*Week, and treatment*prognostic factor as fixed effects. The 
factors to be assessed are as follows:

Age at screening (pediatric, adult)

Age at disease onset (<median, ≥ median)

Sex (male, female)

Baseline PKAN-ADL total score (1st quartile, 2nd quartile, 3rd quartile, 4th quartile).

Duration of Illness (<median, ≥ median)
Factors found to have a significant effect on response (p < 0.10) will be examined further, 
to understand the relationship between prognostic factor and response. For all factors, the 


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LSMs for each treatment, the difference between the LSMs, and the standard error (SE) 
and 95% confidence interval (CI) associated with the difference will be reported at each 
study visit, using the MMRM which includes the given factor as a covariate.
4.10.2
  Secondary Efficacy Endpoint
Part III of the UPDRS consists of 27 items, which correspond to 14 domains related to 
motor abilities such as tremor, stability, and bradykinesia. Each item has responses 
ranging from 0-4, with a higher value indicating greater disability. To compute the 
UPDRS Part III total score, responses are summed across the 27 items, and accordingly, 
will range from 0-108. For domain totals, responses will be summed across all of the 
items in a given domain (when domain corresponds to multiple items). 
For analysis purposes, data from the pediatric and adult age groups will be pooled. All 
descriptive summary tables will be repeated using age group as a subgroup.
Descriptive statistics will be presented for the UPDRS Part III total score, with absolute 
and percent change from baseline, by treatment group for each visit of the double-blind 
period. For post-baseline assessments, categories for change from baseline UPDRS Part 
III total score (e.g., >0, =0, <0, ≤ -1, ≤ -2, ≤ -3, ≤ -4), categories for percent improvement 
(i.e., decrease) in UPDRS Part III total score from baseline (i.e., <0%, =0%, >0%, ≥10%, 
≥20%, ≥30%, ≥40%, ≥50%), and categories for UPDRS Part III total score status  
(improvement, no change, or worsening) will be presented. These categories may be 
adjusted in a way that ensures that the categories contain at least 10% of patients. This 
will be run using the Double-Blind FAS and repeated using the PPS, as a sensitivity 
analysis. 
Frequency tables will display change from baseline for each of the 14 domains, by 
treatment group for each visit of the double-blind period, using categories for change 
from baseline domain score (i.e., >0, =0, <0, ≤ -1, ≤ -2, ≤ -3), and categories for domain 
score status  (improvement, no change, or worsening). These summaries will be run using 
the Double-Blind FAS and repeated using the PPS, as a sensitivity analysis.
The MMRM model described above for the primary efficacy endpoint will also be 
performed for the secondary efficacy endpoint:  change from baseline UPDRS Part III 
total score. The LSMs for each treatment, the difference between the LSMs, and the 
standard error (SE) and 95% confidence interval (CI) associated with the difference will 
be reported at each study visit.  The analysis will be based on the Double-Blind FAS, and 
will be repeated using the PPS, as a sensitivity analysis.
The ANCOVA models, as described in section 4.10.1.1, will be run for change from 
baseline in UPDRS Part III total scores assessed after 3, 6, 12, 18, and 24 weeks of 
treatment for patients in the Double-Blind Full Analysis Set. The models will be run 


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using the observed case (OC) and last-observation-carried-forward (LOCF) procedure to 
account for incomplete data.
The exploratory subgroup analysis, as described in section 4.10.1.3, will also be run for 
the UPDRS Part III total score.
Furthermore, a chi-squared test will be performed at each post-baseline visit to determine 
treatment differences between the percentages of patients who had a total score indicating 
improvement, no change, or worsening. Proportions, with estimated 95% CI, will be 
reported for each treatment group, along with a p-value corresponding to the treatment 
comparison.
Figures will be presented which show the UPDRS Part III total score for each visit during 
the double-blind period, as well as change from baseline score, by treatment group. This 
will be run using the Double-Blind FAS and repeated using the PPS.
A by-patient listing will be provided, which presents UPDRS Part III scores (total and for 
each of the 27 items) across all assessments in the double-blind and open-label periods 
for patients in the Double-Blind FAS.
4.10.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints that are continuous rating scales recorded at multiple 
post-baseline visits (i.e., BAD Scale, Neuro-QOL, Euro-QOL, 25-foot walk test) will be 
evaluated using the MMRM approach described above for the primary efficacy endpoint.  
For endpoints obtained only at the baseline and final (Week 24) visits of the double-blind 
period (i.e., FIM/WeeFIM, DDK), the ANCOVA model will be used. The model will be 
run using the observed case (OC) procedure only. Summary statistics for efficacy 
measures will include graphical plots of mean and mean change from baseline values at 
each study visit during the double-blind period, by treatment group.
For analysis purposes, data from the pediatric and adult age groups will be pooled. All 
descriptive summary tables will be repeated using age group as a subgroup.
Treatment effects on categorical outcomes will be examined using frequency tables and 
tested using the Cochran-Mantel-Haenszel (CMH) chi-square methods with stratification 
by age group (pediatric, adult) (Mantel and Haenszel, 1959).
For the Interim Analysis, the Double-Blind FAS only will be used for analyses involving 
exploratory efficacy endpoints.
Statistical methods and estimation procedures are described below for each of the 
exploratory endpoints.  


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4.10.3.1
Clinician Global Impression of Improvement (CGI-I)  
The CGI-I is measured on a 7-point scale, ranging from 1=very much improved to 
7=very much worse since the start of treatment.  Frequency tables will display the 
distribution of CGI ratings in each treatment group at Weeks 3, 6, 12, 18, and 24 of the 
double-blind treatment period. In addition, the percentages of patients who had a score 
indicating improvement, no change, or worsening, will be presented.  This will be 
repeated using age group (pediatric, adult) as a subgroup.
The Cochran-Mantel-Haenszel test (CMH) row-mean score test (van Elteren test) will be 
used to evaluate the difference between treatment groups in average CGI-I ratings at each 
visit during the double-blind period, with stratification by age group (pediatric, adult).  
A chi-squared test will be performed at Week 24 to determine treatment differences 
between the percentages of patients who had a score indicating improvement, no change, 
or worsening. Proportions, with estimated 95% CI, will be reported for each treatment 
group, along with a p-value corresponding to the treatment comparison.
A by-patient listing will be provided, which presents CGI-I scores across all assessments 
in the double-blind and open-label periods for patients in the Double-Blind FAS.
4.10.3.2
Barry Albright Dystonia (BAD) scale
The BAD scale assesses the signs of dystonia in 8 regions (eyes, mouth, neck, trunk, 
upper left/upper right extremities, and lower left/right extremities), each rated on a 5-
point ordinal scale ranging from 0=absent to 4=severe.  Thus, the total BAD score ranges 
from 0 to 32, with higher scores denoting greater severity of dystonia.  
Frequency tables will display change from baseline for each of the 8 regions, as well as 
shift from baseline, by treatment group across each visit of the double-blind period, using 
categories for change from baseline region score (i.e., >0, =0, <0, ≤ -1, ≤ -2, ≤ -3), and 
categories for region score status  (improvement, no change, or worsening).
Summary statistics will be presented for the total BAD score, including absolute and 
percent change from baseline, across each visit of the double-blind period.  In addition, 
categories for change from baseline total BAD score (e.g., >0, =0, <0, ≤ -1, ≤-2, ≤ -3, ≤ -
4), categories for percent improvement (i.e., decrease) in total BAD score from baseline 
(i.e., <0%, =0%, >0%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%), and categories for total BAD 
score status (improvement, no change, or worsening) will be presented. These tables will 
be repeated using age group (pediatric, adult) as a subgroup.
Furthermore, a chi-squared test will be performed at each post-baseline assessment to 
determine treatment differences between the percentages of patients who had a total score 
indicating improvement, no change, or worsening. Proportions, with estimated 95% CI, 
will be reported for each treatment group, along with a p-value corresponding to the 
treatment comparison.


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The treatment effect on change from baseline in total BAD score will be evaluated at 
Week 12 and the final (Week 24) visit using an MMRM, similar to the one described for 
the primary endpoint.  The model will be run using the Double-Blind FAS.
Figures will be presented which show the total BAD score for each visit during the 
double-blind period, as well as change from baseline score, by treatment group.
A by-patient listing will be provided, which presents BAD scores (total and for each 
region) across all assessments in the double-blind and open-label periods for the Double-
Blind FAS.
4.10.3.3
Quality of Life (QoL)
4.10.3.3.1 Neuro-QoL
The Neuro-QoL scale includes an upper extremity module (fine motor and activities of 
daily living) and a lower extremity module (mobility) with 19 items (20 items in the 
Pediatric Version). 
Frequency tables will display change from baseline scores for each item of each module, 
including shift from baseline, by treatment group for Week 12 and Week 24. In addition, 
categories for change from baseline item score (i.e., <0, =0, >0, ≥ 1, ≥ 2, ≥ 3, ≥ 4), and 
categories for item score status (improvement, no change, or worsening) will be 
presented. For these tables, data from the pediatric and adult versions will be presented in 
separate outputs.
For analytic purposes, responses across each module will be summed, and if necessary, 
rescaled, such that the total score will range from 0-100 for each module in both the 
Pediatric and Adult Versions.  This methodology is described below. 
For the Adult Version of the Neuro-QOL Upper Extremity module, in which there are 20 
items with each response ranging from 1-5, the total score is computed via summation, 
and no rescaling is necessary. In the Adult Version of the Neuro-QOL Lower Extremity 
module, there are 19 items with each response ranging from 1-5. The total score is thus 
computed by summing the responses across the 19 items, and then multiplying this sum 
by (20 / 19).
In each of the Pediatric Version of the Neuro-QOL Upper and Lower Extremity modules,
there are 20 items with each response ranging from 0-4. For all items, each response is 
rescaled to correspond to a 1-5 scale, and then summed to produce the total score.
Within each Neuro-QOL module, the rescaled total scores from the adult and pediatric
versions of the assessment will be pooled. Descriptive statistics of the rescaled total score 
for each of the Neuro-QOL modules, as well as absolute and percent change from 
baseline, will be presented for patients in the Double-Blind FAS at each post-baseline 
assessment during the double-blind period. In addition, categories for change from 
baseline rescaled total score (e.g., <0, =0, >0, ≥ 1, ≥ 2, ≥ 3, ≥ 4), categories for percent 


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improvement (i.e. increase) in rescaled total score from baseline (i.e., <0%, =0% >0%, 
≥10%, ≥20%, ≥30%, ≥40%, ≥50%), categories for rescaled total score status 
(improvement, no change, or worsening) will be presented for each module.  This table 
will be repeated using age group (pediatric, adult) as a subgroup.
Chi-squared tests will be performed for each module at each post-baseline assessment to 
determine treatment differences between the percentages of patients who had a re-scaled 
total score indicating improvement, no change, or worsening. Proportions, with estimated 
95% CI, will be reported for each treatment group, along with a p-value corresponding to 
the treatment comparison.
In addition, the change in Neuro-QoL assessments (rescaled score for each module) from 
baseline to the Week 12 and final (Week 24) visit will be evaluated at each time point 
using an MMRM, similar to the one described for the primary endpoint. The model will 
be run using the Double-Blind FAS. 
A by-patient listing will be provided, which presents the raw responses to all items in the  
Neuro-QOL assessment, along with the rescaled total score for each module, across all 
assessments in the double-blind and open-label periods for patients in the Double-Blind 
FAS.
4.10.3.3.2 Euro-Qol
The EQ-5D-3L (for adult patients) measures 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression), each rated at 3 levels: 1=no problems, 
2=some problems, 3=extreme problems. The scale also records the patient’s self-rated 
health on a visual analogue scale (VAS) from 0=the worst health you can imagine, to 
100=the best health you can imagine.  The EQ5DY (for pediatric patients) measures the 
same 5 dimensions on a similar 3-point scale and uses the same VAS for the patient to 
self-rate health. 
Frequency counts of the change from baseline score across each of the 5 dimensions, as 
well as shift from baseline, will be presented for each visit during the double-blind period. 
Categories for change from baseline dimension score (i.e., >0, =0, <0, ≤ -1), and 
categories for dimension score status (improvement, no change, or worsening) will be 
presented at Week 24, as well. These tables will be repeated using age group (pediatric, 
adult) as a subgroup.
Furthermore, each patient’s 5-digit EQ-5D state will be transformed into a single EQ-
5D™ index score by following the algorithm, or value set, specified for his or her 
relevant country. These value sets are derived based off surveys conducted in 
representative samples of the given countries. The value set is anchored at 0=dead and 
1=full health. The EURO-QOL group provides the value set for performing these 
calculations, and one such reference table can be found in Janssen (2014). If there are any 


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missing data across the 5 dimensions at a given visit, then the index score cannot be 
validly calculated and is considered missing.
Descriptive statistics of the EQ-5D™index score will be presented for patients in the 
Double-Blind FAS at each visit of the double blind period, including absolute change 
from baseline. Categories for percent improvement (i.e., increase) in EQ-5D™index 
score from baseline (i.e., <0%, =0% >0%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%), and 
categories EQ-5D™index score status (improvement, no change, or worsening) will be 
presented. In addition, descriptive statistics of the patient’s self-rated health on the VAS, 
as well as absolute change from baseline, will be presented for each visit of the double-
blind period. This table will be repeated using age group (pediatric, adult) as a subgroup.
A chi-squared test will be performed at each post-baseline assessment to determine 
treatment differences between the percentages of patients who had an EQ-5D™index 
score indicating improvement, no change, or worsening. Proportions, with estimated 95% 
CI, will be reported for each treatment group, along with a p-value corresponding to the 
treatment comparison.
Furthermore, the change in each Euro-QoL assessment (EQ-5D™ index score, and the 
EQ VAS) from baseline to the Week 12 and final (Week 24) visit will be evaluated using 
an MMRM, similar to the one described for the primary endpoint.  The models will be 
run using the Double-Blind FAS. 
A by-patient listing will be provided, which presents Euro-QOL scores (score on 5 
dimensions, EQ-5D™ index score, and VAS score) across all assessments in the double-
blind and open-label periods for patients in the Double-Blind FAS.
4.10.3.4
Functional Independence Measure
The FIM (or WeeFIM for pediatric patients) assesses motor tasks (13 items) and 
cognitive tasks (5 items), each rated on a 7-point ordinal scale, with higher values 
denoting greater functional independence.  The total score ranges from 18 (total 
assistance) to 126 (complete independence); the total subscores range from 13 to 91 for 
the motor component, and from 5 to 35 for the cognitive component. In the WeeFIM, the 
motor component is comprised of two domains: a self-care domain with 8 items 
(subscores ranging from 8 to 56) and a mobility domain with 5 items (subscores ranging 
from 5 to 35). If an item is missing, then the total score and corresponding subscore will 
not be computed.
A descriptive summary of the absolute change from baseline in motor and cognitive 
components of the scale, along with the total score, will be presented by treatment group, 
overall (pooled across age groups) and within each age group (pediatric, adult).  For the 
pediatric group, the subscores for the self-care and mobility domains will also be 
summarized. In addition, at Week 24, categories for change from baseline FIM total score 
(e.g., <0, =0, >0, ≥ 1, ≥ 2, ≥ 3, ≥ 4), categories for percent improvement (i.e., increase) in 


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FIM total score from baseline (i.e., <0%, =0% >0%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%), 
and categories for FIM total score status (improvement, no change, or worsening) will be 
presented.
Frequency counts of the change from baseline score across each FIM item, as well as 
shift from baseline, will be presented for Week 24. Categories for change from baseline 
FIM item score (i.e., <0, =0, >0, ≥ 1, ≥ 2, ≥ 3, ≥ 4), and categories for FIM item score 
status (improvement, no change, or worsening) will be presented, as well. In addition, 
frequency counts will be presented by treatment group for patient locomotion (walk, 
wheelchair or both), comprehension (auditory, visual, or both) and expression (vocal, 
nonvocal, or both) will be presented at baseline and Week 24.
A chi-squared test will be performed at Week 24 to determine treatment differences 
between the percentages of patients who had a total score indicating improvement, no 
change, or worsening. Proportions, with estimated 95% CI, will be reported for each 
treatment group, along with a p-value corresponding to the treatment comparison. 
The change in FIM (or WeeFIM) total score from baseline to the Week 24 visit will be 
evaluated using an ANCOVA model, with treatment and age group (pediatric, adult) as 
fixed effects, and baseline score as a covariate, pooling data across age group (pediatric, 
adult).  The model will be run using the observed case. The adjusted mean treatment 
difference will be reported together with its 95% confidence interval.  
A by-patient listing will be provided, which presents FIM scores (total and for each 
component) across all assessments in the double-blind and open-label periods for patients 
in the Double-Blind FAS.
4.10.3.5
Function Measures
Ambulation: Patients able to attempt this assessment will have 2 trials to walk 25 feet, 
and the average time (in seconds) of these trials will be taken.  Patients must successfully 
complete 2 trials in order for the assessment to have been considered completed. If there 
is only data available for 1 trial, for reasons other than a patient’s inability to perform the 
test, then the time for the single, available trial will be considered as the average.
Descriptive statistics will be used to summarize average walking speeds (in seconds) at 
each study visit of the double-blind treatment period (Baseline, Weeks 6, 12, 18, and 24) 
for patients in the Double-Blind FAS, along with absolute and percent change from 
baseline for post-baseline visits. Categories for percent improvement (i.e., decrease) in 
average walking speed (in seconds) from baseline (i.e., <0%, =0% >0%, ≥10%, ≥20%, 
≥30%, ≥40%, ≥50%), and categories for average walking speed (improvement, no change, 
or worsening) will be presented, as well. This table will be repeated using age group 
(pediatric, adult) as a subgroup.


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Moreover, the walking speeds will be converted to z-scores, using the baseline values of 
patients in the Double-Blind FAS as reference values. The z-score conversion will follow 
the below formula: 
(Observed value [in seconds] – average of all baseline values [in seconds]) / standard 
deviation of all baseline values [in seconds].
Then, the z-score will be adjusted (multiply z-score by -1) so that a higher z-score will 
correspond to a better speed (fewer seconds). For patients who are unable to complete the 
25-foot walk test, a z-score will be imputed using the worst observed z-score across all 
patient visits.
Descriptive statistics of the z-score, including absolute and percent change from baseline, 
will be presented for patients in the Double-Blind FAS at each visit during the double-
blind period. Depending on the number of patients with available data, the MMRM 
model (as described for the primary endpoint) will be used to evaluate the treatment 
effect on change from baseline walking speed z-score. The difference between adjusted 
treatment means will be reported, together with its 95% CI. 
Frequency counts will be presented showing percentages of patients using given assistive 
devices at each visit, percentages of patients who failed to complete 1 or more trials, and 
percentages of patients in the Double-Blind FAS who reported a change in level of 
assistance needed. 
In addition, figures will be presented which show the walking speed for each visit during 
the double-blind period, as well as change from baseline speed by treatment group. A by-
patient listing will be provided, which presents the results from the 25-foot walk test 
(including Trials 3 and 4, if necessary) across all assessments in the double-blind and 
open-label periods for patients in the Double-Blind FAS.
Speech: Diadochokinetic test (DDK) assessments will provide 4 scores for analysis: three 
scores for the alternating motion rate (AMR) and one for the sequential motion rate or 
(SMR). For the three AMR scores, patients will be required to recite a single syllable 
(“puh”, “tuh”, and “kuh”) as rapidly as possible in one breath. The AMR will be derived 
as the number of repetitions over the duration (in seconds). For the SMR scores, patients 
will be required to recite multiple syllables (“puhtuhkuh”) as rapidly as possible in one 
breath. The SMR will be derived as the number of repetitions over the duration (in 
seconds).
The AMR and SMR will be analyzed using descriptive statistics at baseline and Week 24 
of the double-blind period, including absolute and percent change from baseline. 
Categories for percent improvement (i.e., decrease) in AMR/SMR (i.e., <0%, =0% >0%, 
≥10%, ≥20%, ≥30%, ≥40%, ≥50%), and categories for AMR/SMR status (improvement, 
no change, or worsening) will be presented, as well. This will be repeated using age 
group (pediatric, adult) as a subgroup.


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Moreover, for each score, the change from baseline to the Week 24 visit of the double-
blind period will be evaluated using an ANCOVA model, with treatment and age group 
(pediatric, adult) as fixed effects, and baseline score as a covariate. The models will be 
run using observed cases. The adjusted mean treatment difference will be reported 
together with its 95% confidence interval. 
For each of the 4 repetition tasks (“puh”, “tuh”, “kuh”, “puhtuhkuh”), the number of 
repetitions performed will also be summarized descriptively at baseline and Week 24 
during the double-blind period. This will be repeated using age group (pediatric, adult) as 
a subgroup.
A by-patient listing will be provided, which presents the duration, repetitions, and 
repetition rates for the AMR and SMR across all assessments in the double-blind and 
open-label periods for the Double-Blind FAS.
4.10.4
Adjustment for Multiple Hypothesis Testing
To control the Type 1 familywise rate at 5%, the serial gate-keeping approach (proposed 
by Westfall and Krishen, 2001) will be used to test the primary and secondary efficacy 
endpoints (ordered by clinical relevance and importance) during the double-blind period 
in the above specified sequence.  It will be implemented in the following way: If (and 
only if) the null hypothesis associated with the primary endpoint is rejected at the 0.05 
significance level, then the secondary efficacy endpoint will be tested at the 0.05 
significance level. The plan for analysis of other endpoints during the double-blind period 
is purely exploratory, so no further adjustment is warranted. Similarly, efficacy analyses 
of endpoints collected during the open-label period are also exploratory, and do not 
warrant adjustment.
4.10.5
Safety Data Monitoring
An independent Data Monitoring Committee (DMC) will be established to review safety 
data periodically throughout the trial. 
The DMC will operate under a charter that is approved by all committee members and 
the Sponsor. The scope of the review and procedures in place to maintain the integrity of 
the ongoing study will be described in the charter.  
4.11 Safety Analysis
For the Interim Analysis, the safety analyses will cover all data collected until the 
database cut-off, including data from the open-label period. Safety analyses will be 
performed using data from the Double-Blind and Open-Label Safety Populations. Tables 
using the Double-Blind Safety Population will include only data collected during the 


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double-blind period. Tables using the Open-Label Safety Population will include only 
data collected during the open-label period. 
In addition, select safety analyses will be performed using the Fosmetpantotenate Safety 
Population. Tables using the Fosmetpantotenate Safety Population will include data 
collected following the first exposure for fosmetpantotenate (i.e., double-blind and open-
label data for patients administered fosmetpantotenate at baseline of double-blind period, 
open-label data only for patients first administered fosmetpantotenate at baseline of the 
open-label period.)
Safety of fosmetpantotenate will be determined on the basis of treatment-emergent AEs 
(TEAEs), vital signs, weight, physical examinations, clinical laboratory assessments, the 
Columbia Suicide Severity Rating Scale (C-SSRS) (in assessable patients), and ECG 
findings.  
For the Double-Blind Safety Population, table summaries and figures will be presented 
by treatment group as appropriate; for the Open-Label and Fosmetpantotenate Safety 
Populations, safety summaries will be presented for the entire cohort, and (when 
indicated) by treatment received during the prior double-blind period.   
4.11.1
Adverse Events (AEs)
All AEs will be coded by Preferred Term and System Organ Class using MedDRA 
coding dictionary Version 20.0.  
TEAEs in the double-blind period are defined as AEs that are new or are a worsening of 
an existing condition that begin from the day of first dose of investigational product until 
the day after the last dose for the double-blind treatment period.  TEAEs in the open-label 
period are defined as AEs that are new or are a worsening of an existing condition that 
begin from the day of first dose of open-label investigational product.  TEAEs in the 
fosmetpantotenate safety population are defined as AEs that are new or are a worsening 
of an existing condition that begin from the day of first dose of (blinded or open-label) 
fosmetpantotenate.
An overview of adverse events will be provided for each of the three Safety Populations 
that summarizes incidence in the following categories, overall, by age group (pediatric, 
adult), and by sex:

Any AEs

Any TEAEs

TEAEs by relationship to study medication (Not related, Unlikely Related, Possibly 
Related or Related)

TEAEs by severity (mild, moderate, severe)


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
Any TEAEs with an outcome of death

TESAEs

Treatment discontinuation due to TEAEs
The incidence of TEAEs will be summarized for each treatment group by Preferred Term 
as well as by Preferred Term within System Organ Class. The incidence of TEAEs by 
severity and relationship to treatment will be summarized for each treatment group by 
System Organ Class and Preferred Term. A patient with several occurrences of the same 
AE will be counted once and classified by the most severe event (or the event with the 
closest relationship to study drug). If severity or causality is missing, the worst case will 
be assumed (i.e., “Severe” if severity is missing and “Drug Related” if causality is 
missing.) 
In addition, the incidence of Adverse Events of Interest (AEOIs), TESAEs, TEAEs 
leading to treatment discontinuation, and TEAEs leading to death will be summarized for 
each treatment group by System Organ Class and Preferred Term.
Incidence calculations will be based on the numbers and percentages of patients with AEs, 
and sorted by decreasing frequency in the fosmetpantotenate group. Although a MedDRA 
Preferred Term may be reported more than once for a patient, that patient will be counted 
only once for that MedDRA Preferred Term.  For these summaries, patients with multiple 
AEs will be counted only once per SOC and PT. Furthermore, for each category within 
these summaries, the number of adverse events will be presented.
The above incidence tables will each be run using the Double-Blind, Open-Label, and 
Fosmetpantotenate Safety Populations.
In addition, time to event analyses (first event) will be performed for the following 
adverse event categories for patients in the Double-Blind Safety Population: dystonia, 
any AE with gastrointestinal disorder as SOC, any AEOI. Time to event endpoints will be 
summarized using the Kaplan-Meier method; median event times and 2-sided 95% 
confidence interval for each median will be provided (Brookmeyer, 1982). Time to event 
data will be censored using the date of a patient’s last visit during the double-blind 
period. The event or censoring time (days) will be calculated as:
Date of event/censoring – Date of randomization + 1
Moreover, for each AE category, a log-rank test will be performed to compare time to 
event between the treatment groups. The Cox proportional hazard (PH) model will be 
fitted and the estimated hazard ratio and 2-sided 95% confidence interval will be 
provided. Finally, estimates of the time to event curves obtained from the Kaplan-Meier 
method will be presented and displayed graphically, spanning the double-blind period.
For the above three adverse event categories, the duration of each event within the event 
category will be summarized descriptively, for each event occurrence, for patients in the


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Double-Blind Safety Population. In addition, patient-level duration of events will be 
displayed graphically using the MedDRA Preferred Term, spanning the double-blind 
period. Only patients who have had an adverse event in the given adverse event category 
will be presented, and multiple occurrences of a single Preferred Term will be presented 
on the same line. 
By-patient listings of deaths, TESAEs, AEs leading to treatment discontinuation, AEOIs, 
as well as all AEs will be provided.  The by-patient AE data listings will include age 
group, onset and resolution dates, study period, verbatim term, System Organ Class, 
Preferred Term, period, severity, seriousness criteria, relationship to treatment, action 
taken for the event, other action, and outcome. The listings will include all data observed 
across the double-blind and open-label periods, using the Double-Blind Safety Population. 
4.11.2
Clinical Laboratory Tests and Electrocardiogram
Clinical laboratory and ECG data will be presented for each treatment group using 
descriptive statistics based on the observed values and change from baseline values at 
each scheduled visit of the double-blind period, using the Double-Blind Safety 
Population. Summary statistics (n, mean, median, SD, minimum, and maximum) will be 
calculated for quantitative safety data and frequency counts will be compiled for 
classification of qualitative safety data. This will be repeated for visits corresponding to 
the open-label period, using the Open-Label Safety Population.  
The number and percentage of patients with laboratory values that shift categories (i.e., 
below/within/above normal range) will be tabulated for each study visit and worst post-
baseline visit during the double-blind period. This will be repeated using the Open-Label 
Safety Population as well as the Fosmetpantotenate Safety Population, for their respective 
treatment periods.  
In addition, the number and percentage of patients with “potentially clinically significant 
laboratory values” (based on ranges defined below) will be summarized by treatment 
group, using the Double-Blind Safety Population and the Open-Label Safety Population.
Category
Parameter
Potentially Clinically significant 
ranges
Hematology
Hemoglobin 
≤ 95 g/L (female), ≤ 115 g/L (male)
Hematocrit
≤ 0.32 L/L(female);  ≤0.37 L/L (male)
Leukocytes
≤ 2.8 x 10^9/L 
Platelets
≤ 75 x 10^9/L; ≥ 700 x 10^9/L
Coagulation
PT-INR
≥ 2.0
aPTT
≥ 43 seconds


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Category
Parameter
Potentially Clinically significant 
ranges
Blood Chemistry
Calcium
< 1.75 mmol/L
> 3.0 mmol/L
Chloride
< 90 mmol/L
> 115 mmol/L
Creatinine
> 176.8 umol/L
Glucose 
< 2.8 mmol/L
>13.9 mmol/L
Phosphate
< 0.6 mmol/L
> 1.6 mmol/L
Potassium
< 3.0 mmol/L
> 5.5 mmol/L
Sodium
< 130 mmol/L
> 150 mmol/L
Blood urea nitrogen
> 10.7 mmol/L
Liver Function 
Tests
Albumin 
<25 g/L
Total Protein 
< 45 g/L
ALT 
> 3x-, 5x-, 10x-, and 20xULN 
AST 
> 3x-, 5x-, 10x-, and 20xULN
ALT and AST 
Both ALT and AST > 3x-, 5x-, 10x-, 
and 20xULN 
Total Bilirubin 
>ULN and >2xULN 
ALP 
>2.5xULN 
ALT and Total Bilirubin
ALT >3xULN  + total bilirubin >
>2xULN, or international normalized 
ratio (INR) >1.5
AST and Total Bilirubin
AST >3xULN  + total bilirubin > 
>2xULN, or international normalized 
ratio (INR) > 1.5
For ECG measurements, QTc intervals will be determined using the Fridericia correction 
(QTcF) and the Bazett correction (QTcB). The QTcF and QTcB values and their change 
from baseline at each scheduled visit of the double-blind period will be summarized 
using descriptive statistics.  The number and percentage of patient with elevated values 
(per ICH E14 criteria) will also be tabulated.  This will be repeated using the Open-Label 
Safety Population, for visits in the open-label period.  


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All clinical laboratory safety data, including measurements obtained from the 12-lead 
electrocardiogram (ECG), will be listed for individual patients across all visits in the 
double-blind and open-label periods. Values identified as potentially clinically significant 
(laboratory values) or elevated (ECG values) will be flagged.
4.11.3
Physical Examination and Vital Signs
Reported abnormalities during the double-blind period and open label period, will be 
tabulated by body system for patients in the Double-Blind and Open-Label Safety 
Populations, respectively.  Changes in physical examinations will be described in the text 
of the final study report. A by-patient listing will be provided, which presents physical 
examination results across all assessments in the double-blind and open-label periods.
Vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, and 
temperature), and body weight will be summarized by treatment group using descriptive 
statistics.  Summary statistics (n, mean, median, SD, minimum, and maximum) will be 
calculated for both the actual value and the change from baseline value at each scheduled 
visit during the double-blind period. This will be repeated using the Open-Label safety 
population for visits during the open-label period.
For systolic and diastolic blood pressure, as well as weight, figures will be presented 
which show observed values, as well as change from baseline, by treatment group, for 
each visit during the double-blind period and open-label period, for patients in the 
Double-Blind and Open-Label Safety Populations, respectively.
In addition, the number and percentage of patients who meet the following criteria at any 
time during the double-blind period and open-label period will be summarized for each of 
the respective safety populations:

Severe blood pressure elevation 
o
Systolic blood pressure ≥ 180 mm Hg; OR, diastolic blood pressure ≥ 120 mm 
Hg 

Moderate blood pressure elevation 
o
Systolic blood pressure ≥ 140 mm Hg OR, diastolic blood pressure ≥ 90 mm Hg 
Patients with potentially clinically significant changes from baseline (i.e., elevated values 
per criteria above) will be summarized and flagged in data listings.
4.11.4
C-SSRS Scale
Columbia Suicide Severity Rating Scale is a suicide assessment questionnaire, which 
evaluates suicidal ideation and behavior. The questions after the screening visit are all 
based on “since last visit”. 


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Descriptive statistics will include the following tabulations by treatment group, with data 
pooled for pediatric and adult populations, across all visits of the double-blind period:

The number (%) of patients with suicidal ideation or suicidal behavior at each visit:  
A “yes” answer at any time during treatment period to any one of the suicidal ideation 
and behavior questions.

Shift tables that display the frequency of change in C-SSRS categories during the 
treatment period relative to baseline at each visit, as well as worst post-baseline visit.

Severity, frequency, duration, controllability, deterrents, reason (for pediatric patients, 
only severity and frequency are collected) of suicidal ideation at each visit

Actual and Potential Lethality/Medical Damage of Attempted Suicide (for actual 
attempts only) at each visit
The above tables will also be produced for visits in the open-label period, using the 
Open-Label Safety Population.
Data listings will provide individual patients’ responses to the C-SSRS questionnaire at 
all visits for each patient evaluated on this scale.  
4.12 Open-Label Extension
Analyses of data collected during the open-label extension phase will be presented using 
methodologies similar to those described for the double-blind period. Since the main 
objective of the open-label extension phase is to evaluate long-term safety, efficacy 
measurements will mainly be summarized descriptively, with some hypothesis testing for 
exploratory purposes, as part of the Final Analysis. For the Interim Analysis, open-label 
safety data will be summarized and presented in listings, while open-label efficacy data 
will only be presented in listings.
4.12.1
Open-Label Efficacy Analysis
For the Interim Analysis, the scope of analysis of open-label efficacy data is limited to 
double-blind data. Open-label efficacy data will be included in the listings only.
A later version of the SAP will be released, which will describe the scope of open-label 
efficacy analysis for the Final Analysis. The analysis is outlined below:
The effects of fosmetpantotenate during the open-label use will be examined based on 
data from the OL-FAS. 
For each efficacy endpoint collected in the open-label extension phase, scores will be 
tabulated using descriptive summary statistics (i.e., mean, SD, median minimum, and 
maximum for score totals; frequency tables for ordered categorical ratings) and graphical 
plots of mean values and mean change from baseline values at each study visit, overall 


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and by prior treatment in the double-blind period.  For this purpose, baseline is defined as 
the last assessment prior to the first dose of open-label fosmetpantotenate.
On an exploratory basis, hypothesis testing will be applied to the primary and secondary 
efficacy endpoints measured during the open-label period to assess changes from 
Baseline, both overall and in the groups to which patients were initially randomized for 
the double-blind period (i.e., fosmetpantotenate or placebo).  Between-group t tests will 
be used to explore whether improvement is greater for patients who convert to RE 024 
from placebo, compared to those maintained on active investigational product for the 
open-label period.  If the number of patients permits, mixed-effect linear models (as 
described for the primary efficacy analysis) may also be used to explore differences in the 
pattern of change over time between groups.
An additional exploratory analysis of PKAN-ADL may be undertaken using a mixed 
model, with Weeks since start of open-label treatment (continuous variable) as the fixed 
effect, baseline value (for the open-label extension period) as a covariate, and patient as 
the random effect. The first-order autoregressive AR(1) option will be used for modeling 
the covariance structure within-patient.  The estimate of the time effect (i.e., rate of 
change) and its 95% CI will be obtained. 
For all other efficacy measurements collected in the open-label extension phase, 
descriptive summary statistics will be presented by study visit.  Graphs will be provided 
for each efficacy endpoint to display mean values (with standard errors) for all patients 
evaluated at each visit during the open-label extension period.  
4.12.2
Open-Label Safety Analysis
For the Interim Analysis as well as the Final Analysis, all safety data collected for the 
Safety Population during the open-label period of the study will be presented using 
descriptive statistics, including summary tables of AEs, summary tables and graphical 
plots of mean values over time for continuous measurements (e.g., vital signs, weight), 
and frequency tables for categorical data obtained at each study visit.  Statistical methods 
and counting rules similar to those described for the double-blind treatment period will be 
applied.  The last measurement obtained prior to the first dose of open-label 
fosmetpantotenate will serve as the baseline value for assessing change from baseline in 
clinical laboratory data and vital signs during the open-label period of the study. 
4.13 Pharmacokinetic Analysis
Multiple-dose blood concentrations of fosmetpantotenate will be tabulated and 
summarized using descriptive statistics. For each analyte, concentration by patient, by 
nominal sample time, and by study day will be tabulated; summary statistics (n, 
arithmetic mean, geometric mean, coefficient of variation [CV, as percent], minimum, 
median, maximum) will be provided by nominal sample time and study day.  


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Additionally, summary statistics by nominal sample time irrespective of study day will 
also be provided. Graphical presentations of drug concentration will include individual 
concentration versus time from dose, by study day and irrespective of study day, and 
mean concentration versus time from dose, by study day and irrespective of study day.  
Each graph will be provided on linear and log-linear axes. 
Fosmetpantotenate concentrations may also be analyzed by nonlinear mixed-effects 
modeling, either alone or in conjunction with data from other studies. Available 
metabolite concentrations may be analyzed similarly. 
4.14 Biomarkers
Biomarker assessments (succinate, lactate, maleate, pyruvate, alanine, acetone, 
acetoacetic acid, 3-hydroxybutyric acid, 2-hydroxybutyric acid, and acetylCoA) will be 
listed and summarized by treatment group and time point using descriptive statistics 
(mean, median, standard deviation, standard error of the mean, coefficient of variation, 
minimum, and maximum) and graphical displays.  Change from baseline values will be 
evaluated at each time point, using paired t-tests (within-group) and 2-sample t tests to 
evaluate differences between treatment groups. Additional exploratory analyses of 
biomarkers will be described in a separate SAP.
5
References
1. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Statistical Principles for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite 
Guideline, Structure and Content of Clinical Study Reports (E3), 30 November 
1995.
3. Prakash A., et. al. The impact of analytic method on interpretation of outcomes in 
longitudinal clinical trials.  International J. of Clinical Practice. 2008; 62, 8: 1147-
1158.
4. Ouyang J, Carroll KJ, Koch G, Li J. Coping with missing data in phase III pivotal 
registration trials: Tolvaptan in subjects with kidney disease, a case study. 
Pharmaceutical Statistics. 2017;16 (4): 250-266
5. Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley 
& Sons Inc., New York.


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6. Mantel, N. and Haenszel, W. Statistical Aspects of Analysis of Data from 
Retrospective Studies of Disease. Journal of the National Cancer Institute. 1959; 
22, 719–748. 
7. The EuroQol Group  EuroQol-a new facility for the measurement of health-
related quality of life. Health Policy 1990; 16(3):199-208. 
8. Fischer JS, Jak AJ, Kniker JE, Rudick RA, Cutter G, Multiple Sclerosis Functional 
Composite (MSFC): Administration and Scoring Manual. 2001 (41 pages)
9. Coleman C, Sobieraj D, Marinucci L. Minimally important clinical difference of 
the Timed 25-Foot Walk Test: results from a randomized controlled trial in 
patients with multiple sclerosis. Curr Med Res Opin 2012;28:49–56
10. Westfall PH, Krishen A. Optimal weighted, fixed sequence, and gatekeeping 
multiple testing procedures. J Stat Planning Inference; 2001; 99:25-40.
11. Mosteller, RD. Simplified calculation of body-surface area. N Engl J Med 1987. 
317 (17): 1098. 
12. Janssen B, Szende A and Ramos-Goni JM.  Self-Reported Population Health: An 
International Perspective based on EQ-5D. Dordrecht: Springer Open 2014. 
13. Choi, S. W., Podrabsky, T., McKinney, N., Schalet, B. D., Cook, K. F., & Cella, 
D. (2012). PROSetta Stone® Analysis Report: a Rosetta Stone for Patient 
Reported Outcomes. Volume 1. Chicago, IL: Department of Medical Social 
Sciences, Feinberg School of Medicine, Northwestern University.
14. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 1982; 38: 29-41
15. American College of Cardiology (2017, Nov 13) New ACC/AHA High Blood 
Pressure Guidelines Lower Definition of Hypertension. Retrieved from 
http://www.acc.org
6
Programming Considerations
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® Version 9.3 (or higher), except for the population pharmacokinetic outputs. 
Computer-generated output will adhere to the following specifications.
6.1
Table, Listing, and Figure Format
6.1.1
General
1. All TLFs will be produced in landscape format.
2. All TLFs will be produced using the Times New Roman font, size 8 (minimum).


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3. The data displays for all TLFs will have a 1.5-inch binding margin on top of a 
landscape oriented page and a minimum 1-inch margin on the other 3 sides.
4. Headers and footers for figures will be in Times New Roman font, size 8 
(minimum).
5. Legends will be used for all figures with more than 1 variable, group, or item 
displayed.
6. TLFs will be in black and white (no color).
7. Only standard keyboard characters will be used in the TLFs. Special characters, 
such as non-printable control characters, printer-specific, or font-specific 
characters, will not be used. Hexadecimal-derived characters will be used, where 
possible, if they are appropriate to help display math symbols (e.g., μ). Certain 
superscripts (e.g., cm2) will be employed on a case-by-case basis.
8. Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats.
6.1.2
Headers
All output will have the following header at the top of the page:
Retrophin, Inc.
FOSMETPANTOTENATE  (Phosphopantothenate 
Replacement Therapy)
Page n of N
Clinical Study Number 024PKAN15004
All output will have page numbers. TLFs should be internally paginated in relation to the 
total length (i.e., the page number should appear sequentially as page n of N, where N is 
the total number of pages in the table).
6.1.3
Display Titles
Each TLF will be identified by a numeral, and the designation (i.e., Table 1) should be 
centered above the title. A decimal system (14.x-y.z, 14.x.y-z, and 16.2.x-y) will be used 
to identify TLFs with related contents. The title will be centered in initial capital 
characters. The analysis set will be identified on the line immediately following the title. 
The title and table designation will be single spaced. A solid line spanning the margins 
will separate the titles from the column headers. There will be 1 blank line between the 
last title line and the solid line.
Table 14.x.y-z
First Line of Title
Second Line of Title if Needed


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Full Analysis Set
6.1.4
Column Headers
1. Column headings will be displayed immediately below the solid line described 
above, in initial upper-case characters.
2. For numeric variables, units will be included in column or row heading when 
appropriate.
3. Analysis set sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the 
‘n’ used for the descriptive statistics representing the number of patients in the 
analysis set.
4. The order of treatment labels in tables and listings will be: placebo, 
fosmetpantotenate for the double-blind treatment period; and Open-Label 
fosmetpantotenate (after Double-Blind placebo), Open-Label fosmetpantotenate 
(after Double-Blind fosmetpantotenate) for the open-label extension phase; and 
Total (if applicable for either phase of the study).
6.1.5
Body of the Data Display
1. Listings will be sorted for presentation in order of study phase, treatment group, 
as above, patient ID, collection day, and collection time.
2. For ordered categorical parameters, frequency tables will present all categories of 
the parameter between the minimum and maximum level, even if n=0 for all 
treatment groups in a given category.  For example, the frequency distribution for 
symptom severity would appear as:
Severity Rating
n
severe
0
moderate
8
mild
3
Where percentages are presented in these tables, any counts of 0 will be presented 
as 0 and not as 0 (0%).
3. If the categories for a table are not ordered (e.g., Medical History, Reasons for 
Discontinuation from the Study, etc.), then only those categories for which there 
is at least 1 patient represented in 1 or more groups will be included.
4. An Unknown or Missing category will be added to the summary table of any 
categorical parameter for which information is not available for 1 or more patients.
5. Unless otherwise specified, the estimated mean and median for a set of values will 
be displayed to 1 more significant digit greater than the original values; standard 
deviation (SD) will be presented to 2 more significant digits than the original 
values. The minimum and maximum will be reported at the same number of 
significant digits as the original values. LSmeans will be reported to 1 decimal 
place, and corresponding CI’s to 2 decimal places. For example, for systolic blood 
pressure:


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n
XX
Mean
XXX.X
SD
X.XX
Median
XXX.X
Minimum
XXX
Maximum
XXX
6. Data in columns of a table will be formatted as follows:

alphanumeric values left-justified;

whole numbers (e.g., counts) right-justified; and

numbers containing fractional portions decimal-aligned.
7. Percentage values will be formatted with 1 digit to the right of the decimal point 
in parentheses, 1 space after the count (e.g., 7 (12.8%), 13 (5.4%)). Less-than 
signs (e.g., “<0.1%”) will appear when values are >0.0% and <0.1% (but not 
equal to 0.0%). Unless otherwise noted, the denominator for calculating 
percentages will be the number of patients in a given treatment group and analysis 
set. 
8. Tabular displays of data for prior/concomitant medications and all tabular 
displays of adverse event data will be presented by body system, drug class, or 
SOC with the highest occurrence in the fosmetpantotenate treatment group for 
the double-blind period, or in the group maintained on fosmetpantotenate in the 
open-label extension phase, in decreasing order. Within the body system, drug 
class and SOC, medical history (by PT), drugs (by ATC2 code), and adverse 
events (by PT) will be displayed in decreasing order. If the incidences of multiple 
terms are identical, they will be sorted alphabetically.
9. Missing data will be left as blank in patient listings. 
10. Dates will be formatted in SAS Date9 date format ddmmmyyy (e.g., 
“27Jan2018”). Missing portions of dates will be represented on patient listings as 
blank (e.g., “Jan2018”). Dates that are missing because they are not applicable for 
the particular patient will be presented as “N/A”, unless otherwise specified.
11. All observed time values will be presented using a 24-hour clock in hh:mm:ss 
format (e.g., “01:35:45”, “21:26”). Time values will be reported only if they were 
measured as part of the study.
6.1.6
Footnotes
1. A solid line spanning the margins will separate the body of the data display from 
the footnotes. 
2. All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display.
3. Each new footnote will start on a new line.
4. Footnotes will appear on each page. Patient specific footnotes will generally be 
avoided.
5. Footnotes will be used sparingly, and only if they add value to the table, figure, or 
data listing.  If a data display has more than 4 footnotes, they will all appear on a 


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cover page for the data display; only those footnotes essential for clarification of 
the data will be repeated on each page. 
6. All abbreviations used in a given display will be defined in the corresponding 
footnote.
7. The last line of the footnote section will be a standard source line, indicating the 
data source used by the SAS program that produced the data display, the name of 
the SAS program, and the listing source (e.g., “Data source: xyzabc.sas7bdat    
Program source: myprogram.sas   Listing source: 16.x.y.z”).
6.2
Data-Handling Rules
This section describes naming conventions and rules for calculations common to all 
applicable tables. Some rules specific to a table can be found in the relevant mock-ups.
6.2.1
Unit Conversion to Months/Years
If months are calculated for a duration, then the following conversion is used:
Duration_in_months = Duration_in_days / 30.42
If years are calculated for a duration, then the following conversion is used:
Duration_in_years = Duration_in_days / 365.25
6.2.2
Visits
Relative Study Day: The date of first dose of study treatment is Day 1. A minus (–) sign 
indicates days prior to date of first dose (e.g., Day -5 represents 5 days before first dose.) 
There is no Day 0. 
If a visit is before the date of first dose, the relative study day is calculated as (Visit Date 
– Date of First Dose). Otherwise, the relative study day for a specific visit is calculated as 
(Visit Date – Date of First Dose +1).

Baseline: For all study variables, baseline for the double-blind period is defined as the 
last measurement obtained prior to the first dose of double-blind study medication, 
unless otherwise specified; for the open-label extension study, baseline is the last 
measurement obtained prior to the first dose of open-label study medication 
(fosmetpantotenate).

Post baseline: post baseline visits will be nominal visits, as scheduled in the protocol.
6.2.3
Demographics and Baseline Characteristics

Height (in cm) = height (in inches) * 2.54

Weight (in kg) = weight (in lbs) * 0.4535

Body Mass Index (BMI) (kg/m2) = weight (in kg) / [height (in meters)] **2


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
Body Surface Area8 (BSA) (m2) = [height (cm) * weight (kg)/3600]½
6.2.4
Prior and Concomitant Medications
Prior and concomitant medications will be coded and classified using the World Health 
Organization (WHO) Drug Dictionary Sep 2018 B3 Format.
When partial dates are present in the data, both a partial start date and/or a partial stop 
date will be evaluated to determine whether it can be conclusively established that the 
medication either ended prior to first dose of blinded investigational product or started 
after.  If the above cannot be conclusively established based on the partial and/or present 
dates, then the medication will be counted as concomitant for the double-blind period and 
open-label period (if the patient has reached the open-label period). 
The imputation method for the handling of missing or partial dates will be as follows.
When the start date and the stop date are both incomplete for a patient, the start date will 
be imputed first:
Partial start date
Missing Month and Day

If the year of the partial start date is the same as the year of the first dose of 
blinded investigational product, then the month and day of the first dose of 
blinded investigational product will be assigned to the missing fields.

If the year of the partial start date is before the year of the first dose of blinded 
investigational product, December 31 will be assigned to the missing fields.

If the year of the partial start date is after the year of the first dose of blinded 
investigational product, January 1 will be assigned to the missing fields.
Missing Month Only

If only the month is missing, then the month only will be imputed according to the 
procedure above.
Missing Day Only

If the month and year of the partial start date are the same as the month and year 
of the first dose of blinded investigational product, then the day of the first dose of 
blinded investigational product will be assigned to the missing day.

If either the year of the partial start date is before the year of the date of the first 
dose of blinded investigational product or if both years are the same but the month 
of the partial start date is before the month of the date of the first dose of blinded 
investigational product, then the last day of the month will be assigned to the 
missing day.

If either the year of the partial start date is after the year of the date of the first 
dose of blinded investigational product or if both years are the same but the month 
of the incomplete start date is after the month of the date of the first dose of 


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blinded investigational product, then the first day of the month will be assigned to 
the missing day.
If the stop date is complete and the imputed start date as above is after the stop date, then 
the start date will be imputed with the stop date.
Partial stop date 
Missing Month and Day

If the year of the partial stop date is the same as the year of the last dose of 
investigational product (double-blind or open-label), then the month and day of 
the last dose of investigational product (double-blind or open-label) will be 
assigned to the missing fields.

If the year of the incomplete stop date is before the year of the last dose of 
investigational product (double-blind or open-label), December 31 will be 
assigned to the missing fields.

If the year of the incomplete stop date is after the year of the last dose of 
investigational product (double-blind or open-label), January 1 will be assigned 
to the missing fields.
Missing Month Only

If only the month is missing, then the month only will be imputed according to the 
above procedure.
Missing Day Only

If the month and year of the partial stop date are the same as the month and year 
of the last dose of investigational product (double-blind or open-label), then the 
day of the last dose of investigational product (double-blind or open-label) will be 
assigned to the missing day.

If either the year of the incomplete stop date is before the year of the date of the 
last dose of investigational product (double-blind or open-label) or if both years 
are the same but the month of the partial stop date is before the month of the date 
of the last dose of investigational product (double-blind or open-label), then the 
last day of the month will be assigned to the missing day.

If either the year of the partial stop date is after the year of the date of the last 
dose of investigational product (double-blind or open-label) or if both years are 
the same but the month of the partial stop date is after the month of the date of the 
last dose of investigational product (double-blind or open-label), then the first day 
of the month will be assigned to the missing day.
If the imputed stop date is before the start date (imputed or non-imputed start date), then 
the imputed stop date will be equal to the start date.
6.2.5
Adverse Events
Adverse events will be coded and classified using the MedDRA coding dictionary 
Version 20.0. The specific dictionary version will appear in the actual tables/listings.


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AEs with missing start and end dates will be considered as treatment emergent for the 
open-label period, taking a “worst-case” approach. If the patient has not yet reached the 
open-label period, or if the AE has a stop date overlapping with the double-blind study 
period, then the AE will be counted as treatment-emergent for the double-blind period. 


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