Conditions: Hereditary Inclusion Body Myopathy Distal Myopathy With Rimmed Vacuoles Distal Myopathy, Nonaka Type GNE Myopathy Quadriceps Sparing Myopathy Inclusion Body Myopathy 2
Keywords: GNE Myopathy Nonaka GNEM Hereditary Inclusion Body Myopathy HIBM DMRV QSM
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 42
Healthy volunteers: no

Brief summary:
The primary objective of this Phase 2 study is to evaluate the safety of open-label 6 g/day Ace-ER in GNEM participants with severe ambulatory impairment.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Aceneuramic Acid Extended-Release
Intervention descriptions: intervention 1: oral tablets

Protocol document:
Prot_001.pdf: 
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL203 Amendment 1 
15 March 2017 
 
The UX0001-CL203 Original Protocol (dated 04 December 2015) has been modified by 
Amendment 1 to: a) increase the planned number of enrolled subjects; b) clarify the timing 
and conduct of the Safety Follow-up Period for all subjects; c) clarify that study assessments 
for a subject should be performed in a consistent order at each visit; d) add urine microscopic 
examination if abnormal urinalysis results are observed; e) update information regarding 
safety laboratory blood and urine sample collection and the analytes to be assessed in the 
samples; f) instruct that the Short Form Health Survey-36 (SF-36) will only be completed for 
subjects when a validated version is available in the subject’s native language; g) remove the 
requirement for urine collection for assessment of sialic acid (SA), h) update the requirement 
for urine collection for N-acetyl-D-mannosamine (ManNAc); i) clarify safety reporting 
requirements; j) more clearly define the various study period/visits and the associated 
assessments; k) remove reference to the Study Reference Manual; l) clarify what will be done 
with leftover blood and urine samples from this study; m) correct the volume of blood to be 
drawn from subjects; n) correct inconsistencies between sections; o) update the retention 
requirement for subject identifiers, subject files, and other source data; p) update the 
Sponsor’s Responsible Medical Officer information; q) add the designated Coordinating 
Investigator. Minor edits and typographical corrections have also been made. Important 
protocol changes are summarized below: 
1. Section 2 (Synopsis), Section 7.1 (Overall Study Design and Plan), Section 7.4 
(Treatments), and Section 7.6.1 (Determination of Sample Size) were updated to indicate 
that approximately 45 subjects are planned for enrollment, rather than 30. Statements 
about the probability of observing one or more serious adverse events in the study based 
on the planned sample size were consequently also updated.  
Rationale: This change was made to enable enrollment of additional subjects identified 
as potentially eligible for this study.  
2. Table 2.1 (Schedule of Events) and Section 7.4.2 (Selection of Doses and Study 
Duration) were updated and Section 7.5.1.5 (Safety Follow-up Period) was added to 
clarify that a Safety Follow-up telephone call (TC) should be conducted for subjects who 
complete the study and choose not to enroll in the extension study, UX001-CL302, or 
who discontinue the study early. This TC should be conducted 30 (+5) days after the last 
dose of study drug for subjects who complete the study or 30 (+5) days after the ET Visit 
or TC for subjects who discontinue the study early. Information on ongoing or new 
adverse events, serious adverse events, and concomitant medications will be collected. 
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
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Page 3 
Within Table 2.1, this involved adding a new column for this Safety Follow-up and a new 
footnote. 
Rationale: This change was made to clarify the Safety Follow-up. 
3. In Table 2.1 (Schedule of Events) and Section 7.5 (Study Procedures and Assessments), 
the instruction, “Study assessments for a subject should be performed in a consistent 
order at each visit,” was added. In the table, this was included as a new footnote. The 
statement, “Refer to the Clinical Evaluator Manual for additional details on specific 
assessments and the suggested order of administration,” which was already in 
Section 7.5, was also included in this new footnote. 
Rationale: This change was made to ensure that the order of assessments is consistent at 
each visit yet allow flexibility in the order that the assessments are performed, because 
the order of assessments should not affect overall study results if it is consistent across 
visits for an individual subject. 
4. In Table 2.1 (Schedule of Events) and Section 7.5.2.6 (Clinical Laboratory Tests for 
Safety), the following changes were made: 
a. A requirement to perform urine microscopic examination if urinalysis detects protein, 
leukocyte esterase, blood, or nitrite was added. Within Table 2.1, this involved adding 
a new footnote to specify this requirement. 
Rationale: This change was made to ensure that that microscopic evaluation will be 
conducted when abnormal urinalysis results are observed. 
b. The requirement to collect blood and urine samples after administration of hand-held 
dynamometry assessments and prior to administration of study drug was removed. 
Within Table 2.1, this involved removal of the footnote specifying this requirement. 
Rationale: This change was made to align with change #3.  
5. In Table 2.1 (Schedule of Events) and Section 7.5.3.3, instruction that the SF-36 will only 
be completed for subjects when a validated version is available in the subject’s native 
language was added. 
Rationale: This change was made because a validated version of the SF-36 is not 
currently available in the native language of all subjects in this study. Therefore, this 
self-reported instrument will only be administered for those for whom it is available in 
their native language.  
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
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Page 4 
6. In Table 2.1 (Schedule of Events) and Section 7.5.4 (Drug Concentration Measurements), 
the requirement for collection and assessment of first morning void urine SA 
concentration was removed. Consequently, description of analysis of urine SA 
concentration was removed from Section 2 (Synopsis) and Section 7.6.5.  
Rationale: This change was made to decrease the burden of assessments for subjects, 
because assessment of serum SA concentration is being performed and additional urine 
SA data from first morning void urine is unlikely to further inform the PK or PK/PD 
profile of aceneuramic acid in these subjects.    
7. In Table 2.1 (Schedule of Events) and Section 7.5.5 (Urine Testing for ManNAc), 
instruction that an aliquot from the urine sample provided for the standard urinalysis 
testing will be used for assessment of ManNAc throughout the study was added. Within 
Table 2.1, this involved adding a new footnote specifying this. In Section 7.5.5, this 
addition replaced the requirement for first morning void collection of urine for 
assessment of ManNAc.  
Rationale: This change was made to clarify that urine for assessment of the presence of 
ManNAc will come from the safety urinalysis sample, rather than from the first morning 
void.   
8. Table 2.1 (Schedule of Events) was updated to indicate that general medical history, 
height, and weight should not be collected at the Baseline Visit (only at the Screening 
Visit) and that interval history should be assessed at the Baseline Visit rather than the 
Screening Visit. 
Rationale: This change was made to align the timing of collection of general medical 
history, height, and weight and of the interval history assessment between the schedule of 
events and Section 7.5.2. 
9. Within Section 7.3.2 (Exclusion Criteria), the exclusion criteria numbering was updated. 
Rationale: This change was made to make the exclusion criteria numbering in this 
section consistent with that in the Synopsis. 
10.  Section 7.3.3 (Removal of Subjects from Therapy or Assessment), Section 7.5.2.10 
(Adverse Events), Section 8.5.4.1 (General), Section 8.5.4.2 (Serious Adverse Events, 
Serious Adverse Drug Reactions, and Requirements for Immediate Reporting), 
Section 8.5.5.1 (Adverse Drug Reaction Reporting), and Section 8.5.6 (Urgent Safety 
Measures) were updated to clarify the end of the data collection period for safety 
reporting.  
Rationale:  This change was made to clarify the safety reporting period for all subjects 
who take part in the study.  
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
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Page 5 
11. Section 7.4.4.1 (Prohibited Medications) was updated to replace the specification that 
subjects may not be enrolled if they have a history of more than 30 days treatment with 
SA in the past year with the specification that subjects may not be enrolled if they 
participated in another aceneuramic acid study involving treatment with Ace-ER/placebo 
and/or SA-IR in the past year.  
Rationale: This change was made to align Section 7.4.4.1 with the study exclusion 
criteria. 
12. Within Section 7.5.1 (Study Schedule), the following changes were made: 
a. The following statement was added: “The Schedule of Events (Table 2.1) details all 
procedures to be completed at each visit and should serve as the primary section of 
the protocol regarding visit-specific study procedures.” 
Rationale: This statement was added to specify that the Schedule of Events serves as 
the primary reference regarding the procedures to be performed at each study visit.  
b. The content was reorganized and divided into subsections comprising 
Sections 7.5.1.1 (Screening Period), 7.5.1.2 (Baseline Visit), 7.5.1.3 (Treatment 
Period), 7.5.1.4 (End of Study/Early Termination Visit), and 7.5.1.5 (Safety Follow-
up Period). 
Rationale: This reorganization and division was done to more clearly delineate the 
study periods/visits. 
c. Within the new Sections 7.5.1.1, 7.5.1.4, and 7.5.1.5 specified above, additional 
information clarifying visit requirements was provided.  
Rationale: These changes were made to more clearly define the study period/visits 
and the associated assessments. In particular, Section 7.5.1.5 incorporated the 
information about the Safety Follow-up described in Change 2 above. 
d. Within new Section 7.5.1.2, the timeframe for conduct of the Baseline Visit relative 
to the Screening Visit was modified from a requirement to a guideline.  
Rationale: This change was made to allow flexibility if needed for scheduling 
purposes. 
13. In Section 7.5.2 (Safety Measures and General Assessments), the statement, “Refer to the 
Study Reference Manual for additional details on safety measures and general 
assessments” was removed. 
Rationale: This change was made because the Study Reference Manual will no longer be 
used for the UX001-CL203 study. Because the safety reporting information provided in 
the manual is already provided in the study protocols, the manual is not necessary. 
Discontinuing use of the manual will avoid presentation of inconsistent information 
across study documents by eliminating documents that have redundant content.   
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
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14. In Section 7.5.2.5, the instruction that vital signs measurements will be performed before 
any additional assessments are completed was removed. 
Rationale: This change was made to align with change #3.   
15. In Section 7.5.2.6 (Clinical Laboratory Tests for Safety), Table 7.5.2.6.1 was updated to 
include blood/RBC and leukocyte esterase in the urinalysis assessments and to present 
analytes in alphabetical order. In addition, the following text was added to the section: 
“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.”  
Rationale: The table was updated to reflect tests to be performed and for ease of use. The 
text was added to clarify what may be done with leftover blood and urine samples from 
this study for subjects who have provided consent for the use of the leftover samples for 
future research. 
16. In Section 7.5.2.6.1 (Volume of Blood to Be Drawn from Each Subject), 
Table 7.5.2.6.1.1 was updated to indicate that the sample volume of blood drawn for 
serum SA testing is 5 mL and the overall volume of blood that will be obtained during 
the study is 88 mL. 
Rationale:  This change was made to correctly reflect the total blood volume required to 
ensure a primary and back-up serum sialic acid sample are obtained.  
17. In Section 8.4.3 (Record Retention), the minimum retention period for subject identifier, 
subject files, and other source data was increased from 15 to 25 years after the 
completion or discontinuation of the study.   
Rationale: This change was made to align with current regulatory requirements. 
18. The title page was updated to include Dr Hank Mansbach as the Sponsor’s Responsible 
Medical Officer and Dr Tahseen Mozzafar as the Coordinating Investigator for this study. 
Also, Section 8.5.7 (Safety Contact Information) was updated with Dr Hank Mansbach’s 
information.  
 
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
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2 SYNOPSIS 
TITLE OF STUDY: 
A Phase 2 Open-label study to Evaluate the Safety of Aceneuramic Acid Extended Release (Ace-ER) 
Tablets in GNE Myopathy (GNEM) (also known as Hereditary Inclusion Body Myopathy (HIBM)) 
patients with Severe Ambulatory Impairment    
PROTOCOL NUMBER: 
UX001-CL203 
STUDY SITES: 
Approximately 8 sites in U.S., Canada, and Bulgaria 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
GNEM (or HIBM), is a rare, severely debilitating disease of adult onset myopathy and progressive 
muscle weakness 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 reduced SA and the 
resulting reduction of 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 tablets), given SA’s short 
half-life.  A Phase 2, randomized, double-blind, 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 better preserved 
muscle strength compared with placebo or the lower 3 g/day Ace-ER dose. This finding was supported 
by measurements of functional outcome on GNE Myopathy Functional Activities Scale 
(GNEM-FAS). Based on these results, a Phase 3 study is being conducted to confirm, and further 
evaluate the efficacy of Ace-ER 6 g/day in preserving upper extremity muscle strength and function 
(UX001-CL301). The primary objective of this Phase 2 study is to evaluate the safety of open-label 
6 g/day Ace-ER in GNEM subjects with severe ambulatory impairment. The study will also assess 
efficacy to ensure that the full spectrum of patients with GNEM are evaluated.  
For the purposes of this study, a subject with severe ambulatory impairment is defined as:  
• 
Unable to rise from a seated position to standing without help from another person, assistive 
device(s), stationary object, or other support  
AND 
• 
Unable to walk without the assistance of another person OR if able to walk (use of assistive 
device(s) permitted), requires at least 2 minutes to walk 40 meters (one full lap of the Six Minute 
Walk Test (6MWT) course)  
AND 
• 
Use of wheelchair or scooter for activities outside of the home or unable to leave the home 
independently 
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
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OBJECTIVES: 
Primary Objective: Evaluate the safety of Ace-ER in GNEM subjects with severe ambulatory 
impairment 
Secondary Objectives: Evaluate the efficacy of 6 g/day Ace-ER in GNEM subjects with severe 
ambulatory impairment  
Exploratory Objectives: Evaluate the effect of 6g/day Ace-ER on health-related quality of life 
(HRQoL), patient reported outcomes (PRO), and biomarkers of sialyation.  
ENDPOINTS: 
Primary Endpoint: 
The primary endpoint of the study is the incidence and frequency of adverse events (AEs) and serious 
adverse events (SAEs) assessed as related to Ace-ER over the duration of the study. 
Secondary Endpoints: 
Safety Endpoints: 
• 
Clinically significant changes from baseline to scheduled time points in concomitant medications, 
physical examination results, vital signs, clinical laboratory results and interval history during the 
course of the study  
Clinical Endpoints: 
• 
Change in GNEM-FAS Expanded Version total score and mobility, upper extremity and self-care 
domain scores from baseline over the duration of the study  
• 
Change in upper extremity strength in the following muscle groups: grip, key pinch, shoulder 
abductors and wrist extensors as measured by dynamometry over the duration of study   
• 
Change in lower extremity muscle strength in the knee extensors as measured by dynamometry 
over the duration of the study 
Exploratory Endpoints: 
The exploratory endpoints of the study include HRQoL, patient reported outcomes and biomarker 
analyses.  
• 
Change in health-related quality of life as assessed by using Short Form Health Survey -36 
(SF-36) over the duration of the study 
• 
Change in symptom severity as measured by Patient Global Impression of Severity (PGI-S) and 
Patient Global Impression of Change (PGI-C) over the duration of the study 
• 
Changes in serum creatine kinase (CK) as a marker of muscle injury over the duration of the study 
• 
Changes in biomarkers of sialylation 
STUDY DESIGN AND METHODOLOGY: 
This is an open-label, multi-center study to assess the safety of Ace-ER in GNEM patients with severe 
ambulatory impairment.  Efficacy will also be assessed as a secondary objective. Approximately 45 
subjects will be enrolled in the study and receive 6 g/day Ace-ER for 48 weeks.  
Subjects will take 4 tablets (500 mg each for 2 g per dose) orally 3 times per day (TID). 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 48 weeks.  Study visits will occur every 12 weeks during the Treatment 
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Protocol Number:  UX001-CL203 
Amendment 1:  15 Mar 2017 
 
 
Proprietary and Confidential 
Page 10 
AND 
• 
Unable to walk without the assistance of another person OR if able to walk (use of assistive 
device(s) permitted), requires at least 2 minutes to walk 40 meters (one full lap of the 6MWT 
course)  
AND 
• 
Use of wheelchair or scooter for activities outside of the home or unable to leave the home 
independently 
5. Willing and able to comply with all study procedures 
6. 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 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 
7. 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 
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), SA, 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. Prior participation in a clinical trial involving treatment with Ace-ER/placebo and/or Sialic Acid-
immediate release (SA-IR) in the past year 
3. Has had any hypersensitivity to aceneuramic acid or its excipients that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects 
4. Has serum transaminase (i.e. aspartate aminotransferase [AST] or gamma-glutamyl transpeptidase 
[GGT]) levels greater than 3X the upper limit of normal (ULN) for age/gender, or serum 
creatinine of greater than 2X ULN at Screening 
5. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any 
time during the study 
6. 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 
7. 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 
8. 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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INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
Each Ace-ER tablet contains 500 mg of aceneuramic acid 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). 
DURATION OF TREATMENT: 
The total treatment duration will be 48 weeks; all eligible subjects will receive 6 g/day Ace-ER. 
Subjects who complete the study will be eligible to participate in the extensionstudy, UX001-CL302. 
CRITERIA FOR EVALUATION: 
Clinical Safety Variables: 
Safety will be evaluated by the incidence and frequency of AEs and SAEs, and also clinically 
significant changes from baseline to scheduled time points in the following: 
• 
Concomitant medications 
• 
Physical examination results  
• 
Vital signs 
• 
Clinical laboratory results  
• 
Interval history 
• 
The C-SSRS  
Clinical Efficacy Variables: 
Efficacy will be evaluated by changes in upper and lower extremity muscle strength, physical 
functioning, health related quality of life outcome measures, and biomarkers. 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. 
• 
GNEM Functional Activities Scale (GNEM-FAS) – Expanded Version:  Physical functioning will 
be assessed using a disease-specific, clinician-reported outcome measure.  Scores on the mobility, 
self-care and upper extremity domains of the GNEM-FAS Expanded Version will be analyzed 
separately  
• 
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. An Upper 
Extremity Strength Composite Score (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. 
Lower extremity strength will be calculated as the average of the right and left values (measured 
in kg). 
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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  
• 
PGI-S (Patient global Impression of Severity)/PGI-C (Patient Global Impression of Change) 
• 
Biomarkers: 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  
Drug Concentration Measurements: The change in aceneuramic acid levels will be analyzed the 
same as for the primary endpoint. 
• 
Serum Free SA: The change in free SA level will be analyzed to assess the drug concentration in 
the bloodstream resulting from treatment 
Urine Testing for ManNAc: Urine will be tested for the presence of ManNAc to detect compliance 
with prohibited medication restrictions. 
 
 
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STATISTICAL METHODS: 
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. No study drug related SAE has been observed in 
previous clinical studies with Ace-ER. However, if it is assumed that the true rate of study drug related 
SAEs is 10% in this advanced patient population, there is at least 98% probability to observe one or 
more SAEs with N=45 subjects. Subjects who withdraw or are removed from the study after receiving 
study drug may be replaced on a case-by-case basis, at the discretion of Ultragenyx. This study is not 
powered to assess statistically significant changes from baseline in the efficacy endpoints. 
Analyses Sets: 
Full Analysis Set:  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. 
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 subjects with evaluable free serum 
SA levels. 
Safety Analyses: 
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. 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. 
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. 
Efficacy Analyses: 
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).  Dynamometry tests will be administered at the 
Screening visit to introduce subjects to performance testing to minimize training effects and will not 
be used for statistical analysis. 
Efficacy analyses will be based on the Full Analysis Set.  Generalized estimating equation (GEE) 
analysis will be performed with respect to the changes from baseline for all endpoints measured over 
time. 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.  
The final analyses will be conducted at Week 48. 
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Table 2.1: 
Schedule of Events 
 
ASSESSMENTS AND EVENTS a 
SCREENING b 
DAY -28 TO  
-4
  
BASELINE
 c  
WEEK 12 
VISIT 
(± 5 DAYS) 
WEEK 24 
VISIT 
(± 5 DAYS) 
WEEK 36 
VISIT 
(± 5 DAYS) 
WEEK 48 VISIT  
(± 5 DAYS) 
OR EARLY 
TERMINATION 
VISIT
 d 
SAFETY 
FOLLOW-UP r 
(TC) 
INFORMED CONSENT 
X 
 
 
 
 
 
 
INCLUSION/EXCLUSION CRITERIA 
X 
X 
 
 
 
 
 
DEMOGRAPHICS 
X 
X 
 
 
 
 
 
GNEM-SPECIFIC MEDICAL HISTORY e  
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
GENERAL MEDICAL HISTORY, HEIGHT f AND WEIGHT 
X 
 
 
 
 
 
 
PRIOR AND CONCOMITANT MEDICATIONS AND THERAPIES 
X 
X 
X 
X 
X 
X 
X 
INTERVAL HISTORY g  
 
X 
X 
X 
X 
X 
 
PHYSICAL EXAMINATION h 
X 
X 
X 
X 
X 
X 
 
VITAL SIGNS 
X 
X 
X 
X 
X 
X 
 
HEMATOLOGY, CHEMISTRY PANEL AND URINALYSIS i  
X 
X 
X 
X 
X 
X 
 
PREGNANCY TEST j 
X 
X 
X 
X 
X 
X 
 
THE COLUMBIA SUICIDE SEVERITY RATING SCALE 
X 
X 
X 
X 
X 
X 
 
ADVERSE EVENTS 
X 
X 
X 
X 
X 
X 
X 
URINE FOR MANNAC TESTING k 
X 
X 
X 
X 
X 
X 
 
BIOMARKERS: CK, SERUM SA, AND BIOMARKERS OF 
SIALYLATION AND OTHER BIOMARKERS l 
 
X 
X 
X 
X 
X 
 
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ASSESSMENTS AND EVENTS a 
SCREENING b 
DAY -28 TO  
-4
  
BASELINE
 c  
WEEK 12 
VISIT 
(± 5 DAYS) 
WEEK 24 
VISIT 
(± 5 DAYS) 
WEEK 36 
VISIT 
(± 5 DAYS) 
WEEK 48 VISIT  
(± 5 DAYS) 
OR EARLY 
TERMINATION 
VISIT
 d 
SAFETY 
FOLLOW-UP r 
(TC) 
CLINICAL ASSESSMENTS m 
 
 
 
 
 
 
 
MUSCLE STRENGTH TESTING BY HAND-HELD 
DYNAMOMETRY (HHD) n 
X 
X 
X 
X 
X 
X 
 
PATIENT-REPORTED OUTCOMES  
 
 
 
 
 
 
 
GNEM FUNCTIONAL ACTIVITIES SCALE 
(GNEM-FAS) – EXPANDED VERSION 
X 
X 
X 
X 
X 
X 
 
MEDICAL OUTCOMES SURVEY – 36 ITEM 
(SF-36) 
O 
 
X 
X 
X 
X 
X 
 
PGI-S AND PGI-C p 
 
X 
X 
X 
X 
X 
 
DISPENSE DRUG q 
 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE  
 
X 
X 
X 
X 
X 
 
a Study assessments for a subject should be performed in a consistent order at each visit. Refer to the Clinical Evaluator Manual for additional details on specific 
assessments and the suggested order of administration. 
b Potential subjects can be screened up to 28 days before the Baseline Visit.  
c Baseline Visit should be at least 4 days after and within 28 days of Screening visit. Study drug will be dispensed only after all eligibility requirements are 
confirmed and study procedures at the Baseline Visit have been performed.  
d 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 (TC) within 4 weeks of discontinuation from study, 
where appropriate information will be collected by the clinical site.  
e GNEM-specific medical history will include a detailed review of diagnostic and family history, as well as presenting symptoms and progression over time, and 
the use of assistive devices, drugs and therapies to manage the disease. 
f  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 
g Interval history will include any signs, symptoms, or events experienced by the subject since the prior study visit.  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. 
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h Complete physical examination including neurological examination conducted at Baseline and Week 48 (or Early Termination, if applicable) study visits. Brief 
physical examination at all other study visits.  
i  If urinalysis detects protein, leukocyte esterase, blood, or nitrite, urine microscopic examination will be conducted. 
j Pregnancy test by urine dipstick (local lab) is acceptable; a serum pregnancy test should be performed in the event of a positive or equivocal urine pregnancy test result. 
k An aliquot from the urine sample provided for the standard safety urinalysis testing will be used to test for the presence of ManNAc. 
l 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. 
m The muscle strength (HHD) assessment will be administered to all subjects. The number of clinical assessments performed at each visit will be determined by the subject’s 
extent of disease involvement. The physical therapist conducting the testing will choose the appropriate number and type of assessments guided by their clinical judgment, study 
training, and Clinical Evaluator Manual. 
n Lower extremity muscle strength for knee extensors muscle group only. 
o The SF-36 will only be completed for subjects when a validated version is available in the subject’s native language. 
p PGI-S (Patient global Impression of Severity) and PGI-C (Patient Global Impression of Change): PGI-S is to be administered only at baseline. PGI-C to be administered at all 
subsequent visits, including Early Termination. 
q Study drug will be dispensed only after all eligibility requirements are confirmed and study procedures at the Baseline Visit have been performed 
r This Safety Follow-up TC is to be completed only for subjects who complete the study and choose not to enroll in the extension study, UX001-CL302, or who discontinue the 
study early. This call is not required for subjects who are eligible and choose to take part in Study UX001-CL302. The site personnel should initiate the Safety Follow-up TC 
30 (+5) days after a subject’s last dose of study drug for subjects who complete the 48-week Treatment Period or 30 (+5) days after the ET Visit or ET TC for subjects who 
discontinue the study early. Information on any ongoing or new AEs, SAEs, and concomitant medications will be collected. Appropriate follow-up should continue until all safety 
concerns, in the Investigator’s opinion, are resolved. 
 
 
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3 TABLE OF CONTENTS 
1 TITLE PAGE……………………………………………………………………...............1 
2 SYNOPSIS ...........................................................................................................................7 
3 TABLE OF CONTENTS ...................................................................................................17 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................21 
5 INTRODUCTION .............................................................................................................25 
5.1 Overview of GNE Myopathy ....................................................................................26 
5.2 Brief Overview of Ace-ER Development .................................................................28 
5.2.1 
Brief Description of Ace-ER .......................................................................28 
5.2.1.1 
Mechanism of Action in GNE Myopathy ....................................29 
5.2.2 
Nonclinical Studies ......................................................................................29 
5.2.3 
Previous Clinical Studies .............................................................................30 
5.2.4 
Summary of Overall Risks and Potential Benefits ......................................32 
5.3 Study Rationale .........................................................................................................33 
6 STUDY OBJECTIVES ......................................................................................................35 
6.1 Study Endpoints ........................................................................................................35 
6.1.1 
Primary Endpoint ........................................................................................35 
6.1.2 
Secondary Endpoints ...................................................................................35 
6.1.3 
Exploratory Endpoints .................................................................................35 
7 INVESTIGATIONAL PLAN ............................................................................................36 
7.1 Overall Study Design and Plan .................................................................................36 
7.2 Discussion of Study Design ......................................................................................36 
7.3 Selection of Study Population ...................................................................................37 
7.3.1 
Inclusion Criteria .........................................................................................37 
7.3.2 
Exclusion Criteria ........................................................................................38 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................39 
7.3.3.1 
Stopping Rules .............................................................................40 
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7.4 Treatments .................................................................................................................40 
7.4.1 
Investigational Product ................................................................................40 
7.4.2 
Selection of Doses and Study Duration .......................................................40 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................41 
7.4.4 
Prior and Concomitant Therapy ..................................................................42 
7.4.4.1 
Prohibited Medications ................................................................42 
7.4.4.2 
Permitted Medications .................................................................42 
7.4.5 
Treatment Compliance ................................................................................42 
7.5 Study Procedures and Assessments ..........................................................................42 
7.5.1 
Study Schedule ............................................................................................43 
7.5.1.1 
Screening Period ..........................................................................43 
7.5.1.2 
Baseline Visit ...............................................................................43 
7.5.1.3 
Treatment Period ..........................................................................43 
7.5.1.4 
End of Study (Week 48)/Early Termination Visit .......................43 
7.5.1.5 
Safety Follow-up Period ..............................................................44 
7.5.2 
Safety Measures & General Assessments ...................................................44 
7.5.2.1 
Medical History ...........................................................................44 
7.5.2.2 
Height and Weight .......................................................................44 
7.5.2.3 
Interval History ............................................................................45 
7.5.2.4 
Physical Examination...................................................................45 
7.5.2.5 
Vital Signs ....................................................................................45 
7.5.2.6 
Clinical Laboratory Tests for Safety ............................................45 
7.5.2.7 
Pregnancy Testing ........................................................................47 
7.5.2.8 
Suicidal Ideation and Behavior ....................................................48 
7.5.2.9 
Concomitant Medications ............................................................48 
7.5.2.10 
Adverse Events ............................................................................48 
7.5.3 
Efficacy Measures .......................................................................................48 
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7.5.3.1 
Dynamometry ..............................................................................49 
7.5.3.2 
GNEM Functional Activities Scale (Expanded Version) ............50 
7.5.3.3 
Medical Outcomes Survey – 36 Item (SF-36) .............................50 
7.5.3.4 
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) ........................................50 
7.5.3.5 
Creatine Kinase Levels ................................................................51 
7.5.4 
Drug Concentration Measurements .............................................................51 
7.5.5 
Urine Testing for ManNAc .........................................................................51 
7.5.6 
Appropriateness of Measures ......................................................................51 
7.6 Statistical Methods and Determination of Sample Size ............................................52 
7.6.1 
Determination of Sample Size .....................................................................52 
7.6.2 
Subject Information .....................................................................................52 
7.6.3 
Populations Analyzed ..................................................................................52 
7.6.4 
Efficacy Analysis ........................................................................................53 
7.6.5 
Analyses of Drug Concentration Measurements .........................................53 
7.6.6 
Safety Analyses ...........................................................................................53 
8 STUDY CONDUCT ..........................................................................................................55 
8.1 Ethics .........................................................................................................................55 
8.1.1 
Institutional Review Board or Ethics Committee ........................................55 
8.1.2 
Ethical Conduct of Study ............................................................................55 
8.1.3 
Subject Information and Consent ................................................................55 
8.2 Investigators and Study Administrative Structure ....................................................56 
8.3 Investigational Product Accountability .....................................................................56 
8.4 Data Handling and Record Keeping .........................................................................57 
8.4.1 
Case Report Forms and Source Documents ................................................57 
8.4.2 
Data Quality Assurance ...............................................................................57 
8.4.3 
Record Retention .........................................................................................58 
8.5 Reporting and Follow-up of Adverse Events ............................................................58 
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8.5.1 
Definition of Adverse Events ......................................................................58 
8.5.2 
Severity of Adverse Events .........................................................................59 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................60 
8.5.4 
Adverse Event Reporting ............................................................................60 
8.5.4.1 
General .........................................................................................60 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................61 
8.5.4.3 
Pregnancy Reports .......................................................................61 
8.5.5 
Communication Plan ...................................................................................61 
8.5.5.1 
Adverse Drug Reaction Reporting ...............................................61 
8.5.6 
Urgent Safety Measures ..............................................................................62 
8.5.7 
Safety Contact Information .........................................................................62 
8.6 Financing and Insurance ...........................................................................................63 
8.7 Publication Policy .....................................................................................................63 
9 REFERENCES ..................................................................................................................64 
10 SIGNATURE PAGE .........................................................................................................67 
 
LIST OF TABLES 
Table 2.1: 
Schedule of Events ...............................................................................14 
Table 7.5.2.6.1: 
Clinical Laboratory Assessments for Safety ........................................46 
Table 7.5.2.6.1.1: 
Volume of Blood to be Drawn from Each Subject ..............................47 
 
LIST OF FIGURES 
Figure 2.1: 
Study Schema.........................................................................................9 
Figure 5.2.1.1.1: 
The Biosynthetic Pathway of Sialic Acid in its Subcellular 
Locations ..............................................................................................29 
Figure 7.1.1: 
Study Schema.......................................................................................36 
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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
Six Minute Walk Test 
Ace-ER 
Aceneuramic Acid Extended Release   
AE 
adverse event 
AFO 
ankle foot orthosis/orthoses  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CK 
CRC 
creatine kinase 
child-resistant caps 
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 
GGT 
N acetyl-glucosamine  
gamma-glutamyl transpeptidase 
GNE 
glucosamine (UDP-N-acetyl)-2-epimerase 
GNE/MNK 
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine 
kinase 
GNEM 
GNE Myopathy 
GNEM-FAS 
GNE Myopathy Functional Activities Scale 
hERG 
HDPE 
human ether-à-go-go-related gene 
high-density polyethylene 
HIBM 
hereditary inclusion body myopathy 
HIPAA 
HRQoL 
Health Insurance Portability and Accountability Act 
Health-related Quality of Life 
IB 
Investigator’s Brochure 
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ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IVIG 
intravenous immune globulin 
IWRS 
interactive web-based response system 
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 
Pharmacodynamics 
PGI-S  
PGI-C 
PK 
PRO 
Patient Global Impression of Severity  
Patient Global Impression of Change 
pharmacokinetic(s) 
patient reported outcomes 
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 
SA-ER 
Sialic Acid-Extended Release 
SA-IR 
Sialic Acid Immediate Release 
SAP 
SF-36 
Statistical Analysis Plan 
Short Form Health Survey - 36 
SOC 
System Organ Class 
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SUSAR 
suspected unexpected serious adverse reactions  
TC 
telephone call 
TEAE 
treatment-emergent adverse event 
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 or 
placebo 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 
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). GNEM is a rare and severely debilitating disease of 
adult onset myopathy and progressive muscle weakness. GNEM is an autosomal recessive 
disorder caused by a mutation in the GNE gene, which encodes an enzyme critical to the 
biosynthesis of sialic acid (SA). GNEM is typically characterized clinically by distal muscle 
weakness and the first symptom for most patients is unilateral or bilateral foot drop. 
Subsequently, impairment of both the lower and upper extremities proceeds proximally with 
relative sparing of the quadriceps. This impairment ultimately leads to significant 
compromise of upper and lower extremity function. Currently there are no approved 
treatments for the disease and patients eventually become wheelchair-bound as well as reliant 
on others for care within 10-20 years of initial diagnosis (Nonaka et al. 2005).  
SA is an essential, naturally occurring amino sugar found in humans and most organisms.  
Defects in the SA biosynthetic pathway cause GNEM and 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.  This rationale is supported by results of Murine GNE knock-out/knock-in models 
that demonstrated that mice with low SA levels have a phenotype resembling human GNE 
myopathy with impaired muscle strength and that replacement therapy with SA or its 
derivatives improves muscle function and histopathology associated with the disease 
(Yonekawa et al. 2014), (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.  These results form the scientific basis for the use of SA as a replacement therapy in 
GNEM patients.  
The product under investigation is a substrate replacement of sialic acid (SA) administered in 
extended release; aceneuramic acid extended release (previously known as sialic acid –
extended release (SA-ER)) tablets. The sponsor has developed aceneuramic acid extended 
release (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 to increase free sialic acid levels in serum, thus driving uptake into muscle cells. 
This should restore sialylation of muscle tissues resulting in improved biochemical functions 
and stabilization of muscle strength and function.  
The Ace-ER (previously known as SA-ER) formulation was evaluated in an initial Phase 1 
study to establish the safety and pharmacokinetic (PK) profile of a single dose (fed and 
fasted) and 7 days of repeat dosing in GNEM patients.  The study drug was well tolerated at 
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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 showed clinically meaningful, objective improvement in UE muscle strength 
and was supported by measurements of functional outcome on the GNEM-FAS at the higher 
6 g/day Ace-ER dose level. The drug had acceptable safety profile at all doses and no SAEs 
were reported.  
After 48 weeks of treatment, subjects from the Phase 2 randomized study entered into an 
open-label extension study. The open-label extension was designed in several parts to 
provide additional long-term safety and clinical efficacy at 6g/day dose level for continuing 
subjects (Part I), and evaluate the safety and efficacy of SA replacement at the 12 g/day dose 
level via co-administration of Ace-ER tablets with Sialic Acid immediate-release (SA-IR) 
capsule formulation of (Part II). (Refer to the Investigator’s Brochure (IB) for additional 
details on SA-IR.). Most muscles tested remained stable over the course of therapy. There 
was an increase in AEs related to gastrointestinal (GI) tolerability at the higher 12 g/day dose 
and no drug related SAEs were reported. There was no additional benefit beyond the 6 g/day 
dose. Based on the totality of the data the 6 g/day dose demonstrated the optimal benefit to 
risk profile and is being further evaluated in an ongoing Phase 3 study. 
The Phase 3 study is a randomized, double-blind, placebo-controlled 48-week study to 
evaluate efficacy and safety of Ace-ER (6 g/day) in patients with GNEM. The study will also 
evaluate outcome measures to determine the effect of muscle function on subject’s quality of 
life.  
In addition to interventional studies, Ultragenyx is sponsoring a GNEM Disease Monitoring 
Program (GNEM-DMP) which includes a disease registry (a longitudinal patient-reported 
disease outcome survey) and a natural history study (a physician-reported protocol-driven 
formal study).  The GNEM-DMP is being conducted in parallel with the aceneuramic acid 
clinical development program to collect data on disease characteristics and progression.   
This Phase 2 open-label study is designed to primarily evaluate the safety of 6 g/day Ace-ER 
tablets in GNEM patients who have severe ambulatory impairment. Efficacy will also be 
assessed as a secondary objective to ensure that the full spectrum of patients with GNEM is 
evaluated across the development program. 
5.1 
Overview of GNE Myopathy 
GNEM was first described in the Japanese population (Nonaka et al. 1981), and in a group of 
Iranian Jews in Israel (Argov et al. 1984). The patients showed progressive muscle weakness 
and atrophy, and rimmed vacuoles on biopsy. The genetic basis of GNEM as a mutation in 
GNE was determined in 2001 (Eisenberg et al. 2001). Since then, patients of Italian, 
Japanese, Thai, Indian, American and African origin have been identified, clearly making it a 
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worldwide disorder (Huizing et al. 2009). GNEM is a rare disease; the incidence is low and 
an estimated prevalence of 1/1,000,000 (higher prevalence is seen in Middle Eastern Jews 
and Japanese) (Nishino et al. 2015).  An estimated 220 total cases worldwide have been 
reported in the scientific literature (Jay et al. 2009). The Iranian Jewish population has a 
substantially higher incidence at approximately 1 per 1500 births (Jay et al. 2009). 
Patients with GNEM have a genetic defect in the first step of the biosynthetic pathway for 
SA caused by mutations in the GNE gene coding for the bifunctional enzyme glucosamine 
(UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE/MNK)  
(Eisenberg et al. 2001); (Jay et al. 2009).  The enzyme is the rate-controlled and regulated 
first step in the biosynthesis of SA required for the glycosylation of proteins and lipids.  
Studies in tissues and mouse models have shown that the deficiency of SA production is a 
key factor in the disease state, though the exact pathophysiologic effect of decreased 
sialylation on proteins or lipids is still debated.  
The clinical course in GNEM patients typically  includes an onset usually after age 20 (mean 
26 years, range 15–40 years) though patients can be symptomatic earlier (Nalini et al. 2010); 
(Nonaka et al. 2005); (Sadeh et al. 1993); (Sunohara et al. 1989).  Patients often have foot 
drop due to tibialis anterior weakness as a first sign and general weakness is more 
pronounced distally which then progresses proximally.  Both weakness and atrophy are noted 
in muscles with fatty and fibrous tissue replacement as the disease advances.  In many 
patients, there is a relative sparing of the quadriceps for unknown reasons.  The forearm 
flexors and axial musculature may become more involved over time.  The rate of progression 
is gradual and variable between patients over a 10–20 year period (mean of 12 years) 
(Nonaka et al. 2005) leading to a wheelchair-bound state and reliance on others for care.  The 
ocular, pharyngeal and respiratory muscles are relatively spared clinically though they may 
show some abnormal pathology in some patients (Argov et al. 1984).  Disease progression is 
not rapid compared with some myopathies but ultimately the level of function reached is 
severely compromised.   
Other clinical or physiological evaluations of these patients show a variable number of 
abnormalities all consistent with the myopathic pathologic process.  Unlike other 
myopathies, creatine kinase (CK) activities are mildly elevated or in normal range 
(22/58 patients reported by 3 publications had 2x or higher elevations; (Sadeh et al. 1993); 
(Mizusawa et al. 1987b); (Sunohara et al. 1989).  The mouse model of HIBM exhibits 
elevated CK levels that improve on treatment (Malicdan et al. 2009).  The decline in muscle 
bulk and function is substantial but the time course of decline may be sufficiently slow as to 
not cause acute CK elevations as observed in other disorders like Duchenne Muscular 
Dystrophy.  Imaging studies of the muscle by computed tomography (Sadeh et al. 1993), 
(Mizusawa et al. 1987a) or magnetic resonance imaging (Huizing et al. 2009) show 
substantial and diffuse abnormalities to muscle structure with significant fat infiltration in 
affected muscles but the quadriceps have a more normal appearance.  Many muscles have 
limited muscle tissue left, which could impact the potential for optimal treatment and 
substantial disease reversal in advanced patients. 
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Currently there are no approved treatments for GNEM; existing treatment methods are 
supportive to manage function but do not treat the underlying disease.  Treatment options 
may include physical and occupational therapy to improve muscle strength and, when 
necessary, the use of various assistive devices including braces (e.g. ankle-foot orthoses 
[AFOs]) or wheelchairs. 
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 primarily 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). In the animal models, exogenously administered SA 
was 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). In addition, 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). Nonclinical studies have been conducted in HIBM mice and multiple 
species of normal animals.  Two clinical studies and an extension study have been conducted 
to characterize the PK, tolerability, safety and efficacy of SA replacement in GNEM patients. 
A brief overview of existing information on Ace-ER is provided below; a comprehensive 
review of available data is contained in the 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. The 
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tablet formulation contains approximately 41.6% active pharmaceutical ingredient in a mixed 
polymer matrix developed for extended release of aceneuramic acid. Tablets are 
manufactured by a formulation process using wet aqueous granulation; the blend is then 
dried and compressed into tablet cores. Ace-ER 500 mg tablets are 1200 mg in total weight 
and packaged in 500 cc white high-density polyethylene (HDPE) bottles with screw-top 
polypropylene child-resistant caps (CRC) with heat-activated induction seal. Each HDPE 
bottle is filled with 168 tablets and contains a 3.5 gram silica gel desiccant pouch along with 
polyester coil. 
5.2.1.1 
Mechanism of Action in GNE Myopathy 
GNE/MNK is an enzyme which 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. 
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).  The rational basis for the use of SA as a therapy 
in GNEM is primarily dependent on these results.  Key safety pharmacology, PK, and 
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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 SA 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 mole/L.  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 studies with SA were conducted in rats following intravenous 
administration of a 20 mg/kg [14C]-Neu5Ac. SA was quickly excreted primarily through the 
urine (92.4% of radioactivity). 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.  
Chronic toxicology studies in rats and dogs:  In an oral 26-week rat study, there were no 
SA 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 this study 
was 2000 mg/kg/day, which is equivalent to approximately a 17 g daily human dose, 
providing a safety margin of approximately 3–fold over the proposed dose (6 g/day) in this 
clinical study.  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 this study 
was 2000 mg/kg/day which is equivalent to a 60 g daily human dose, thereby providing a 
safety margin of approximately 10–fold over the proposed dose (6 g/day) in this clinical 
study. 
Reproductive and developmental toxicology studies in rats and rabbits: To date, 
reproductive and developmental 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, or treatment-related 
effects on pregnant females or embryo-fetal development parameters in rats and rabbits. 
5.2.3 
Previous Clinical Studies 
Key results from studies to support the use of aceneuramic acid (also known as Sialic Acid) 
in treating GNEM are summarized below; additional details may be found in the IB.   
Phase 1 Pharmacokinetic and Safety Study (UX001-CL101):  A Phase 1 study to evaluate 
the safety and PK of single and repeat doses of Ace-ER tablets was conducted in GNEM 
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subjects.  Twenty-seven (27) subjects were assigned to treatment; 26 were dosed with 
Ace-ER and completed dosing.  Subjects received Ace-ER tablets orally at one of five dose 
levels (650 – 6000 mg) in the single dose phase (fasting and fed), and one of four dose levels 
in the repeat dose phase (1950 – 6000 mg/day divided into three equal doses).   
PK analysis showed acceptable absorption of the product with SA exposure that covered 
about 8-16 hours.  Repeat dosing for 7 days with Ace-ER showed that trough levels could be 
maintained above the pre-dose baseline level, as expected for a sustained release formulation.  
Ace-ER was well tolerated in this group of GNEM subjects based on the AE profile, the 
absence of SAEs, and the lack of treatment emergent changes in any parameter (AEs, 
physical examinations, vital signs and clinical laboratory evaluations).  The AE profile was 
unremarkable; the most common treatment-emergent adverse event (TEAE) reported was 
headache.  However, there was no dose-dependent pattern for any drug-related or unrelated 
event. 
Phase 2 Pharmacokinetic, Pharmacodynamic and Safety Study (UX001-CL201):  
A Phase 2 randomized, double-blind, placebo-controlled, parallel group study was conducted 
to evaluate the efficacy and safety of two doses and PD of Ace-ER tablets in 47 GNEM 
patients (Argov et al. 2014).  Subjects were randomized to receive placebo or 3 g/day or 
6 g/day Ace-ER. After 24 weeks, placebo subjects crossed over (blinded) to either 3 g/day or 
6 g/day Ace-ER for an additional 24 weeks. Assessments included drug concentration 
measurements, upper extremity composite (UEC) and lower extremity composite (LEC) 
muscle strength scores, other clinical endpoints, patient reported outcomes, and safety. 
At Week 24, the UEC score showed a statistically significant difference in the 6 g/day group 
compared with placebo (+2.33 kg; p=0.040).  At Week 48, a statistically significant 
difference between the combined 6 g/day group and the combined 3 g/day group was 
observed (+3.46 kg; p=0.0031). Subjects with less advanced disease (able to walk more than 
200 meters at screening in the six-minute walk test, 6MWT), a predefined subset that 
comprised approximately 70% of total enrollment, showed a more pronounced difference at 
48 weeks (+4.69 kg; 9.7% relative difference from baseline; p=0.0005).   
A similar pattern of response was observed in the LEC, but was not statistically significant 
between the dose groups.  None of the treatment groups showed a significant decline in 
function.  There was no significant difference (increase or decline) in the 6MWT.   
The GNE Myopathy Functional Activities Scale (GNEM-FAS) did not show differences at 
Week 24; After 48 weeks, the combined 6g/day treatment group had significantly greater LS 
mean scores than the combined 3 g/day group for the total score (p=0.086), mobility domain 
subscore (p=0.087), and upper extremity scores (p=0.096) when analyzed by the 
pre-specified, primary ANCOVA analysis. Changes in total, mobility, and upper extremity 
scores were also significant in the combined 6 g/day vs 3 g/day groups when analyzed in a 
post-hoc analysis. 
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Ace-ER appeared to be well tolerated with no SAEs reported in either dose group and no 
dose-dependent TEAEs identified. Common TEAEs included GI events (diarrhea, flatulence, 
abdominal pain, and dyspepsia), headache, arthralgia, back pain, fatigue, influenza-like 
illness, musculoskeletal pain, myalgia, nasal congestion and nasopharyngitis. Most AEs were 
mild to moderate in severity. 
Phase 2 Efficacy and Safety Extension Study (UX001-CL202):  An open-label Phase 2 
extension study is ongoing to assess the long-term safety and efficacy of 6 g/day Ace-ER and 
12 g/day SA-ER/SA-IR in GNEM patients.  In Part I of the study, 46 subjects were enrolled 
following successful completion of the UX001-CL201 study.  Throughout the Part I 
Treatment Period of the study, all subjects continued on 6 g/day Ace-ER tablets administered 
three times a day (TID).  In Part II of the study, all subjects crossed over to the 12 g/day 
SA-ER/SA-IR dosing regimen.  An additional 13 treatment naïve GNEM subjects were also 
enrolled into Part II of the study to receive 12 g/day. In Part III of the study, some subjects 
had their dose reduced from 12 g/day to 6 g/day.  The treatment-naïve group and a subset of 
rollover subjects who showed potential clinical benefit at 12 g/day had the option to remain 
on the 12 g/day dose. 
Evaluations include safety, changes in clinical endpoints such as muscle strength, mobility, 
and function, and changes in exploratory serum biomarkers.  Data from assessment at the end 
of Part II (Month 12 Visit) suggest that the 12 g/day dose does not confer additional benefit 
than the 6 g/day dose in muscle strength or clinical endpoints. At this cut-off, after 2.5 years 
of SA treatment (combined duration of UX001-CL201 and 12 month cut-off of 
UX001-CL202) three of the four muscle group that comprise UE strength and four of the five 
muscle groups that comprise LE strength remained stable in the combined 0/6 g/day and  
6/6 g/day group as evidenced by an increase in LS mean strength or a reduction in LS mean 
strength of < 1.0 kg from the UX001-CL201 Baseline Visit.   
The 12 g/day dose of SA was generally well tolerated but AEs related to GI tolerability were 
increased. AEs were generally mild to moderate in severity and similar to those observed in 
previous studies. 
Phase 3 Efficacy and Safety Study (UX001-CL301): A Phase 3, randomized, double-blind, 
placebo-controlled study to evaluate efficacy and safety of 6 g/day Ace-ER in GNEM 
patients is currently ongoing and enrolling patients. Currently there are no data available 
from this study. 
5.2.4 
Summary of Overall Risks and Potential Benefits 
Since SA is an endogenous monosaccharide with native pathways for degradative 
metabolism and rapid renal clearance, and there is no evidence or expectation of a significant 
safety issue with SA replacement therapy.  Data from nonclinical and clinical studies to date 
suggest Ace-ER administered alone or with SA-IR does not pose any significant safety risks 
that can be identified at this time.  Toxicology or adverse pharmacology findings were not 
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observed in SA-treated animals; at very high doses, osmotic diarrhea may be observed in 
treated dogs.   
In the 48-week Phase 2 study in 47 GNEM subjects, there were no deaths or drug related 
SAEs. The majority of subjects had TEAEs that were graded as mild to moderate severity. 
A single subject in the 3 g/day Ace-ER group discontinued due to an AE of abnormal liver 
enzymes; the subject was subsequently identified as having a history of elevated liver 
function test results.  The only AE experienced by a greater proportion of Ace-ER treated 
subjects was abnormal liver function tests (5 subjects vs. 0 in the placebo group).  It is likely 
alanine aminotransferase (ALT) elevations resulted from skeletal muscle disease rather than 
from liver damage, since gamma-glutamyl transpeptidase (GGT) was generally normal and 
serum CK was also elevated in these subjects.  The time course of abnormality and lack of 
dose response suggest that these results are not study drug related. Sporadic abnormal levels 
of aspartate aminotransferase (AST) and ALT were also reported throughout the study, 
irrespective of time point or treatment group. 
The most common treatment-related TEAEs were GI events (diarrhea, flatulence, 
abdominal pain, and dyspepsia), headache, and fatigue. The patterns of AEs were similar 
in the placebo-controlled phase of the study (the first 24 weeks) and for all 48 weeks. 
No correlation was observed between the GI events and free SA serum levels suggesting the 
frequency of GI events does not appear to be dose dependent.  No subjects from the Placebo 
group reported diarrhea or abdominal pain, or had abnormal liver function tests after crossing 
over to Ace-ER treatment in the continuation phase of the study. 
Safety results in the ongoing Phase 2 study (UX001-CL202) indicate the most common 
TEAE reported by subjects receiving a higher dose of 12 g/day SA-ER/SA-IR involve 
GI disorders, including diarrhea, flatulence, dyspepsia, and abdominal pain. 
In clinical studies conducted to date, 6 g/day Ace-ER provided a sustained exposure, a 
clinical efficacy signal, and acceptable safety profile.  Overall the risk-benefit ratio appears 
to be favorable based on the excellent safety record to date, and the potential benefit 
observed in nonclinical and clinical studies. 
5.3 
Study Rationale 
GNEM (or HIBM), is a rare, severely debilitating disease of adult onset myopathy and 
progressive muscle weakness 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 reduced SA and resulting reduction of 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 aceneuramic acid extended release [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 better preserved muscle 
strength compared with placebo or the lower 3 g/day Ace-ER dose, and the difference in 
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upper extremity muscle strength (UEC score) between the highest and lowest exposure group 
was statistically significant. This finding was supported by measurements of functional 
outcome on the GNE Myopathy Functional Activities Scale (GNEM-FAS). Based on these 
results, a Phase 3 study is being conducted to further evaluate and confirm the efficacy of 
Ace-ER 6 g/day to preserve upper extremity muscle strength and function (UX001-CL301). 
The primary objective of this Phase 2 study will be to evaluate the safety of open-label 
6 g/day Ace-ER in GNEM subjects with severe ambulatory impairment; efficacy will also be 
assessed as a secondary objective to ensure that the full spectrum of patients with GNEM are 
evaluated. 
For the purposes of this study, a subject with severe ambulatory impairment is defined as:  
• Unable to rise from a seated position to standing without help from another person, 
assistive device(s), stationary object, or other support  
AND 
• Unable to walk without the assistance of another person OR if able to walk (use of 
assistive device(s) permitted), requires at least 2 minutes to walk 40 meters (one full lap 
of the 6MWT course)  
AND 
• Use of wheelchair or scooter for activities outside of the home or unable to leave the 
home independently 
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6 STUDY OBJECTIVES 
Primary Objective: Evaluate the safety of Ace-ER in GNEM subjects with severe 
ambulatory impairment 
Secondary Objectives: Evaluate the efficacy of 6 g/day of Ace-ER in GNEM subjects with 
severe ambulatory impairment 
Exploratory Objectives: Evaluate the effect of 6g/day Ace-ER on HRQoL, patient reported 
outcomes (PRO), and biomarkers of sialyation 
6.1 
Study Endpoints 
6.1.1 Primary 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. 
6.1.2 Secondary Endpoints 
The secondary safety endpoints of the study are: 
• Clinically significant changes from baseline to scheduled time points in concomitant 
medications, physical examination results, vital signs, clinical laboratory results and 
interval history during the course of the study 
The secondary efficacy endpoints of the study are: 
• Change in GNEM-FAS Expanded Version total score and mobility, upper extremity and 
self-care domain scores from baseline over the duration of the study  
• Change in upper extremity strength in the following muscle groups: grip, key pinch, 
shoulder abductors and wrist extensors as measured by dynamometry over the duration of 
study  
• Change in lower extremity muscle strength in the knee extensors as measured by 
dynamometry over the duration of the study 
6.1.3 Exploratory Endpoints 
The exploratory endpoints of the study include HRQoL, patient reported outcomes and 
biomarker analyses.  
• Change in health-related quality of life as assessed by using Short Form Health 
Survey - 36 (SF-36) over the duration of the study 
• Change in symptom severity as measured by Patient Global Impression of Severity 
(PGI-S) and Patient Global Impression of Change (PGI-C) over the duration of the study 
• Changes in serum CK as a marker of muscle injury over the duration of the study 
• Changes in biomarkers of sialylation 
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objective. In addition, information on biomarkers will be collected to assess their value in 
predicting clinical severity and disease progression.  
The study will be conducted as an open-label study as its primary objective is to assess the 
safety in GNEM patients with severe ambulatory impairment. There will be no control arm in 
the study.  
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 and interval history will also be part of the safety evaluation.  
The study population comprises adult GNEM patients with severe ambulatory impairment, 
since the onset of disease usually occurs after age 20, and seeks to evaluate the safety of 
Ace-ER in this patient population. Enrolled subjects will have a confirmed diagnosis of 
GNEM; however the population is inherently limited to only those subjects with severe 
ambulatory impairment. These subjects have advanced disease and while not all of them are 
entirely wheelchair bound, they do require assistance from another person or assistive device 
to stand from a seated position and for performing activities outside the home. Please see 
Inclusion Criteria Section 7.3.1 for the definition on severe ambulatory impairment.  
The 48-week treatment design is intended to allow for a sufficient duration to observe any 
potential safety impact of the 6g/day dose level in this severely compromised GNE myopathy 
patient group. In addition, it will allow for a minimal collection of efficacy data to determine 
the clinical effect of aceneuramic acid in these patients.  
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.   
7.3.1 
Inclusion Criteria 
1. Male or female, aged ≥ 18 years old 
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. Have a documented diagnosis of GNEM, HIBM, DMRV, or Nonaka disease due to 
previously demonstrated mutations in the gene encoding the GNE/MNK enzyme 
(genotyping will not be conducted in this study) 
4. Should meet the criteria for severe ambulatory impairment defined below: 
• Unable to rise from a seated position to standing without help from another person, 
assistive device(s), stationary object, or other support  
AND 
• Unable to walk without the assistance of another person OR if able to walk (use of 
assistive device(s) permitted), requires at least 2 minutes to walk 40 meters (one full lap 
of the 6MWT course)  
AND 
• Use of wheelchair or scooter for activities outside of the home or unable to leave the 
home independently 
5. Willing and able to comply with all study procedures 
6. 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 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 
7. 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), SA, 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. Prior participation in a clinical trial involving treatment with Ace-ER/placebo and/or 
SA-IR in the past year 
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3. Has had any hypersensitivity to aceneuramic acid or its excipients that, in the judgment 
of the investigator, places the subject at increased risk for adverse effects 
4. Has serum transaminase (i.e. aspartate aminotransferase [AST] or gamma-glutamyl 
transpeptidase [GGT]) levels greater than 3X the upper limit of normal (ULN) for 
age/gender, or serum creatinine of greater than 2X ULN at Screening 
5. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at 
any time during the study 
6. 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 
7. 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 
8. 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 
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 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 by the 
time of the Safety Follow-up TC or, if applicable, until the date the subject receives their first 
dose of study drug in the extension study, UX001-CL302, whichever occurs sooner , their 
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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 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 by the Medical Monitor as to whether the subject will 
continue on the study.   
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 
the trial following an internal safety review, this will be done only following approval by 
Regulatory Authorities.  
7.4 
Treatments 
Approximately 45 subjects will be enrolled in to the study and treated with Ace-ER tablets; 
6 g/day divided TID.   
7.4.1 
Investigational Product 
Each Ace-ER tablet contains 500 mg of aceneuramic acid in an extended release formulation 
for a total weight of 1200 mg/tablet. The 6000 mg (6 g) total daily 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 
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 less efficacious, and that a 
higher dose of 12 g/day did not result in a significant improvement over 6 g/day. These data 
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were derived from a randomized, placebo-controlled Phase 2 study and a corresponding 
extension study.   
The Phase 2, double-blind, randomized, placebo-controlled study (UX001-CL201) evaluated 
treatment with Ace-ER at two dose levels (3 g/day and 6 g/day). The study was placebo 
controlled for the first 24 weeks and then all subjects received Ace-ER at one of the 
two doses (blinded) for the next 24 weeks.  In this study, the group of patients treated with 
higher dose of 6 g/day (placebo or 6 g/day for first 24 weeks followed by 6 g/day for next 
24 weeks) stabilized upper extremity muscle strength compared with patients treated with 
lower dose of 3 g/day (placebo or 3 g/day dose for first 24 weeks then 3 g/day for the next 
24 weeks). This finding was also supported by measurements of functional outcome on the 
GNEM-FAS indicating the difference in muscle strength was clinically meaningful to 
subjects.  
A higher 12 g/day dose administered as 1.5 g Ace-ER and 1.5 g SA-IR orally four times 
daily was evaluated in Part II of the Phase 2 extension study (UX001-CL202) in existing 
subjects who transitioned from 6 g/day to 12 g/day, and in 13 treatment-naïve subjects who 
initiated treatment at 12 g/day. No additional efficacy benefit was conveyed by the 12 g/day 
dose over the 6 g/day dose.  The safety of the 12 g/day dose appeared generally similar to 
6 g/day but with a notable increase in GI symptoms, including flatulence.   
Given these biochemical and clinical results, the 6 g/day Ace-ER dose has been selected for 
further study as the dose with a treatment effect that will provide the best opportunity for 
efficacy in all subjects with a good safety profile.  
Study Duration: 
Individual subject participation in this study will be a maximum of approximately 56 weeks, 
including up to 4 weeks between Screening and Baseline,  48 weeks of treatment, and a 
Safety Follow-up Period of approximately 4 weeks. Subjects who complete the study may be 
eligible to participate in the open-label extension study, UX001-CL302. 
All subjects will receive Ace-ER 6 g/day during the 48-week Treatment Period. The 48-week 
treatment duration is intended for adequate collection of safety data on the Ace-ER tablets 
and to provide insight on sustained clinical effects and improvements in adult GNEM 
patients with severe ambulatory impairment.   
7.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study and consists of one treatment arm. All subjects will be treated 
with Ace-ER 6 g/day. 
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7.4.4 
Prior and Concomitant Therapy 
7.4.4.1 Prohibited Medications 
Patients may not be enrolled if they have participated in another aceneuramic acid study 
involving treatment with Ace-ER/placebo and/or SA-IR in the past year, used any 
investigational product 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 or related metabolites; IVIG; or anything that can be 
metabolized to produce SA in the body is prohibited during the 60 days prior to Screening 
and throughout the study.  If ManNAc, SA 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 urine for the presence of ManNAc to 
detect noncompliance with this essential requirement. 
7.4.4.2 
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, dose, route and the reason the medication was taken. 
7.4.5 
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. All used product packaging and containers must also be returned at in-clinic visits.  
Drug accountability will be assessed by site personnel and recorded.  Measurements of free 
SA levels in the serum may also analyzed to 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 
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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-CL203, along with timing of assessments, are 
provided in the Schedule of Events (Table 2.1). Study assessments for a subject should be 
performed in a consistent order at each visit. Refer to the Clinical Evaluator Manual for 
additional details on specific assessments and the suggested order of administration.  
7.5.1 
Study Schedule 
The Schedule of Events (Table 2.1) details all procedures to be completed at each visit and 
should serve as the primary section of the protocol regarding visit-specific study procedures. 
7.5.1.1 
Screening Period 
Informed consent must be obtained prior to administering any Screening procedures. 
Screening procedures may take place across multiple days to allow enough time to complete 
all procedures and confirm initial subject eligibility. Screening procedures and dates should 
be well documented in the source documents and CRF. For recording purposes, the date of 
the Screening Visit is the date the patient has signed informed consent for this study.  
7.5.1.2 
Baseline Visit 
The Baseline (Week 0) Visit should take place at least 4 days after and within 28 days of the 
Screening Visit. Baseline visit (Week 0) assessments must be completed prior to first dose of 
study drug.   
7.5.1.3 
Treatment Period 
Subjects will return to the clinic at 12-week intervals (± 5 days) throughout the Treatment 
Period (Weeks 0 – 48).  For subjects who discontinue prior to completing the 48-week 
Treatment Period, every reasonable effort should be made to perform the Early Termination 
Visit procedures within four weeks of discontinuation (Section 7.5.1.4).  
7.5.1.4 
End of Study (Week 48)/Early Termination Visit 
All enrolled subjects who complete the study or discontinue early (i.e., prior to completing 
the 48-week Treatment Period) should complete the Week 48/Early Termination Visit.  
For subjects who discontinue early, 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 (TC) within 4 weeks of discontinuation from study, where information on any 
ongoing or new AEs, SAEs, and concomitant medications will be collected by the clinical 
site. 
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7.5.1.5 
Safety Follow-up Period 
A Safety Follow-up TC should be initiated by the site personnel 30 (+5) days after a 
subject’s last dose of study drug for subjects who complete the 48-week Treatment Period 
and choose not to enroll in the extension study, UX001-CL302, or 30 (+5) days after the ET 
Visit or TC for subjects who discontinue the study early. Information on any ongoing or new 
AEs, SAEs, and concomitant medications should be collected. Appropriate follow-up of 
ongoing AE/SAEs should continue until all safety concerns, in the Investigator’s opinion, are 
resolved. 
Subjects who have completed the Week 48 Visit of this study, meet the requirements of 
extension Study UX001-CL302, and choose to enroll in the extension study will not be 
required to complete the Safety Follow-up TC. However, note that for these subjects, 
AEs/SAEs should continue to be collected in the parent study until the date of their first dose 
of study drug in the extension study (see Section 8.5.4). 
7.5.2 
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, and also 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.   
7.5.2.1 
Medical History 
A detailed medical history will be obtained at the Screening 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. 
7.5.2.2 
Height and Weight 
Height and weight will be captured at the Screening Visit and should be measured by the 
trained clinician administering the performance testing.  A calibrated stadiometer must be 
used for all height measurements. If a patient is unable to stand or has significant postural 
issues that interfere with the collection of a standing height, self-reported final adult height 
should be captured.  Height should be measured in 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 kilograms without shoes. 
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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 
Visit will be used for all derivations of percent predicted. 
7.5.2.3 
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 (except Screening). 
7.5.2.4 
Physical Examination 
Complete physical examinations including neurological examinations will be performed at 
Baseline and the Week 48 study visit (or Early Termination, if applicable) and brief physical 
examinations at all other visits.  Complete physical examinations will include assessments 
of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, 
lymphatic, respiratory, GI, 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 
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. 
7.5.2.5 
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. 
7.5.2.6 
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 are listed in 
Table 7.5.2.6.1.  Clinical laboratory testing will be performed at every visit.  Refer to the 
Laboratory Manual for details regarding collection and processing instructions of samples. 
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Table 7.5.2.6.1: 
Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Basophil count (absolute and %) 
Appearance 
Alkaline phosphatase 
Eosinophil count (absolute and %) 
Blood/RBC 
Amylase 
Hematocrit 
Bilirubin 
Aspartate aminotransferase (AST) 
Hemoglobin 
Color 
Bilirubin (direct and total) 
Lymphocyte count (absolute and %) 
Creatinine 
Blood urea nitrogen (BUN) 
Mean corpuscular hemoglobin (MCH) 
Glucose 
Calcium 
MCH concentration (MCHC) 
Hemoglobin 
Chloride 
Mean corpuscular volume (MCV) 
 Ketones 
Cholesterol (total) 
Monocyte count (absolute and %) 
 Leukocyte esterase 
Creatine kinase  
Neutrophil count (absolute and %)  
 ManNAc 
Creatinine 
 Platelet count 
Nitrite 
Gamma-glutamyl transpeptidase (GGT) 
 Red blood cell (RBC) count 
pH 
Glucose 
 Reticulocyte count 
Protein 
Lactate dehydrogenase (LDH) 
 White blood cell (WBC) count 
Specific gravity 
Lipase 
 WBC differential 
Urobilinogen 
Phosphorus 
 
 
Potassium 
 
Pregnancy test 
(if applicable) 
Protein (albumin and total) 
 
*Special assessment 
Sodium 
 
Serum pregnancy test if a 
positive urine pregnancy 
test 
Triglycerides 
 
 
 
If urinalysis detects protein, leukocyte esterase, blood, or nitrite, urine microscopic 
examination will be conducted. The microscopic examination will include white blood cells 
(WBCs); red blood cells (RBCs); epithelial cells: squamous, transitional, and renal tubular; 
casts: hyaline, WBC, RBC, waxy, and granular; crystals: calcium oxalate, uric acid, and 
triphosphate; yeast; bacteria; amorphous urates; and amorphous phosphates. 
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. 
7.5.2.6.1 
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 
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(Table 7.5.2.6.1.1).  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 7.5.2.6.1.1: 
Volume of Blood to be Drawn from Each Subject 
Assessment 
Sample Volume (mL) 
Number of 
Samples 
Total Volume (mL) 
Safety 
Chemistry 1 
7.5 
6 
45 
Hematology 
3 
6 
18 
PK 
Sialic Acid  
5 
5 
25 
Total mL through study completion 
88 
1 Includes CK, an efficacy variable 
7.5.2.7 
Pregnancy Testing 
Female subjects of childbearing potential with a positive pregnancy test at Screening will not 
be eligible to enroll in the study.  Female subjects will have urine pregnancy tests at the 
Baseline visit and at 12-week intervals throughout the study (or Early Termination). 
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 
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).  
7.5.2.7.1 
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 
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female partner’s consent for release of protected health information.  The sponsor or it’s 
designee will provide details on the reporting procedures to follow in the event of pregnancy. 
7.5.2.8 
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  
(FDA Draft Guidance 2012).  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 (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 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.  
7.5.2.9 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit, beginning at the Screening visit.  Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 30 days prior to 
Screening 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 7.4.4. 
7.5.2.10 Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent through the 
Safety Follow-up TC, or, if applicable, until the date the subjects receive their first dose of 
study drug in the extension study, UX001-CL302, whichever occurs sooner.  
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. 
7.5.3 
Efficacy Measures 
Efficacy will be evaluated by changes in physical functioning, upper and lower extremity 
muscle strength, HRQoL outcome measures, and biomarkers. In addition to total score, 
scores of mobility, self-care and upper extremity domains of the GNEM-FAS Expanded 
Version will be analyzed separately. Results from baseline assessments will be compared 
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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. 
7.5.3.1 
Dynamometry 
Dynamometry testing of multiple muscle groups will be used to measure strength.  
Dynamometry sessions will occur at each visit beginning with the Screening Visit.  Test 
administration at the Screening visit is intended as practice for the evaluator and the subject 
and data collected will not be used for analysis.  See Clinical Evaluator Manual for details on 
the administration procedure for dynamometry.  
Formal training will be conducted with the clinicians administering dynamometry 
(preferably 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: shoulder abductors, wrist extensors and 
knee extensors.  Specialized dynamometers for the measurement of gross grip and pinch 
strength will also be used.   
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); (Peters et al. 2011).   
Muscle strength and percent predicted values for each muscle group tested will be analyzed 
(Section 7.6.4). 
7.5.3.1.1 
Upper Extremity Strength Composite (UEC) Score 
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 change from baseline in mean UEC 
score will be measured and reported.    
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 (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.   
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7.5.3.1.2 
Lower Extremity Muscle Strength 
Muscle strength based on MVIC against a dynamometer will be measured bilaterally in the 
knee extensors muscle group for subjects who are able to be positioned properly for valid 
testing. Lower extremity muscle strength will be calculated as the average of the right and 
left values (measured in kg).  
7.5.3.2 
GNEM Functional Activities Scale (Expanded Version) 
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 GNEM-FAS will be administered at each visit beginning 
with the Screening Visit to evaluate physical functioning. Test administration at the 
Screening visit is intended as practice for the evaluator and the subject, and data collected 
will not be used for analysis.  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 original GNEM-FAS was developed as a clinician-reported outcome 
measure (ClinRo) for ambulatory GNEM patients but has since been modified to include 
additional items to accommodate weaker patients.  This modified version is referred to as the 
GNEM-FAS Expanded Version and will be used in this study.  
7.5.3.3 
Medical Outcomes Survey – 36 Item (SF-36) 
The SF-36 will be completed by subjects at each visit beginning with the Baseline Visit 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 only be completed for subjects when a validated version is available in the 
subject’s native language. 
7.5.3.4 
Patient Global Impression of Severity (PGI-S) and Patient Global Impression 
of Change (PGI-C) 
The PGI-S/PGI-C is an instrument widely used in chronic pain clinical trials to indicate the 
patient’s perception about the efficacy of treatment (Mease et al. 2011). It’s a self-
administered tool and improvement is rated on a 7-point categorical scale ranging from “very 
much better” to “very much worse.”  A 7-point PGI-S instrument will be administered at the 
Baseline visit to ascertain patient perception of disease severity before start of the study 
treatment. The PGI-C will be completed at all subsequent visits including Early Termination 
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Visit, if applicable, to ascertain the change in patient’s perception of disease severity over the 
duration of treatment. 
7.5.3.5 
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 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. 
7.5.4 
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 (including Early Termination, if 
applicable) a serum sample will be collected, prior to the morning dose of study medication 
(pre-dose) if possible, to assess levels of free SA.   
Collection and processing instructions can be found in the Laboratory Manual. 
7.5.5 
Urine Testing for ManNAc 
An aliquot from the urine sample provided for the standard urinalysis testing at Screening, 
Baseline and each subsequent visit (including Early Termination, if applicable) will be 
analyzed for the presence of ManNAc to detect noncompliance with prohibited medication 
restrictions.  
Collection and processing instructions can be found in the Laboratory Manual. 
7.5.6 
Appropriateness of Measures 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, serum 
chemistry, and other routine clinical and laboratory procedures.  In addition, symptoms of 
increasing muscle weakness 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). 
The secondary efficacy parameters to be evaluated in this study include changes in upper and 
lower extremity muscle strength, changes in self-reported functional disability using a 
disease-specific questionnaire, and changes in self –reported health related quality of life.   
Based on results from Phase 2 studies and published studies (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).  A disease-specific, self-reported measure designed to evaluate ability in 
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GNEM patients (GNEM-FAS Expanded Version) will be administered in this study to 
support the clinical meaningfulness of changes in muscle strength.    
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).   
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. No study drug related 
SAE have been observed in previous clinical studies with Ace-ER. However, if it is assumed 
that the true rate of study drug related SAEs is 10% in this advanced patient population, there 
is at least 98% probability to observe one or more SAEs with N=45 subjects. Subjects who 
withdraw or are removed from the study after receiving study drug may be replaced on a 
case-by-case basis, at the discretion of Ultragenyx. This study is not powered to assess 
statistically significant changes from baseline in the efficacy endpoints. 
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 randomized 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. 
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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 
Baseline values for each endpoint will be defined as the last scheduled data collection visit 
before beginning treatment according to the Schedule of Events (Table 2.1).  Dynamometry 
will be administered at the Screening visit to determine eligibility and introduce subjects to 
performance testing to minimize training effects and will not be used for analysis purposes. 
Efficacy analyses will be based on the Full Analysis Set.  Generalized estimating equation 
(GEE) analysis will be performed to assess the changes from baseline of all efficacy 
endpoints with repeated measurements. Baseline will be included as a covariate in the model.  
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.  All analyses and 
tabulations will be performed using SAS®.  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.  The 
final analysis will be conducted at Week 48. 
7.6.5 
Analyses of Drug Concentration Measurements 
The SA analysis set will be used to evaluate free serum SA levels . Changes from baseline 
will be analyzed using the GEE method for repeated measures analysis.  
7.6.6 
Safety Analyses 
The safety analysis set will be used for the analyses of all safety parameters.  Safety will be 
evaluated by the incidence, frequency and severity of AEs and SAEs, and also clinically 
significant changes from study baseline to scheduled time points during the course of the 
study in: 
• Concomitant medications 
• Physical examination results  
• Vital signs 
• Clinical laboratory results  
• Interval history 
• The C-SSRS  
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. A by-subject listing will be provided 
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for those subjects who experience a SAE, including death, or experience an 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.  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 IRB/Ethics Committee (EC) must be a properly constituted board or committee 
operating in accordance with 21 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 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 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 
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 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time.   
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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.   
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 
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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. 
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 
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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 two years after the last approval of a marketing 
application in the US or an ICH region and until:  1) there are no pending or contemplated 
marketing applications in the US or an ICH region, or 2) at least two years have elapsed since 
the formal discontinuation of clinical development of the investigational product under study.  
The Investigator/institution should retain subject identifiers for at least 25 years after the 
completion or discontinuation of the study.  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.  These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by an Ultragenyx agreement.  
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 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. 
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 
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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 collected from the time the subject signs informed consent through the 
Safety Follow-up TC or, if applicable, until the date the subject receives the first dose of 
study drug in the extension study, UX001-CL302, whichever occurs sooner. In addition, for 
those subjects choosing not to enroll in Study UX001-CL302, the Investigator should report 
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any AE they are made aware of that occurs after the Safety Follow-up TC and that is 
believed to have a reasonable possibility of being associated with study drug.  
AEs ongoing at the time of the Safety Follow-up TC or the date of the first dose of study 
drug in the extension study 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  the 
Safety Follow-up TC or, if applicable, until the date the subject receives the first dose of 
study drug in the extension study, UX001-CL302, whichever occurs sooner, 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 
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 suspected unexpected serious adverse reactions 
(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.  
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 Ace-ER, major 
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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 
Aitkens, S, Lord, J, Bernauer, E, Fowler, WM, Jr., Lieberman, JS, and Berck, P. 1989. 
"Relationship of manual muscle testing to objective strength measurements." Muscle 
Nerve 12 (3):173-177. 
Argov, Z, Caraco, Y, H., L, Pestronk, A, Shieh, P, Skrinar, A, Mayhew, J, Marinisi, J, and 
Kakkis, E. 2014. Oral sialic acid extended release (SA-ER) stabilizes upper extremity 
muscle strength in human GNE myopathy: A Phase 2 study. In 66th American 
Academy of Neurology Annual Meeting.  26 April - 3 May 2014, Philadelphia, PA. 
[abstract]. 
Argov, Z, and Yarom, R. 1984. ""Rimmed vacuole myopathy" sparing the quadriceps: A 
unique disorder in iranian jews." J Neurol Sci. 64 (1):33-43. 
Bardor, M, Nguyen, DH, Diaz, S, and Varki, A. 2005. "Mechanism of uptake and 
incorporation of the non-human sialic acid N-glycolylneuraminic acid into human 
cells." J Biol.Chem. 280 (6):4228-4237. 
Bohannon, RW. 1997. "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. 
Eisenberg, I, Avidan, N, Potikha, T, Hochner, H, Chen, M, Olender, T, Barash, M, Shemesh, 
M, Sadeh, M, Grabov-Nardini, G, Shmilevich, I, Friedmann, A, Karpati, G, Bradley, 
WG, Baumbach, L, Lancet, D, Asher, EB, Beckmann, JS, Argov, Z, and Mitrani-
Rosenbaum, S. 2001. "The UDP-N-acetylglucosamine 2-epimerase/N-
acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body 
myopathy." Nat.Genet. 29 (1):83-87. 
FDA. Draft Guidance 2012. Guidance for Industry: Suicidal Ideation and Behavior:  
Prospective Assessment of Occurrence in Clinical Trials (Draft), Available at: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf.  Accessed 07 Jul 
2013. 
Huizing, M, and Krasnewich, DM. 2009. "Hereditary inclusion body myopathy: a decade of 
progress." Biochim.Biophys.Acta 1792 (9):881-887. 
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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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. 
Mizusawa, H, Kurisaki, H, Takatsu, M, Inoue, K, Mannen, T, Toyokura, Y, and Nakanishi, 
T. 1987a. "Rimmed vacuolar distal myopathy. An ultrastructural study." J.Neurol. 
234 (3):137-145. 
Mizusawa, H, Kurisaki, H, Takatsu, M, Inoue, K, Mannen, T, Toyokura, Y, and Nakanishi, 
T. 1987b. "Rimmed vacuolar distal myopathy: a clinical, electrophysiological, 
histopathological and computed tomographic study of seven cases." J Neurol 234 
(3):129-136. 
Nalini, A, Gayathri, N, and Dawn, R. 2010. "Distal myopathy with rimmed vacuoles: report 
on clinical characteristics in 23 cases." Neurol India 58 (2):235-241. 
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. 
Nishino, I, Carrillo-Carrasco, N, and Argov, Z. 2015. "GNE myopathy: current update and 
future therapy." J Neurol Neurosurg Psychiatry 86 (4):385-392. 
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. 
Nonaka, I, Sunohara, N, Ishiura, S, and Satoyoshi, E. 1981. "Familial distal myopathy with 
rimmed vacuole and lamellar (myeloid) body formation." J Neurol Sci. 51 (1):141-
155. 
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. 
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. 
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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. 
Sadeh, M, Gadoth, N, Hadar, H, and Ben-David, E. 1993. "Vacuolar myopathy sparing the 
quadriceps." Brain 116 ( Pt 1):217-232. 
Sisto, SA, and Dyson-Hudson, T. 2007. "Dynamometry testing in spinal cord injury." 
J.Rehabil.Res.Dev. 44 (1):123-136. 
Sunohara, N, Nonaka, I, Kamei, N, and Satoyoshi, E. 1989. "Distal myopathy with rimmed 
vacuole formation. A follow-up study." Brain 112 ( Pt 1):65-83. 
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. 
 
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SAP_000.pdf: 
Study Number: UX001-CL203  
Clinical Study Report 
09 Jul 2018 
 
 
16.1.9 Documentation of Statistical Methods 
16.1.9.1 Statistical Analysis Plan 
Statistical Analysis Plan, V 1.0, dated 15 March 2017 
 
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Page 1


 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Title 
A Phase 2 Open-label study to Evaluate Safety of 
Aceneuramic Acid Extended Release (Ace-ER) Tablets in 
GNE Myopathy (GNEM) (also known as Hereditary 
Inclusion Body Myopathy (HIBM)) patients with Severe 
Ambulatory Impairment 
Protocol: 
UX001-CL203 
Protocol Version 
Amendment 1 (15 March 2017) 
Investigational  
Product: 
Aceneuramic Acid Extended Release (Ace-ER) 
Phase: 
2 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Author: 
 
Statistical Consultant, Biometrics 
Date: 
29 March 2017 
Version  
Number: 
1.0 
 
 
 
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UX001-CL203 
Statistical Analysis Plan 
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TABLE OF CONTENTS 
1 INTRODUCTION ...............................................................................................................7 
2 STUDY OBJECTIVE(S) .....................................................................................................8 
2.1 Primary Objective .......................................................................................................8 
2.2 Secondary Objective ...................................................................................................8 
2.3 Exploratory Objectives ...............................................................................................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 Sample Size Considerations ......................................................................................10 
3.5 Interim Analysis ........................................................................................................10 
4 STUDY ENDPOINTS AND COVARIATES ...................................................................11 
4.1 Primary Endpoints.....................................................................................................11 
4.2 Secondary Endpoints.................................................................................................11 
4.3 Exploratory Endpoints ..............................................................................................11 
4.4 Covariate(s) ...............................................................................................................12 
5 DEFINITIONS ...................................................................................................................13 
5.1 Baseline .....................................................................................................................13 
5.2 UX001 Treatment Start/END Date ...........................................................................13 
5.3 Derived Efficacy Variables .......................................................................................13 
5.3.1 
Predicted Normal HHD values ....................................................................13 
6 ANALYSIS POPULATIONS ...........................................................................................14 
6.1 Full Analysis Set .......................................................................................................14 
6.2 Safety Analysis Set ...................................................................................................14 
6.3 Sialic Acid Analysis Set ............................................................................................14 
7 DATA SCREENING AND ACCEPTANCE ....................................................................15 
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7.1 General Principles .....................................................................................................15 
7.2 Handling of Missing and Incomplete Data ...............................................................15 
7.2.1 
Missing Date of the Last Dose of Investigational Product ..........................15 
7.2.2 
Missing Medical History Related Dates (eg, diagnosis date) or Birth 
Date .............................................................................................................15 
7.2.3 
Missing Date Information for Adverse Events and Concomitant 
Medications .................................................................................................15 
7.2.4 
Missing Causal Relationship to Investigational Product for Adverse 
Events ..........................................................................................................16 
7.2.5 
Visit Time Windows ...................................................................................16 
7.3 Testing/Validation Plan.............................................................................................17 
7.4 Software ....................................................................................................................17 
8 STATISTICAL METHODS OF ANALYSES ..................................................................18 
8.1 General Principles .....................................................................................................18 
8.2 Repeated Measure Model: General Estimating Equations .......................................18 
8.3 Subject Disposition ...................................................................................................18 
8.4 Protocol Deviations ...................................................................................................18 
8.5 Demographic and Baseline Characteristics...............................................................18 
8.6 Disease Characteristics and Medical History............................................................19 
8.7 Extent of Exposure ....................................................................................................19 
8.8 Efficacy Analyses .....................................................................................................19 
8.8.1 
Dynamometry ..............................................................................................19 
8.8.2 
GNEM-FAS Expanded Version ..................................................................20 
8.9 Exploratory Analyses ................................................................................................20 
8.9.1 
Short Form - 36 Health Survey ...................................................................20 
8.9.2 
Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C) ...................................................................21 
8.9.3 
Biomarkers and Drug Concentration Measurements ..................................21 
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8.10 Safety Analyses .........................................................................................................22 
8.10.1 Adverse Events ............................................................................................22 
8.10.1.1 
Adverse Events to Monitor ..........................................................23 
8.10.2 Laboratory Parameters ................................................................................23 
8.10.3 Prior and Concomitant Medications ............................................................23 
8.10.4 Physical Examinations ................................................................................23 
8.10.5 Vital Signs ...................................................................................................24 
8.10.6 Interval History ............................................................................................24 
8.10.7 Suicidal ideation and behavior ....................................................................24 
8.10.8 Urine Testing for ManNAc .........................................................................24 
8.10.9 Pregnancy Test ............................................................................................24 
9 REFERENCES ..................................................................................................................25 
10 APPENDICES ...................................................................................................................26 
10.1 Efficacy Endpoints Definition Details ......................................................................26 
10.1.1 GNEM Functional Activities Scale Expanded Version ..............................26 
10.1.2 Short Form – 36 Item (SF-36) .....................................................................26 
10.2 Predicted HHD Normal Muscle Strength .................................................................28 
10.3 Missing Observation in Hand Held Dynamometry...................................................31 
10.4 SF-36 v2® Scoring Algorithm ...................................................................................33 
10.5 Schedule of Events ....................................................................................................37 
10.6 Summary of Efficacy Endpoints and Analyses.........................................................40 
10.7 Adverse Events to Monitor .......................................................................................41 
10.7.1 Gastrointestinal MedDRA Query ................................................................41 
10.7.2 Liver-Related Investigations .......................................................................42 
 
List of Figures 
Figure 3.1: 
Study Schema.........................................................................................9 
 
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ABBREVIATIONS 
6MWT 
six minute walk test 
Ace-ER 
Aceneuramic Acid Extended Release 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomic Therapeutic Classification 
CK 
creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
the Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
ECG 
electrocardiogram, electrocardiographic 
GEE 
generalized estimating equations 
GNE 
glucosamine (UDP-N-acetyl)-2-epimerase 
GNEM 
GNE myopathy 
HIBM 
hereditary inclusion body myopathy 
INQoL 
individual neuromuscular quality of life questionnaire 
IWRW 
interactive web randomization system 
MedDRA 
medical dictionary of regulatory activities 
MMRM 
mixed-effects model for repeated measures 
QIC 
Quasi-Likelihood Information Criterion 
PD 
pharmacodynamics 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetic 
PRO 
patient reported outcomes 
PT 
preferred term  
SA 
sialic acid 
SAE 
serious adverse event 
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SA-ER 
sialic acid-extended release 
SAP 
statistical analysis plan 
SI 
Le Système International d’Unités (International System of Units) 
SMQs 
Standardized MedDRA Queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse even 
 
 
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UX001-CL203 
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-CL203 original protocol dated 
04 December 2015 and protocol Amendment 1 dated 15 March 2017.  
The data collected in this study will be used to evaluate the safety of Aceneuramic Acid 
Extended Release (Ace-ER) Tablets in GNE Myopathy (GNEM) (also known as Hereditary 
Inclusion Body Myopathy (HIBM)) patients with Severe Ambulatory Impairment. 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. Should there be a difference between the 
SAP and the protocol with respect to analysis methods, the SAP will take precedence over 
the protocol. 
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2 STUDY OBJECTIVE(S) 
2.1 
Primary Objective 
Evaluate the safety of Ace-ER in GNEM subjects with severe ambulatory impairment. 
2.2 
Secondary Objective 
Evaluate the potential efficacy of 6 g/day of Ace-ER in GNEM subjects with severe 
ambulatory impairment. 
2.3 
Exploratory Objectives 
Evaluate the effect of 6g/day Ace-ER on health-related quality of life (HRQoL), patient 
reported outcomes (PRO), and biomarkers of sialyation.  
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3 STUDY DESIGN 
UX001-CL203 is an open-label, multicenter study to assess the safety of Ace-ER in GNEM 
patients with severe ambulatory impairment.  Efficacy will also be assessed as a secondary 
objective. Approximately 45 subjects will be enrolled in the study and receive 6 g/day of 
Ace-ER for 48 weeks.  
Subjects will take 4 tablets (500 mg each for 2 g per dose) orally 3 times per day (TID). 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 48 weeks.  Study visits will occur every 12 weeks during the 
Treatment Period during which the scheduled assessments will be administered as outlined in 
the Schedule of Events (Appendix 10.5). 
Safety will be evaluated by review of the incidence and frequency of AEs and SAEs, and 
clinically significant changes in interval history, physical examination results, vital signs, 
clinical laboratory test results, concomitant medications, and suicidal ideation and behavior 
(assessed using the Columbia Suicide Severity Rating Scale [C-SSRS]). 
Information on biomarkers will be collected to assess their value in predicting clinical 
severity and disease progression, as well as the ability to determine the long-term impact of 
disease-targeted treatments and therapies for GNEM. 
Efficacy will be evaluated by dynamometry as a measure of muscle strength and patient-
reported outcome measures as measures of physical functioning and quality of life.  
Figure 3.1 provides a schematic of the study design. The schedule of assessments is shown in 
Appendix 10.5. 
Figure 3.1: 
Study Schema 
 
 
 
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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) and meet the criteria for severe ambulatory impairment defined 
in protocol. 
3.2 
Dosage and Administration 
The 6 g/day Ace-ER dose has been selected. Individual subject participation in this study will 
be a maximum of 56 weeks, including up to 4 weeks between Screening and Baseline, 
48 weeks of treatment, and a Safety Follow-up Visit occurring 4 weeks after last study drug 
administration. 
3.3 
Blinding and Randomization Methods 
This is an open-label study and consists of one treatment arm. All subjects will be treated 
with Ace-ER 6 g/day. Randomization, blinding and stratification factors are not applicable in 
this study. 
3.4 
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. No study drug related 
SAE has been observed in previous clinical studies with Ace-ER. However, if it is assumed 
that the true rate of study drug related SAEs is 10% in this advanced patient population, there 
is at least 98% probability to observe one or more SAEs with N=45 subjects. Subjects who 
withdraw or are removed from the study after receiving study drug may be replaced on a 
case-by-case basis, at the discretion of Ultragenyx. This study is not powered to assess 
statistically significant changes from baseline in the efficacy endpoints. 
3.5 
Interim Analysis 
No interim analysis is planned for this study. 
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4 STUDY ENDPOINTS AND COVARIATES  
All data are collected according to the schedule of assessments (Appendix 10.5). 
4.1 
Primary Endpoints 
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. 
4.2 
Secondary Endpoints 
The secondary safety endpoints of the study are clinically significant changes from baseline 
to scheduled time points in: 
• Concomitant medications; 
• Physical examinations; 
• Vital signs,  
• Clinical laboratory results; 
• Interval history. 
The secondary efficacy endpoints of the study are changes from baseline over the duration of 
the study: 
• Changes from baseline in the total scores and scores on the mobility, self-care and upper 
extremity domains 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. 
4.3 
Exploratory Endpoints 
The exploratory endpoints of the study include health related QoL, patient reported outcomes 
and biomarkers as listed below: 
• 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 symptom severity score as measured by Patient Global 
Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) over 
the duration of the study; 
• Changes from baseline in serum biomarkers: creatine kinase (CK), serum SA, and 
potential biomarkers of sialylation and other markers of muscle injury and remodeling; 
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• Changes in free serum SA levels to assess the drug concentration in the bloodstream 
resulting from treatment; 
• Frequency and percentage of subjects with the presence of ManNac detected from urine 
testing. 
4.4 
Covariate(s) 
All models used for each individual clinical endpoint will incorporate the baseline value as a 
covariate. 
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5 DEFINITIONS 
5.1 
Baseline 
Baseline is defined as the last non-missing measurement taken prior to the first dose of study 
drug administration in CL203 study 
5.2 
UX001 Treatment Start/END Date 
The treatment start date is defined as the first dosing date of study drug recorded in the EDC 
database. The treatment end date is defined as the last dosing date of study drug recorded in 
the EDC database. For each subject, the total duration of study drug exposure is defined as 
the sum of exposures. 
5.3 
Derived Efficacy Variables 
5.3.1 Predicted Normal HHD values 
• HHD Individual Muscle Strength Average Score is calculated as the average of the 
right and left raw measurements in kg for an individual muscle group: individual muscle 
strength raw score = (left-side measurement + right-side measurement) / 2. If a value 
from the right or left side of an individual muscle group is missing, the missing value will 
be imputed using the non-missing value from the other side.  
• Predicted Normal HHD Values will be derived for the raw right/left strength values 
from the muscle groups: grip, key pinch, shoulder abductors, wrist extensors and knee 
extensors collected at Baseline using the regression equations outlined in Appendix 10.2. 
Predicted normal HHD scores for individual muscle raw score will use the same 
computation method for raw scores as described above but replace the observed values 
with the predicted normal HHD values.  
• % of Predicted Normal HHD Values for the individual muscle groups and composite 
scores will be calculated as follows:  (Observed Value / Predicted Normal HHD Value) 
*100%. Baseline predicted normal values will be used to derive % of predicted normal 
values for all post-baseline study time points. 
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6 ANALYSIS POPULATIONS 
6.1 
Full Analysis Set 
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 primary analyses of all efficacy 
endpoints. 
6.2 
Safety Analysis Set 
The safety analysis set consists of all enrolled subjects who receive at least one dose of study 
drug. This set will be used for the analyses of all safety endpoints. 
6.3 
Sialic Acid Analysis Set  
The SA analysis set will consist of all enrolled subjects with evaluable free serum SA levels. 
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7 DATA SCREENING AND ACCEPTANCE 
7.1 
General Principles 
Data will be reviewed periodically. Any questionable data will be reported to clinical data 
manager promptly. 
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 a review of tables and listings for this study.  Missing and incomplete data 
will be identified for investigation, and possible resolution, by Data Management prior to the 
study database lock. 
Missing or invalid safety events and assessments will not be imputed or replaced. Missing 
measurements in HHD individual muscle group test will be imputed as 0 if the reason for 
missing is due to weakness. When the measurement for one side is missing, the measurement 
from the other side will be used to impute the missing value. Details of missing observation 
handling in HHD are provided in Appendix 10.3. Other efficacy endpoints will not be 
imputed. 
7.2.1 Missing Date of the Last Dose of Investigational Product 
When the date of the last dose of investigational product is 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 Medical History Related Dates (eg, diagnosis date) or Birth Date 
• If only the day is missing, impute the day to first day of the month. 
• If day and month are missing, impute to the 1st January. 
• If year is missing, then no imputation will be done, the date will be missing. 
If the imputed date is earlier than birth date, then birth date will be used. 
7.2.3 Missing Date 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.   
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Missing Start Dates 
• If the day is unknown, then: 
 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. 
 Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
 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. 
 Otherwise, assign ‘January’  
• 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 double-blind 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 scheduled visits will be used for by-visit analyses.  If an unscheduled visit has to be 
used, the principle of proximity will be applied.   
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7.3 
Testing/Validation Plan 
Data will be reviewed by cross functional team periodically and issues will be addressed by 
clinical data management.  
7.4 
Software 
SAS® software version 9.4 or higher will be used to perform all statistical analyses. 
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8 STATISTICAL METHODS OF ANALYSES 
8.1 
General Principles 
The statistical analyses will be reported using summary tables, figures, and data listings. 
Statistical tests, if any, will be 2-sided at the 5% level of significance. All p-values will be 
presented as nominal p-values. No adjustment on multiplicity will be made. Confidence 
intervals will be 2-sided 95% confidence intervals, unless stated otherwise. 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. 
The final analysis will be conducted when all patients enrolled in the study have completed 
the Week 48 visit or have discontinued the study. 
8.2 
Repeated Measure Model: General Estimating Equations 
The efficacy endpoints are collected over time and  will be analyzed using a generalized 
estimation equation (GEE) model that includes time as the categorical variable and adjusted 
for baseline measurement. The covariance structure that will be used for the GEE model is 
compound symmetry which specifies constant variance for the assessments and constant 
covariance between the assessments over time. If the compound symmetry covariance 
structure leads to non-convergence, Quasi-Likelihood Information Criterion (QIC) will be 
used to select the best covariance structure. Model based estimates of the changes from 
baseline and corresponding 95% confidence intervals will also be provided along with 
p-values for assessing statistical significance.   
8.3 
Subject Disposition 
Subject disposition summaries will include the number of subjects who received study 
medication, the number of subjects who completed the study, and the reasons for study 
discontinuation. The number of subjects included in the safety, efficacy, and SA analyses, 
respectively, will be presented.  
8.4 
Protocol Deviations 
Protocol deviations will be listed. 
8.5 
Demographic and Baseline Characteristics 
The following key demographic and baseline factors will be summarized descriptively for the 
Full Analysis Set:  
• Gender 
• Age 
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• Ethnicity/Race 
• Age at diagnosis 
• Age at start of treatment 
• Height (cm) 
• Weight (kg) 
8.6 
Disease Characteristics and Medical History 
Disease characteristics and medical history of GNEM including GNEM symptoms, 
adaptations, assisted devices, orthotics, medications, and treatment history will be 
summarized for the Full Analysis Set. 
8.7 
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.   
Dosing compliance will also be summarized for the Safety Analysis Set. The compliance for 
each subject is defined as: 
Compliance = Total Dose Received / Total Dose Planned * 100%. 
8.8 
Efficacy Analyses 
For each efficacy endpoint, summary statistics will be reported at each visit for the observed 
measures and their respective changes from baseline. 
The efficacy endpoints measured over time will be analyzed using GEE using the Full 
Analysis Set. Changes from baseline will be the dependent variable, and baseline, visit will 
be the independent variables in the model. All efficacy endpoints were assessed at Baseline, 
Week 12, Week 24, Week 36, and Week 48. 
8.8.1 
Dynamometry 
Hand held dynamometry testing of multiple muscle groups will be used to measure strength. 
Test administration at the Screening visit is intended to provide experience and familiarize 
the subject with the assessments for the evaluator and the subject and data collected will not 
be used for analysis. The maximum voluntary isometric contraction (MVIC) against a 
dynamometer will be used to measure bilateral strength in the following muscle groups: 
shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the 
measurement of grip and key pinch strength will also be used. The total force (in kg) for each 
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 
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after the testing using published normative data (Appendix 10.2). Missing measurements in 
dynamometry will be handled according to specified rules in the Appendix 10.3. 
8.8.2 
GNEM-FAS Expanded Version 
The original GNEM-FAS was developed as a clinician-reported outcome measure (ClinRo) for 
ambulatory GNEM patients but has since been modified to include additional items to 
accommodate weaker patients. This modified version is referred to as the GNEM-FAS Expanded 
Version and will be used in this study. The scale consists of 3 domains: upper extremity, 
mobility, and self-care; scores for each domain and a total score will be calculated. Test 
administration at Screening Visit is intended as practice for the evaluator and the subject, and 
data collected will not be used for analysis. The GNEM-FAS Expanded Version used in this 
study is a modified version of the original GNEM-FAS with added questions to 
accommodate weaker patients.  Three items regarding sitting ability were added to mobility 
domain; one item of picking up small items was added to upper extremity domain; and one 
item of chewing and swallowing was added to self-care domain. 
8.9 
Exploratory Analyses 
The exploratory endpoints of the study include health related QoLs (SF-36v2, PGI-S and 
PGI-C) and biomarkers. The exploratory efficacy analyses will be mostly performed in 
descriptive statistics.  Analysis for SF-36v2can be performed in a similar fashion as 
described for secondary efficacy analyses if appropriate.  
8.9.1 
Short Form - 36 Health Survey 
The Short Form -36 Health Survey (SF-36v2) version 2 is a validated 36-item questionnaire 
that yields an 8-domain scale scores and two component summary measures of health-related 
quality of life. It will be evaluated at Baseline, Week 12, Week 24, Week 36, and Week 48. 
The domain scales are as follows:  
• Physical Functioning (PF): Items 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j .   
• Role-Physical (RP): Items 4a, 4b, 4c, 4d.   
• Bodily Pain (BP): Items 7, 8.   
• General Health (GH): Items 1, 11a, 11b, 11c, 11d.   
• Vitality (VT): Items 9a, 9e, 9g, 9i.   
• Social Functioning (SF): Items 6, 10.   
• Role-Emotional (RE): Items 5a, 5b, 5c.   
• Mental Health (MH): Items 9b, 9c, 9d, 9f, 9h 
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The overall summary measures are as follows: 
• Physical Health Component Score (PCS): domain scales PF, RP, BP, GH.   
• Mental Health Component Score (MCS): domain scales VT, SF, RE, MH. 
Descriptive summary statistics and GEE modeling will be presented for the eight scale scores 
and PCS and MCS component scores at each time point as well as the change from baseline. 
8.9.2 
Patient Global Impression of Severity (PGI-S) and Patient Global Impression of 
Change (PGI-C) 
The PGI-S/PGI-C is a self-administered tool widely used in chronic pain clinical trials to 
indicate the patient’s perception about the efficacy of treatment. The PGI-S is conducted at 
baseline and patient rates the severity of his/her condition on a 7-point categorical scale; the 
PGI-C is conducted at follow-up visits and a patient rate the change of his/her condition on a 
7-point categorical scale. The scales are presented in the table below.  
Summary statistics of baseline PGI-S will be reported. The number and percentage of 
subjects in each category of PGI-S will also be reported. For PGI-C, both summary statistics 
and GEE estimates will be presented for each time point. 
PGI-S 
PGI-C 
1=Normal, not affected at all  
2=Borderline affected 
3=Mildly affected 
4= Moderately affected 
5=Markedly affected  
6=Severely affected  
7=Extremely affected 
-3=Very much worse 
-2=Much worse 
-1=Somewhat worse 
0=No change 
+1=Somewhat better 
+2=Much better 
+3=Very much better 
 
8.9.3 
Biomarkers and Drug Concentration Measurements 
Serum Creatine Kinase (CK), serum SA, and urine ManNAc will be collected at baseline, 
week 12, week 24, week 36, and week 48 or termination visit.  
• Free SA: Free SA levels in serum assess the drug concentration in the bloodstream 
resulting from treatment and are the best indicator of compliance with the treatment 
regimen.  Free SA levels in serum are expressed in micrograms of SA per ml of serum 
• 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. 
• Presence of ManNAc: To detect noncompliance with prohibited medication restrictions 
during the study period. 
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The changes from baseline will be summarized and analyzed for the duration of the treatment 
using GEE. 
8.10 Safety Analyses 
Adverse event (AE) serves the primary endpoint of the study. Secondary endpoint of Safety 
Analysis summarizes clinically significant changes from baseline to scheduled time points in: 
• Vital signs; 
• Concomitant medications; 
• Physical examination findings; 
• Clinical laboratory evaluations; 
• Interval history; 
• Suicidal ideation and behavior assessments. 
Safety endpoints will be analyzed by using descriptive statistics in the Safety Analysis Set. 
8.10.1 Adverse Events 
The following AEs will be collected: 
• All AEs; 
• All SAEs; 
• Treatment-related AEs; 
• Treatment-related SAEs; 
• AEs leading to the discontinuation of study drug or discontinuation of study; 
• Deaths. 
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 number and proportion of subjects with any treatment-emergent adverse events (TEAEs) 
(defined as any AE occurred 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. 
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. 
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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. 
8.10.1.1 Adverse Events to Monitor 
Adverse events to be monitored are included in Appendix 10.7 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. 
8.10.2 Laboratory Parameters 
Clinical laboratory data will be summarized descriptively by the type of laboratory test and 
by time point. 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 reported by shift tables. 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. 
8.10.3 Prior and Concomitant Medications 
Prior medication is defined as any medication started before the date of the first dose of 
investigational product. Concomitant medication is defined as any medication taken on or 
after the date of the first dose of investigational product. Any concomitant medications 
started after the date of the last dose of investigational product will not be presented in the 
summary tables but will be included in the subject data listings. 
Each medication will be coded to a preferred name and an Anatomic Therapeutic 
Classification (ATC) code using WHODrug. The number and percentage of subjects taking 
each concomitant medication will be displayed by preferred name. 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. Prior and 
concomitant medications will be listed. 
8.10.4 Physical Examinations 
Physical examinations will be performed at baseline, week 12, week 24, week 36, and week 
48 or termination visit. At baseline and week 48, a full physical examination will be 
conducted including a neurological examination. A brief physical examination will be 
conducted at other visits. The full examination assesses the general appearance, HEENT, 
cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, and musculoskeletal; 
the brief physical examination assesses the general appearance, cardiovascular, and 
respiratory; the neurological examination assesses the cognition, cranial nerves, motor 
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function, coordination and gait, reflexes, and sensory function. Full physical and neurological 
examinations will be summarized using shift tables. Results from brief physical examinations 
will be listed. 
8.10.5 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 and will be reported in a listing. 
8.10.6 Interval History 
Each interval history is intended to record 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 identify under-reported 
AEs. Interval history for all subjects will be reported in a listing.   
8.10.7 Suicidal ideation and behavior 
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 (Posner et al. 2011) 
and will be administered at each visit.  The C-SSRS will be listed.  
8.10.8 Urine Testing for ManNAc 
ManNAc will be assessed at each visit to detect noncompliance with prohibited medication 
restrictions. The ManNAc results for all subjects in the Safety Analysis Set will be reported 
in listing format. 
8.10.9 Pregnancy Test 
Pregnancy test will be conducted at each study visit and the results will be provided in a 
listing. 
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9 REFERENCES 
Bohannon, RW. 1997. "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. 
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. 
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. 
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10 APPENDICES 
10.1 Efficacy Endpoints Definition Details 
10.1.1 GNEM Functional Activities Scale Expanded Version 
The GNEM-FAS (also referred to as HIBM-FAS in some studies) expanded version 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 GNEM-FAS expanded version will 
be administered at each visit beginning with the Screening Visit to evaluate physical 
functioning. Test administration at the Screening visit is intended to provide experience and 
familiarize the subject with the assessments for the evaluator and the subject, and data 
collected will not be used for analysis.  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 original GNEM-FAS was developed as a clinician-reported outcome 
measure (ClinRo) for ambulatory GNEM patients but has since been modified to include 
additional items to accommodate weaker patients.  This modified version is referred to as the 
GNEM-FAS Expanded Version and will be used in this study.  
GNEM Functional Activities Scale (GNEM-FAS) Expanded Version Total Score will be 
calculated as the sum of the Total Scores range from 0 to 120 with higher scores representing 
greater independence with functional activities. Subscale scores will be calculated for the 
Mobility, Upper Extremity and Self-Care domains.  Mobility subscale scores have 13 items 
and range from 0 to 52 with higher scores representing greater mobility.  Upper Extremity 
subscale scores have 9 items and range from 0 to 36 with higher scores representing more 
skilled, independent use of the arms during functional activity performance.  Self-Care 
subscale scores have 8 items range from 0 to 32 with higher scores representing greater 
independence with functional care activities. The maximum possible for the total score is 
120.  
10.1.2 Short Form – 36 Item (SF-36) 
The SF 36 will be completed by subjects at each visit beginning with the Baseline Visit 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 scale and component scores will be calculated according to the standard scoring 
algorithm published along with the SF-36 (Ware et.al. 1995 and Ware et.al. 2007). The z 
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scores of domain scales will be aggregated to generate the component scores PCS and MCS 
using weights derived from the U.S. general population. The component scores will be scaled 
to have a mean of 50 and standard deviation of 10 using a linear transformation. The 
component scores will not be calculated unless all relevant domain scale scores are available. 
Details of the scoring algorithm can be found in Appendix 10.4. 
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10.2 Predicted HHD Normal Muscle Strength 
Muscle strength of interest for this study includes grip, key pinch, shoulder abductors, wrist 
extensors, and knee extension. 
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. 
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 
(Bohannon 1997) 
*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 for all study time points. 
Gross Grip 
Normative grip strength values for the Jamar dynamometer for clinical use (in pounds) 
Age 
(years) 
Females (n = 355) 
Males (n = 365) 
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. 
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Wrist extension (Bohannon 1997) 
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10.3 Missing Observation in Hand Held Dynamometry 
Missing observations in HHD 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 
 
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 a joint 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 strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
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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 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 injury.  
• 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 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 evaluator and 
a valid value could not be obtained. 
• 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 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 strength for this muscle group.  The muscle group IS 
counted as part of the UE or LE composite. 
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10.4 SF-36 v2® Scoring Algorithm 
Prior to any summary scores being calculated, ten items in the questionnaire will be re- coded 
according to the developer's instructions as follows:  
 
Response Choices 
Pre-coded Item Value 
Final 
Item 
Value 
Item1 
Excellent 
1 
5.0 
 
Very Good 
2 
4.4 
 
Good 
3 
3.4 
 
Fair 
4 
2.0 
 
Poor 
5 
1.0 
Item 6 
Not At All 
1 
5 
 
Slightly 
2 
4 
 
Moderately 
3 
3 
 
Quite A Bit 
4 
2 
 
Extremely 
5 
1 
Item 7 
None 
1 
6.0 
 
Very Mild 
2 
5.4 
 
Mild 
3 
4.2 
 
Moderate 
4 
3.1 
 
Severe 
5 
2.2 
 
Very Severe 
6 
1.0 
Item 8 
If both item 7 and 
item 8 are answered 
Item 8 pre-coded value 
Item 7 pre-coded value 
 
 
Not At All 
1                                                                  1 
6 
 
Not At All 
1                                                 2 through 6 
5 
 
A Little Bit 
2                                                 2 through 6 
4 
 
Moderately 
3                                                 2 through 6 
3 
 
Quite A Bit 
4                                                 2 through 6 
2 
 
Extremely 
5                                                 2 through 6 
1 
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Response Choices 
Pre-coded Item Value 
Final 
Item 
Value 
Item 8 
If Item 7 is not 
answered 
 
 
 
Not At All 
1 
6.0 
 
A Little Bit 
2 
4.75 
 
Moderately 
3 
3.5 
 
Quite A Bit  
4 
2.25 
 
Extremely  
5 
1.0 
Item 9a, 9d, 
9e and 9h 
All Of The Time 
1 
6 
Most Of The Time 
2 
5 
A Good Bit Of The 
Time 
3 
4 
Some Of The Time 
4 
3 
A Little Of The Time 
5 
2 
None Of The Time 
6 
1 
Item 11b and 
11d 
Definitely True 
1 
5 
Mostly True 
2 
4 
Don't Know 
3 
3 
Mostly False 
4 
2 
Definitely False 
5 
1 
 
Upon appropriate re-coding of individual items, the raw scale score will be calculated as the 
average score over non-missing items in that scale and scaled between 0 and 100, with higher 
score representing better health status. The raw scale score will not be calculated unless 
≥ 50% of relevant questions are answered in a scale domain.  
The raw scale scores will be computed by taking the sum of the items for that particular 
scale. Each raw scale score will then be transformed to a 0 to 100 scale using the following 
formula: 
Transformed Scale = [Actual raw score - Lowest possible raw score] x 100 
 
Possible raw score range 
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This information is summarized in the following table. 
Formulae for Scoring and Transforming Scales 
Scale 
Sum Final Item Values 
Lowest And Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Physical Functioning (PF) 
3a + 3b + 3c + 3d + 3e + 
3f + 3g + 3h + 3I + 3j 
10, 30 
20 
Role-Physical (RP) 
4a + 4b + 4c + 4d 
4, 8 
4 
Bodily Pain (BP) 
7 + 8 
2, 12 
10 
General Health (GH) 
1 + 11a + 11b + 11c + 11d 
5, 25 
20 
Vitality (VT) 
9a + 9e + 9g + 9i 
4, 24 
20 
Social Functioning (SF) 
6 + 10 
2, 10 
8 
Role-Emotional (RE) 
5a + 5b + 5c 
3, 6 
3 
Mental Health (MH) 
9b + 9c + 9d + 9f +9h 
5, 30 
25 
 
A norm-based z score for each scale will then be computed using the U.S. general population 
data for each scale score. 
 
The z-scores for the raw scales will be combined to form the two raw summary scores by 
multiplying each one by its corresponding scoring coefficient from the general U.S. 
population and taking the sum of those values.  
 
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The general U.S. population means, standard deviations, and scoring coefficients are 
summarized in the following table: 
 
Finally, the PCS and MCS will be standardized as follows: 
PCS = (AGG_PHYS x 10) +50 
MCS = (AGG_MENT x 10) +50 
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10.5 Schedule of Events 
 
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10.6 Summary of Efficacy Endpoints and Analyses 
Test / Instrument 
Endpoint 
Type of 
analysis 
Time points for 
Assessment 
Statistical 
approach at 
week 48/ET 
analysis 
GNEM Functional 
Activities Scale 
(GNEM-FAS) – 
Expanded Version 
Change from baseline in  
GNEM-FAS Expanded Version 
total score and mobility, upper 
extremity and self-care domain 
scores from baseline over the 
duration of the study 
Secondary 
efficacy 
analysis 
Baseline,  
Weeks 12, 24, 36, 
and 48 
GEE Model / 
Descriptive 
statistics 
Physical therapy – 
Hand-held 
Dynamometry 
(HHD) 
Change from baseline in upper 
extremity strength in the 
following muscle groups: grip, 
key pinch, shoulder abductors and 
wrist extensors over the duration 
of study 
Secondary 
efficacy 
analysis 
Baseline,  
Weeks 12, 24, 36, 
and 48 
GEE Model / 
Descriptive 
statistics 
Change from baseline in lower 
extremity muscle strength in the 
knee extensors as measured by 
HHD over the duration of the 
study 
% of Predicted Normal HHD 
Values 
Medical Outcome 
Survey – 36 Items 
(SF-36) 
Change in health-related quality 
of life as assessed by using SF-36 
over the duration of the study 
Exploratory 
efficacy 
analysis 
Baseline,  
Weeks 12, 24, 36, 
and 48 
GEE Model / 
Descriptive 
statistics 
Patient Global 
Impression of 
Severity & Change 
(PGI-S & PGI-C) 
Change in symptom severity as 
measured by PGI-S (baseline 
only) and PGI-C over the duration 
of the study 
Exploratory 
efficacy 
analysis 
Baseline,  
Weeks 12, 24, 36, 
and 48 
Descriptive 
statistics 
 
 
 
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10.7 Adverse Events to Monitor 
10.7.1 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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10.7.2 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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