Clinical trial NCT02736188
Conditions: Hereditary Inclusion Body Myopathy Distal Myopathy With Rimmed Vacuoles Distal Myopathy, Nonaka Type GNE Myopathy Quadriceps Sparing Myopathy
Keywords: GNE Myopathy GNEM Nonaka Hereditary Inclusion Body Myopathy HIBM DMRV QSM
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2016-05-02; Completion date: 2018-01-10
Enrollment: 143 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to evaluate the long-term safety and efficacy of Ace-ER treatment in subjects with GNEM.

Detailed description:
This Phase 3b extension study will assess the long-term safety of Ace-ER in patients who participated in and completed study UX001-CL301 (NCT02377921), study UX001-CL202 (NCT01830972), and study UX001-CL203 (NCT02731690).

Arms: arm 1: Participants will take 4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day (TID).
Interventions: intervention 1: Aceneuramic Acid Extended-Release Tablets
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_001.pdf: 
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Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL302 Amendment 1 
17 June 2016 
 
 
The original protocol of UX001-CL302 (dated 10 Feb 2016) has been modified by 
Amendment 1 to incorporate a number of changes based on additional information acquired 
since the beginning of the study.  The major changes to the protocol impacting the conduct of 
the study are summarized below.  Additional changes have also been made to provide 
supportive background information and rationale for the proposed changes (along with minor 
edits for consistency and clarity) but are not detailed in this summary. 
1. The protocol was amended to allow for the inclusion of subjects who complete the 
UX001-CL202 study. This change affected multiple sections of the protocol, 
including the synopsis, Table 2.1, and Inclusion Criterion 1 (Section 7.3.1). Subjects 
enrolling from the UX001-CL202 study will follow the same schedule of events as 
subjects who roll over from the UX001-CL301 study.  
Rationale: This change was made to provide subjects in UX001-CL202 an 
opportunity to continue treatment with Ace-ER (6 g/day) and obtain long-term safety 
and efficacy data in UX001-CL302. 
2. With regard to Change #1 above, the amendment clarifies that subjects who rollover 
from UX001-CL202 will receive 6 g/day of Ace-ER. No subjects will receive 
12 g/day in this study. 
Rationale: Evaluations of Ace-ER in patients with GNEM have shown that the 
6 g/day is the optimal dose. Clinical efficacy with 6 g/day surpassed the 3 g/day dose 
and 12 g/day did not appear to confer additional benefit beyond that observed with 
6 g/day, with an increase in GI disturbance, most notably flatulence. 
3. Treatment duration language changed to remove “until commercial availability of 
study drug in subject’s region.” This change affected multiple sections of the 
protocol, including Synopsis, Figure 2.1 and Section 7. The treatment duration on the 
study will be 24 Months. 
Rationale: This change was made to incorporate feedback from MHRA in order to 
clarify end of study. 
4. Table 7.5.5.5.1 was updated to include blood/RBC and leukocyte esterase to the 
urinalysis panel and to add a footnote indicating that microscopic evaluation will be 
conducted for abnormal urine test results.  


Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 3 
Rationale:  The change was made to clarify the analytes that will be tested in 
urinalysis and confirm that microscopic evaluation will be conducted for abnormal 
test results.  
5. Language was added to the synopsis and multiple sections of the protocol instructing 
that for UX001-CL202 subjects, assessments that cannot be safely performed due to 
disease progression should not be administered.   
Rationale:  This added text will ensure the safety of subjects who rollover from the 
UX001-CL202 study and are unable to perform an assessment due to disease 
progression. 
6. The number of samples drawn from each subject (Table 7.5.5.5.1.1) was increased for 
the serum sialic acid assessments from 2 samples to 5 samples. The total volume of 
blood sample to be obtained increased from 87 mL to 108 mL for subjects rolling 
over from UX001-CL203 and from 108 to 129.5 for subjects rolling over from 
UX001-CL301. 
Rationale:  The change was made to clarify the total blood volume required to ensure 
a primary and back-up serum sialic acid sample are obtained and also to clarify the 
total volume of blood to be obtained during the study. 
7. Record Retention: Section 8.4.3 has been updated to state that all study records must 
be retained for at least 25 years after the end of the clinical trial or in accordance with 
national law. 
Rationale: This administrative change has been made to reflect upcoming changes to 
EU clinical trial regulations and current regulations by other health authorities. 
 


Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 4 
2  SYNOPSIS 
TITLE OF STUDY: 
A Phase 3b Open-label Extension Study to Evaluate the Safety and Efficacy of Aceneuramic Acid 
Extended-Release (Ace-ER) Tablets in Patients with GNE Myopathy (GNEM) or Hereditary Inclusion 
Body Myopathy (HIBM) 
PROTOCOL NUMBER: 
UX001-CL302 
STUDY SITES: 
Approximately 15 sites, globally  
PHASE OF DEVELOPMENT: 
Phase 3b 
RATIONALE: 
GNEM (or HIBM), is a severe, progressive myopathy caused by a defect in the biosynthetic pathway 
for sialic acid (SA).  Substrate replacement is a potential therapeutic strategy based on the success of 
replacing missing SA and reducing muscle disease in a relevant mouse model of the human disease. 
Successful use of SA replacement therapy in humans is believed to depend upon providing steady, 
long-term exposure to the compound in an extended-release form (such as Ace-ER), given SA’s short 
half-life. A Phase 2, placebo-controlled study evaluating Ace-ER at 2 doses for 48 weeks 
(UX001-CL201) found that the higher dose of 6 g/day Ace-ER stabilized a composite of upper 
extremity muscle strength (UEC score) compared with placebo or the lower 3 g/day dose; this finding 
was supported by improvements in functional outcome on the GNE Myopathy Functional Activities 
Scale (GNEM-FAS). This Phase 3b extension study will assess the long-term safety of Ace-ER in 
patients who participated in and completed the UX001-CL202, UX001-CL301, or UX001-CL203 
studies; in addition, efficacy of 6 g/day Ace-ER will be further evaluated in GNEM patients, including 
those able to walk ≥200 m in the 6-minute walk test (6MWT) (roll over subjects from UX001-CL301 
and naïve subjects from UX001-CL202) and GNEM patients with severe ambulatory impairment (roll 
over subjects from UX001-CL203).  
OBJECTIVE: 
• 
To evaluate the long-term safety and efficacy of Ace-ER treatment of GNE Myopathy subjects 
ENDPOINTS: 
Overall Safety Endpoint (Primary Endpoint): Evaluate the long-term safety of 6 g/day Ace-ER 
treatment in subjects with GNE Myopathy 
Overall Efficacy Endpoints:  Evaluate the long-term effect of 6 g/day of Ace-ER treatment in 
subjects with GNEM. Efficacy will be evaluated as follows: 
 
For Subjects Enrolling from UX001-CL202 and UX001-CL301:  
• 
Muscle strength as measured by dynamometry 
• 
Mobility, strength, and function using a series of physical performance measures 
• 
Functional disability using an patient- and clinician-reported questionnaire 


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Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 6 
NUMBER OF SUBJECTS PLANNED: 
Approximately 165 adult subjects with GNEM are expected to roll-over from the UX001-CL202, 
UX001-CL301 or UX001-CL203 studies to participate in this extension study. 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Have completed the UX001-CL202, UX001-CL301, or UX001-CL203 studies 
2. Willing and able to provide written, signed informed consent after the nature of the study has been 
explained, and before any research-related procedures are conducted 
3. Willing to comply with all study procedures 
4. Female participants of child‐bearing potential or male participants with female partners of 
child-bearing potential who have not undergone a bilateral salpingo‐oophorectomy and are 
sexually active must consent to use a highly effective method of contraception as determined by 
the site investigator (i.e., oral hormonal contraceptives, patch hormonal contraceptives, vaginal 
ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, 
tubal ligation or true abstinence [when this is in line with the preferred and usual lifestyle of the 
subject], which means not having sex because the subject chooses not to), from the  period 
following the signing of the informed consent through 30 days after last dose of study drug 
5. Females of childbearing potential must have a negative pregnancy test at Screening and be willing 
to have additional pregnancy tests during the study.  Females considered not of childbearing 
potential include those who have been in menopause for at least two years, have had tubal ligation 
at least one year prior to Screening, or who have had a total hysterectomy or bilateral 
salpingo-oophorectomy 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Ingestion of N-acetyl-D-mannosamine (ManNAc) or related metabolites; intravenous 
immunoglobulin (IVIG); or anything that can be metabolized to produce SA in the body within 
60 days prior to the Screening Visit 
2. Has had any hypersensitivity to SA or its excipients that, in the judgment of the investigator, 
places the subject at increased risk for adverse effects 
3. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any 
time during the study 
4. Use of any investigational product (except for Ace-ER/SA-ER as part of the parent study) or 
investigational medical device within 30 days prior to Screening, or anticipated requirement for 
any investigational agent prior to completion of all scheduled study assessments 
5. Has a condition of such severity and acuity, in the opinion of the investigator, that it warrants 
immediate surgical intervention or other treatment or may not allow safe participation in the study 
6. Has a concurrent disease, active suicidal ideation, or other condition that, in the view of the 
investigator, places the subject at high risk of poor treatment compliance or of not completing the 
study, or would interfere with study participation or would affect safety 


Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 7 
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
Each Ace-ER tablet contains 500 mg of SA in an extended release formulation for a total weight of 
1200 mg/tablet. The drug will be administered by the oral route and will be divided into a TID 
regimen: 4 tablets taken in the morning, early evening, and before bedtime (qHS). The dose should be 
taken with food (i.e., within 30 minutes after a meal or snack). 
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION: 
Not applicable  
DURATION OF TREATMENT: 
The total treatment duration will be 24 months. A Safety Follow-up visit will be conducted by phone 
30 days (+5 days) after last dose of study drug. 
CRITERIA FOR EVALUATION: 
Safety: 
Safety will be evaluated by the incidence frequency, and severity of AEs and SAEs, and clinically 
significant changes from baseline to scheduled time points in the following:  
• 
Interval history 
• 
Vital signs 
• 
Physical examination results 
• 
Clinical laboratory results 
• 
C-SSRS (a measure of suicidal ideation and behavior) 
• 
Concomitant medications 
 
Drug Concentration Measurements:  
Serum Free Sialic Acid: The change in free SA level in serum (trough) will reflect the absorption of 
SA during treatment. 
Urine Sialic Acid - Free, Total and Bound: The urine SA level (corrected for creatinine) will reflect 
the absorption of SA and the incorporation into sialylated proteins and oligosaccharides during 
treatment.   
Urine Testing for ManNAc: Urine will be tested for the presence of ManNAc to detect compliance 
with prohibited medication restrictions. 
Efficacy: 
Efficacy evaluations will be based on the parent study (UX001-CL202, UX001-CL301, or 
UX001-CL203) from which the subjects enroll. Subjects enrolling from UX001-CL202 will follow the 
same schedule of events as subjects who roll over from UX001-CL301. For UX001-CL202 subjects, 
assessments that cannot be safely performed by a subject due to disease progression should not be 
administered.  
UX001-CL301 and UX001-CL202: For subjects enrolling from these studies, efficacy will be 
evaluated by changes in upper and lower extremity muscle strength and function, and self-reported 
physical functioning.  Results from baseline assessments in this study will be compared with those of 
post-treatment assessments listed in the Schedule of Events (Table 2.1), with efficacy conclusions 


Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 8 
based on change from baseline over the treatment period.  
Primary Clinical Efficacy Variable :    
Upper Extremity Composite Score: Muscle strength based on the maximum voluntary isometric 
contraction (MVIC) against a dynamometer will be measured bilaterally in the following upper 
extremity muscle groups: gross grip, shoulder abductors, elbow flexors, and elbow extensors.  
The UEC is derived from the sum of the average of the right and left total force values (measured 
in kg).  
Secondary Clinical Efficacy Variables:  
• 
GNEM Functional Activities Scale:  Physical functioning will be assessed using a disease-specific 
measure.  Scores on the mobility domain and the upper extremity domain of the GNEM-FAS will 
be analyzed separately as secondary variables. 
• 
Lower Extremity Composite (LEC) Score:  Muscle strength based on MVIC against a 
dynamometer will be measured bilaterally in the following lower extremity muscle groups: knee 
flexors, hip flexors, hip extensors, hip abductors and hip adductors. The LEC is derived from the 
sum of the average of the right and left total values (measured in kg).  
• 
Number of Stands in the Sit-to-Stand Test:  Lower extremity function will be assessed using a 
sit-to-stand test.  The number of times the subject can rise from a seated to a standing position in a 
30-second period will be recorded. 
• 
Number of Lifts in the 30-second Weighted Arm Lift Test:  Upper extremity function will be 
assessed using a weighted arm lift test performed bilaterally.  The number of times the subject can 
raise a 1 kg weight above the head in a 30-second period will be recorded. 
• 
Total Force (kg) and Percent Predicted Force in the Knee Extensors:  Bilateral total force will be 
reported. The percent predicted total force value will be determined based on reference equations 
adjusting for age, gender, height, and weight. 
• 
Meters Walked in the Six-Minute Walk Test:  The total distance walked (meters) in a six minute 
period will be measured as well as the percent predicted distance based on normative data for age 
and gender.  
Tertiary Efficacy Variables:   
• 
Upper Extremity Composite and Lower Extremity Composite Percent Predicted:  The percent 
predicted total force values will be determined based on reference equations adjusting for age, 
gender, height, and weight. The percent predicted force will be calculated for each side and the 
bilateral percent predicted values will be averaged for each upper extremity muscle group.  
The mean of the four averages in percent predicted scores will be calculated to create a percent 
predicted UEC score, and analyzed relative to baseline to create a UEC mean change in percent 
predicted score.  Similar methodology will be used to determine the percent predicted total force 
values for the LEC.   
• 
Total Force (kg) and Percent Predicted in Each Individual Muscle Group: Bilateral total force and 
percent predicted total force for each individual muscle group included in the UEC and LEC will 
be reported.  
• 
Total Score on the GNEM-FAS 
• 
Self-Care Domain Score on the GNEM-FAS 
• 
Score on the Individualized Neuromuscular Quality of Life Questionnaire:  The scores on a 45-


Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 9 
item self-report questionnaire on the impact of key muscle disease symptoms on the ability to 
perform basic activities of daily living, functional independence, relationships and overall 
well-being will be recorded.  
• 
Creatine Kinase Levels:  CK levels in serum will be measured to assess the degree of reduction of 
CK levels observed as a surrogate for muscle injury.   
UX001-CL203: Efficacy will be evaluated by changes in upper and lower extremity muscle strength, 
self-reported physical functioning, and health related quality of life outcome measures. Results from 
baseline assessments will be compared with those of post-treatment assessments listed in the Schedule 
of Events (Table 2.1), with efficacy conclusions based on change from baseline over the treatment 
period. 
Clinical Efficacy Variables:   
• 
GNEM-FAS – Expanded Version: Physical functioning will be assessed using a disease-specific, 
self-reported outcome measure. Scores on the mobility, self-care and upper extremity domains of 
the GNEM-FAS Expanded Version will be analyzed separately as secondary variables 
• 
Upper Extremity Muscle Strength: Muscle strength measured as the maximum voluntary isometric 
contraction (MVIC) against a dynamometer will be measured bilaterally in the following upper 
extremity muscle groups: grip, key pinch, shoulder abductors and wrist extensors. A UEC, will be 
derived as the sum of the average of the right and left total force values (measured in kg) when 
force values are available for all muscle groups tested 
• 
Lower Extremity Muscle Strength: Muscle strength based on the maximum voluntary isometric 
contraction (MVIC) against a dynamometer will be measured bilaterally for the knee extensors in 
subjects that can be positioned for testing. 
Exploratory Variables: 
• 
Short Form Health Survey-36 (SF-36): Quality of life will be assessed using the SF-36 with scores 
reported for the Physical Component Summary, Mental Component Summary and the eight 
subscales, including physical functioning, role-physical, bodily pain, general health, social 
functioning, role-emotional, vitality, and mental health 
• 
Biomarkers: Serum will be obtained at all study visits to evaluate CK, serum aceneuramic acid, 
and potential biomarkers of sialylation and other markers of muscle injury and remodeling 


Protocol Number:  UX001-CL302  
Amendment 1: 17 June 2016 
 
 
Proprietary and Confidential 
Page 10 
STATISTICAL METHODS: 
Sample Size: 
Approximately 165 adult subjects with GNEM are expected to roll-over from UX001-CL202 (N=55), 
UX001-CL301 (N=80), and UX001-CL203 (N=30) studies to participate in this extension study. 
Efficacy Analyses: 
Separate analyses will be performed for subjects enrolling from each parent study. 
The full analysis set will include all subjects with a baseline measurement and at least one 
post-baseline measurement. This set will be used for the analyses of all efficacy endpoints. 
Baseline values for each endpoint will be defined as the last scheduled data collection visit before first 
dose according to the Schedule of Events (Table 2.1).  
Efficacy analyses will use generalized estimating equation (GEE) to evaluate trends over time with 
respect the changes from baseline for the primary variables, and all secondary and tertiary efficacy 
variables. Baseline will be included as a covariate in the model. This method will be the primary 
analysis method for all repeated measures endpoints.  
The statistical analyses will be reported using summary tables, figures, and data listings. Statistical 
tests will be 2-sided at the alpha=0.05 significance level. Continuous variables will be summarized 
with means, standard deviations, medians, minimums, and maximums. Categorical variables will be 
summarized by counts and by percentages of subjects in corresponding categories. 
Safety Analyses: 
Safety will be evaluated for the overall study population as well as for subjects from the 
UX001-CL202, UX001-CL301, and UX001-CL203 studies. The safety analysis set consists of all 
subjects who receive at least one dose of study drug. Safety will be evaluated by the incidence, 
frequency, and severity of AEs and SAEs, and clinically significant changes from study baseline to 
scheduled time points in: interval history, vital signs, physical examination findings, clinical 
laboratory evaluations, C-SSRS, and concomitant medications 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), Preferred 
Term (PT), severity, and relationship to treatment. The numbers (frequency) and incidence rates of 
AEs and SAEs will be summarized by treatment group. A by-subject listing will be provided for those 
subjects who experience a serious adverse event (SAE), including death, or experience an adverse 
event (AE) associated with early withdrawal from the study or study drug treatment. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e. outside of reference 
ranges) and/or clinically significant abnormalities will be presented for each clinical laboratory 
measurement.  


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Table 2.1: 
Schedule of Events 
ASSESSMENTS AND EVENTS* 
SCREENING/ 
BASELINEa 
TREATMENT PERIOD 
 
  
MONTH 2 
(WEEK 8) 
VISIT  
(± 5 DAYS)
 ǂ 
MONTH 4 
(WEEK 16) 
VISIT 
(± 5 DAYS) ǂ  
MONTH 6 
(WEEK 24) 
VISIT 
(± 5 DAYS) 
MONTH 12 
VISIT (WEEK 
48) 
(± 2WEEKS) 
MONTH 18 
VISIT 
(WEEK 72) 
(± 2WEEKS) 
MONTH 24 
(WEEK 96) 
OR EARLY 
TERMINATION 
VISIT  
(± 2WEEKS) l 
SAFETY 
FOLLOW 
UP (+ 5 
DAYS) m 
SAFETY ASSESSMENTS (ALL SUBJECTS) 
 
INFORMED CONSENT  
X 
 
 
 
 
 
 
 
MEDICAL HISTORY 
X 
 
 
 
 
 
 
 
INTERVAL HISTORY b 
X 
X 
X 
X 
X 
X 
X 
 
PHYSICAL EXAMINATION  c 
X 
X 
X 
X 
X 
X 
X 
 
VITAL SIGNS  
X 
X 
X 
X 
X 
X 
X 
 
HEMATOLOGY, CHEMISTRY PANEL, 
URINALYSIS 
X 
X 
X 
X 
X 
X 
X 
 
PREGNANCY TEST 
X 
X 
X 
X 
X 
X 
X 
 
CONCOMITANT MEDICATIONS 
X 
X 
X 
X 
X 
X 
X 
X 
SUICIDAL IDEATION AND BEHAVIOR  (C-
SSRS) d 
X 
X 
X 
X 
X 
X 
X 
 
ADVERSE EVENTS  
X  
X 
X 
X 
X 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS (ALL SUBJECTS) 
 
BIOMARKERS: CK, FREE SERUM SA, AND 
BIOMARKERS OF SIALYATION AND OTHER 
BIOMARKERS e 
X 
X 
X 
X 
X 
X 
X 
 
FREE, TOTAL AND BOUND URINE SA LEVELS f 
X 
X 
X 
X 
X 
X 
X 
 
URINE TEST FOR MANNAC g 
X 
X 
X 
X 
X 
X 
X 
 


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ASSESSMENTS AND EVENTS* 
SCREENING/ 
BASELINEa 
TREATMENT PERIOD 
 
  
MONTH 2 
(WEEK 8) 
VISIT  
(± 5 DAYS)
 ǂ 
MONTH 4 
(WEEK 16) 
VISIT 
(± 5 DAYS) ǂ  
MONTH 6 
(WEEK 24) 
VISIT 
(± 5 DAYS) 
MONTH 12 
VISIT (WEEK 
48) 
(± 2WEEKS) 
MONTH 18 
VISIT 
(WEEK 72) 
(± 2WEEKS) 
MONTH 24 
(WEEK 96) 
OR EARLY 
TERMINATION 
VISIT  
(± 2WEEKS) l 
SAFETY 
FOLLOW 
UP (+ 5 
DAYS) m 
TREATMENT DISPENSING AND COMPLIANCE (ALL SUBJECTS) 
 
TREATMENT DISPENSED h 
X 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE 
 
X 
X 
X 
X 
X 
X 
 
EFFICACY ASSESSMENTS (UX001-CL202 AND UX001-CL301 SUBJECTS) i 
 
DYNAMOMETRY 
X 
X 
X 
X 
X 
X 
X 
 
6-MINUTE WALK TEST (6MWT)  
X 
X 
X 
X 
X 
X 
X 
 
SIT-TO-STAND TEST  
X 
X 
X 
X 
X 
X 
X 
 
WEIGHTED ARM LIFT TEST   
X 
X 
X 
X 
X 
X 
X 
 
GNE MYOPATHY FUNCTIONAL 
ACTIVITIES SCALE (GNEM-FAS) 
X 
X 
X 
X 
X 
X 
X 
 
INDIVIDUALIZED NEUROMUSCULAR 
QUALITY OF LIFE QUESTIONNAIRE  
(INQOL) 
X 
X 
X 
X 
X 
X 
X 
 
EFFICACY ASSESSMENTS (UX001-CL203 SUBJECTS) 
 
DYNAMOMETRY j 
X 
 
 
X 
X 
X 
X 
 
GNEM-FAS k 
X 
 
 
X 
X 
X 
X 
 
SHORT FORM HEALTH SURVEY-36 
(SF-36) 
X 
 
 
X 
X 
X 
X 
 
 
* 
Refer to study-related materials for recommended timing and order of assessments to be administered at each study visit. 


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ǂ 
Subjects who roll-over from the UX001-CL203 study will not have a Month 2 or Month 4 visit. Assessments at these visits will only be performed for 
subjects who roll-over from the UX001-CL202 and UX001-CL301 studies. UX001-CL202 subjects will complete the same efficacy assessments as the 
subjects who rollover from UX001-CL301.  
a. 
Potential subjects can be screened up to 5 days after the last dose on the parent study.  Baseline Visit should be not be more than 5 days after Screening 
visit. Subjects can have a concurrent Screening and Baseline visits. Study drug will be dispensed only after all study procedures at the Baseline Visit 
have been performed. For subjects who discontinue prior to completing the study, every reasonable effort should be made to perform the Early 
Termination (ET) procedures within four weeks of discontinuation. 
b. Interval history will include any signs, symptoms, or events (i.e. falls) experienced by the subject since the prior study visit that are not related to study 
procedure(s) performed at prior study visits or study drug.  Interval history may include exacerbation or improvement in existing medical conditions 
(including the clinical manifestations of GNEM) that might interfere with study participation, safety, and/or positively or negatively impact performance 
of functional assessments. 
c. 
The physical examinations at Baseline/Screening, including a neurological examination; all others will be brief physical examinations. If a patient is 
unable to stand or has significant postural issues that interfere with collection of a standing height, self-reported adult height should be captured. 
d. 
Baseline C-SSRS administered at Baseline/Screening visit (may be same as last visit in parent study). Since Last Visit C-SSRS administered at all 
subsequent visits. 
e. 
Serum will be obtained at all study visits to evaluate creatine kinase (CK), serum SA and potential biomarkers of sialylation, and other markers of 
muscle injury and remodeling. 
f. 
Blood samples, preferably pre dose, and first-morning void urine will be collected to assess trough SA levels; record volume of urine collected.  
g. An aliquot from first morning void urine will be used for assessment of ManNAc; record volume of urine collected. 
h. 
Subjects should be instructed to return unused study drug and packaging to every visit. Note that all subjects being treated with 12 g/day Ace-ER in 
UX001-CL202 will be transitioned to 6 g/day Ace-ER dose in this protocol.  
i. 
For UX001-CL202 subjects, assessments that cannot be safely performed by a subject due to disease progression should not be administered.   
j. 
For subjects enrolling from UX001-CL203, lower extremity muscle strength for knee extensors muscle group only. 
k. For subjects enrolling from UX001-CL203, the GNEM-FAS Expanded version will be used.  
l. 
The Early Termination Visit occurs if a subject discontinues prior to completing the study or no longer wants to participate in the study. Every 
reasonable effort should be made to have subjects return to the clinic within 4 weeks of discontinuation and perform the Early Termination procedures; 
however, subjects who are unable to return to the clinic will be given the option of having an Early Termination Visit telephone call within 4 weeks of 
discontinuation from study, where appropriate information will be collected by the clinical site. 
m. Safety Follow-up visit to be conducted by phone 30 days (+5 days) after last dose of study drug. 


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................4 
3 TABLE OF CONTENTS ...................................................................................................14 
LIST OF TABLES ...................................................................................................................17 
LIST OF FIGURES .................................................................................................................17 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................18 
5 INTRODUCTION .............................................................................................................21 
5.1 Overview of GNE Myopathy ....................................................................................22 
5.2 Brief Overview of Ace-ER Development .................................................................22 
5.2.1 
Brief Description of Ace-ER .......................................................................23 
5.2.1.1 
Mechanism of Action in GNE Myopathy ....................................23 
5.2.2 
Nonclinical Studies ......................................................................................24 
5.2.3 
Previous Clinical Studies .............................................................................26 
5.2.4 
Summary of Overall Risks and Potential Benefits ......................................27 
5.3 Study Rationale .........................................................................................................28 
6 STUDY OBJECTIVES ......................................................................................................29 
6.1 Study Endpoints ........................................................................................................29 
7 INVESTIGATIONAL PLAN ............................................................................................30 
7.1 Overall Study Design and Plan .................................................................................30 
7.2 Discussion of Study Design ......................................................................................31 
7.3 Selection of Study Population ...................................................................................31 
7.3.1 
Inclusion Criteria .........................................................................................31 
7.3.2 
Exclusion Criteria ........................................................................................32 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................33 
7.3.3.1 
Stopping Rules .............................................................................33 
7.4 Treatments .................................................................................................................34 


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7.4.1 
Investigational Product ................................................................................34 
7.4.2 
Reference Therapy ......................................................................................34 
7.4.3 
Selection of Doses and Study Duration .......................................................34 
7.4.4 
Method of Assigning Subjects to Treatment Groups ..................................35 
7.4.5 
Blinding .......................................................................................................35 
7.4.6 
Prior and Concomitant Therapy ..................................................................35 
7.4.6.1 
Prohibited Medications ................................................................35 
7.4.6.2 
Permitted Medications .................................................................35 
7.4.7 
Treatment Compliance ................................................................................35 
7.5 Study Procedures and Assessments ..........................................................................36 
7.5.1 
Visit Schedule ..............................................................................................36 
7.5.2 
Efficacy Measures .......................................................................................36 
7.5.2.1 
Dynamometry ..............................................................................37 
7.5.2.2 
GNEM Functional Activities Scale .............................................38 
7.5.2.3 
Sit-to-Stand Test ..........................................................................39 
7.5.2.4 
Weighted Arm Lift Test ...............................................................39 
7.5.2.5 
Six Minute Walk Test ..................................................................39 
7.5.2.6 
Individualized Neuromuscular Quality of Life 
Questionnaire ...............................................................................40 
7.5.2.7 
Medical Outcomes Survey – 36 Item (SF-36) .............................40 
7.5.2.8 
Creatine Kinase Levels ................................................................40 
7.5.3 
Drug Concentration Measurements .............................................................41 
7.5.4 
Urine Testing for ManNAc .........................................................................41 
7.5.5 
Safety Measures & General Assessments ...................................................41 
7.5.5.1 
Medical History ...........................................................................41 
7.5.5.2 
Interval History ............................................................................42 
7.5.5.3 
Physical Examination...................................................................42 
7.5.5.4 
Vital Signs ....................................................................................42 


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7.5.5.5 
Clinical Laboratory Tests for Safety ............................................43 
7.5.5.6 
Pregnancy Testing ........................................................................44 
7.5.5.7 
Suicidal Ideation and Behavior ....................................................45 
7.5.5.8 
Concomitant Medications ............................................................45 
7.5.5.9 
Adverse Events ............................................................................45 
7.5.6 
Appropriateness of Measures ......................................................................46 
7.6 Statistical Methods and Determination of Sample Size ............................................47 
7.6.1 
Determination of Sample Size .....................................................................47 
7.6.2 
Subject Information .....................................................................................47 
7.6.3 
Populations Analyzed ..................................................................................47 
7.6.4 
Efficacy Analysis ........................................................................................47 
7.6.5 
Analyses of Drug Concentration Measurements .........................................48 
7.6.6 
Safety Analyses ...........................................................................................48 
8 STUDY CONDUCT ..........................................................................................................50 
8.1 Ethics .........................................................................................................................50 
8.1.1 
Institutional Review Board or Ethics Committee ........................................50 
8.1.2 
Ethical Conduct of Study ............................................................................50 
8.1.3 
Subject Information and Consent ................................................................50 
8.2 Investigators and Study Administrative Structure ....................................................51 
8.3 Investigational Product Accountability .....................................................................51 
8.4 Data Handling and Record Keeping .........................................................................52 
8.4.1 
Case Report Forms and Source Documents ................................................52 
8.4.2 
Data Quality Assurance ...............................................................................52 
8.4.3 
Record Retention .........................................................................................53 
8.5 Reporting and Follow-up of Adverse Events ............................................................53 
8.5.1 
Definition of Adverse Events ......................................................................53 
8.5.2 
Severity of Adverse Events .........................................................................54 


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8.5.3 
Relationship of Adverse Events to Study Drug ...........................................55 
8.5.4 
Adverse Event Reporting ............................................................................55 
8.5.4.1 
General .........................................................................................55 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................56 
8.5.4.3 
Pregnancy Reports .......................................................................56 
8.5.5 
Communication Plan ...................................................................................56 
8.5.5.1 
Adverse Drug Reaction Reporting ...............................................56 
8.5.6 
Urgent Safety Measures ..............................................................................57 
8.5.7 
Safety Contact Information .........................................................................57 
8.6 Financing and Insurance ...........................................................................................58 
8.7 Publication Policy .....................................................................................................58 
9 REFERENCES ..................................................................................................................59 
10 SIGNATURE PAGE .........................................................................................................61 
LIST OF TABLES 
Table 2.1: 
Schedule of Events ...............................................................................11 
Table 7.5.5.5.1: 
Clinical Laboratory Assessments for Safety ........................................43 
Table 7.5.5.5.1.1: 
Volume of Blood to Be Drawn From Each Subject ............................44 
LIST OF FIGURES 
Figure 2.1: 
Study Schema.........................................................................................5 
Figure 5.2.1.1.1: 
The Biosynthetic Pathway of Sialic Acid in its Subcellular 
Locations ..............................................................................................24 
Figure 7.1.1: 
Study Schema.......................................................................................30 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CK 
creatine kinase 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMRV 
EC 
distal myopathy with rimmed vacuoles 
Ethics Committee 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
GI 
gastrointestinal 
GlcNAc 
N acetyl-glucosamine  
GNE/MNK 
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase 
GNEM 
GNE Myopathy 
GNEM-FAS 
GNE Myopathy Functional Activities Scale 
hERG 
human ether-à-go-go-related gene 
HIBM 
hereditary inclusion body myopathy 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
INQoL 
Individualized Neuromuscular Quality of Life Questionnaire 
IRB 
Institutional Review Board 
IVIG 
intravenous immune globulin 


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LDH 
lactate dehydrogenase 
LEC 
Lower extremity composite 
ManNAc 
N-acetyl-D-mannosamine 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MVIC 
maximum voluntary isometric contraction 
NANA 
N-acetylneuraminic acid 
NF 
National Formulary 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
qHS 
at the time of sleep (i.e., at bedtime) 
QSM 
quadriceps sparing myopathy 
RBC 
red blood cell 
RSI 
Reference Safety Information  
SA 
sialic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions  
TID 
three times per day 
UEC 
Upper extremity composite 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White blood cell 


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Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient being 
tested or used as a reference in a clinical trial, including a product with a marketing 
authorization when used or assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when used to gain further 
information about an approved use” (from International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH] 
Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice).  
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 


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5 INTRODUCTION 
The product under investigation is sialic acid (SA) administered in extended release 
(Ace-ER) tablets.  Ace-ER is intended for use as a substrate replacement therapy for the 
treatment of GNE Myopathy (GNEM), also known as Hereditary Inclusion Body Myopathy 
(HIBM), Quadriceps Sparing Myopathy (QSM), Inclusion Body Myopathy type 2, Distal 
Myopathy with Rimmed Vacuoles (DMRV), and Nonaka myopathy (Huizing et al. 2009); 
(Jay et al. 2009); (Malicdan et al. 2008).  Currently there are no approved treatments for 
GNEM.  
SA is an essential, naturally occurring amino sugar found in humans and most organisms.  
Defects in the SA biosynthetic pathway cause GNEM, a severe progressive myopathy.  
By replacing SA substrate, sialylation should be restored on key target glycoproteins and 
glycolipids, leading to restoration of biochemical function, improved muscle physiology and 
improved clinical function.  The scientific rationale is primarily based on the nature of the 
underlying genetic defect supported by proof of concept work in a knockout mouse that 
models the muscle disease and pathology of  HIBM (Malicdan et al. 2009).  The safety of SA 
has been studied in chronic treatment studies in HIBM mice and toxicology studies in 
multiple species of normal animals.  These data demonstrated reasonable safety for SA and 
established a no adverse effect level (NOAEL) of 2,000 mg/kg in rats and dogs, enabling 
clinical studies in GNEM patients.   
Ultragenyx has developed Ace-ER tablets since successful use of SA replacement therapy in 
humans is believed to depend upon optimized exposure to the compound.  SA has a half-life 
of less than 1 hour in the circulation (Malicdan et al. 2009).  Ace-ER was developed to 
improve the stability of exposure to SA and allow more appropriate dosing and efficient 
substrate replacement. The Ace-ER formulation was evaluated in an initial Phase 1 study to 
establish the safety and pharmacokinetic (PK) profile of a single dose and 7 days of repeat 
dosing in SA-deficient GNEM patients.  The study drug was well tolerated at all dose levels. 
There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to 
moderate with no dose relationship or pattern.    
A Phase 2 randomized, placebo-controlled study evaluated chronic dosing of Ace-ER at two 
dose levels to establish the pharmacodynamic (PD) effects of SA on sialylation, identify the 
appropriate dose level, and provide insight into clinical efficacy and safety.  Data from the 
Phase 2 study demonstrated efficacy and acceptable safety profile at the 6 g/day Ace-ER 
dose level.  In addition, a Phase 3 study (UX001-CL301) in subjects able to walk at least 
200 m in the 6-minute walk test (6MWT) and a Phase 2 open-label study (UX001-CL203) 
designed primarily to evaluate the safety of 6 g/day Ace-ER tablets in GNEM patients who 
have severe ambulatory impairment are currently ongoing. Although safety is the primary 
objective, efficacy in this study will also be assessed as a secondary objective to ensure that 
the full spectrum of patients with GNEM is evaluated across the development program. 
Ultragenyx is also sponsoring a GNEM Disease Monitoring Program (GNEM-DMP) which 
includes a disease registry (a longitudinal patient reported disease outcome survey) and a 


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natural history study (a physician-reported protocol-driven formal study).  The GNEM-DMP 
is being conducted in parallel with the SA clinical development program to collect data on 
disease characteristics and progression.   
This Phase 3b extension study is designed to confirm the long-term safety and efficacy of 
6 g/day Ace-ER tablets in GNEM patients. 
5.1 
Overview of GNE Myopathy 
GNE Myopathy (GNEM) is a rare and severely debilitating disease of adult onset myopathy 
and progressive muscle weakness. The disease has been known by other names such as 
HIBM and Nonaka disease but the new name of GNEM is preferred because it reflects the 
underlying genetic cause of the disease (Huizing et al. 2014). GNEM is an autosomal 
recessive disorder caused by a mutation in the GNE gene, which encodes an enzyme critical 
to the biosynthesis of SA. SA is an endogenous monosaccharide that is thought to play a role 
in stabilization of muscle cell membranes through sialylation of extracellular proteins. 
Magnetic resonance imaging (MRI) radiography and muscle biopsy analysis demonstrate 
irreversible replacement of muscle tissue with fat and fibrosis, suggesting that the 
hyposialylated proteins in GNEM are dysfunctional and lead to cell death (Huizing et al. 
2009). 
Patients with GNEM typically present with distal muscle weakness, most commonly but not 
exclusively presenting as foot drop. As the disease progresses, the atrophy spreads to affect 
not only the lower extremities but the upper extremities as well, leading to loss of ambulation 
and as reliance on others for care (to feed oneself, for example). Assistive devices such as 
ankle-foot orthoses (AFOs) with a rigid base are often used to allow the patients to walk, 
albeit with a slow, unsteady gait, through leveraging the quadriceps muscle, which is 
typically spared in GNEM. There are no approved medical therapies to treat the disease and 
patients typically become wheelchair bound after 10-20 years from initial diagnosis (Nonaka 
et al. 2005).  
The identification of the genetic deficiency of SA biosynthesis in GNEM suggested that SA 
replacement provided exogenously to GNEM patients may be able to restore SA levels in the 
cell and thereby restore sialylation of proteins and lipids in the muscle.  
5.2 
Brief Overview of Ace-ER Development 
Ace-ER tablets are in development as a treatment for GNEM.  The scientific rationale for SA 
substrate replacement therapy is based on the identification of the genetic deficiency of SA 
biosynthesis in GNEM which suggested that SA replacement provided exogenously to 
GNEM patients may be able to restore SA levels in the cell and thereby restore sialylation of 
proteins and lipids in the muscle. Studies in animal models showed that GNE missense 
mutations caused decreased sialylation and that the phenotype resembles human disease 
(Malicdan et al. 2009). Specifically, murine GNEM knockout/knockin models have low SA 
levels, decreased muscle strength and function, and histopathology resembling the human 
phenotype (Malicdan et al. 2009). In the animal models, exogenously administered SA was 


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absorbed and taken up into cells, leading to increased sialyation in muscle tissue (Malicdan et 
al. 2009, Bardor et al. 2005, Oetke et al. 2001). Prophylactic or symptomatic substrate 
replacement therapy with SA or its derivatives substantially improved muscle strength and 
histology with only relatively small increases in SA levels (Malicdan et al. 2009), 
(Yonekawa et al. 2014). Nonclinical studies have been conducted in HIBM mice and 
multiple species of normal animals. Two clinical studies and an extension study have also 
been conducted to characterize the PK, tolerability, safety, and efficacy of SA replacement in 
GNEM patients; in addition, UX001-CL301 and UX001-CL203 are currently ongoing.  
A brief overview of existing information on Ace-ER is provided below; a comprehensive 
review of available data is contained in the investigator’s brochure (IB) provided by 
Ultragenyx Pharmaceutical Inc. (Ultragenyx), which should be reviewed prior to initiating 
the study.     
5.2.1 
Brief Description of Ace-ER 
SA (also known as N-acetylneuraminic acid [NANA]) is an essential, naturally 
occurring amino sugar found in man and most organisms.  An extended-release form of SA 
was developed to improve the stability of exposure to SA in vivo and allow more appropriate 
dosing and efficient substrate replacement. The choice of an extended release formulation is 
based on the fact that SA has a short half-life in the circulation and its rapid clearance makes 
it difficult to use as a therapeutic replacement substrate in which a steady and constant supply 
of SA is needed.  
The active SA pharmaceutical ingredient is produced synthetically in an enzyme-catalyzed 
two step reaction where N acetyl-glucosamine (GlcNAc) is converted into SA.  
No mammalian sourced products are used in the production of SA.  The product is purified 
and crystallized yielding high purity SA which is formulated into Ace-ER tablets using 
United States Pharmacopoeia (USP)/National Formulary (NF) excipients commonly used for 
this purpose.  
Ace-ER 500 mg tablets are white to off-white, film-coated, extended-release, oval tablets, 
which may be debossed with the code U-1 and are designed for oral administration.  
5.2.1.1 
Mechanism of Action in GNE Myopathy 
The glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE/MNK) 
enzyme is the rate-controlled and regulated first step in the biosynthesis of SA required for 
the glycosylation of proteins and lipids (Figure 5.2.1.1.1).  Genetic defects in the SA 
biosynthetic pathway cause GNEM, a severe progressive myopathy.  By replacing SA 
substrate via Ace-ER, sialylation should be restored on key target glycoproteins and 
glycolipids, and lead to restoration of biochemical function, improved muscle physiology and 
improved clinical function. 


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Figure 5.2.1.1.1: 
The Biosynthetic Pathway of Sialic Acid in its Subcellular 
Locations 
 
5.2.2 
Nonclinical Studies 
Published studies in the HIBM mouse model have shown that SA replacement can reduce 
muscle weakness and atrophy, improve muscle pathology and function, and restore 
sialylation in muscle (Malicdan et al. 2009; Yonekawa et al. 2014). The rational basis for the 
use of SA as a therapy in GNEM is primarily dependent on these results.  Key safety 
pharmacology, PK, and toxicology studies to support the use of SA in treating GNEM are 
summarized below; additional details may be found in the IB.   
Safety pharmacology:  Ultragenyx conducted the core battery of safety pharmacology 
studies of Ace-ER that are recommended by ICH guidelines. These studies consisted of 
in vitro human ether-à-go-go-related gene (hERG) channel inhibition, neurobehavior in rats, 
and respiratory and cardiovascular evaluations in dogs after oral administration of SA.  
SA did not show any potential for QT prolongation in the hERG assay at concentrations as 
high as 6 x 10-3 mol/L (1855 µg/mL). No adverse effects on neurobehavior in rats or on 
respiratory and cardiovascular function in dogs were observed at oral SA doses as high as 
2000 mg/kg/day. 
Pharmacokinetics:  PK of aceneuramic acid has been demonstrated through a series of 
experiments, including pharmacology studies in HIBM mice, supportive PK studies in rats 
with SA or KI-111, a single dose non-GLP PK study with aceneuramic acid, a pilot single 
dose non-GLP PK study of aceneuramic acid in dogs, and three multiple dose non-GLP PK 
studies of aceneuramic acid in dogs. Additionally, toxicokinetics were evaluated as part of a 
26-week GLP toxicology study in and a 39-week GLP toxicology study in dogs. Finally, a 


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series of in vitro experiments was conducted for aceneuramic acid to investigate the potential 
for cytochrome P450 inhibition, cytochrome P450 induction, and to determine if 
aceneuramic acid is an inhibitor or a substrate of human efflux and uptake transporters. 
These PK studies demonstrated that SA was quickly excreted primarily through the urine. 
High tissue distribution was observed in the kidney and bladder, and distribution of 
radioactivity to skeletal muscle was confirmed. Radioactivity levels in most tissues, 
including serum, reached their highest concentration within 0.5 hours post dose, then fell 
quickly up to 3 hours post-dose. Radioactivity extraction by methanol suggested existing 
forms in the serum at 3 hours post-dose are not unchanged. PK in the HIBM mouse model 
confirmed that the serum concentration of SA peaked quickly and was rapidly excreted in the 
urine.  Additional PK studies conducted with aceneuramic acid (extended release compared 
with co-administration of extended release and immediate release formulations, or with a 
bilayer tablet) administered orally to dogs showed that the prolonged release tablet maintains 
an extended duration of plasma levels of SA in comparison to free SA. Furthermore, the in 
vitro cytochrome P450 and transporter studies indicated that there is no potential for 
interference by aceneuramic acid on the metabolism of other drugs.  
Chronic toxicology studies in rats and dogs:  In an oral 26-week rat study, there were no 
Ace-ER treatment-related effects on clinical condition, body weight, food consumption, 
ophthalmology, clinical pathology (hematology, blood chemistry, and urinalysis) or in 
pathologic evaluations (gross, organ weight, and histopathology).  The NOAEL in the 
26-week toxicity study in rats was 2000 mg/kg/day, which reflects a safety margin of 
approximately 3.2-fold by dose (13-fold by Cmax; 2.9-fold by AUC) over the proposed 
efficacious dose of 6g/day.  A 39-week oral toxicity study in dogs did not show any adverse 
effects on clinical condition, body weight, food consumption ophthalmology, 
electrocardiography, and clinical pathology (hematology, blood chemistry, and urinalysis). 
The NOAEL in the 39-week toxicity study in dogs was 2000 mg/kg/day, which reflects a 
safety margin of approximately 11–fold by dose (136-fold by Cmax; 28-fold by AUC) over 
the proposed efficacious dose of 6 g/day. 
Reproductive and developmental toxicology studies in rats and rabbits: Developmental and 
reproductive toxicity studies at oral doses as high as 2000 mg/kg/day have not shown any 
adverse effects on fertility of male or female rats, treatment-related effects on dams or 
embryo-fetal development parameters in rats and rabbits, or treatment-related effects on 
pre-and post-natal development in rats. 
Genotoxicity: A standard battery of GLP genotoxicity tests was performed with aceneuramic 
acid and there was no evidence of any genotoxic, clastogenic or mutagenic effects. In these 
studies, aceneuramic acid was tested at concentrations of 1.58 to 5000 μg/plate in the in vitro 
bacterial mutation assay and 0.625 to 310 µg/mL in the in vitro clastogenicity assay in 
human peripheral blood lymphocytes. For the mouse micronucleus assay, aceneuramic acid 
was given as 2 doses, 24 hours apart, by oral gavage (500, 1000, or 2000 mg/kg/day). 


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5.2.3 
 Previous Clinical Studies 
Key results from studies to support the use of SA in treating GNEM are summarized below; 
additional details may be found in the IB.   
Phase 1 Pharmacokinetic and Safety Study (UX001-CL101):   
The exposure of aceneuramic acid in adult GNEM patients was characterized in study 
UX001 CL101 following single (fasted and fed) and repeat doses of Ace-ER up to 
6000 mg/day for 7 days. The PK parameters derived from traditional non-compartmental 
analysis are presented in UX001-CL101 following single dose administration (fasted and fed 
states) and repeat dosing (steady state).  Following single oral administration of Ace-ER 
(fasted or fed), the maximum baseline-adjusted SA concentration in serum was achieved in 
approximately 3 to 10 hours. The Cmax increased in a less than dose proportional fashion 
across the dose range studied, showing a 2.7-fold increase between the 650 mg and 6000 mg 
dose groups.  
Observed results from single-dose administration demonstrate that adequate absorption of the 
drug, with or without food, occurs at all dose levels. The impact of food on exposure is 
complex with some dose levels showing higher AUC with fasted conditions (650 mg and 
4875 mg dose), similar AUC under both fasted and fed conditions (2925 mg dose), and 
higher AUC with food (1950 and 6000 mg dose). For the 6000 mg dose, the AUC was 
significantly greater (~46%) when administered in the fed state at 3.934 mcg*hr/ml 
compared with 2.592 mcg*hr/ml fasted. Given that the 6000 mg dose was administered using 
the 500 mg tablet, the differences observed may be due to a subtle effect of the larger tablet 
size on the absorption rate and/or duration, even though in vitro dissolution data is 
comparable for the 325 mg and 500 mg tablets. The larger tablet may have a longer time of 
release in vivo. This difference coupled with a food effect prolonging aceneuramic acid exit 
from the stomach may enhance the overall absorption of aceneuramic acid (acidity should 
improve aceneuramic acid absorption by neutralizing its charge). 
Phase 2 Pharmacokinetic, Pharmacodynamic and Safety Study (UX001-CL201):   
The Phase 2, randomized, double-blind, placebo-controlled study UX001-CL201 evaluated 
the safety and efficacy of Ace-ER 3 g/day or 6 g/day, versus placebo in ambulatory subjects 
with GNEM (n=47). Because the study evaluated both efficacy and safety in a blinded 
manner for the full 48 weeks (first 24 weeks placebo controlled and last 24 weeks all subjects 
on either 6 g/day or 3 g/day), it  allows for evaluation of efficacy during one year. 
The inclusion criteria for UX001-CL201 also allowed for the enrollment of subjects with a 
broad spectrum of physical disability, with at least 60% of enrolled subjects having residual 
lower extremity strength and function sufficient to walk ≥ 200 m in the 6MWT at screening. 
Enrolling subjects across a spectrum of disease severity allowed the study to fully evaluate 
the safety and efficacy profile.  
Ace-ER at a dose of 6 g/day stabilized upper extremity muscle strength compared with 
declines for placebo at 24 weeks and 3g/day at 48 weeks. The result is consistent as each 


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muscle group included in the composite evaluation favored 6 g/day over 3 g/day or placebo 
in all analyses. Additionally, a larger treatment difference was observed in subjects with 
more viable muscle tissue (able to walk at least 200 m in the 6MWT at Baseline) who had a 
larger treatment difference over 48 weeks (+4.69 kg; p=0.0005).  
Overall, a lower extremity composite (LEC) results were directionally in favor of the 6 g/day 
group over 48 weeks, although not statistically significant. Baseline muscle strength is far 
more impaired in the lower extremities, which may impact the ability to have and/or see a 
treatment effect. An analysis of changes in LEC scores over 48 weeks for the 6/6 g/day 
Ace-ER group versus the 0/3 g/day Ace-ER group was conducted to evaluate LE outcomes 
when comparing the highest and lowest exposure groups. The difference between the groups 
was +3.37 kg; p=0.16. In comparing the highest and lowest dose exposure groups over 
48 weeks, the high dose group that received 6 g/day throughout the 48 weeks retained 
substantially more LE strength than the subjects who received placebo for 24 weeks followed 
by 3 g/day treatment. 
Phase 2 Efficacy and Safety Extension Study (UX001-CL202):   
In addition to the study data from UX001-CL201, the UX001-CL202 study allowed for the 
continuation of open-label treatment with 6 g/day of Ace-ER in the original 46 subjects who 
crossed over to UX001-CL202. In addition, 13 subjects who were naïve to Ace-ER and who 
could walk ≥ 200 m in the 6MWT were enrolled. 
In the UX001-CL202 extension study, after approximately 2.5 years of treatment over the 
course of two studies in subjects with a progressive, debilitating disease, muscle strength 
remained stable in 7 of 9 of the individual muscle groups comprising the upper extremity 
composite (UEC) and the LEC muscle strength scores in the combined 0/6 and 6/6 group. 
Grip strength and hip abductors decreased modestly from original study baseline, resulting in 
decreases in overall UEC and LEC muscle strength scores.   
For both the upper and lower extremities, subjects treated with 6 g/day at the beginning of 
the 201 study had the greatest strength at the end of approximately 2.5 years compared to 
patients who started 6g at Week 24 or received 3 g/day at any time during the first year.  
5.2.4 
Summary of Overall Risks and Potential Benefits 
GNEM is a rare and severely debilitating disease of adult onset myopathy and progressive 
muscle weakness with no currently approved therapy and significant unmet medical need. 
Strong pre-clinical evidence demonstrated that direct substrate replacement therapy may be a 
promising therapeutic approach for patients with GNEM. Aceneuramic acid is chemically 
identical to the endogenous monosaccharide sialic acid and its extended release formulation 
leads to stable improvement of SA levels.  
Aceneuramic acid at a dose of 6 g/day has demonstrated positive pharmacodynamic effects 
such as increasing tissue and serum SA levels as well as lowering of serum creatine kinase 


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(CK) levels that support the clinical efficacy observed in a randomized, double-blind, 
placebo-controlled study. The clinical efficacy data at 6 g/day demonstrates muscle strength 
stabilization and preservation of functional independence relative to placebo or lower dose 
treatment. Safety information collected over approximately 2.5 years demonstrates that 
aceneuramic acid has a favorable safety profile.  
Each clinical study assessed AEs and SAEs at every scheduled study visit from the time of 
informed consent. As expected with a substrate replacement therapy, Ace-ER has been well 
tolerated in clinical studies to date. Levels of free SA in serum during 6 g/day administration 
were only 2 fold greater than in healthy volunteers. There have been no treatment-related 
serious adverse events and only one withdrawal due to an adverse event over the 2.5 years of 
observation. Acceptable tolerability has also been demonstrated by a high treatment 
compliance rate as well by the fact that all subjects who completed the pivotal study elected 
to participate in the extension study. The incidence of adverse events of gastrointestinal (GI) 
disturbance including flatulence, dyspepsia, and diarrhoea were greater in the treatment 
groups than placebo during the first 24 weeks of the pivotal study. Exposure adjusted rates of 
these GI events were similar when comparing 6 g/day to placebo. Mildly elevated 
transaminases occurred but were considered most likely related to the underlying skeletal 
muscle disease rather than to liver injury.  
Ace-ER treatment at 6 g/day clearly has a positive benefit-risk profile that supports the 
proposed indication of treatment of adult patients with GNEM, and has the potential to 
impact an unmet medical need for GNEM patients. 
5.3 
Study Rationale 
GNEM (or HIBM), is a severe, progressive myopathy caused by a defect in the biosynthetic 
pathway for SA. Substrate replacement is a potential therapeutic strategy based on the 
success of replacing missing SA and reducing muscle disease in a relevant mouse model of 
the human disease. Successful use of SA replacement therapy in humans is believed to 
depend upon providing steady, long-term exposure to the compound in an extended-release 
form (such as Ace-ER), given SA’s short half-life. A Phase 2, placebo-controlled study 
evaluating Ace-ER at 2 doses for 48 weeks (UX001-CL201) found that the higher dose of 
6 g/day Ace-ER stabilized UEC score compared with placebo or the lower 3 g/day dose; this 
finding was supported by measurements of functional outcome on the GNE Myopathy 
Functional Activities Scale (GNEM-FAS). This Phase 3b extension study will assess the 
long-term safety of Ace-ER in subjects who completed the UX001-CL202, UX001-CL301, 
or UX001-CL203 studies; in addition, efficacy of 6 g/day Ace-ER will be further evaluated 
in GNEM patients, including those able to walk ≥200 m in the 6MWT (roll over subjects 
from UX001-CL301 and naïve subjects from UX001-CL202) and GNEM patients with 
severe ambulatory impairment (roll over subjects from UX001-CL203).  
  


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6 STUDY OBJECTIVES 
• To evaluate the long-term safety and efficacy of Ace-ER treatment of GNE Myopathy 
subjects  
6.1 
Study Endpoints 
Overall Safety Endpoint (Primary Endpoint): Evaluate the long-term safety of 6 g/day 
Ace-ER treatment in subjects with GNE Myopathy  
Overall Efficacy Endpoint:  Evaluate the long-term effect of 6 g/day of Ace-ER treatment 
in subjects with GNEM. Efficacy will be evaluated as follows: 
For Subjects Enrolling from UX001-CL202 and UX001-CL301:  
• Muscle strength as measured by dynamometry 
• Mobility, strength, and function using a series of physical performance measures 
• Functional disability using an patient- and clinician-reported questionnaire 
 
For Subjects Enrolling from UX001-CL203: 
• Change in GNEM-FAS Expanded Version total score and mobility, upper extremity and 
self-care domain scores 
• Change in upper extremity strength in grip, key pinch, shoulder abductors and wrist 
extensors and in lower extremity muscle strength in the knee extensors as measured by 
dynamometry 
• Evaluate the effect on 6g/day Ace-ER on health-related quality of life, patient reported 
outcomes (PRO), and biomarkers of sialyation 


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7.2 
Discussion of Study Design 
This Phase 3b study is designed to be a long-term safety and efficacy study of 6 g/day 
Ace-ER in GNEM patients.  The study will assess long-term effects of Ace-ER on clinical 
measures of muscle strength, mobility, function, ability and health-related quality of life. 
The primary endpoint of the study is safety.   
The treatment duration of up to 24 months is intended to evaluate the long-term safety and 
efficacy of Ace-ER. The study is limited to GNEM patients who have completed 
UX001-CL202 (open label, safety study in GNEM patients), UX001-CL301 (randomized, 
double-blind, placebo-controlled, Phase 3 study), or UX001-CL203 (open label, safety study 
in GNEM patients with severe ambulatory impairment).   
The study will assess the safety of the study drug by the incidence and frequency of adverse 
events and serious adverse events. Any significant changes from baseline to scheduled time 
points in concomitant medications, physical examination results, vital signs, clinical 
laboratory test results, interval history, and C-SSRS will also be part of the safety evaluation. 
7.3 
Selection of Study Population 
This study will be conducted in adults who have previously documented mutations in the 
gene for the GNE/MNK enzyme leading to a diagnosis of GNEM (variously termed HIBM, 
DMRV, or Nonaka disease).  These patients have an impaired ability to synthesize 
endogenous SA, which leads to muscle weakness and atrophy.  Consequently, this is the 
relevant population for testing SA replacement therapy, and for determining if SA 
replacement leads to improved protein and lipid sialylation and stabilized or improved 
muscle structure and performance. 
Individuals who have ingested N-acetyl-D-mannosamine (ManNAc) or similar other 
SA-producing compounds during the 60 days prior to the Screening Visit will be excluded as 
it could confound interpretation of the results. See Section 7.3.1 and 7.3.2 for complete 
Inclusion and Exclusion criteria.  
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Have completed UX001-CL202, UX001-CL301, or UX001-CL203 studies 
2) Willing and able to provide written, signed informed consent after the nature of the 
study has been explained, and before any research-related procedures are conducted 


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3) Willing to comply with all study procedures 
4) Female participants of child‐bearing potential or male participants with partners of 
child-bearing potential who have not undergone a bilateral salpingo‐oophorectomy 
and are sexually active must consent to use a highly effective method of 
contraception as determined by the site investigator (i.e. oral hormonal 
contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, 
physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation or 
true abstinence [when this is in line with the preferred and usual lifestyle of the 
subject], which means not having sex because the subject chooses not to), from 
the  period following the signing of the informed consent through 30 days after last 
dose of study drug 
5) Females of childbearing potential must have a negative pregnancy test at Screening 
and be willing to have additional pregnancy tests during the study.  Females 
considered not of childbearing potential include those who have been in menopause 
for at least two years, have had tubal ligation at least one year prior to Screening, or 
who have had a total hysterectomy or bilateral salpingo-oophorectomy 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1) Ingestion of N-acetyl-D-mannosamine (ManNAc) or related metabolites; intravenous 
immunoglobulin (IVIG); or anything that can be metabolized to produce SA in the 
body within 60 days prior to the Screening Visit 
2) Has had any hypersensitivity to SA or its excipients that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects 
3) Pregnant or breastfeeding at Screening or planning to become pregnant (self or 
partner) at any time during the study 
4) Use of any investigational product or investigational medical device within 30 days 
prior to Screening, or anticipated requirement for any investigational agent prior to 
completion of all scheduled study assessments 
5) Has a condition of such severity and acuity, in the opinion of the investigator, that it 
warrants immediate surgical intervention or other treatment or may not allow safe 
participation in the study 
6) Has a concurrent disease, active suicidal ideation, or other condition that, in the view 
of the investigator, places the subject at high risk of poor treatment compliance or of 
not completing the study, or would interfere with study participation or would affect 
safety 


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7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason.  The Investigator and Ultragenyx also have the right to 
remove subjects from the study.  Ultragenyx must be notified of all subject withdrawals as 
soon as possible.  Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or Investigator due to poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
• Occurrence of an unacceptable adverse event (AE) 
• A condition or illness that, in the judgment of the Investigator or Ultragenyx, might place 
the subject at risk or invalidate the study  
• At the request of the subject, Investigator, or Ultragenyx, for administrative or other 
reasons 
• Protocol deviation or unreliable behavior 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the case 
report form (CRF).  Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve.  If such abnormalities do not return to normal within 
30 days after the last dose given, their etiology should be identified and Ultragenyx should be 
notified.  All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within four weeks of discontinuation. 
7.3.3.1 
Stopping Rules 
Individual subjects who experience an unexpected and possibly, probably, or definitely 
drug-related serious adverse event (SAE) (Section 8.5.3) that represents a change in the 
nature or an increase in frequency of the serious event from their prior medical history or 
known GNEM-related medical issues will be evaluated as to whether the subject will 
continue on the study.  Periodic safety reviews will be conducted to look at aggregate data on 
serious adverse event, adverse events, vital signs, and laboratory abnormalities to determine 
if the study should be stopped.  
Regulatory Authorities, as well as the IRBs/ECs, will be informed should unexpected and 
possibly, probably, or definitely study drug-related SAEs occur.  A full evaluation of the 
event will be performed in order to make a decision regarding what actions to take, including 
whether to recommend stopping the study. Regulatory Authorities, as well as IRBs/ECs, will 
be informed if the study is paused or stopped. If the Sponsor deems it appropriate to restart 


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the trial following an internal safety review, this will be done only following approval by 
Regulatory Authorities.  
7.4 
Treatments 
Approximately 165 subjects will be eligible to enroll in the study and receive open-label 
Ace-ER tablets; 6 g/day divided TID. 
7.4.1 
Investigational Product 
Each Ace-ER tablet contains 500 mg of SA in an extended release formulation for a total 
weight of 1200 mg/tablet. The 6000 mg (6 g) total daily SA dose will be administered by the 
oral route and will be divided into a TID regimen: 4 tablets taken in the morning, early 
evening, and before bedtime (qHS). The dose should be administered with food (i.e. within 
30 minutes of a meal or snack).  
The study drug is manufactured, packaged, and labeled according to current Good 
Manufacturing Practice (cGMP) regulations.   
7.4.2 
Reference Therapy 
Not applicable. 
7.4.3 
Selection of Doses and Study Duration 
Selection of Doses: 
Successful use of SA replacement therapy in humans is believed to depend upon optimized 
exposure to the compound in the bloodstream to drive uptake of SA into the muscle.  
The 6 g/day Ace-ER dose was selected based on biochemical and clinical data collected to 
date showing that 6 g/day is an efficacious dose, that 3 g/day is not efficacious, and that a 
higher dose of 12 g/day did not result in a significant improvement in effect over 6 g/day. 
These data derive from a randomized, placebo-controlled Phase 2 study and a corresponding 
extension study.   
Given the biochemical and clinical results from UX001-CL201 and UX001-CL202 
(Section 5.2.3), the 6 g/day Ace-ER dose was selected for further study in UX001-CL301 
and UX001-CL203; this dose will be continued in the current extension study. All subjects 
being treated with 12 g/day Ace-ER in UX001-CL202 who rollover will be transitioned to 
6 g/day in this protocol.  
Study Duration: 
The total treatment duration will be 24 months. In addition, a Safety Follow-up visit will be 
conducted by phone 30 days (+5 days) after the last dose of study drug. 


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7.4.4 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study and consists of one treatment arm. All subjects will receive 
Ace-ER 6g/day. 
7.4.5 
Blinding 
Not applicable. 
7.4.6 
Prior and Concomitant Therapy 
7.4.6.1 
Prohibited Medications 
Subjects may not be enrolled if they used any investigational product (except for 
Ace-ER/SA-ER as part of the parent study) or investigational medical device within 30 days 
prior to Screening, or if they require any investigational agent prior to completion of all 
scheduled study assessments.  Ingestion of ManNAc, SA (other than Ace-ER) or 
related metabolites, and IVIG are prohibited throughout the study.  If ManNAc, SA (other 
than Ace-ER) or another substrate was used more than 60 days prior to Screening, the time 
period of use, the compound used, and the dose and dose regimen should be recorded. If a 
patient has been on substrate replacement therapy in the past, the investigator must consider 
the potential confounding effects of this therapy before enrolling the patient as a subject in 
the study.  
It is essential that the subject commit to not ingesting ManNAc or similar other 
SA-producing compounds during the conduct of this study as it could confound the 
interpretation of the results.  The study will analyze subject’s urine sample for the presence 
of ManNAc to detect noncompliance with this essential requirement.  
7.4.6.2 
Permitted Medications 
Other than medications specifically prohibited in this study, subjects may receive 
concomitant medications as required.  Medications (prescription, over-the-counter, and 
herbal) and nutritional supplements taken during the 30 days prior to Screening will be 
reviewed and recorded at the Screening visit.  At the Baseline visit, current medications will 
be recorded.  At each visit, any concomitant medications added or discontinued during the 
study should be recorded on the CRF. 
The site personnel should record the following in the CRF: date and time the medication was 
taken, the name of the medication, and the reason the medication was taken. 
7.4.7 
Treatment Compliance 
Site personnel will maintain a record of all medication dispensed to each subject.  
Subjects will be instructed to bring all unused study drug and product packaging to every 
visit.  Drug accountability will be assessed by site personnel and recorded.  All used 
containers and unused study drug must be returned at in-clinic visits.  Measurements of 


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trough free SA levels in the serum and urine may also provide an estimate of treatment 
compliance in this study. 
7.5 
Study Procedures and Assessments 
The individual indicated in each scale description will perform all assessments listed below.  
Whenever possible, study site staff (including trained clinicians, physical therapists, and the 
Investigator or site designee) performing the assessments should be consistent from visit to 
visit throughout the study. 
The parameters to be assessed in Study UX001-CL302, along with timing of assessments, are 
provided in the Schedule of Events (Table 2.1). Refer to study-related materials for 
additional details on specific assessments and the suggested order of administration. 
7.5.1 
Visit Schedule 
Informed consent must be obtained prior to any Screening/Baseline procedures.  
Subjects will be enrolled only after inclusion/exclusion criteria have been confirmed.  
Screening/Baseline assessments must be completed prior to first dose of study drug.  
Study visits will occur at every 8 weeks for 24 weeks and then every 6 months for subjects 
enrolling from UX001-CL202 or UX001-CL301. For subjects enrolling from study 
UX001-CL203, study visits will occur every 6 months. A Safety Follow-up visit will be 
conducted by phone 30 days (+5 days) after the last dose of study drug. For subjects who 
discontinue prior to completing the study, every reasonable effort should be made to 
perform the Early Termination Visit procedures within four weeks of discontinuation. 
Subjects who are unable to return to the clinic will be given the option of having an Early 
Termination Visit telephone call within 4 weeks of discontinuation from study, where 
appropriate information will be collected by the clinical site.  
7.5.2 
Efficacy Measures 
Efficacy will be evaluated by changes in upper and lower extremity muscle strength and 
function, and physical functioning.  Results from baseline assessments will be compared with 
those of post-treatment assessments listed in the Schedule of Events (Table 2.1), with 
efficacy conclusions based on change from baseline over the treatment period.   
The following section describes the assessments that will be performed throughout the study 
to derive efficacy variables. However, only applicable assessments based on the subject’s 
parent study prior to roll-over should be administered to each subject. For UX001-CL202 
subjects, assessments that cannot be safely performed by a subject due to disease progression 
should not be administered. 


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7.5.2.1 
Dynamometry 
Dynamometry testing of multiple muscle groups will be used to measure strength.  
Dynamometry sessions will occur at each visit beginning with the Screening/Baseline Visit. 
See Clinical Evaluator Manual for details on the administration procedure of dynamometry.    
Formal training will be conducted with the clinicians administering dynamometry (a licensed 
physical therapist) to standardize technique and minimize variability.  The maximum 
voluntary isometric contraction (MVIC) against a dynamometer will be used to measure 
strength in the following muscle groups, as applicable:  shoulder abductors, elbow flexors, 
elbow extensors, hip abductors, hip adductors, hip flexors, hip extensors, knee flexors and 
knee extensors.  A hand dynamometer will be used to assess gross grip strength and pinch 
strength.  Refer to the Clinical Evaluator manual for details on the dynamometry testing. 
The total force (in kg) will be recorded at the time of test administration.  The highest force 
value collected for each muscle group will be used for data analysis.  The percent predicted 
values will be calculated after the testing using published normative data (Mathiowetz et al. 
1985); (NIMS 1996); (Bohannon 1997); (Bohannon et al. 2006); (Peters et al. 2011).  
Muscle strength and percent predicted values for each muscle group tested will be analyzed 
as secondary or tertiary endpoints. 
7.5.2.1.1 
Upper Extremity Composite Score 
For UX001-CL202 and UX001-CL301 Subjects: Muscle strength based on the MVIC 
against a dynamometer will be measured bilaterally in the following upper extremity muscle 
groups: gross grip, shoulder abductors, elbow flexors, and elbow extensors.  The UEC is 
derived from the sum of the average of the right and left total force values (measured in kg) 
for each muscle group.  
The percent predicted total force values will be determined based on reference equations 
adjusting for age, gender, height, and weight. The percent predicted force will be calculated 
for each side and the bilateral percent predicted values will be averaged for each upper 
extremity muscle group (gross grip, shoulder abductors, elbow flexors, and elbow extensors).  
The mean of the four averages in percent predicted scores will be calculated to create a 
percent predicted UEC score, and analyzed relative to baseline to create a UEC mean change 
in percent predicted score.    
For UX001-CL203 Subjects: Muscle strength based on the MVIC against a dynamometer 
will be measured bilaterally in the following upper extremity muscle groups: grip, key pinch, 
shoulder abductors and wrist extensors. The UEC is derived from the sum of the average of 
the right and left total force values (measured in kg) for each muscle group. 
The percent predicted total force values will be determined based on reference equations 
adjusting for age, gender, height, and weight. The percent predicted force will be calculated 
for each side and the bilateral percent predicted values will be averaged for each upper 


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extremity muscle group (grip, key pinch, shoulder abductors and wrist extensors).  The mean 
of the four averages in percent predicted scores will be calculated to create a percent 
predicted UEC score, and analyzed relative to baseline to create a UEC mean change in 
percent predicted score. 
7.5.2.1.2 
Lower Extremity Composite Score 
For UX001-CL202 and UX001-CL301 Subjects: muscle strength based on MVIC against a 
dynamometer will be measured bilaterally in the following lower extremity muscle groups: 
knee flexors, hip flexors, hip extensors, hip abductors and hip adductors. The LEC is derived 
from the sum of all muscle groups.  Each muscle group is the average of the right and left 
total values (measured in kg).  
The percent predicted total force values for the LEC will also be determined and analyzed as 
a tertiary endpoint. The percent predicted force will be calculated for each side and the 
bilateral percent predicted values will be averaged for each lower extremity muscle group 
(knee flexors, hip flexors, hip extensors, hip abductors and hip adductors).  The mean of the 
five averages in percent predicted scores will be calculated to create a percent predicted LEC 
score, and analyzed relative to baseline to create a LEC mean change in percent predicted 
score. 
7.5.2.1.3 
Knee Extensor Score (UX001-CL203) 
For UX001-CL203 Subjects: Muscle strength based on MVIC against a dynamometer will 
be measured bilaterally in the knee extensors muscle group. Lower extremity muscle strength 
is the average of the right and left total values (measured in kg). 
7.5.2.2 
GNEM Functional Activities Scale 
For UX001-CL202 and UX001-CL301 Subjects: The GNEM-FAS (also referred to as 
HIBM-FAS in some studies) is a disease-specific measure developed to assess the functional 
impact of changes in muscle strength.  The scale consists of 3 domains:  upper extremity, 
mobility, and self-care; scores for each domain and a total score will be obtained.  The scale 
has been developed specifically for patients with GNEM based on feedback received from 
affected individuals on the impact of the disease on their function.  Items in the scale assess 
the subject’s ability to independently perform various activities of living that involve 
self-care, mobility and use of the upper and lower extremities.  The scale will be 
administered in an interview format by a trained clinician (preferably a licensed physical 
therapist) and scored after the testing.  The physical therapists’ role is a combination of 
observing subjects conducting activities and asking subjects questions to assess performance 
of these activities. 
For UX001-CL203 Subjects: The original GNEM-FAS was developed as a 
clinician-reported outcome measure (ClinRO) for ambulatory GNEM patients but has since 
been modified to a self-report PRO format with items added to accommodate weaker 


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patients. This modified version is referred to as the GNEM-FAS Expanded Version and will 
be used for subjects rolling over from the UX001-CL203 study. 
7.5.2.3 
Sit-to-Stand Test 
For UX001-CL202 and UX001-CL301 Subjects: The sit-to-stand test (Agarwal et al. 
2006); (Ozalevli et al. 2007) will be administered at Screening for training purposes, and 
each subsequent scheduled study visit through Week 48 (or Early Termination), to assess 
lower extremity function.  The test will be administered by a trained clinician (preferably a 
licensed physical therapist).  The subject will be asked to stand upright from a seated position 
in a chair, return to a seated position, and then repeat the sequence at a comfortable pace 
according to their own rhythm for the 30-second duration of the test.  Use of an arm chair or 
a stationary object for leverage will be permitted if preferred by the subject.  The number of 
times the subject can rise from a seated to a standing position in a 30-second period will be 
recorded. 
The sit-to-stand test will not be performed in subjects who roll-over from the UX001-CL203 
study. 
7.5.2.4 
Weighted Arm Lift Test 
For UX001-CL202 and UX001-CL301 Subjects: Upper extremity function will be assessed 
using a weighted arm lift test.  The weighted arm lift test (Agarwal et al. 2006) will be 
administered at the Screening Visit for training purposes, then at each subsequent scheduled 
visit through Month 24 (or Early Termination).  The subject will be asked to sit in a chair 
holding a 1 kg barbell with the shoulder adducted, the elbow in full flexion, and the forearm 
in supination.  On command, the subject will be asked to lift the arm above the head until the 
elbow is fully extended, then to lower the arm back to the starting position.  The subject will 
be asked to repeat the action at a comfortable pace according to their own rhythm for the 
30 second duration of the test.  The test will be performed bilaterally and the final score will 
be the mean of the total number of completed repetitions from both arms.  The number of 
times the subject can raise the 1 kg weight above the head in the 30-second test period will be 
recorded. 
The weighted arm lift test will not be performed in subjects who roll-over from the 
UX001-CL203 study. 
7.5.2.5 
Six Minute Walk Test     
For UX001-CL202 and UX001-CL301 Subjects: The 6MWT will be administered once 
per test day at each subsequent scheduled study visit through Month 24 (or Early 
Termination). Refer to study-related materials for detailed instructions on conducting the 
6MWT.     
The 6MWT will be conducted based on American Thoracic Society guidelines (ATS/ERS 
2002).  Subjects will be instructed to walk the length of a pre-measured course for 


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6 consecutive minutes.  If applicable, the use of any AFOs and assistive devices in the 
performance of the 6MWT will be noted.  The total distance walked (meters) following the 
six minute period will be recorded.  The percent predicted distance walked (for age and 
gender) will also be determined based on published normative data (Gibbons et al. 2001). 
The six-minute walk test will not be performed in subjects who roll-over from the 
UX001-CL203 study. 
7.5.2.6 
Individualized Neuromuscular Quality of Life Questionnaire 
For UX001-CL202 and UX001-CL301 Subjects: The Individualized Neuromuscular 
Quality of Life Questionnaire (INQoL) (Vincent et al. 2007) is an individualized self-report 
measure of health-related quality of life designed specifically for adults with muscle disease. 
The INQoL will be presented to the subject in paper format for completion prior to the 
administration of the performance tests. The INQoL is a 45-item measure consisting of 
ten subscales; four measure the impact of muscle disease symptoms, including weakness, 
locking (seizing), pain and fatigue of muscles. Five additional subscales evaluate the degree 
of symptom impact on particular areas of life, including activities, independence, social, 
emotional, and body image. The final domain assesses perceived and expected treatment 
effects and will not be administered due to the blinded nature of the study. All responses are 
given in a seven-point Likert scale, with higher scores indicating greater impact.   
The INQoL will not be performed in subjects who roll-over from the UX001-CL203 or 
UX001-CL202 studies. 
7.5.2.7 
Medical Outcomes Survey – 36 Item (SF-36) 
For UX001-CL203 Subjects: The SF-36 will be completed by subjects rolling over from the 
UX001-CL203 study to assess physical and mental health based on 8 scaled scores that are 
the weighted sums of the questions in their section: vitality, physical functioning, bodily 
pain, general health perceptions, physical role functioning, emotional role functioning, social 
role functioning, and mental health. Each scale is directly transformed into a 0 to 100 scale 
on the assumption that each question carries equal weight. Lower scores indicate more 
diminished health-related quality of life. 
The SF-36 will not be performed in subjects who roll-over from the UX001-CL301 or 
UX001-CL202 studies. 
7.5.2.8 
Creatine Kinase Levels 
CK is a biochemical marker of muscle injury in many muscular system disorders.  
Most GNEM patients have some modest elevation of CK; in approximately 50% of patients 
CK levels are increased at least two-fold above the upper limit of normal (ULN).  CK levels 
in serum will be measured as indicated in the Schedule of Events (Table 2.1) to assess the 
degree of reduction associated with treatment. 


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7.5.3 
Drug Concentration Measurements 
The concentration of free SA in serum will be measured to further characterize the PK of 
Ace-ER.  At the Baseline Visit and each subsequent visit a serum sample will be collected, 
preferably, prior to the morning dose of study medication (pre-dose) to assess trough levels 
of free SA.   
The free, total, and bound urine SA levels (corrected for creatinine) will reflect the 
absorption of SA and the incorporation into sialylated proteins and oligosaccharides during 
treatment with Ace-ER tablets.  The change in urine SA levels will be analyzed the same as 
for the primary endpoint.  At Baseline/Screening, and each clinic visit, first-morning void 
urine will be collected (pre-dose) to assess trough levels; the volume obtained will be 
recorded.   
Collection and processing instructions can be found in the Laboratory Manual. 
7.5.4 
Urine Testing for ManNAc 
First morning void urine specimens will be analyzed for the presence of ManNAc at 
Baseline/Screening, and each clinic visit to detect noncompliance with prohibited medication 
restrictions. The urine volume obtained will be recorded. 
Collection and processing instructions can be found in the Laboratory Manual. 
7.5.5 
Safety Measures & General Assessments 
General assessments include medical history, demographics, height, and weight.  Safety will 
be evaluated by the incidence, frequency and severity of AEs and SAEs, including clinically 
significant changes from study baseline to scheduled time points in interval history, physical 
examinations, vital signs, clinical laboratory evaluations, suicidal ideation and behavior, and 
concomitant medications.  Pregnancy testing (or pregnancy of partner, if needed) will also be 
conducted as appropriate.  Refer to study-related materials for additional details on safety 
measures and general assessments. 
7.5.5.1 
Medical History 
A detailed medical history will be obtained at the Screening/Baseline Visit to solicit 
information on any prior or existing medical conditions that might interfere with study 
participation or safety.  General medical information includes subject demographics (date of 
birth, ethnicity, and sex) and a history of major medical illnesses, diagnoses, and surgeries.  
The GNEM-specific medical history should elicit all major illnesses, diagnoses, and 
surgeries to date.  Any relevant concomitant therapy, including physical/occupational therapy 
will be recorded. 


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7.5.5.2 
Interval History 
The interval history is intended to record any signs, symptoms, or events (e.g. falls) 
experienced by the subject since the prior study visit that are not related to study procedure(s) 
performed at prior study visits or study drug.  Interval history may include exacerbation or 
improvement in existing medical conditions (including the clinical manifestations of GNEM) 
that might interfere with study participation, safety, and/or positively or negatively impact 
performance of functional assessments.  Interval history may identify under-reported AEs 
and will be collected at each study visit. 
7.5.5.3 
Physical Examination 
Complete physical examinations will be performed at Baseline/Screening.  
Physical examinations will include assessments of general appearance; head, eyes, ears, nose, 
and throat; the cardiovascular, dermatologic, lymphatic, respiratory, GI, genitourinary, 
musculoskeletal, and neurologic systems. The neurologic system examination will include 
assessments of cognition, cranial nerves, motor function, coordination and gait, reflexes, and 
sensory function.  Brief physical examinations will be conducted at all other study visits and 
will include assessments of general appearance, cardiovascular and respiratory systems, and 
a focus on any presenting complaints. Clinically significant changes from baseline will be 
recorded as AEs. 
7.5.5.3.1 
Height and Weight 
Height and weight will be captured at the Baseline/Screening Visit and should be measured 
by the trained clinician administering the performance testing.  A stadiometer must be used 
for all height measurements; if a patient is unable to stand or has significant postural issues 
that interfere with collection of a standing height, self-reported adult height should be 
captured.  Height should be measured in inches or centimeters without shoes with the subject 
standing on a flat surface. A calibrated scale must be used for all weight measurements. 
Weight should be measured in pounds or kilograms without shoes. 
Height and weight data will be used to evaluate each subject’s muscle strength and function 
using published normative data where available.  The measurement obtained at the 
Screening/Baseline Visit will be used for all derivations of percent predicted. 
7.5.5.4 
Vital Signs  
Vital signs will include seated systolic blood pressure and diastolic blood pressure measured 
in millimeters of mercury (mmHg), heart rate in beats per minute, respiration rate in breaths 
per minute, and temperature in degrees Celsius (°C).  Vital signs measurements will be 
performed at every visit before any additional assessments are completed. 


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7.5.5.5 
Clinical Laboratory Tests for Safety 
The clinical laboratory evaluations to be performed in this study include a serum chemistry, 
complete blood count (hematology), and urinalysis. Specific analytes that will be evaluated 
are listed in Table 7.5.5.5.1.  Clinical laboratory testing will be performed at every visit, 
except for the safety follow-up call.  Blood samples, preferably pre-dose, and first-morning 
void urine samples will be collected prior to administration of study drug; fasting is not 
required.  Refer to the Laboratory Manual for additional details. 
Table 7.5.5.5.1: 
Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis+ 
Alanine aminotransferase (ALT) 
Hematocrit 
Appearance 
Alkaline phosphatase 
Hemoglobin 
Color 
Amylase 
Mean corpuscular hemoglobin (MCH) 
pH 
Aspartate aminotransferase (AST) 
MCH concentration (MCHC) 
Specific gravity 
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
Ketones 
Blood urea nitrogen (BUN) 
Platelet count 
Protein  
Calcium 
Red blood cell (RBC) count 
Glucose  
Chloride 
Reticulocyte count 
Bilirubin 
Cholesterol (total) 
Neutrophil count (absolute and %) 
Nitrite 
Creatine kinase 1 
 
Urobilinogen 
Creatinine 
Lymphocyte count (absolute and %) 
Hemoglobin  
Gamma-glutamyl transpeptidase (GGT) 
Monocyte count (absolute and %) 
Creatinine 2 
Glucose 
Eosinophil count (absolute and %) 
ManNAc 3 
Lactate dehydrogenase (LDH) 
Basophil count (absolute and %) 
Leukocyte 
esterase 
Lipase 
White blood cell (WBC) count 
Pregnancy test 
(if applicable) 
Phosphorus 
WBC differential 
Blood/RBC 
Potassium 
 
 
Protein (albumin and total) 
 
*Special 
assessment 
Sodium 
 
Serum pregnancy  
test if a positive 
urine pregnancy 
test 
Triglycerides 
 
 
+ Microscopic examination will be performed only if dip stick is abnormal for protein, leukocyte esterase, blood or nitrite. Microscopic examination may include WBC, 
RBC, Epithelial Cells, Squamous, Epithelial Cells, Transitional, Epithelial Cells, Renal Tubular, Hyaline Casts, WBC Casts, RBC Casts, Waxy Casts, Granular 
Casts, Calcium Oxalate Crystals, Uric Acid Crystals, Triphosphate Crystals, Yeast, Bacteria, Amorphous Urates and Amorphous Phosphates 
1 Also designated as PD variable (Section 7.5.2.8) 
2 Relevant to Drug Concentration Measurements (Section 7.5.3) 
3 To screen for use of prohibited medications (Section 7.4.6.1) 


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Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the Investigator (and/or medical monitor), have additional 
blood samples taken for safety laboratory tests. 
Upon completion of protocol-specified laboratory tests, leftover blood and urine samples 
from each visit may be used for additional exploratory research, eg, biomarker research. 
The leftover samples from this study will not be used for genetic testing.  
7.5.5.5.1 
Volume of Blood to Be Drawn from Each Subject 
During this study, it is expected that a maximum of approximately 16 mL of blood will be 
drawn from each subject, at each required time point, regardless of gender or age 
(Table 7.5.5.5.1.1).  The amount of blood to be drawn for each assessment is an estimate, and 
may vary according to the instructions provided by the manufacturer or laboratory for an 
individual assessment.  Samples indicated at the time point/period may be utilized for more 
than one assessment if the same type of tube is required (e.g. CK and serum chemistry).  
Table 7.5.5.5.1.1: 
Volume of Blood to Be Drawn From Each Subject 
Assessment 
Sample Volume (mL) 
Number of 
Samples 2 
Total Volume (mL) 2 
Safety 
Chemistry 1 
7.5 
7/9 
52.5/67.5 
Hematology 
3 
7/9 
21/27 
Drug 
Concentration 
Sialic Acid  
5 
7/7 
35/35 
Total mL through study completion 
108.5/129.5 
1 Includes CK 
2 UX001-CL203 subjects/UX001-CL202 and UX001-CL301 subjects 
7.5.5.6 
Pregnancy Testing 
Female subjects of childbearing potential with a positive pregnancy test at Baseline/ 
Screening will not be enrolled in the study.  Female subjects will have urine pregnancy tests 
throughout the study. 
Additional pregnancy tests will be performed at any visit in which pregnancy status is in 
question.  A serum pregnancy test will be performed in the event of a positive or equivocal 
urine pregnancy test result, or can be performed if pregnancy test by urine is not feasible.   
Experience with UX001 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby which are currently unknown.  Participants of child‐bearing 
potential or with partners of child bearing potential who have not undergone a bilateral 
salpingo‐oophorectomy and are sexually active must consent to use a highly effective method 
of contraception as determined by the site investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug.  Examples of highly 


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effective methods of contraception include oral hormonal contraceptives, patch hormonal 
contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical 
hysterectomy, vasectomy, tubal ligation or true abstinence (when this is in line with the 
preferred and usual lifestyle of the subject), which means not having sex for the duration 
specified above because the subject chooses not to.  
7.5.5.6.1 
Pregnancy in Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee.  The Investigator must make every effort to follow the 
pregnancy of either subject or partner through resolution of the pregnancy (delivery or 
termination) and report the resolution to Ultragenyx or its designee. In the event of a 
pregnancy in the partner of a subject, the Investigator should make every effort to obtain the 
female partner’s consent for release of protected health information.  Refer to study-related 
materials for details on the reporting procedures to follow in the event of pregnancy. 
7.5.5.7 
Suicidal Ideation and Behavior 
Prospective assessment of suicidal ideation and behavior is a regular part of development 
programs involving any drug being developed for any psychiatric indication, as well as for 
all antiepileptic drugs and other neurologic drugs with central nervous system activity 
(Food and Drug Administration [FDA] Draft Guidance, 2012).  The C-SSRS is a 
standardized rating instrument used to assess the suicidal ideation and behavior in an at-risk 
population (Posner et al. 2011).  To prospectively assess suicidal ideation and behavior, the 
C-SSRS will be administered by trained site personnel. The Baseline/Screening C-SSRS 
(may be same as last visit in parent study) will be administered at the Screening and Baseline 
visits; the Since Last Visit C-SSRS will be administered at all subsequent visits. 
The responses to the questionnaire will be reviewed by site personnel during the study visit; 
if emergent suicidal ideation or behavior is indicated, the investigator should promptly 
evaluate the subject to ensure proper management and protection of subject safety.  
7.5.5.8 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit, beginning at the Screening/Baseline visit.  Medications (investigational, 
prescription, over-the-counter, and herbal) and nutritional supplements taken during the 
30 days prior to Screening/Baseline will be reviewed and recorded. At each subsequent visit, 
change in medications since the previous visit will be recorded.  A discussion of concomitant 
medications is provided in Section 7.4.6. 
7.5.5.9 
Adverse Events 
All AEs will be recorded from the time subjects sign informed consent for this extension 
study and completion of the End of treatment visit in the parent study until 30 days after the 
last dose of study drug. Adverse events reported as ongoing at parent study’s End of 


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treatment visit and any new AEs prior to Baseline for this study will be reviewed and 
recorded at the Baseline visit.  
The determination, evaluation, reporting, and follow-up of AEs will be performed as 
outlined in Section 8.5. At each visit subjects will be asked about any new or ongoing AEs 
since the previous visit. Assessments of AEs will occur at each study visit. 
Clinically significant changes from study baseline in interval history, physical and 
neurological examination findings, vital signs, weight, clinical laboratory parameters, and 
concomitant medications will be recorded as AEs or SAEs, if appropriate. 
7.5.6 
Appropriateness of Measures 
There are two different types of patients in this extension study (those with severe 
ambulatory impairment [UX001-CL203] and subjects from UX001-CL202 and 
UX001-CL301); specific measures vary depending on their functional status. The efficacy 
parameters to be evaluated in this study include clinical changes in muscle strength, subject 
mobility, and function.  The clinical assessments in the study employ standard performance 
measures used in other neuromuscular diseases and conditions that cause muscle weakness 
and impaired function.  Based on results from Phase 2 studies with Ace-ER and published 
studies in other muscle diseases (Aitkens et al. 1989), the study will focus on quantitative 
muscle testing.  The strength of a set of muscle groups in the upper and lower extremities 
will be assessed by dynamometry, a form of quantitative muscle testing that uses a device 
with a strain gauge to measure force during a MVIC (Sisto et al. 2007).  The GNEM-FAS 
will be administered in this study to support the clinical meaningfulness of changes in muscle 
strength. In addition, walking ability will be assessed using the 6MWT test, a test of 
endurance commonly used in clinical trials for various indications that has served as the basis 
for many product approvals.    
The level of free SA in serum will reflect the absorption of and exposure of the muscles to 
SA during treatment. Serum CK level will be assessed as a measure of muscle injury 
throughout the study; a positive dose-dependent decrease in serum CK levels was observed 
in the UX001-CL201 Week 24 analysis.  Unlike other myopathies, CK activities are mildly 
elevated or in the normal range for these patients.  The mouse model of HIBM showed 
elevated CK levels that improved substantially on treatment (Malicdan et al. 2009).   
The safety parameters to be evaluated in this study include standard assessments such as 
recording of AEs and SAEs, concomitant medications, medical history, physical examination 
(including neurological examination), vital signs, serum chemistry, and other routine clinical 
and laboratory procedures.  In addition, symptoms of increasing muscle weakness and pain 
which are characteristic of myopathy will be recorded in interval histories. Suicidal ideation 
and behavior will be assessed using C-SSRS, a standardized rating instrument recommended 
in clinical trials of any investigational drug with potential neurological activity (FDA Draft 
Guidance, 2012). 


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7.6 
Statistical Methods and Determination of Sample Size 
The completeness of the data affects the integrity and accuracy of the final study analysis.  
Therefore, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data.  The procedures for handling missing, unused, or spurious data, 
along with the detailed method for analysis of each variable will be presented in the 
Statistical Analysis Plan (SAP); the information below is intended as a guide to planned 
analyses. 
7.6.1 
Determination of Sample Size 
The current study is primarily designed to evaluate safety and the sample size is intended to 
provide the maximum amount of information regarding UX001 tolerability along with 
indicators of long-term safety and efficacy in this patient population. Approximately 
165 adult subjects with GNEM are expected to roll-over from UX001-CL202 (N=55), 
UX001-CL301 (N=80), and UX001-CL203 (N=30) studies to participate in this extension 
study. 
7.6.2 
Subject Information 
Summaries and listings will be provided for all subjects who received at least 1 dose of study 
drug and provided at least 1 safety or efficacy evaluation.  Subject disposition summaries 
will include the number of enrolled subjects, the number of subjects receiving study 
medication, the number of subjects completing the study, and the reasons for discontinuation.  
Demographic variables include age, sex, and race.  
7.6.3 
Populations Analyzed 
Full Analysis Set:  The full efficacy set will include all subjects with a baseline 
measurement and at least one post-baseline measurement.  This set will be used for the 
primary analyses of all efficacy endpoints. 
Safety Analysis Set:  The safety analysis set consists of all subjects who receive at least one 
dose of study drug. This set will be used for the analyses of all safety endpoints. 
Sialic Acid Analysis Set:  The SA analysis set will consist of all randomized subjects with 
evaluable free serum SA levels. 
7.6.4 
Efficacy Analysis 
Separate analyses will be performed for subjects coming from each parent study. 
The full analysis set will include all subjects with a baseline measurement and at least one 
post-baseline measurement. This set will be used for the analyses of all efficacy endpoints. 
Baseline values for each endpoint will be defined as the last scheduled data collection visit 
before first dose according to the Schedule of Events (Table 2.1).  


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Efficacy analyses will use generalized estimating equation (GEE) to evaluate trends over 
time with respect the changes from baseline for the primary efficacy endpoint, and all 
secondary and tertiary efficacy endpoints. Baseline will be included as a covariate in the 
model. This method will be the primary analysis method for all repeated measures endpoints.  
The statistical analyses will be reported using summary tables, figures, and data listings.  
Statistical tests will be 2-sided at the alpha=0.05 significance level.  
Continuous variables will be summarized with means, standard deviations, medians, 
minimums, and maximums. Categorical variables will be summarized by counts and by 
percentages of subjects in corresponding categories. 
7.6.5 
Analyses of Drug Concentration Measurements 
The SA analysis set will be used to evaluate free serum SA levels and urine SA levels (free, 
bound and total; corrected for creatinine) at trough (pre-dose) using the SA analysis set. 
Changes from baseline will be analyzed using the GEE method for repeated measures 
analysis.  
7.6.6 
Safety Analyses 
Safety will be evaluated for the overall study population as well as for subjects from the 
UX001-CL202, UX001-CL301, and  UX001-CL203 study.  
The safety analysis set will be used for the analyses of all safety endpoints.  Safety will be 
evaluated by the incidence, frequency and severity of AEs and SAEs, and clinically 
significant changes from study baseline to scheduled time points in: 
• Interval history 
• Vital signs 
• Physical examination findings 
• Clinical laboratory evaluations 
• Suicidal ideation and behavior assessments (C-SSRS) 
• Concomitant medications 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), 
Preferred Term (PT), severity, and relationship to treatment.  The numbers (frequency) and 
incidence rates of AEs and SAEs will be summarized by treatment group. A by-subject 
listing will be provided for those subjects who experience a SAE, including death, or 
experience an AE associated with early withdrawal from the study or study drug treatment. 


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Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e. outside of 
reference ranges) and/or clinically significant abnormalities will be presented for each 
clinical laboratory measurement.  For each clinical laboratory measurement, descriptive 
statistics will be provided for study baseline and all subsequent post-treatment scheduled 
visits.  Changes from study baseline to the post-treatment visits will also be provided.   
Changes in findings from study baseline physical examinations will be tabulated for each 
subject by examination category.  If there are examination findings that change in more than 
one subject, these will be tabulated in a separate table and expressed as the number of 
subjects with the change out of the total.  No statistics will be applied to the physical 
examination findings. 
The SAP will provide additional details on the planned safety analyses.  


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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee 
The Institutional Review Board (IRB)/Ethics Committee (EC) must be a properly constituted 
board or committee operating in accordance with 21 Code of Federal Regulations (CFR)  
Part 56, "Institutional Review Boards."  This protocol, any protocol amendments, and the 
associated informed consent forms (ICFs) must be submitted to the IRB/EC for review and 
must be approved before screening of any subject into the study.  Study drug may not be 
shipped to the Investigator until Ultragenyx or its designee has received a copy of the letter 
or certificate of approval from the IRB/EC for the protocol and any protocol amendments, as 
applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/EC and 
Ultragenyx or its designee for review and approval prior to implementation.  IRB/EC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety.  In such cases, the chair of the IRB/EC should be notified immediately and the 
amendment forwarded to the IRB/EC for review and approval. 
8.1.2 
Ethical Conduct of Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The Sponsor and Investigator will make 
every effort to assure the study described in this protocol is conducted in full conformance 
with those principles, current FDA regulations, ICH Good Clinical Practices (GCP) 
guidelines, and local ethical and regulatory requirements. Should a conflict arise, the Sponsor 
and Investigator will follow whichever law or guideline affords the greater protection to the 
individual subject. The investigator will also make sure he or she is thoroughly familiar with 
the appropriate administration and potential risks of administration of the study drug, as 
described in this protocol and the IB, prior to the initiation of the study.  
8.1.3 
Subject Information and Consent 
Appropriate forms for documenting written informed consent will be provided by the 
Investigator and reviewed and approved by Ultragenyx or its designee before submission to 
the IRB/EC.  Ultragenyx or its designee must receive a copy of the IRB/EC's approval of the 
informed consent form (ICF) before the shipment of study drug to the study site. 
It is the Investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures.  This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject.  The Investigator must explain 


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to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time.     
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements.  Subjects will be given a copy 
of the signed ICF and will be provided any new information during the course of the study 
that might affect their continued participation in the study.  The Investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction.  If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
The date of written informed consent will be documented in each potential subject’s CRF.  
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each Investigator must provide Ultragenyx and/or its designee a completed and signed 
Form FDA 1572 and a Financial Disclosure Form.  All sub-investigators must be listed on 
Form FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators 
listed on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines.  Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site to 
perform source document verification.  The monitor will verify the Investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
A Coordinating Investigator will be identified for multicenter trials.  The Coordinating 
Investigator will be selected on the basis of active participation in the trial, thorough 
knowledge of the therapeutic area being studied, and the ability to interpret data.  
The Coordinating Investigator will read and sign the Clinical Study Report (CSR). 
8.3 
Investigational Product Accountability 
While at the clinical site, study drug must be stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging.  
The storage facility must be available for inspection by the study monitor at any time during 
the study.   


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A drug accountability record must be maintained for all study drug received, dispensed, 
returned, and/or lost during the study.  This record must be kept current and made available 
to the study monitor for inspection.  Following the close-out of the study, all unused study 
drug must be returned to Ultragenyx and/or its designee unless other instructions have been 
provided for final disposition of the study drug.  
8.4 
Data Handling and Record Keeping 
8.4.1 
Case Report Forms and Source Documents 
The Investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject.  A validated electronic data capture (EDC) system will be used for entry of the data 
into electronic CRFs.  Data must be recorded on CRFs approved by Ultragenyx or its 
designee.  All information recorded on CRFs for this study must be consistent with the 
subject's source documentation. 
Initial data entry and any changes to the data will be made only by Ultragenyx-authorized 
users, and data entries and changes will be captured in an electronic audit trail.  
An explanation of any data change should be recorded in the CRF.  All data entered in to the 
CRF must be verifiable; therefore, CRFs will be routinely checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records by Ultragenyx or its designee.  
The Investigator must allow direct access to all source documents. 
8.4.2 
Data Quality Assurance 
Monitoring and auditing procedures developed by Ultragenyx and/or its designee will be 
implemented to ensure compliance with FDA and ICH GCP guidelines.  Ultragenyx's 
designated representative (the monitor) will contact the Investigator and conduct regular 
visits to the study site.  The monitor will be expected and allowed to verify the Investigator's 
qualifications, to inspect clinical site facilities, and to inspect study records, including proof 
of IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements.  The monitor 
will also be responsible for confirming adherence to the study protocol, inspecting CRFs and 
source documents, and ensuring the integrity of the data.  CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents 
including progress notes, laboratory test reports and other subject records.  Instances of 
missing or uninterruptable data will be resolved in coordination with the Investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The monitor will 
maintain contact with the site through frequent direct communications via e-mail, telephone, 
facsimile, and/or mail.  The Investigator and all other site personnel agree to cooperate fully 
with the monitor and will work in good faith with the monitor to resolve any and all 
questions raised and any and all issues identified by the monitor. 


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The Investigator understands that regulatory authorities, the IRB/EC, and/or Ultragenyx or 
its designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least two years after the last approval of a marketing application or for at least two 
years after clinical development of the study drug for the indication being studied has been 
discontinued.  The Investigator is required to guaranty access to these documents and to 
cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, but not less 
than 25 years. Ultragenyx must be notified and will assist with retention should the 
Investigator/institution be unable to continue maintenance of subject files for the full 
25 years. All study records must be stored in a secure and safe facility.  
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) products. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
Life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the Investigator or Ultragenyx, places the patient 
or subject at immediate risk of death.  It does not include an AE or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
current Investigators Brochure’s Reference Safety Information (RSI) or is not listed at the 
specificity or severity that has been observed.  


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An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at 
any dose, in the view of either the Investigator or Ultragenyx, results in any of the following 
outcomes:  
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4.03).  
The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions.  
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and of a minor 
irritant type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death or 
are disabling. 
• Death (Grade 5): Events that result in death. 


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To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided.  The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This is not the same 
as "serious" which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject's life or functioning.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
• Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure. 
• Unlikely Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure.  
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Adverse Event Reporting 
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the CRF. The Principal Investigator is responsible for evaluating all AEs, obtaining 
supporting documents, and ensuring documentation of the event is adequate. Details of the 
AE must include severity, relationship to study drug, duration, and outcome.  
All AEs will be recorded from the time subjects sign informed consent for this extension 
study and completion of the End of treatment visit in the parent study until 30 days after the 


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last dose of study drug. Adverse events reported as ongoing at parent study’s End of 
treatment visit and any new AEs prior to Screening /Baseline visit for this study will be 
reviewed and recorded at the Screening/Baseline visit.  
In addition, the Investigator should report any AE that occurs after this time period that is 
believed to have a reasonable possibility of being associated with study drug. 
AEs ongoing at 30 days following the last dose of study drug should have a comment in the 
source document by the Investigator that the event has recovered, recovered with sequelae, or 
stabilized.  
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Ultragenyx or its designee must be notified of the occurrence of any SAE that occurs during 
the reporting period within 24 hours of the Investigator, designee, or site personnel’s 
knowledge of the event. SAEs will be reported by completing and submitting SAE report 
forms to Ultragenyx or designee.   
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected.  
All deaths, regardless of causality, occurring from signing of the informed consent until  
30 days following the last dose of study drug are to be reported as SAEs to Ultragenyx or its 
designee within 24 hours of knowledge.   
8.5.4.3 
Pregnancy Reports 
Reported pregnancy of a subject or a subject’s partner, while participating in the study, will 
be monitored for the full duration and/or followed until the outcome of the pregnancy is 
known. Pregnancy associated SAEs will be processed and submitted, as necessary, as per the 
suspected unexpected serious adverse reactions (SUSAR) reporting process indicated in 
Section 8.5.5.1. 
8.5.5 
Communication Plan 
8.5.5.1 
Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit SUSAR to appropriate Regulatory Authorities 
(including Competent Authorities in all Member States concerned), ECs, and Investigators as 
per local laws and regulations. Fatal and life-threatening SUSARs will be submitted no later 
than 7-calendar days of first knowledge of the event and follow-up information submitted 
within an additional eight (8) days. All other SUSARs will be submitted within 15-calendar 
days of first knowledge of the event.  


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Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
ECs, and Investigators of any events (e.g. change to the safety profile of SA, major safety 
findings) that may occur during the clinical trial that do not fall within the definition of a 
SUSAR but may affect the safety of subjects participating in the clinical trials, as required, in 
accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from the signing of the ICF through 30 days following the last dose of 
study drug. 
The Investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs and urgent 
safety matters, in accordance with IRB/REB/EC requirements and local laws and regulations. 
A copy of this notification must be provided to Ultragenyx or its designee. 
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and ECs, as per local laws and regulations. 
8.5.6 
Urgent Safety Measures 
The regulations governing clinical studies state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations.  According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard.  The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
EC is notified at the same time.”  The reporting period for urgent safety measures is the 
period from the signing of the ICF through completion of the last study visit.  Investigators 
are required to report any urgent safety measures to Ultragenyx within 24 hours. 
8.5.7 
Safety Contact Information 
Drug Safety 
Medical Monitor 
PrimeVigilance 
Fax:     
 
e-mail: 
 
 
Ed Conner, MD 
Telephone:   
 
e-mail:         
 
 


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8.6 
Financing and Insurance 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements 
with the study site. 
8.7 
Publication Policy 
Any publication or presentation by the Investigator and/or the Institution based on data or 
results resulting from the Ultragenyx study shall only be done in strict accordance with the 
Publication section in the Clinical Trial Agreement executed between Ultragenyx and the 
Institution and/or the Investigator. 


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9 REFERENCES 
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ATS/ERS. 2002. "American Thoracic Society Statement: Guidelines for the six-minute walk 
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Bardor, M, Nguyen, DH, Diaz, S, and Varki, A. 2005. "Mechanism of uptake and 
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Bohannon, RW. 1997. "Reference values for extremity muscle strength obtained by hand-
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Bohannon, RW, Peolsson, A, Massy-Westropp, N, Desrosiers, J, and Bear-Lehman, J. 2006. 
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Gibbons, WJ, Fruchter, N, Sloan, S, and Levy, RD. 2001. "Reference values for a multiple 
repetition 6-minute walk test in healthy adults older than 20 years." J 
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Guy, W. 1976. "The Clinical Global Impression Scale." In Handbook of Psychiatric 
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Huizing, M, Carrillo-Carrasco, N, Malicdan, MC, Noguchi, S, Gahl, WA, Mitrani-
Rosenbaum, S, Argov, Z, and Nishino, I. 2014. "GNE myopathy: new name and new 
mutation nomenclature." Neuromuscul Disord 24 (5):387-9. 
Huizing, M, and Krasnewich, DM. 2009. "Hereditary inclusion body myopathy: a decade of 
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Jay, CM, Levonyak, N, Nemunaitis, G, Maples, PB, and Nemunaitis, J. 2009. "Hereditary 
Inclusion Body Myopathy (HIBM2)." Gene Regul.Syst.Bio 3:181-190. 
Malicdan, MC, Noguchi, S, Hayashi, YK, Nonaka, I, and Nishino, I. 2009. "Prophylactic 
treatment with sialic acid metabolites precludes the development of the myopathic 
phenotype in the DMRV-hIBM mouse model." Nat.Med 15 (6):690-695. 


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Amendment 1: 17 June 2016 
 
 
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Malicdan, MC, Noguchi, S, and Nishino, I. 2008. "Recent advances in distal myopathy with 
rimmed vacuoles (DMRV) or hIBM: treatment perspectives." Curr.Opin.Neurol 21 
(5):596-600. 
Mathiowetz, V, Kashman, N, Volland, G, Weber, K, Dowe, M, and Rogers, S. 1985. "Grip 
and pinch strength: normative data for adults." Arch Phys Med Rehabil 66 (2):69-74. 
Mease, PJ, Spaeth, M, Clauw, DJ, Arnold, LM, Bradley, LA, Russell, IJ, Kajdasz, DK, 
Walker, DJ, and Chappell, AS. 2011. "Estimation of minimum clinically important 
difference for pain in fibromyalgia." Arthritis Care Res (Hoboken) 63 (6):821-6. 
NIMS. 1996. "Muscular weakness assessment: use of normal isometric strength data. The 
National Isometric Muscle Strength (NIMS) Database Consortium." Arch Phys Med 
Rehabil 77 (12):1251-5. 
Nonaka, I, Noguchi, S, and Nishino, I. 2005. "Distal myopathy with rimmed vacuoles and 
hereditary inclusion body myopathy." Curr.Neurol.Neurosci.Rep. 5 (1):61-65. 
Oetke, C, Hinderlich, S, Brossmer, R, Reutter, W, Pawlita, M, and Keppler, OT. 2001. 
"Evidence for efficient uptake and incorporation of sialic acid by eukaryotic cells." 
Eur.J.Biochem. 268 (16):4553-4561. 
Ozalevli, S, Ozden, A, Itil, O, and Akkoclu, A. 2007. "Comparison of the Sit-to-Stand Test 
with 6 min walk test in patients with chronic obstructive pulmonary disease." Respir 
Med 101 (2):286-93. 
Peters, MJ, van Nes, SI, Vanhoutte, EK, Bakkers, M, van Doorn, PA, Merkies, IS, Faber, 
CG, and PeriNom, SSg. 2011. "Revised normative values for grip strength with the 
Jamar dynamometer." J Peripher Nerv Syst 16 (1):47-50. 
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, 
Melvin, GA, Greenhill, L, Shen, S, and Mann, JJ. 2011. "The Columbia-Suicide 
Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults." Am J Psychiatry 168 (12):1266-77. 
Sisto, SA, and Dyson-Hudson, T. 2007. "Dynamometry testing in spinal cord injury." 
J.Rehabil.Res.Dev. 44 (1):123-136. 
Vincent, KA, Carr, AJ, Walburn, J, Scott, DL, and Rose, MR. 2007. "Construction and 
validation of a quality of life questionnaire for neuromuscular disease (INQoL)." 
Neurology 68 (13):1051-7. 
Yonekawa, T, Malicdan, MC, Cho, A, Hayashi, YK, Nonaka, I, Mine, T, Yamamoto, T, 
Nishino, I, and Noguchi, S. 2014. "Sialyllactose ameliorates myopathic phenotypes in 
symptomatic GNE myopathy model mice." Brain 137 (Pt 10):2670-9. 


Protocol Number: UX001-CL302 
Amendment 1: 17 June 2016 
10 SIGNATURE PAGE 
Protocol Title: A Phase 3b Open-label Study to Evaluate the Safety and Efficacy of 
Aceneuramic Acid Extended-Release (Ace-ER) Tablets in Patients with GNE Myopathy 
(GNEM) or Hereditary Inclusion Body Myopathy (HIBM) 
Protocol Number: UX001-CL302, Amendment 1 
I have read Protocol UX001-CL302, Amendment 1. I agree to conduct the study as detailed 
in this protocol and in compliance with the Declaration of Helsinki, Good Clinical Practices 
(GCP), and all applicable regulatory requirements and guidelines. 
· 
Investigator Signature 
Date 
Printed Name: ------------------------------------------------------
Accepted for the Sponsor: 
As the Sponsor representative, I confirm that Ultragenyx will comply with all Sponsor 
obligations as detailed in all applicable regulations and guidelines. I will ensure the 
Investigator is informed of all relevant information that becomes available during the conduct 
of this s dy. 
Ed Conner, MD 
Vice President, Clinical Science 
Ultragenyx Pharmaceutical Inc. 
Proprietary and Confidential 
Date 
Page 61 

SAP_000.pdf: 
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Study Number: UX001-CL302  
Statistical Analysis Plan  
15 June 2017, Version 1.0 
 
 
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Page 2 
 
TABLE OF CONTENTS 
ABBREVIATIONS ...................................................................................................................5 
1 INTRODUCTION ...............................................................................................................7 
2 STUDY OBJECTIVE(S) .....................................................................................................8 
2.1 Overall Safety Objective(s) .........................................................................................8 
2.2 Overall Efficacy Objective(s) .....................................................................................8 
3 STUDY DESIGN.................................................................................................................9 
3.1 Study Population .......................................................................................................10 
3.2 Dosage and Administration .......................................................................................10 
3.3 Blinding and Randomization Methods .....................................................................10 
3.4 Stratification Factors .................................................................................................10 
3.5 Sample Size Considerations ......................................................................................10 
3.6 Interim Analysis ........................................................................................................10 
3.7 Data Monitoring Committee .....................................................................................10 
4 STUDY ENDPOINTS AND COVARIATES ...................................................................11 
4.1 Safety Endpoints .......................................................................................................11 
4.1.1 
Primary Safety Endpoint .............................................................................11 
4.1.2 
Other Safety Endpoints ...............................................................................11 
4.2 Efficacy Endpoints ....................................................................................................11 
5 DEFINITIONS ...................................................................................................................14 
5.1 Baseline .....................................................................................................................14 
5.2 Subgroup ...................................................................................................................14 
6 ANALYSIS SETS .............................................................................................................15 
7 DATA SCREENING AND ACCEPTANCE ....................................................................16 
7.1 General Principles .....................................................................................................16 
7.2 Handling of Missing and Incomplete Data ...............................................................16 
7.2.1 
Missing Date of the Last Dose of Investigational Product ..........................16 


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7.2.2 
Missing Efficacy Data .................................................................................16 
7.2.3 
Missing Dates Information for Adverse Events and Concomitant 
Medications .................................................................................................16 
7.2.4 
Missing Causal Relationship to Investigational Product for Adverse 
Events ..........................................................................................................17 
7.2.5 
Visit Time Windows ...................................................................................17 
7.3 Handling of Multiple Measurements in HHD ...........................................................17 
7.4 Testing/Validation Plan.............................................................................................17 
7.5 Software ....................................................................................................................17 
8 STATISTICAL METHODS OF ANALYSES ..................................................................18 
8.1 General Principles .....................................................................................................18 
8.2 Subject Disposition ...................................................................................................19 
8.3 Protocol Deviations ...................................................................................................19 
8.4 Demographic and Baseline Characteristics...............................................................20 
8.5 Investigational Product Administration ....................................................................20 
8.5.1 
Extent of Exposure ......................................................................................20 
8.5.2 
Measurement of Treatment Compliance .....................................................20 
8.6 Efficacy Analysis ......................................................................................................20 
8.7 Safety Analysis .........................................................................................................21 
8.7.1 
Adverse Events ............................................................................................21 
8.7.1.1 
Adverse Events to Monitor ..........................................................22 
8.7.2 
Concomitant Medication .............................................................................22 
8.7.3 
Clinical Laboratory Parameters ...................................................................22 
8.7.4 
Vital Signs ...................................................................................................22 
8.7.5 
Physical and Neurological Exams ...............................................................22 
8.7.6 
Interval History ............................................................................................23 
8.7.7 
Suicidal Ideation ..........................................................................................23 
8.7.8 
Pregnancy Test ............................................................................................23 


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Statistical Analysis Plan  
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9 REFERENCES ..................................................................................................................24 
10 APPENDICES ...................................................................................................................25 
10.1 Summary of Efficacy Endpoints and Analyses.........................................................25 
10.2 Missing Observation in Hand Held Dynamometry and GNEM-FAS ......................28 
10.3 Computation Formula for Derived HHD Variables ..................................................31 
10.3.1 Predicted Normal HHD Muscle Strength ....................................................32 
10.4 Summary of Efficacy Assessment in Parent Studies and in Current Study 
CL302 .......................................................................................................................37 
10.5 Schedule of Events ....................................................................................................39 
10.6 Adverse Events to Monitor .......................................................................................42 
10.6.1 Gastrointestinal MedDRA Query ................................................................42 
10.6.2 Liver-Related Investigations .......................................................................43 
10.7 Table templates for efficacy and safety analysis presentation ..................................44 
 
List of Tables 
Table 4.2.1:  Efficacy Assessments Performed by Parent Study .............................................13 
Table 8.1.1:  Analysis Presentation ..........................................................................................19 
 
List of Figures 
Figure 3.1: 
Study Schema.........................................................................................9 
 


Study Number: UX001-CL302  
Statistical Analysis Plan  
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ABBREVIATIONS 
6MWT 
Six Minute Walk Test 
Ace-ER 
Aceneuramic Acid Extended-Release 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical  
CK 
creatine kinase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
DMRV 
distal myopathy with rimmed vacuoles 
ET 
early termination 
GEE 
generalized estimating equation 
GNE/MNK 
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine 
kinase 
GNEM 
GNE Myopathy 
GNEM-FAS 
GNE Myopathy Functional Activities Scale 
HHD 
hand held dynamometry 
HIBM  
hereditary inclusion body myopathy 
INQoL 
Individualized Neuromuscular Quality of Life Questionnaire 
IP 
investigational product 
LEC  
lower extremity composite 
ManNAc 
N-acetyl-D-mannosamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS 
mental component summary 
CTCAE 
Common Terminology Criteria for Adverse Events 
PCS 
physical component summary 
PT 
preferred term 
qHS 
at the time of sleep (i.e., at bedtime) 
SA 
sialic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 


Study Number: UX001-CL302  
Statistical Analysis Plan  
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Page 6 
 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SF-36v2 
Short Formc-36 Health Survey version 2 
SOC  
system organ Class 
TEAE 
treatment-emergent adverse event 
TID 
three times per day 
UEC 
upper extremity composite 
US 
United States 


Study Number: UX001-CL302  
Statistical Analysis Plan  
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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the UX001-CL302 original protocol dated 
10 February 2016 and the UX001-CL302 Protocol Amendment 1 dated 17 June 2016. 
Should there be a difference between the SAP and the protocol with respect to analysis 
methods, the SAP will take precedence over the protocol. 


Study Number: UX001-CL302  
Statistical Analysis Plan  
15 June 2017, Version 1.0 
 
 
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2 STUDY OBJECTIVE(S) 
The study objective is to evaluate the long-term safety and efficacy of Ace-ER treatment of 
GNE Myopathy subjects. 
2.1 
Overall Safety Objective(s) 
Primary objective is to evaluate the long-term safety of 6 g/day Ace-ER treatment in subjects 
with GNE Myopathy.  
2.2 
Overall Efficacy Objective(s) 
Secondary objective is to evaluate the long-term effect of 6 g/day Ace-ER treatment in 
subjects with GNE Myopathy. 


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Study Number: UX001-CL302  
Statistical Analysis Plan  
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Page 10 
 
3.1 
Study Population 
This study will be conducted in adults who have previously documented mutations in the 
gene for the GNE/MNK enzyme leading to a diagnosis of GNEM (variously termed HIBM, 
DMRV, or Nonaka disease).  These patients have an impaired ability to synthesize 
endogenous SA, which leads to muscle weakness and atrophy.  Consequently, this is the 
relevant population for testing SA replacement therapy, and for determining if SA 
replacement leads to improved protein and lipid sialylation and stabilized or improved 
muscle structure and performance. 
Individuals who have ingested N-acetyl-D-mannosamine (ManNAc) or similar other 
SA-producing compounds during the 60 days prior to the Screening Visit will be excluded as 
it could confound interpretation of the results. 
3.2 
Dosage and Administration 
Each Ace-ER tablet contains 500 mg of SA in an extended release formulation for a total 
weight of 1200 mg/tablet. The drug will be administered by the oral route and will be divided 
into a TID regimen: 4 tablets taken in the morning, early evening, and before bedtime (qHS). 
The dose should be taken with food (i.e., within 30 minutes after a meal or snack). 
Treatment will be administered for a total of 24 months (96 weeks).  
3.3 
Blinding and Randomization Methods 
This is open-label extension study consists of one treatment arm. All subjects will be treated 
with Ace-ER 6 g/day. Randomization and blinding are not applicable. 
3.4 
Stratification Factors 
No stratification factors are planned. 
3.5 
Sample Size Considerations 
The current study is primarily designed to evaluate safety and the sample size is intended to 
provide the maximum amount of information regarding UX001 tolerability along with 
indicators of long-term safety and efficacy in this patient population.  
Approximately 180 adult subjects with GNEM are expected to roll-over from 
UX001-CL202, UX001-CL301, and UX001-CL203 studies to participate in this extension 
study. 
3.6 
Interim Analysis 
No interim analysis is planned for this study. 
3.7 
Data Monitoring Committee 
No formal DMC is planned for this study in the protocol. Conduct of the study and safety of 
the patients will be monitored by Ultragenyx on a regular basis. 


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Statistical Analysis Plan  
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4 STUDY ENDPOINTS AND COVARIATES  
All data are collected according to the schedule of assessments (Appendix 10.4). 
Overall safety endpoints serve to evaluate the long-term safety of 6 g/day Ace-ER treatment 
in subjects with GNE Myopathy (primary objective). 
Overall efficacy endpoints serve to evaluate the long-term effect of 6 g/day of Ace-ER 
treatment in subjects with GNEM.  
4.1 
Safety Endpoints 
4.1.1 
Primary Safety Endpoint 
The primary endpoint of the study is the incidence and frequency of AEs and SAEs assessed 
as related to Ace-ER over the duration of the study. 
4.1.2 
Other Safety Endpoints 
Other safety endpoints include clinically significant changes from baseline to scheduled time 
points in the following: 
• Interval History 
• Vital signs 
• Physical examination results 
• Clinical laboratory results 
• C-SSRS (a measure of suicidal ideation and behavior) 
• Concomitant medications 
Drug concentration endpoints will be evaluated for the following: 
• Changes from baseline in free SA level in serum; 
• Changes from baseline in urine SA level; 
• Frequency and percentage of subjects with the presence of ManNac detected from 
urine testing. 
4.2 
Efficacy Endpoints 
Efficacy evaluations will be based on the parent study (UX001-CL202, UX001-CL301, or 
UX001-CL203) from which the subjects enroll. Subjects enrolling from UX001-CL202 
follow the same schedule of visits for the efficacy assessments as subjects who roll over from 
UX001-CL301.  Subjects enrolling from UX001-CL203 follow a different schedule of visits. 


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For subjects enrolling from UX001-CL202 and UX001-CL301:  
Primary Clinical Efficacy Endpoint:  
• Changes from baseline in upper extremity composite score (UEC) based on bilateral 
strength recorded in the following muscle groups: gross grip, shoulder abductors, elbow 
flexors, and elbow extensors as measured by dynamometry. The UEC is derived from the 
sum of the average of the right and left total force values (measured in kg); 
Secondary Clinical Efficacy Endpoints:  
• Changes from baseline in the scores on the mobility domain of GNEM-FAS; 
•  Change from baseline in the scores on the upper extremity domain of GNEM-FAS; 
• Changes from baseline in lower extremity composite score (LEC) based on bilateral 
strength recorded in the following muscle groups: knee flexors, hip flexors, hip extensors, 
hip abductors and hip adductors as measured by dynamometry. The LEC is derived from 
the sum of the average of the right and left total force values; 
• Change from baseline in the number of stands in the Sit-to-Stand test; 
• Changes from baseline in the number of lifts in 30 second weighted arm lift; 
• Changes from baseline in meters walked in 6MWT and percent predicted distance based 
on normative data for age and gender; 
• Changes from baseline in total force and percent predicted total force in the Knee 
Extensors. The percent predicted total force value will be determined based on reference 
equations adjusting for age, gender, height, and weight. 
Tertiary Efficacy Endpoints:  
• Changes from baseline in UEC and LEC percent predicted based on reference equations 
adjusting for age, gender, height, and weight; 
• Changes from baseline in bilateral total force and percent predicted total force for each 
individual muscle group included in the UEC and LEC; 
• Changes from baseline in the score on self-care domain on GNEM-FAS; 
• Changes from baseline in the total score on GNEM-FAS; 
• Change from baseline in in the total score from a 45-item self-report questionnaire 
(INQoL) on the impact of key muscle disease symptoms on the ability to perform basic 
activities of daily living, functional independence, relationships and overall well-being; 
• Changes from baseline in CK levels in serum to assess the degree of reduction of CK 
levels observed as a surrogate for muscle injury. 


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For subjects enrolling from UX001-CL203:   
Primary Clinical Efficacy Endpoints:  
• Changes from baseline in the mobility  domain of GNEM-FAS Expanded Version; 
• Changes from baseline in the upper extremity domain of GNEM-FAS Expanded Version;  
• Changes from baseline in the self-care domain of GNEM-FAS Expanded Version; 
• Changes from baseline in the total scores of GNEM-FAS Expanded Version;  
• Changes from baseline in upper extremity muscle strength and percent predicted in the 
following muscle groups: grip, key pinch, shoulder abductors and wrist extensors as 
measured by HHD 
• Changes from baseline in lower extremity muscle strength and percent predicted in the 
knee extensors as measured by HHD 
Exploratory endpoints: 
• Changes from baseline in 8 subscales and summary scores (PCS and MCS) in 
health-related quality of life as assessed by using Short Form Health Survey – 36 
(SF-36v2); 
• Changes from baseline in creatine kinase (CK) and serum aceneuramic acid.  
Assessments, upon which efficacy endpoints are based on, are shown in Table 4.2.1. Detailed 
information on efficacy endpoints and visit schedules by study can be found in 
Appendix 10.1. 
Table 4.2.1:  Efficacy Assessments Performed by Parent Study 
 
CL202 and CL301 
CL203 
Assessment 
Week 0, 8, 16, 24, 48, 72, 96 
Week 0, 24, 48, 72, 96 
Functional 
HHD*  
6MWT 
Sit-to-Stand Test 
Weighted Arm Lift Test 
GNEM FAS 
HHD^ 
GNEM FAS expanded version 
QoL Questionnaire 
INQoL 
SF-36 short form 
Biomarker 
CK 
Free serum SA 
Urine ManNAc  
* Measured by HHD, the Upper Extremity Composite (UEC) Score is based on gross grip, shoulder abductors, 
elbow flexors, and elbow extensors. The Lower Extremity Composite (LEC) Score is based on knee flexors, hip 
flexors, hip extensors, hip abductors, and hip adductors.  
^ Measured by HHD, UEC is not defined in this study for analysis, since different muscle groups from the other 
two studies are measured.  Lower extremity muscle strength of knee extensors is included. 


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5 DEFINITIONS 
5.1 
Baseline 
Two baselines are defined for the statistical analysis variable derivations. 
• Current study baseline is defined as the last observed value before the first dosing 
of the study drug for CL302. 
• Parent study baseline is defined as the last observed value before the first dosing of 
the IP study drug from CL202, CL203, or CL301 depending on which study the 
subject was enrolled from. 
Current study baseline is defined for all safety summaries and analyses.   
Efficacy summaries and analyses will be performed upon the parent study baseline and the 
current study baseline as specified in Table 8.1.1. 
5.2 
Subgroup 
The following subgroups are defined for this study: 
• Gender (Male and Female) 
• Age (above and below median) 
• Ethnicity (small groups may be combined) 
• Genetic Mutation  
- 
Genotype: Homozygote, Heterozygote, and Compound Heterozygote 
- 
Mutation type: Exon and Intron 
Genetic mutation subgroup analysis will be done for the following primary efficacy 
endpoints: the changes from baseline in UEC score in subjects enrolled from CL301 and 
CL202; and the changes from baseline in lower extremity muscle strength of knee extensors 
in subjects enrolled from CL203. 
Gender, age, and ethnicity subgroup summaries will be done to support the safety. 


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6 ANALYSIS SETS 
Three analysis sets are defined for the study. 
Full Analysis Set: The full analysis set will include all subjects with a CL302 baseline 
measurement and at least one post-baseline measurement in CL302. This set will be used for 
the efficacy analysis. 
Safety Analysis Set: The safety analysis set consists of all subjects who receive at least 
one dose of study drug in CL302. This set will be used for safety analysis. 
Sialic Acid Analysis Set: The SA analysis set will consist of all subjects with evaluable free 
serum SA levels in CL302. 


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7 DATA SCREENING AND ACCEPTANCE 
7.1 
General Principles 
Data will be reviewed periodically. And any questionable data will be reported to the clinical 
data manager promptly for query and resolution. 
7.2 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified through the data quality review plan for this study.  Missing and incomplete data 
will be identified for investigation, and possible resolution, by Data Management prior to the 
study database lock or snapshot. Unless specified otherwise, only the observed data (not 
imputed data) will be presented in listings. 
7.2.1 
Missing Date of the Last Dose of Investigational Product 
When the date of the last dose of investigational product is found missing for a subject, all 
efforts should be made to obtain the date from the Investigator. If after all efforts are made it 
is still missing, the last dosing visit date will be used as the last dose date. 
7.2.2 
Missing Efficacy Data 
Details of missing HHD observations for individual muscle groups and individual questions 
for GNEM-FAS are provided in Appendix 10.2. 
7.2.3 
Missing Dates Information for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.  In those circumstances, the imputed value may 
be replaced by a date that will lead to a more conservative analysis. 
Missing Start Dates 
• If the day is unknown, then: 
o If the month and year match the first dose of investigational product start date 
month and year in this study, then impute the day of the first dose date. 
o Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
o If the year matches the year of the first dose of investigational product date in 
this study, then impute the month and day of the first dose date in this study. 
o Otherwise, assign ‘January’  


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• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
If the imputed date is earlier than birth date, then birth date will be used 
Missing Stop Dates 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December.’ 
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
If the resulting end date is after the date of study completion / discontinuation/ data cutoff, 
set the imputed end date as the date of study completion / discontinuation/ data cutoff.  
7.2.4 
Missing Causal Relationship to Investigational Product for Adverse Events 
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of investigational product, a causality of “definitely related” 
will be assigned. The imputed values for causal relationship to investigational product will be 
used for the incidence summary; the values will be shown as missing in the data listings. 
7.2.5 
Visit Time Windows 
There is no visit time window applied to handle the missing values for a scheduled visit.  
Nominal visits will be used for by-visit analyses.  If an unscheduled visit has to be used, the 
principle of proximity will be applied. 
7.3 
Handling of Multiple Measurements in HHD 
Each muscle strength is assessed three times in Hand Held Dynamometry (HHD) 
measurement.  The highest value of the three will be used for summary and derivation of 
efficacy endpoints.  
7.4 
Testing/Validation Plan 
Data will be reviewed by cross functional team periodically and issues will be addressed by 
clinical data management.  
7.5 
Software 
SAS® software version 9.2 or higher will be used to perform statistical analyses unless 
otherwise specified. 


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8 STATISTICAL METHODS OF ANALYSES 
8.1 
General Principles 
All statistical tests will be two-sided and a difference resulting in a p-value of less than or 
equal to 0.05 will be considered statistically significant.  All p-values will be rounded to and 
displayed in four decimals.  If a p-value less than 0.0001 occurs, it will be shown in the table 
as <0.0001.  
Continuous variables will be summarized by number of subjects and mean, SD/SE, median, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage. No imputation on missing data will be made, unless stated otherwise. 
Data collected will be presented in listings.  Data not subject to analysis according to this 
plan will not appear in any tables or graphs but will be included in the data listings. 
Post-hoc exploratory analyses not identified in this SAP may be performed to further 
examine the study data.  These analyses will be clearly identified as such in the final clinical 
study report. The SAP will not be amended for post-hoc or additional analyses identified 
after planned analyses are completed. Similarly, additional tables and figures may be defined 
to further evaluate study results and the SAP will not be amended to list them. 
Efficacy analyses will be presented by the parent study as illustrated in Table 8.1.1: 
UX001-CL301, CL202 or CL203.  Different efficacy endpoints at different scheduled time 
points were collected depending on which parent study the subjects were enrolled from.   
Safety analyses will be presented by the parent studies and overall as illustrated in 
Table 8.1.1.  Subjects enrolling from UX001-CL301 will be further examined by the 
treatment group assigned in the parent study: placebo, Ace-ER 6 g/day, and All. 
Table 8.1.1 also provides the guidance for the treatment groups to be displayed for biomarker 
analyses as well as efficacy analyses and safety analyses, which have been described above. .  
Baseline used for the analyses are specified as well.  Example table templates are provided in 
Appendix 10.6 for efficacy and safety. 


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Table 8.1.1:  Analysis Presentation 
Analysis Category 
Analysis Set 
Parent Study 
Treatment Group 
Baseline Applied 
Week 96/ET efficacy 
analysis  
Full Analysis Set  
CL301 
Placebo* 
Parent Study Baseline 
Ace-ER 6 g/day  
Placebo* 
Current Study 
Baseline 
ACE-ER 6 g/day   
All 
Week 96/ET efficacy 
analysis  
Full Analysis Set  
CL202 
Ace-ER 6 g/day  
Current Study 
Baseline 
Week 96 /ET efficacy 
analysis  
Full Analysis Set  
CL203 
Ace-ER 6 g/day  
Parent Study Baseline 
Ace-ER 6 g/day  
Current Study 
Baseline 
Week 96/ET safety 
analysis 
Safety Analysis 
Set 
CL301 
Placebo* 
Current Study 
Baseline  
Ace-ER 6 g/day   
All 
CL202 
Ace-ER 6 g/day   
CL203 
Total 
Week 96/ET analysis 
on biomarkers  
Sialic Acid 
Analysis Set 
CL301 
Ace-ER 6 g/day  
Current Study 
Baseline 
CL202 
CL203 
Total 
* This refers to the enrolled subjects who had received placebo treatment in parent study CL301. 
8.2 
Subject Disposition 
All subjects screened for the study will be used for reporting of disposition.  
Subject disposition summaries will include the number and percentage of subjects who are 
included in the safety, efficacy, and SA analysis sets; the number and percentage of subjects 
who received study drug treatment, completed the study or discontinued the study (with 
reasons) will be summarized by parent study and total.  
8.3 
Protocol Deviations 
Major protocol deviations will be summarized. All protocol deviations will be listed. 


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8.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the full 
analysis set.  
• Gender 
• Age 
• Age at start of parent study 
• Race 
• Ethnicity 
• Height (cm) 
• Weight (kg) 
• Genotype: Homozygote, Heterozygote, and Compound Heterozygote 
• Mutation type: Exon and Intron 
8.5 
Investigational Product Administration 
8.5.1 
Extent of Exposure 
The total number of doses administered, the total dose administered, and the total treatment 
duration will be summarized for the Safety Analysis Set. The calculation will be based on the 
current study baseline unless otherwise specified. 
Study medication dispensing and treatment compliance will also be listed. 
8.5.2 
Measurement of Treatment Compliance 
Dosing compliance for a CL302 study period is defined as: 
Actual total dosage taken during CL302 / Planned dosage for CL302 * 100%. 
Descriptive statistics will be reported for compliance on the Safety Analysis Set. 
8.6 
Efficacy Analysis 
Efficacy analyses will use generalized estimating equation (GEE) (Hanley et al. 2003) to 
evaluate trends over time with respect to the changes from baseline for all continuous 
efficacy endpoints. Baseline will be included as a covariate in the model. GEE will be the 
primary analysis method for all repeated measures endpoints. The statistical analyses will be 
reported in summary tables, figures, and data listings. Statistical tests will be 2-sided at the 
alpha=0.05 significance level.  


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Efficacy analysis will be based on the full analysis set. 
Additional efficacy analyses may be performed for subjects enrolled in CL301 by 
incorporating data from both the parent study and the current study to compare the placebo 
versus UX001 treatment groups using the methodology described in (Hu et al. 2007). Such 
analyses examine the extended treatment effect of UX001 on the placebo subjects who now 
are taking UX001 in the extension study.  
Parent study baseline will be used to evaluate the long-term study drug effect from the parent 
study drug administration, except for subjects enrolling from CL202.  
Current study baseline will be used to evaluate the continuous long-term study drug effect 
going on after the parent study. 
8.7 
Safety Analysis 
The safety analysis will be performed on the safety analysis set. Descriptive statistics will be 
provided for safety reporting by parent study and overall.  
8.7.1 
Adverse Events 
All AEs recorded from the time the subject signs the informed consent through the safety 
follow-up will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 17.1 or beyond).  
The following AEs were collected: 
• All AEs; 
• All SAEs; 
• Treatment-related AEs; 
• Treatment-related SAEs; 
• AEs leading to the discontinuation of study drug or discontinuation of study; 
• Deaths. 
The number and proportion of subjects with any treatment-emergent adverse events (TEAEs) 
(defined generally as any AE started on or after the first dose of study drug) will be 
summarized by System Organ Class (SOC), Preferred Term (PT), severity, grade, outcome 
and relationship to treatment for the following types of AEs. Additional summaries of subject 
incidence (by preferred term) will also be provided. 
An AE continued from the parent study would be excluded since they were summarized in 
the parent study.  However, if an AE continued from the parent study and the severity 
changed to worse will be considered as a TEAE and be summarized.   


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The severity of AEs will be based on Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.03. If an AE cannot be graded based on CTCAE, the investigator will 
assign a severity based on 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and  
5 = Death. 
For those AEs that occurred more than once during the study, the maximum severity or 
highest grade will be used to summarize the subject incidence. 
Detailed listings for all AEs, serious AEs, AEs leading to the discontinuation of study, and 
death will also be provided. 
Subgroup analyses by gender, age (above and below median), and ethnicity (small group 
may be combined) will be performed to support the safety in GNEM patients.   
8.7.1.1 
Adverse Events to Monitor 
Adverse events to be monitored are included in Appendix 10.5 by MedDRA preferred terms 
in categories of gastrointestinal AEs and liver-related investigations.  
Tables summarizing patient incidents for the monitored adverse events will be generated. 
8.7.2 
Concomitant Medication 
The number and percent of concomitant medications in CL302 will be summarized by ATC 
class and preferred term (per WHO-drug dictionary) in the safety analysis set. 
If a subject took a specific medication multiple times or took multiple medications within a 
specific therapeutic class, that subject will be counted only once for the coded drug name or 
therapeutic class. 
8.7.3 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from the CL302 baseline 
values at each visit will be presented. The number and percentage of abnormalities for each 
lab parameter at each assessment time point will be reported. 
8.7.4 
Vital Signs 
Descriptive statistics for vital signs including blood pressures, respiration rate, and heart rate 
and changes from CL302 baseline values at each scheduled visit and at the end of study will 
be presented. All results of vital signs will be listed. 
8.7.5 
Physical and Neurological Exams 
A complete physical examination including neurological exam is performed at CL302 
baseline. At post-baseline visit, a subset of physical examination (brief exam including 


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general appearance, cardiovascular exam, and respiratory exam) is conducted. The number 
and percentage of abnormal findings will be summarized for the complete physical exam.  
The number and percentage of deficit findings will be summarized for the neurological exam. 
The number and percentage of abnormal findings for the brief exam will be summarized for 
post-baseline visits in a similar fashion.   
8.7.6 
Interval History 
The Interval history in CL302 will be summarized for number and percentage of patients 
who reported changes at each visit from the last visit. 
8.7.7 
Suicidal Ideation 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a standardized rating instrument 
used to assess the suicidal ideation and behavior in an at-risk population and will be 
administered at each visit.  Any ‘Yes’ response from C-SSRS will be listed. 
8.7.8 
Pregnancy Test 
Pregnancy test will be conducted at the scheduled study visit and the results will be provided 
in a listing. 


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9 REFERENCES 
Bohannon, RW. 1997a. "Comfortable and maximum walking speed of adults aged 20-79 
years: reference values and determinants." Age Ageing 26 (1):15-9. 
Bohannon, RW. 1997b. "Reference values for extremity muscle strength obtained by hand-
held dynamometry from adults aged 20 to 79 years." Arch.Phys.Med.Rehabil. 78 (1):26-32. 
Hanley, JA, Negassa, A, Edwardes, MD, and Forrester, JE. 2003. "Statistical analysis of 
correlated data using generalized estimating equations: an orientation." Am J Epidemiol 157 
(4):364-75. 
Hu, Z, and Follmann, D. 2007. "Statistical methods for active extension trials." Stat Med 26 
(12):2433-48. 
NIMS. 1996. "Muscular weakness assessment: use of normal isometric strength data. The 
National Isometric Muscle Strength (NIMS) Database Consortium." Arch Phys Med Rehabil 
77 (12):1251-5. 
Peters, MJ, van Nes, SI, Vanhoutte, EK, Bakkers, M, van Doorn, PA, Merkies, IS, Faber, 
CG, and PeriNom, SSg. 2011. "Revised normative values for grip strength with the Jamar 
dynamometer." J Peripher Nerv Syst 16 (1):47-50. 
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, 
Melvin, GA, Greenhill, L, Shen, S, and Mann, JJ. 2011. "The Columbia-Suicide Severity 
Rating Scale: initial validity and internal consistency findings from three multisite studies 
with adolescents and adults." Am J Psychiatry 168 (12):1266-77. 
Stoll, T, Huber, E, Seifert, B, Michel, BA, and Stucki, G. 2000. "Maximal isometric muscle 
strength: normative values and gender-specific relation to age." Clin Rheumatol 19 (2):105-
13. 
Visser, J, Mans, E, de Visser, M, van den Berg-Vos, RM, Franssen, H, de Jong, JM, van den 
Berg, LH, Wokke, JH, and de Haan, RJ. 2003. "Comparison of maximal voluntary isometric 
contraction and hand-held dynamometry in measuring muscle strength of patients with 
progressive lower motor neuron syndrome." Neuromuscul Disord 13 (9):744-50. 
 
 


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10 APPENDICES 
10.1 Summary of Efficacy Endpoints and Analyses 
Test / 
Instrument 
Endpoint 
Type of  
analysis 
Time points for 
Assessment  
Statistical 
approach at 
week 96/ET 
analysis 
Subjects enrolling from UX001-202 and UX001-301 
Physical therapy – 
Hand-held 
Dynamometry 
(HHD) 
The changes from baseline in 
Upper Extremity Composite 
(UEC) Score  based on bilateral 
strength recorded in the following 
muscle groups: gross grip, 
shoulder abductors, elbow flexors, 
and elbow extensors 
Primary analysis 
Weeks 8, 16, 24, 
48, 72, and 96  
GEE Model 
GNEM 
Functional 
Activities Scale 
(GNEM-FAS) 
Changes from baseline on Upper 
Extremity Domain score  
Secondary 
efficacy analysis 
Weeks 8, 16, 24, 
48, 72, and 96  
GEE Model 
Changes on Mobility Domain 
score  
Physical therapy – 
Hand-held 
Dynamometry 
(HHD) 
Changes from baseline in lower 
extremity composite score (LEC) 
based on bilateral strength 
recorded in the following muscle 
groups: knee flexors, hip flexors, 
hip extensors, hip abductors and 
hip adductors. 
Secondary 
efficacy analysis 
Weeks 8, 16, 24, 
48, 72, and 96  
GEE Model  
Changes from baseline in total 
force and percent predicted total 
force in the Knee Extensors. 
Sit to Stand 
Change from baseline in the 
number of stands in the Sit-to-
Stand test  
Secondary 
efficacy analysis 
Weeks 8, 16, 24, 
48, 72, and 96  
GEE Model 
Weighed Arm  
Lift Test 
Changes from baseline in the 
number of lifts in 30 second 
weighted arm lift tests  
Secondary 
efficacy analysis 
Weeks 8, 16, 24, 
48, 72, and 96  
GEE Model 
6-Minute Walk 
Test 
 
Changes from baseline in meters 
walked in 6MWT and percent 
predicted 
Secondary 
efficacy analysis 
Weeks 8, 16, 24, 
48, 72, and 96  
GEE Model 


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Test / 
Instrument 
Endpoint 
Type of  
analysis 
Time points for 
Assessment  
Statistical 
approach at 
week 96/ET 
analysis 
Physical therapy – 
Hand-held 
Dynamometry 
(HHD) 
Changes from baseline in UEC 
and LEC percent predicted based 
on reference equations adjusting 
for age, gender, height, and 
weight. 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
48, 72, and 96 
Summary 
statistics 
Changes from baseline in bilateral 
total force and percent predicted 
total force for each individual 
muscle group included in the UEC 
and LEC.  
Summary 
statistics 
GNEM 
Functional 
Activities Scale 
(GNEM-FAS) 
Changes from baseline on the total 
score on the GNEM-FAS 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
48, 72, and 96 
Summary 
statistics 
Changes from baseline on the 
Self-Care Domain Score on the 
GNEM-FAS 
Individual 
Neuromuscular 
Quality of Life 
Questionnaire 
(INQoL) 
(Not including 
CL202 subjects) 
Changes from baseline on the total 
score on a 45-item self-report 
questionnaire on the impact of key 
muscle disease symptoms on the 
ability to perform basic activities 
of daily living, functional 
independence, relationships and 
overall well-being 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
48, 72, and 96 
Summary 
statistics 
Creatine Kinase 
(CK) 
Changes from baseline in CK 
levels in serum to assess the 
degree of reduction of CK levels 
observed as a surrogate for muscle 
injury 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
48, 72, and 96 
Summary 
statistics 
Subjects enrolling from UX001-203  
GNEM 
Functional 
Activities Scale 
(GNEM-FAS) 
Expanded 
Version 
Changes from baseline in the total 
scores  
Primary efficacy 
analysis 
Weeks 24, 48, 
72, and 96 
GEE Model 
Changes from baseline in the 
mobility domain 
Changes from baseline in the 
upper extremity domain 
Changes from baseline in the self-
care domain 


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Test / 
Instrument 
Endpoint 
Type of  
analysis 
Time points for 
Assessment  
Statistical 
approach at 
week 96/ET 
analysis 
Physical therapy – 
Hand-held 
Dynamometry 
(HHD) 
Changes from baseline in upper 
extremity muscle strength and 
percent predicted in the following 
muscle groups: grip, key pinch, 
shoulder abductors and wrist 
extensors 
Primary efficacy 
analysis 
Weeks 24, 48, 
72, and 96 
GEE Model 
Changes from baseline in lower 
extremity muscle strength and 
percent predicted in the knee 
extensors 
Short Form 
Health Survey – 
36 (SF-36v2) 
Changes from baseline in 8 
subscales and summary scores 
(PCS and MCS) in SF-36v2 
Exploratory 
efficacy analysis 
Weeks 24, 48, 
72, and 96 
Summary 
statistics 
Biomarker 
Changes from baseline in serum 
biomarkers: creatine kinase (CK), 
serum aceneuramic acid 
Exploratory 
efficacy analysis 
Weeks 24, 48, 
72, and 96 
Summary 
statistics 
 


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10.2 Missing Observation in Hand Held Dynamometry and GNEM-FAS 
Imputation rules outlined in this section for dynamometry are defined below and are based on 
the distinct pattern of muscle weakness associated with GNE Myopathy and the features of 
the dynamometers used in this study.  The most common cause of missing data is muscle 
weakness severe enough to prevent the subject from registering the minimum amount of 
force against the dynamometer required to obtain a measurement during a maximum 
voluntary isometric contraction maneuver.  In those cases, the value is imputed to 0, and 
preserves the ability to calculate the UEC and LEC scores. There are some scenarios in 
which non-random missing HHD data values result in missing UEC and LEC values.  When 
strength in a particular muscle group exceeds the resistance that can be applied by the 
administrator, a reliable value cannot be obtained from the dynamometer.  This is a 
recognized limitation of a hand-held device (Visser et al. 2003). In GNE Myopathy, the only 
muscle group at risk for this scenario is the knee extensors, due to the relative sparing of the 
quadriceps.  All other non-random missing HHD data are related to the clinical condition of 
the subject at the time of the testing where a test may not be administered due to pain, injury, 
contracture or another extenuating circumstance that could cause discomfort to the subject. 
The proposed plan for the handling of this data is intended to provide the most accurate 
estimate of muscle strength and physical function possible based on knowledge of the disease 
and the outcome measures obtained during the conduct of previous studies. 
Missing observations in HHD for individual muscle group will be imputed based on reason 
for missing and if the muscle strength measurement is missing on both sides or one side. The 
table below provides a summary of the imputation rule followed by detailed descriptions. 
Instrument 
Missing Reason 
Imputation 
HHD missing BOTH sides 
Too Weak 
0 
 
Too Strong 
NA , UE/LE composite not computed  
 
Pain 
NA , UE/LE composite not computed 
 
Injury 
NA , UE/LE composite not computed 
 
Contracture 
NA , UE/LE composite not computed 
 
Other 
NA , UE/LE composite not computed 
HHD missing ONE side 
Too Weak 
0 
 
All other reasons 
The value from the other side that was 
measured 
 


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Missing Reason = Weakness 
A value of 0 should be imputed for a W.   
• If both sides are W, a value of 0 is assigned to each side and the muscle group IS counted 
as part of the UE or LE composite. 
• If one side is W, a value of 0 is assigned to that side and the 0 is averaged with the value 
from the other side.  The muscle group IS counted as part of the UE of LE composite. 
Missing Reason = Contracture 
A value of 0 should NOT be imputed for a C.  A C is missing data because the test was not 
performed due to the contracture.  
• If both sides are C (which would be rare), then the data for this muscle group is missing 
and the UE or LE composite will be set to missing. 
• If one side is C, then the data is missing from this side and the value from the other side 
should be used to reflect the total strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
Missing Reason = Pain 
A value of 0 should NOT be imputed for a P.  A P is missing data because the test was not 
performed due to pain.  
• If both sides are P, then the data for this muscle group is missing and the UE or LE 
composite will be set to missing. 
• If one side is P, then the data is missing from this side and the value from the other side 
should be used to reflect the total strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
Missing Reason = Injury 
A value of 0 should NOT be imputed for an I.  An I is missing data because the test was not 
performed due to pain.  
• If both sides are I, then the data for this muscle group is missing and the UE or LE 
composite will be set to missing. 
• If one side is I, then the data is missing from this side and the value from the other side 
should be used to reflect the total strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
Missing Reason = Too Strong 
An S indicates that the test was attempted but that the subject overpowered the administrator 
and a valid value could not be obtained. 


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• If both sides are S, then the data for this muscle group is missing and the UE or LE 
composite will be set to missing. 
• If one side is S, then the data is missing from this side and the value from the other side 
should be used to reflect the total strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
Missing Reason = OTHER 
No value should be imputed if there is an O.   
• If both sides are O, then the data for this muscle group is missing and the UE or LE 
composite will be set to missing. 
• If one side is O, then the data is missing from this side and the value from the other side 
should be used to reflect the total strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
When an individual question is missing in GNEM-FAS. The average score is calculated for 
the domain and then multiplied by the number of questions in the domain:  
Mobility Subscale Score = 10 x Sum(Available Items) / Number of Available Items 
Upper Extremity Subscale Score = 8 x Sum(Available Items) / Number of Available Items 
Self-Care Subscale Score = 7 x Sum(Available Items) / Number of Available Items 
If a domain has more than 50% (inclusive) items missing (≥5 for Mobility, ≥4 for Upper 
Extremity, ≥3 for Self-Care),  the domain score will not be calculated. The Total FAS core 
will only be calculated if all three domain scores are avaialble. 


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10.3 Computation Formula for Derived HHD Variables 
Individual Muscle Strength Average Score = (left-side measurement + right-side 
measurement) / 2 
UE Composite Score = sum( Individual Muscle Strength Average Score for muscle group 
gross grip, shoulder abductors, elbow flexors and elbow extensors) 
LE Composite Score = sum(Individual Muscle Strength Average Score for muscle group 
knee flexors, hip flexors, hip extensors, hip abductors and hip adductors) 
Predicted Normal for Individual Muscle Strength Average Score = (left-side predicted 
normal + right-side predicted normal) / 2 
Predicted Normal for UE Composite Score = sum(Predicted Normal for Individual Muscle 
Strength Average Score for muscle group gross grip, shoulder abductors, elbow flexors and 
elbow extensors) 
Predicted Normal for LE Composite Score = sum(Predicted Normal for Individual Muscle 
Strength Average Score for muscle group hip flexors, hip extensors, hip adductors and knee 
flexors) 
% of predicted normal HHD values = (Observed strength value/  Predicted normal strength 
value) *100%.  
Predicted normal HHD values can be derived using the regression equations outlined in 
Appendix 10.3.1.  


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10.3.1 Predicted Normal HHD Muscle Strength 
Muscle Strength  
Note: Many of the HHD derived variables detailed below rely on regression equations that 
have predictor variables in units different than what is found in the analysis datasets.  
Care will be taken to convert dataset variables to the correct units before they are entered into 
the prediction equation.  The resulting predicted value will then, in turn, be converted to the 
appropriate unit for analysis. 
Hand-Held Dynamometry 
Shoulder abduction and hip abduction  
Regression Equations and Multiple Correlations of Sex, Age, and Weight with Muscle 
Strength  
Muscle Action 
Side 
Equation* 
R 
R2 
Shoulder Abduction 
Nondominant 
165.16 – 74.9S   – .910A  + .126W 
.843 
.710 
 
Dominant 
178.90 – 77.1S   –  1.128A  + .134W 
.843 
.710 
Hip Abduction 
Nondominant 
203.32 – 73.3S   – 1.247A  + .192W 
.794 
.630 
 
Dominant 
195.24 – 62.4S   –  1.184A  + .198W 
.764 
.584 
(Bohannon 1997b) 
*Muscle strength results in Newtons (N). S, sex (male=0, female=1); A, age (years); W, weight (Newtons). 
Note: Age and weight values collected at the Baseline visit will be used for the calculation of 
predicted values for shoulder abduction and hip abduction for all study time points. 
Hip adduction 
Muscle Action 
Gender 
Side 
Age (years) 
Equation 
Hip Adduction 
Female 
Left 
< 55 
19.1 – 0.30*(age -55) 
 
Female 
Right 
< 55 
19.5 – 0.00*(age -55) 
 
Female  
Left 
> 55 
19.1 – 0.212*(age -55) 
 
Female 
Right 
> 55 
19.5 – 0.245*(age - 55) 
Hip Adduction 
Male 
Left 
< 49 
31.8 + 0.044*(age – 49) 
 
Male 
Right 
< 49 
31.6 - 0.082*(age – 49) 
 
Male 
Left 
> 49 
31.8 - 0.280*(age – 49) 
 
Male 
Right 
> 49 
31.6 - 0.206*(age – 49) 
(Stoll et al. 2000)  
Median strength results in kiloponds (kp) also known as kilogram-force (kgf) 


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Note: The age category that applies for a subject at the Baseline visit will be used for the 
calculation of hip adduction predicted values for all study time points. 
Elbow flexion, elbow extension, hip flexion, hip extension, knee flexion, knee extension   
Regression Equations for Strength Prediction  
Muscle Action 
Equation 
Right Elbow Flexion 
- (age * 0.13) + (gender * 11.24) + ((weight/height2) * 0.07) + 22.78 
Left Elbow Flexion 
- (age * 0.11) + (gender * 10.63) + ((weight/height2) * 0.05) + 19.66 
Right Elbow Extension 
- (age * 0.08) + (gender * 8.33) + ((weight/height2) * 0.16) + 12.37 
Left Elbow Extension 
- (age * 0.07) + (gender * 8.18) + ((weight/height2) * 0.17) + 11.32 
Right Hip Flexion 
- (age * 0.33) + (gender * 19.19) + ((weight/height2) * 0.66) + 34.44 
Left Hip Flexion 
 - (age * 0.29) + (gender * 18.75) + ((weight/height2) * 0.47) + 36.05 
Right Hip Extension 
-(age * 0.21 + (gender * 15.19) + ((weight/height2) * 0.14) + 33.52 
Left Hip Extension 
-(age * 0.23) + (gender * 15.02) + ((weight/height2) * 0.17) + 33.88 
Right Knee Flexion 
-(age * 0.16) + (gender * 8.78) + ((weight/height2) * 0.08) + 22.47 
Left Knee Flexion 
-(age * 0.17) + (gender * 7.67) + ((weight/height2) * 0.14) + 21.10 
Right Knee Extension 
- (age * 0.38) + (gender * 18.44) + ((weight/height2) * 0.62) + 34.41 
Left Knee Extension 
- (age * 0.38) + (gender * 17.68) + ((weight/height2) * 0.62) + 33.61 
(NIMS 1996) 
Strength prediction results in kilograms (kg) 
Age = years; gender: male = 1, female = 0; weight = kg;; height = meters 
Note: Age, height and weight values collected at the Baseline visit will be used for the 
calculation of predicted values for elbow flexion, elbow extension, hip flexion, hip extension, 
knee flexion and knee extension for all study time points. 


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Gross Grip 
Normative grip strength values for the Jamar dynamometer for clinical use (in pounds) 
 
Females (n = 355) 
Males (n = 365) 
Age 
(years) 
Number 
of 
subjects 
5th %ile 
Jamar values 
(lbs) 
Median 
Jamar values 
(lbs) 
Number of 
subjects 
5th %ile 
Jamar values 
(lbs) 
Median 
Jamar values 
(lbs) 
20 - 29 
51 
50 
62 
50 
81 
100 
30 – 39 
50 
49 
64 
51 
80 
105 
40 – 49 
50 
48 
63 
50 
78 
107 
50 – 59 
51 
45 
61 
54 
73 
104 
60 – 69 
49 
40 
56 
58 
64 
95 
70 - 79 
50 
32 
46 
50 
51 
77 
> 80 
54 
22 
34 
52 
34 
54 
(Peters et al. 2011)  
Note: The age category that applies for a subject at the Baseline visit will be used for the 
calculation of predicted grip values for all study time points. 
Walking Ability 
Calculation of Predicted Six-Minute Walk Test Distance 
6MWT Distance (meters) = 868.8 - (2.99*Age) – (74.7*Gender) 
Age in years. Men = 0 and Women = 1.  
Gibbons WJ,  Fruchter N,  Sloan S, Levy RD. Reference Values for a Multiple Repetition 6-
Minute Walk Test in Healthy Adults Older than 20 Years. J Cardpulm Rehabil. 2001 
Mar/Apr; 21(2):87-93 
Note: The age of a subject at the Baseline visit will be used for the calculation of 6MWT 
predicted values for all study time points. 


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Wrist extension (Bohannon 1997a) 


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10.4 Summary of Efficacy Assessment in Parent Studies and in Current Study CL302 
Study 
Functional Test 
Questionnaire 
Biomarker 
CL-202  
Week 0, 12, 36, 60, 84, 108, 
132, 156 
 
Muscle strength as measured by 
HHD; 
Walking ability as measured by 
the 6MWT; 
Arm raising ability as measured 
by the weighted arm lift test; 
Functional disability as 
measured by the GNEM-FAS. 
Week 0, 12, 36, 84, 156 
 
None 
Week 0, 12, 16, 36, 60, 108, 156 
 
CK 
Free Serum SA 
Free and total urine SA  
(Part I only, Week 0, 12) 
Serum protein markers  
(Part I only, Week 0, 12) 
CL-301 
Week 8, 16, 24, 32, 40, 48 
 
Muscle strength as measured by 
HHD; 
Walking ability as measured by 
the 6MWT; 
Arm raising ability as measured 
by the weighted arm lift test; 
Muscle strength on mobility 
domain score by GNEM-FAS 
Week 8, 16, 24, 32, 40, 48 
 
The total score on a 
45-item self-report of 
INQoL. 
Week 24, 48 
The CGI Severity scale 
(CGI-S, baseline only), and 
improvement scale (CGI-I, 
at each subsequent visit). 
Week0, 8, 16, 24, 32, 40, 48 
 
CK 
Serum SA 
Week0, 16, 32, 48 
Free, total and bound urine SA  
Urine ManNAc  
CL-203 
Week 0, 12, 24, 36, 48 
 
Muscle strength by GNEM-FAS 
Expanded Version total score; 
Upper extremity strength as 
measured by HHD 
Lower extremity muscle 
strength as measured by HHD 
Week 0, 12, 24, 36, 48 
 
Health-related quality of 
life as assessed by SF-36 
Symptom severity as 
measured by PGI-S 
(baseline only) and PGI-C 
(at each subsequent visit) 
Week 0, 12, 24, 36, 48 
 
CK 
Free serum SA 
Serum aceneuramic acid 
Free, total and bound Urine SA  
Urine ManNAc  
CL-302  
(Patients 
from 
202/301) 
Week  0, 8, 16, 24, 48, 72, 96 
 
Muscle strength as measured by 
HD; 
Walking ability as measured by 
the 6MWT; 
Arm raising ability as measured 
by the weighted arm lift test; 
Change in muscle strength on 
mobility domain score by 
GNEM-FAS. 
Week  0, 8, 16, 24, 48, 72, 
96 
 
The total score on a 45-
item self-report of INQoL. 
Week  0, 8, 16, 24, 48, 72, 96 
 
CK 
Free serum SA. 
Urine ManNAc  


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Study 
Functional Test 
Questionnaire 
Biomarker 
CL-302 
(Patients 
from 
CL203) 
Week 0, 24, 48, 72, 96 
 
Muscle strength in GNEM-FAS 
Expanded Version total score;  
Muscle strength as measured by 
HHD. 
Week 0, 24, 48, 72, 96 
 
Health-related quality of 
life as assessed by SF-36 
Week 0, 8, 16, 24, 48, 72, 96 
 
CK 
Free serum SA. 
Urine ManNAc 
 


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10.5 Schedule of Events 
ASSESSMENTS AND EVENTS* 
SCREENING/ 
BASELINEa 
TREATMENT PERIOD 
 
 
MONTH 2 
(WEEK 8) 
VISIT  
(± 5 DAYS)
 ǂ 
MONTH 4 
(WEEK 16) 
VISIT 
(± 5 DAYS) ǂ  
MONTH 6 
(WEEK 24) 
VISIT 
(± 5 DAYS) 
MONTH 12 
VISIT (WEEK 
48) 
(± 2WEEKS) 
MONTH 18 
VISIT 
(WEEK 72) 
(± 2WEEKS) 
MONTH 24 
(WEEK 96) 
OR EARLY 
TERMINATION 
VISIT  
(± 2WEEKS) l 
SAFETY 
FOLLOW 
UP (+ 5 
DAYS) m 
SAFETY ASSESSMENTS (ALL SUBJECTS) 
 
INFORMED CONSENT  
X 
 
 
 
 
 
 
 
MEDICAL HISTORY 
X 
 
 
 
 
 
 
 
INTERVAL HISTORY b 
X 
X 
X 
X 
X 
X 
X 
 
PHYSICAL EXAMINATION  c 
X 
X 
X 
X 
X 
X 
X 
 
VITAL SIGNS  
X 
X 
X 
X 
X 
X 
X 
 
HEMATOLOGY, CHEMISTRY PANEL, 
URINALYSIS 
X 
X 
X 
X 
X 
X 
X 
 
PREGNANCY TEST 
X 
X 
X 
X 
X 
X 
X 
 
CONCOMITANT MEDICATIONS 
X 
X 
X 
X 
X 
X 
X 
X 
SUICIDAL IDEATION AND BEHAVIOR  (C-
SSRS) d 
X 
X 
X 
X 
X 
X 
X 
 
ADVERSE EVENTS  
X  
X 
X 
X 
X 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS (ALL SUBJECTS) 
 
BIOMARKERS: CK, FREE SERUM SA, AND 
BIOMARKERS OF SIALYATION AND OTHER 
BIOMARKERS e 
X 
X 
X 
X 
X 
X 
X 
 
FREE, TOTAL AND BOUND URINE SA LEVELS f 
X 
X 
X 
X 
X 
X 
X 
 
URINE TEST FOR MANNAC g 
X 
X 
X 
X 
X 
X 
X 
 


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ASSESSMENTS AND EVENTS* 
SCREENING/ 
BASELINEa 
TREATMENT PERIOD 
 
 
MONTH 2 
(WEEK 8) 
VISIT  
(± 5 DAYS)
 ǂ 
MONTH 4 
(WEEK 16) 
VISIT 
(± 5 DAYS) ǂ  
MONTH 6 
(WEEK 24) 
VISIT 
(± 5 DAYS) 
MONTH 12 
VISIT (WEEK 
48) 
(± 2WEEKS) 
MONTH 18 
VISIT 
(WEEK 72) 
(± 2WEEKS) 
MONTH 24 
(WEEK 96) 
OR EARLY 
TERMINATION 
VISIT  
(± 2WEEKS) l 
SAFETY 
FOLLOW 
UP (+ 5 
DAYS) m 
TREATMENT DISPENSING AND COMPLIANCE (ALL SUBJECTS) 
 
TREATMENT DISPENSED h 
X 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE 
 
X 
X 
X 
X 
X 
X 
 
EFFICACY ASSESSMENTS (UX001-CL202 AND UX001-CL301 SUBJECTS) i 
 
DYNAMOMETRY 
X 
X 
X 
X 
X 
X 
X 
 
6-MINUTE WALK TEST (6MWT)  
X 
X 
X 
X 
X 
X 
X 
 
SIT-TO-STAND TEST  
X 
X 
X 
X 
X 
X 
X 
 
WEIGHTED ARM LIFT TEST   
X 
X 
X 
X 
X 
X 
X 
 
GNE MYOPATHY FUNCTIONAL 
ACTIVITIES SCALE (GNEM-FAS) 
X 
X 
X 
X 
X 
X 
X 
 
INDIVIDUALIZED NEUROMUSCULAR 
QUALITY OF LIFE QUESTIONNAIRE  
(INQOL) 
X 
X 
X 
X 
X 
X 
X 
 
EFFICACY ASSESSMENTS (UX001-CL203 SUBJECTS) 
 
DYNAMOMETRY j 
X 
 
 
X 
X 
X 
X 
 
GNEM-FAS k 
X 
 
 
X 
X 
X 
X 
 
SHORT FORM HEALTH SURVEY-36 
(SF-36) 
X 
 
 
X 
X 
X 
X 
 
Refer to study-related materials for recommended timing and order of assessments to be administered at each study visit. 
ǂ 
Subjects who roll-over from the UX001-CL203 study will not have a Month 2 or Month 4 visit. Assessments at these visits will only be performed for 
subjects who roll-over from the UX001-CL202 and UX001-CL301 studies. UX001-CL202 subjects will complete the same efficacy assessments as the 
subjects who rollover from UX001-CL301.  


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a. 
Potential subjects can be screened up to 5 days after the last dose on the parent study.  Baseline Visit should be not be more than 5 days after Screening visit. 
Subjects can have a concurrent Screening and Baseline visits. Study drug will be dispensed only after all study procedures at the Baseline Visit have been 
performed. For subjects who discontinue prior to completing the study, every reasonable effort should be made to perform the Early Termination (ET) 
procedures within four weeks of discontinuation. 
b. Interval history will include any signs, symptoms, or events (i.e. falls) experienced by the subject since the prior study visit that are not related to study 
procedure(s) performed at prior study visits or study drug.  Interval history may include exacerbation or improvement in existing medical conditions 
(including the clinical manifestations of GNEM) that might interfere with study participation, safety, and/or positively or negatively impact performance of 
functional assessments. 
c. 
The physical examinations at Baseline/Screening, including a neurological examination; all others will be brief physical examinations. If a patient is unable 
to stand or has significant postural issues that interfere with collection of a standing height, self-reported adult height should be captured. 
d. 
Baseline C-SSRS administered at Baseline/Screening visit (may be same as last visit in parent study). Since Last Visit C-SSRS administered at all 
subsequent visits. 
e. 
Serum will be obtained at all study visits to evaluate creatine kinase (CK), serum SA and potential biomarkers of sialylation, and other markers of muscle 
injury and remodeling. 
f. 
Blood samples, preferably pre dose, and first-morning void urine will be collected to assess trough SA levels; record volume of urine collected.  
g. An aliquot from first morning void urine will be used for assessment of ManNAc; record volume of urine collected. 
h. 
Subjects should be instructed to return unused study drug and packaging to every visit. Note that all subjects being treated with 12 g/day Ace-ER in UX001-
CL202 will be transitioned to 6 g/day Ace-ER dose in this protocol.  
i. 
For UX001-CL202 subjects, assessments that cannot be safely performed by a subject due to disease progression should not be administered.   
j. 
For subjects enrolling from UX001-CL203, lower extremity muscle strength for knee extensors muscle group only. 
k. For subjects enrolling from UX001-CL203, the GNEM-FAS Expanded version will be used.  
l. 
The Early Termination Visit occurs if a subject discontinues prior to completing the study or no longer wants to participate in the study. Every reasonable 
effort should be made to have subjects return to the clinic within 4 weeks of discontinuation and perform the Early Termination procedures; however, 
subjects who are unable to return to the clinic will be given the option of having an Early Termination Visit telephone call within 4 weeks of discontinuation 
from study, where appropriate information will be collected by the clinical site. 
m. Safety Follow-up visit to be conducted by phone 30 days (+5 days) after last dose of study drug. 


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10.6 Adverse Events to Monitor 
10.6.1 Gastrointestinal MedDRA Query 
The following MedDRA PTs are included in the gastrointestinal SMQ version 17.1. 
Narrow Scope 
Broad Scope 
Abdominal discomfort 
Abdominal distension 
Abdominal pain 
Abdominal pain lower 
Abdominal pain upper 
Abdominal symptom 
Abdominal tenderness 
Abnormal faeces 
Aerophagia 
Anorectal discomfort 
Bowel movement irregularity 
Change of bowel habit 
Constipation 
Defaecation urgency 
Diarrhoea 
Epigastric discomfort 
Eructation 
Faecal volume decreased 
Faecal volume increased 
Faeces hard 
Faeces soft 
Flatulence 
Frequent bowel movements 
Gastrointestinal pain 
Gastrointestinal sounds abnormal 
Gastrointestinal toxicity 
Infrequent bowel movements 
Nausea 
Non-cardiac chest pain 
Oesophageal discomfort 
Oesophageal pain 
Premenstrual cramps 
Vomiting 
 
Anorectal swelling 
Antacid therapy 
Antidiarrhoeal supportive care 
Antiemetic supportive care 
Breath odour 
Chest pain 
Colonic lavage 
Dysphagia 
Early satiety 
Gastritis prophylaxis 
Gastrointestinal disorder therapy 
Gastrointestinal tract irritation 
Gastrooesophageal reflux prophylaxis 
Glycogenic acanthosis 
Hypovolaemia 
Laxative supportive care 
Malabsorption 
Mucous stools 
Oesophageal polymer implantation 
Pernicious anaemia 
Post procedural constipation 
Post procedural diarrhea 
Post-tussive vomiting 
Probiotic therapy 
Procedural nausea 
Procedural vomiting 
Prophylaxis against diarrhoea 
Prophylaxis of nausea and vomiting 
Regurgitation 
Retching 
Steatorrhoea 
Vomiting projectile 
 
 


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10.6.2 Liver-Related Investigations 
The following MedDRA PTs are included in the category “liver-related investigations.” 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
Gamma-glutamyl transferase abnormal 
Gamma-glutamyl transferase increased 
Hepatic enzyme abnormal 
Hepatic enzyme increased 
Liver function test abnormal 
Transaminases abnormal 
Transaminases increased 
 


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10.7 Table templates for efficacy and safety analysis presentation 
Table 14.x.x.x 
Summary of HHD Upper Extremity Component (UEC) Scores – Parent Study CL301 
 (Full Analysis Set) 
 Visit 
   Statistics 
ACE-ER 6 g/day 
Treatment in Parent Study CL301 
(Parent study baseline) 
Treatment in Parent Study CL301 
(Current study baseline) 
Placebo 
(N=xx) 
 Ace-ER 6 g/day 
(N=xx) 
Placebo 
(N=xx) 
 Ace-ER 6 g/day 
(N=xx) 
Total 
 
 
 
 
 
 
Week 8  
 
 
 
 
 
   n  
xx 
xx 
xx 
xx 
xx 
   Mean 
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
   SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
   Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
   Min, Max   
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
         
 
 
 
 
 
   Change from Baseline to Week 8  
 
 
 
 
 
  …… 
 
 
 
 
 
 
 
 
 
 
 
Week 96  
 
 
 
 
 
 
 
 
 
 
 
SD=standard deviation. 
Study UX001-CL301 is a placebo-controlled efficacy study. 


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Table 14.x.x.x 
Summary of HHD Upper Extremity Component (UEC) Scores – Parent Study CL202 
 (Full Analysis Set) 
 Visit 
   Statistics 
Ace-ER 6 g/day 
Current Study Baseline 
(N=xx) 
 
 
Week 8  
 
   n  
xx 
   Mean 
xx.xx  
   SD 
xx.xxx 
   Median 
xx.xx 
   Min, Max   
xx.x, xx.x 
         
 
   Change from Baseline to Week 8  
 
  …… 
 
 
 
Week 96  
 
 
 
SD=standard deviation. 
Study UX001-CL202 is an extension study of CL201 with 10 naïve subjects. 


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Table 14.x.x.x 
Summary of HHD Individual Raw Strength Scores: Knee Extensors – Parent Study CL203 
 (Full Analysis Set) 
Visit 
   Statistics 
Ace-ER 6 g/day 
Parent Study Baseline 
(N=xx) 
 Current Study Baseline 
(N=xx) 
 
 
 
Week 24  
 
 
   n  
xx 
xx 
   Mean 
xx.xx  
xx.xx  
   SD 
xx.xxx 
xx.xxx 
   Median 
xx.xx 
xx.xx 
   Min, Max   
xx.x, xx.x 
xx.x, xx.x 
         
 
 
   Change from Baseline to Week 24  
 
 
  …… 
 
 
 
 
 
Week 96  
 
 
 
 
 
SD=standard deviation, Min=minimum, Max=maximum. 
Study UX001-CL203 is a safety study. 


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Table 14.x.x.x 
Overall Summary of Treatment Emergent Adverse Events 
(Safety Analysis Set) 
 
  
 
Ace-ER 6 g/day 
Treatment in Parent Study CL301  
Parent Study 
 
Total 
(N=xx) 
n (%) 
Placebo 
(N=xx) 
n (%) 
Ace-ER 6 
g/day 
(N=xx) 
n (%) 
All 
(N=xx) 
n (%) 
CL202 
(N=xx) 
n (%) 
CL203 
(N=xx) 
n (%) 
Number of subjects with TEAEs 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Maximum severity 
 
 
 
 
 
 
  Grade 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Grade 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Grade 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Grade 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Grade 5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Number of subjects with treatment-
related TEAEs 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Number of serious TEAEs 
xx  
xx  
xx  
xx  
xx  
xx  
Number of subjects with serious 
TEAEs 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Number of TEAEs causing 
discontinuation 
xx  
xx  
xx  
xx  
xx  
xx  
Number of subjects with TEAEs 
causing discontinuation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x)