Clinical trial NCT02377921
Conditions: Hereditary Inclusion Body Myopathy Distal Myopathy With Rimmed Vacuoles Distal Myopathy, Nonaka Type GNE Myopathy
Keywords: GNE Myopathy GNEM HIBM Nonaka Hereditary Inclusion Body Myopathy DMRV
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2015-05-20; Completion date: 2017-06-09
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the effect of 6 g/day aceneuramic acid extended-release (Ace-ER) treatment of participants with GNEM on upper extremity muscle strength (upper extremity composite \[UEC\] score) as measured by dynamometry.

Detailed description:

Arms: arm 1: Ace-ER 6 g/day, divided 3 times per day (TID) for 48 weeks. arm 2: Matching placebo TID for 48 weeks.
Interventions: intervention 1: aceneuramic acid extended-release (Ace-ER) intervention 2: Placebo
Intervention descriptions: intervention 1: tablets for oral use intervention 2: tablets for oral use

Protocol documents:
Prot_000.pdf: 
 
 
 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Sialic Acid Extended-Release Tablets in Patients with 
GNE Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM) 
                                   
Protocol Number:       
UX001-CL301 
                                      
Original Protocol:      
22 January 2015 
                                           Amendment 1:            
16 March 2015 
 
Amendment 2:            
23 September 2015 
 
Amendment 3 (Italy):      16 December 2015 
 
Amendment 4:  
25 March 2016 
Amendment 5:  
25 May 2017 
 
Investigational Product: 
Sialic Acid Extended-Release (SA-ER) Tablets 
Indication: 
Treatment of GNE myopathy (GNEM), also known as 
hereditary inclusion body myopathy (HIBM), distal myopathy 
with rimmed vacuoles (DMRV), or Nonaka disease 
IND/EudraCT Number: 
109,334 / 2014-005432-33 
Sponsor: 
Ultragenyx Pharmaceutical Inc.  
60 Leveroni Court 
Novato, CA  94949 USA 
Sponsor’s Responsible 
 
 
Medical Officer: 
Senior Medical Director 
  
 
Coordinating Investigator:    
 
 
 
 
 
 
 
 
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), and 
applicable regulatory requirements. 
Confidentiality Statement:  This document and the information it contains is confidential and proprietary and 
is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx).  Unauthorized disclosure, reproduction, 
transmission, or use of this document or information is strictly prohibited.  By accepting this document, the 
recipient agrees that the information it contains will not be disclosed without written authorization from 
Ultragenyx, except to the extent required to satisfy Institutional Review Board /Ethics Committee procedures, to 
obtain written informed consent from potential subjects, or as required by law. 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL301 Amendment 1 
16 March 2015 
 
 
The Protocol UX001-CL301 (dated 22 January 2015) has been modified by Amendment 1 
based on additional information acquired since the beginning of the study and review by 
Health Authorities.  The changes to the protocol impacting the conduct of the study are 
summarized below.  Additional changes may have also been made to provide supportive 
information and rationale for the proposed changes (along with minor edits and corrections 
for consistency and clarity) but are not detailed in this summary. 
1. Inclusion Criterion 7 (synopsis and Section 7.3.1) was updated to state that 
participants of child‐bearing potential or with partners of child-bearing potential must 
consent to use a highly effective method of contraception. A similar change was made 
in Section 7.5.5.7. The abstinence language in Section 7.5.5.7 and in Inclusion 
Criterion 7 was also updated. 
Rationale:  This change was made to clarify the contraception language and further 
clarify the definition and required duration of abstinence required for inclusion in 
this study. 
 
2. Stopping Rules in Section 7.3.3.1 were updated to state that Regulatory Authorities, 
as well as Institutional Review Boards (IRBs) and Ethics Committees (ECs), will be 
informed should unexpected and possibly, probably, or definitely drug-related SAEs 
occur and/or if the study is paused or stopped per recommendation from the Data 
Monitoring Committee (DMC). Language was also added stating that, if paused or 
stopped, the trial will only be restarted following approval by Regulatory Authorities.  
Rationale: This change was made to clearly convey that Regulatory Authorities will 
be contacted if any of the above occurs during the course of this study. 
3. Section 7.5.5.8 was updated to include language that if emergent suicidal ideation or 
behavior is indicated upon review of the Columbia Suicide Severity Rating Scale 
(C-SSRS), the investigator should promptly evaluate the subject to ensure proper 
management and protection of subject safety. 
Rationale: The change was made to ensure subject safety. 


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4. Multiple sections of the protocol (Sections 8.5.1, 8.5.4, and 8.5.5) have been updated 
to define the Sponsor’s responsibilities with regard to reporting SAEs/SUSARs. 
Rationale: These changes were made in accordance with European Directive 
2001/20/EC. 
 
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL301 Amendment 2 
23 September 2015 
 
The Protocol UX001-CL301 Amendment 1 (dated 16 March 2015) has been modified by 
Amendment 2 to add the name of the Coordinating Principal Investigator, to extend the upper 
age limit for study inclusion, and to allow for leftover biological samples to be used for 
future research acquired since the beginning of the study. The major changes to the protocol 
are summarized below.   
1. Inclusion Criterion 1 (synopsis and Section 7.3.1) was updated to increase the upper 
age limit from 50 to 55.  
Rationale:  This change was made based on feedback from the sites regarding 
symptomatic patients who were above the original upper limit of 50 years of age.  
 
2. Section 7.5.5.6  was updated to clarify that leftover biological samples (from the 
protocol-specified blood and urine requirements) may be used for future research, 
including but not limited to biomarker research.  
Rationale: This change was made to clarify that leftover volume of blood and urine 
samples may be used for future research purposes.  
 
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL301 Amendment 4 
25 March 2016 
 
The Protocol UX001-CL301 Amendment 2 (dated 23 September 2015) has been modified by 
Amendment 3 (Italy) to provide additional rationale on the selection of the endpoints for this 
study, as requested by Agenzia Italiana del Farmaco (AIFA), and Amendment 4 to 
harmonize the study protocol with the Italy-country specific amendment, to clarify the 
frequency of DMC meetings, to clarify the assessments that will be conducted at Screening, 
to clearly define the safety follow-up call, and to clearly define safety reporting requirements. 
The major changes to the protocol are summarized below.   
1. Synopsis, Data Monitoring Committee (Section 7.6.7), and Review of Safety Data 
(Section 8.5.5.1) were updated to indicate that DMC meetings will occur at least two 
times per year instead of quarterly.  
Rationale:  This change was made to align the meeting frequency between the 
protocol and the DMC Charter.   
2. Schedule of Events (Table 2.1) was updated to remove the Free, Total and Bound 
Urine SA Levels from the Screening Visit. Drug Concentrations Measurements 
(Section 7.5.3) was also updated to reflect this change. 
Rationale:  This change was made to clarify the visits when drug concentration 
measurements will be conducted. The total volume of the first morning void is needed 
to calculate Urine SA levels and cannot be assessed at the Screening Visit.    
3. Schedule of Events (Table 2.1), Footnote g was updated to clarify how the urine 
sample for ManNAc testing will be collected. Urine Testing for ManNAc 
(Section 7.5.4) was also updated to reflect this change. 
Rationale:  This change was made to clarify that the urine for this test will come from 
the urinalysis sample, rather than from the first morning void.   
4. Schedule of Events (Table 2.1) and Selection of Doses and Study Duration 
(Section 7.4.3) were updated to reflect the safety-follow up visit is to be conducted by 
phone, including clarifications around the Safety Follow-Up Call. Based on this 
change, the assessments to be conducted at this visit and Footnote c were updated to 
indicate that the safety follow-up call is 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 the extension study, UX001-CL302. Information on any ongoing or new AEs, 
serious adverse events (SAEs), and concomitant medications will be collected in this 
phone call.  


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Rationale:  This change was made to clarify the safety follow-up call assessments.   
5. Discussion of Study Design, Including Choice of Control Group (Section 7.2) was 
updated to include additional rationale for the 6-minute walk test (6WMT) as a 
secondary endpoint.  
Rationale:  This change was made based on feedback from AIFA.   
6. List of Abbreviations and Definition of Terms (Section 4) was updated to include TC, 
defined as telephone call.  
Rationale:  This addition was made to ensure the List of Abbreviations is complete. 
7. Removal of Subjects from Therapy or Assessment (Section 7.3.3), Adverse Events 
(Section 7.5.5.10), Adverse Event Reporting, General (Section 8.5.4.1), Serious 
Adverse Events, Serious Adverse Drug Reactions, and Requirements for Immediate 
Reporting (Section 8.5.4.2), Adverse Drug Reaction Reporting (Section 8.5.5.2), and 
Urgent Safety Measures (Section 8.5.6) were updated to clarify the end of the data 
collection period for safety reporting events based on the change to the Safety 
Follow-Up Call (refer to Summary of Change #4 above).  
Rationale:  This change was made to clarify the safety follow-up period for all 
subjects who take part in the study.  
8. Study Schedule (Section 7.5.1) was updated based on the change to the Safety 
Follow-Up Call (refer to Summary of Change #4 above) and to clarify that Screening 
procedures may take place across multiple days to allow enough time to complete all 
procedures and confirm initial subject eligibility.  
Rationale:  This change was made to clarify the study periods and requirements for 
the Safety Follow-Up Call.  
9. Dynamometry (Section 7.5.2.1) was updated to clarify the number of test attempts 
that will be administered for each muscle group (three versus up to three). For data 
analysis, the highest value (rather than an average of the three values) will still be 
utilized as was specified in the original protocol.     
Rationale:  The change was made to ensure standardization in the number of 
dynamometry attempts to be administered per muscle group.   
10. Dynamometry (Section 7.5.2.1) was updated to remove an outdated reference for 
normative grip strength data.  
Rationale:  This deletion was made as the Peters et al 2011 reference is the 
appropriate reference for normative grip strength data.  
11. Six Minute Walk Test (Section 7.5.2.5) was updated to clarify the six-minute walk 
test administration for this protocol.  


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Rationale:  This update was made to ensure consistency across testing sites.  
12. Table 7.5.5.6.1 and Clinical Laboratory Tests for Safety (Section 7.5.5.6) were 
updated to clarify the analytes that will be tested in the urinalysis (added blood and 
leukocyte esterase) and to clarify that microscopic evaluation will be conducted for 
abnormal urine test results.  
Rationale:  The change was made to clarify the analytes that will be tested in 
urinalysis and confirm that microscopic evaluation will be conducted for abnormal 
test results.      
13. Volume of Blood to Be Drawn from Each Subject (Section 7.5.5.6.1) and 
Table 7.5.5.6.1.1 were updated to clarify the volume of blood that will be drawn for 
the serum sialic acid tests, to reduce the number of chemistry and hematology 
samples obtained, and to clarify the overall volume of blood that will be obtained 
during the study. The total mL of blood collected through study completion was 
increased from 108.5 mL to 119.0 mL. 
Rationale:  The change was made to clarify the total blood volume required to ensure 
a primary and back-up serum sialic acid sample are obtained and also to clarify the 
total volume of blood to be obtained during the study.  
14. Individual Neuromuscular Quality of Life Questionnaire (Section 7.5.2.6) was 
updated to provide guidance on administering the test to subjects when the scale is 
not available in the subject’s native language.  
Rationale:  This addition was made to clarify that the questionnaire is not to be 
administered to subjects when a validated version of the scale is not available in the 
subject’s native language.  
15. Pregnancy Testing (Section 7.5.5.7) was updated to remove the reference to a 
pregnancy test at the Safety Follow-Up Visit.  
Rationale:  Since the safety follow-up visit is now a safety follow-up call, the final 
pregnancy test will be at the Week 48 visit.  
16. Populations Analyzed (Section 7.6.3) was updated to match the definition of the 
Sialic Acid Analysis Set between the synopsis and the protocol body (i.e., urine SA 
levels was added to Section 7.6.3).  
Rationale:  This update was made to ensure consistency between the synopsis and the 
main body of the protocol.   
17. Subject Information and Consent (Section 8.1.3) was modified to remove the 
requirement for assent from subjects under the age of 18.  
Rationale:  This change was made since the text is not applicable due to the protocol 
minimum age requirement.  


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18. Safety Contact Information (Section 8.5.7) was updated with the correct email 
address for the Medical Monitor.  
Rationale:  This change was made to provide the correct email address for the 
Medical Monitor.   
19. References (Section 9) was updated to remove the outdated normative grip strength 
data reference.  
Rationale:  This deletion was made to align the reference list with the text of the 
protocol.  
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL301 Amendment 5 
25 May 2017 
 
Protocol UX001-CL301 Amendment 4 (dated 25 March 2016) has been modified by 
Amendment 5 to align the order of the study objectives and identification of key secondary 
endpoints between the Protocol and the Statistical Analysis Plan (SAP) documents as 
requested by the US Food and Drug Administration. In addition, the Protocol’s planned 
statistical analyses were updated to include multiplicity adjustment for the 3 key secondary 
clinical efficacy endpoints, and to include geographic region and gender as covariates for the 
primary clinical efficacy endpoint. Minor edits and typographical corrections were also 
made. Important changes to the protocol are summarized below.   
1. Study Objectives. In Section 6, the study objectives have been modified to designate 
3 secondary objectives as “key” secondary objectives. These 3 secondary objectives 
are To evaluate the effect of 6 g/day of SA-ER treatment of subjects with GNEM on 
the following: 
• Lower extremity composite muscle strength score as measured by dynamometry  
• Muscle strength in the knee extensors as measured by dynamometry  
• Physical functioning as measured using the GNEM-FAS mobility domain score 
Rationale: These changes to study objectives were made to ensure the consistency in 
the designation of objectives between the Protocol and the SAP and to clearly identify 
the key secondary objectives for the study that represent muscle strength and physical 
functioning. 
2. Secondary Efficacy Endpoints: In Section 7.6.4.2.1 and related sections, 
3 secondary clinical efficacy endpoints were designated as “key” secondary 
endpoints. These include the following:  
• Lower extremity composite (LEC) score based on a sum of the mean bilateral 
strength recorded in the following muscle groups: knee flexors, hip flexors, hip 
extensors, hip abductors, and hip adductors  
• Muscle strength in the knee extensors: bilateral total force (in kg)  
• GNEM-FAS mobility domain score 
Percent predicted muscle strength in the knee extensors was previously included as a 
secondary endpoint (in addition to total force) and is now listed separately as a 
tertiary endpoint. 
Rationale: These changes were made to ensure the consistency of the Protocol and 
the SAP documents. Those secondary endpoints designated as “key” represent both 
muscle strength and physical functioning and represent key aspects of GNEM 
disease. 


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3. Statistical Analysis: In Section 7.6.4.2.1, text was added to indicate that Hochberg’s 
adjustment for multiplicity will be applied for the 3 key secondary endpoints. 
In addition, geographic region and gender were added as covariates for the primary 
efficacy analysis. 
Rationale: These changes were made to align the Protocol with the SAP. The addition 
of Hochberg’s multiplicity adjustment for the 3 key secondary endpoints was 
implemented to provide increased statistical rigor (reduced risk for type I statistical 
errors) with the testing of multiple hypotheses. The second change, addition of region 
and gender as covariates, was made to account for potential heterogeneity of the 
disease in different regions due to genetic variations and to account for potential 
differences in muscle strength between males and females. 
4. Urinary Sialic Acid Assessment: In Section 6 and Section 7.5.3, the language 
regarding urinary SA as a tertiary objective and its assessment has been modified. 
Urinary SA will be measured but will not be used as a determination of SA-ER 
absorption, excretion, and pharmacodynamics.  
Rationale: Because formal pharmacokinetics analyses are not being performed in the 
study, urinary SA levels will have limited use as measures of absorption, excretion, 
and pharmacodynamics.  


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2 SYNOPSIS 
TITLE OF STUDY: 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety 
of Sialic Acid Extended-Release Tablets in Patients with GNE Myopathy (GNEM) or Hereditary 
Inclusion Body Myopathy (HIBM) 
PROTOCOL NUMBER: 
UX001-CL301 
STUDY SITES: 
Approximately 15 sites, globally 
PHASE OF DEVELOPMENT: 
Phase 3 
RATIONALE: 
GNEM (or HIBM), is a severe, progressive myopathy caused by a defect in the biosynthetic pathway 
for sialic acid (SA).  Substrate replacement is a potential therapeutic strategy based on the success of 
replacing missing SA and reducing muscle disease in a relevant mouse model of the human disease. 
Successful use of SA replacement therapy in humans is believed to depend upon providing steady, 
long-term exposure to the compound in an extended-release form (such as SA-extended release 
[SA-ER]), given SA’s short half-life.  A Phase 2, placebo-controlled study evaluating SA-ER at 
2 doses for 48 weeks found that the higher dose of 6 g/day SA-ER stabilized a composite of upper 
extremity muscle strength (UEC score) compared with placebo or the lower 3 g/day dose; this finding 
was supported by measurements of functional outcome on the GNE Myopathy Functional Activities 
Scale (GNEM-FAS). This Phase 3 study is being conducted to further evaluate and confirm the 
efficacy of SA-ER 6 g/day to preserve upper extremity muscle strength and function. The study will 
also assess the effects of SA-ER on lower extremity muscle strength and function; patient-reported 
ability and quality of life; and safety. 
OBJECTIVES: 
Primary Objective: Evaluate the effect of 6 g/day SA-ER treatment of subjects with GNEM on upper 
extremity muscle strength (UEC score) as measured by dynamometry. 
Key Secondary Objectives: Evaluate the effect of 6 g/day of SA-ER treatment of subjects with 
GNEM on: 
• Lower extremity composite muscle strength score (LEC score) as measured by dynamometry 
• Muscle strength in the knee extensors as measured by dynamometry 
• Physical functioning as measured using the GNEM-FAS mobility domain score 
Other Secondary Objectives: Evaluate the effect of 6 g/day of SA-ER treatment of subjects with 
GNEM on: 
• Physical functioning as measured using the GNEM-FAS upper extremity domain score 
• Lower extremity function as measured by a timed sit-to-stand test 


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• Upper extremity function as measured by a timed weighted arm lift test 
• Lower extremity function as measured by distance walked in the six-minute walk test (6MWT) 
Tertiary Objectives: To evaluate the effect of 6 g/day SA-ER treatment of subjects with GNEM on: 
• Percent predicted UEC and LEC muscle strength scores as measured by dynamometry 
• Muscle strength total force for each individual muscle group comprising the UEC and LEC 
muscle strength scores, as measured by dynamometry 
• Percent predicted strength in each individual muscle group comprising the UEC and LEC muscle 
strength scores, as measured by dynamometry 
• Percent predicted strength in the knee extensors, as measured by dynamometry 
• Physical functioning as measured using the GNEM-FAS total score  
• Physical functioning as measured using the GNEM-FAS self-care domain score  
• Health-related quality of life as measured by the Individual Neuromuscular Quality of Life 
Questionnaire (INQoL) 
• Investigator-assessed symptom severity as measured by the Clinical Global Impression (CGI) 
Scale 
• Changes in serum creatine kinase (CK) as a marker of muscle injury 
Drug Concentration Measurements: To evaluate the effect of 6 g/day SA-ER treatment of subjects 
with GNEM on: 
• Free SA levels in serum  
• Free, total, and bound SA levels in urine  
Safety Objective: Evaluate the safety of 6 g/day SA-ER treatment of subjects with GNEM 
PRIMARY EFFICACY HYPOTHESIS: 
Treatment with 6 g/day SA-ER tablets is more effective than placebo at maintaining the UEC score 
based on changes from baseline in bilateral strength recorded in the following muscle groups using 
dynamometry: gross grip, shoulder abductors, elbow flexors, and elbow extensors. 


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STUDY DESIGN AND METHODOLOGY: 
This is a randomized, double-blind, placebo-controlled, multicenter study to assess the clinical 
effect of 6 g/day SA-ER treatment as compared with placebo in subjects with GNEM.  Approximately 
80 subjects will be randomized in a 1:1 ratio to receive 6 g/day of SA-ER or matching placebo for 
48 weeks. Randomization of subjects will be stratified by gender with a planned enrollment of no 
more than 60% of subjects of either gender.  
Subjects will take 4 tablets (500 mg SA-ER each for 2 g per dose), or matching placebo, 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 8 weeks during 
the Treatment Period with assessments as outlined in the Schedule of Events (Table 2.1). Subjects who 
complete the study may be eligible to participate in an open-label extension study. 
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, and concomitant medications.   
Figure 2.1 provides a schematic of the study design. 
Figure 2.1: 
Study Schema 
 
NUMBER OF SUBJECTS PLANNED: 
Approximately 80 adult subjects with GNEM are planned for the study. 


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DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
The criteria below should be applied to all patients who are screened for the study.   
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Male or female, aged 18 − 55 years, inclusive 
2. Willing and able to provide written, signed informed consent after the nature of the study has been 
explained, and before any research-related procedures are conducted 
3. Have a documented diagnosis of GNEM, HIBM, distal myopathy with rimmed vacuoles (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. Able to provide reproducible force in elbow flexors (i.e. two dynamometry force values with no 
more than 15% variability in the dominant arm) at Screening  
5. Able to walk a minimum of 200 meters during the 6MWT at Screening without the use of assistive 
devices, including a cane, crutch(es), walker, wheelchair or scooter (ankle foot orthoses [AFOs] 
are permitted) 
6. Willing and able to comply with all study procedures 
7. 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 (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 3 months after last dose of study drug 
8. Females of childbearing potential must have a negative pregnancy test at Screening and be willing 
to have additional pregnancy tests during the study.  Females considered not of childbearing 
potential include those who have been in menopause for at least two years, have had tubal ligation 
at least one year prior to Screening, or who have had a total hysterectomy or bilateral 
salpingo-oophorectomy 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Ingestion of N-acetyl-D-mannosamine (ManNAc), 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. History of more than 30 days treatment with SA-ER and/or SA-IR in prior clinical trials in the past 
year 
3. Has had any hypersensitivity to SA or its excipients that, in the judgment of the investigator, 
places the subject at increased risk for adverse effects 
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 


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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 
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
Each SA-ER tablet contains 500 mg of SA in an extended release formulation for a total weight of 
1200 mg/tablet. The drug will be administered by the oral route and will be divided into a TID 
regimen: 4 tablets taken in the morning, early evening, and before bedtime (qHS). The dose should be 
taken with food (i.e. within 30 minutes after a meal or snack). 
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION: 
Placebo is matched in appearance and overall size to the SA-ER tablet. Both placebo and SA-ER 
tablets have a white coating to assure matched color/appearance. The placebo daily dose will be given 
orally TID as 4 tablets taken in the morning, early evening, and 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 be randomized to receive either 
6 g/day SA-ER or placebo.  
CRITERIA FOR EVALUATION: 
Efficacy: 
Efficacy will be evaluated by changes in upper and lower extremity muscle strength and function, and 
self-reported physical functioning.  Results from baseline assessments will be compared with those of 
post-treatment assessments listed in the Schedule of Events (Table 2.1), with efficacy conclusions 
based on change from baseline over the treatment period in comparison with placebo. 
Primary Clinical Efficacy Endpoint:   
Upper Extremity Composite Score: Muscle strength based on the maximum voluntary isometric 
contraction (MVIC) against a dynamometer will be measured bilaterally in the following upper 
extremity muscle groups: gross grip, shoulder abductors, elbow flexors, and elbow extensors.  
The UEC is derived from the sum of the average of the right and left total force values (measured 
in kg).  
Key Secondary Clinical Efficacy Endpoints: 
• 
Lower Extremity Composite Score:  Muscle strength based on MVIC against a dynamometer 
will be measured bilaterally in the following lower extremity muscle groups: knee flexors, hip 
flexors, hip extensors, hip abductors and hip adductors. The LEC is derived from the sum of the 
average of the right and left total force values (measured in kg). 
• 
Muscle strength in the Knee Extensors:  Bilateral total force defined as the average of the right 
and left force values (measured in kg).  


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• 
GNEM Functional Activities Scale Mobility Domain Score:  Physical functioning will be 
assessed using the Mobility domain of the GNEM-FAS instrument, a disease-specific measure 
developed to assess the functional impact of changes in muscle strength on mobility (reflective 
of the lower extremities). 
Other Secondary Clinical Efficacy Endpoints:  
• 
GNEM Functional Activities Scale Upper Extremity Domain Score: Upper extremity use and 
function will be assessed using the Upper Extremity domain of the GNEM-FAS instrument, a 
disease-specific measure developed to assess the functional impact of changes in upper extremity 
muscle strength. 
• 
Number of Stands in the Sit-to-Stand Test:  Lower extremity function will be assessed using a 
sit-to-stand test.  The number of times the subject can rise from a seated to a standing position in a 
30-second period will be recorded. 
• 
Number of Lifts in the 30 second Weighted Arm Lift Test:  Upper extremity function will be 
assessed using a weighted arm lift test performed bilaterally.  The number of times the subject can 
raise a 1 kg weight above the head in a 30-second period will be recorded. 
• 
Meters Walked in the Six-Minute Walk Test:  The total distance walked (meters) in a six minute 
period will be measured as well as the percent predicted distance based on normative data for age 
and gender.  
Tertiary Efficacy Endpoints:   
• 
Upper Extremity Composite Percent Predicted:  The percent predicted total force values will be 
determined based on reference equations adjusting for age, gender, height, and weight. The 
percent predicted force will be calculated for each side and the bilateral percent predicted values 
will be averaged for each upper extremity muscle group.  The mean of the four averages in percent 
predicted scores will be calculated for each subject to create a percent predicted UEC score, and 
analyzed relative to baseline to create a UEC mean change in percent predicted score.   
• 
Lower Extremity Composite Percent Predicted:  The percent predicted total force values will be 
determined based on reference equations adjusting for age, gender, height, and weight. The 
percent predicted force will be calculated for each side and the bilateral percent predicted values 
will be averaged for each lower extremity muscle group.  The mean of the five averages in percent 
predicted scores will be calculated for each subject to create a percent predicted LEC score, and 
analyzed relative to baseline to create a UEC mean change in percent predicted score.  
• 
Muscle strength (Total Force in kg)) for Each Individual Muscle Group: Bilateral total force for 
each individual muscle group included in the UEC and LEC will be reported.  
• 
Percent of Predicted Muscle Strength in Each Individual Muscle Group: Bilateral percent 
predicted total force for each individual muscle group included in the UEC and LEC will be 
reported. 
• 
Percent of Predicted Muscle Strength in the Knee Extensors: Percent predicted total force for the 
knee extensors will be reported. 
• 
Total Score on the GNEM-FAS 
• 
Self-Care Domain Score on the GNEM-FAS 
• 
Individual Neuromuscular Quality of Life Questionnaire:  A 45-item self-report questionnaire on 
the impact of key muscle disease symptoms on the ability to perform basic activities of daily 


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living, functional independence, relationships and overall well-being will be administered. 
Dimension scores and a Quality of Life score will be calculated. 
• 
Clinical Global Impression Scale:  Investigator assessment of severity of subject’s GNEM using 
the CGI-improvement scale (CGI-I) during treatment, in 3 target areas.  
• 
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.  
Drug Concentration Measurements:  
• Serum Free Sialic Acid: Change in free serum SA level. 
• Urine Sialic Acid - Free, Total and Bound: Changes from baseline in urine free, total and bound 
SA levels.   
Urine Testing for ManNAc: Urine will be tested for the presence of ManNAc to detect compliance 
with prohibited medication restrictions. 
Safety: 
Safety will be evaluated by the incidence and frequency of AEs and SAEs, including clinically 
significant changes from baseline to scheduled time points in the following:  
• 
Interval history 
• 
Vital signs 
• 
Physical examination results 
• 
Clinical laboratory results 
• 
Suicidal ideation and behavior  
• 
Concomitant medications 
STATISTICAL METHODS: 
Sample Size: 
Based on the results of the Phase 2 study (UX001-CL201), approximately 80 subjects will be 
randomized in this Phase 3 study. This sample size will provide 90% power to detect a difference of 
about 5 kg in the UEC score change from baseline between the SA-ER treatment and the placebo 
groups, assuming a standard deviation of 6, and a two-sided alpha of 0.05. 
Data Monitoring Committee (DMC):   
An independent and appropriately constituted DMC will act in an advisory capacity to monitor subject 
safety on a routine basis throughout the trial. 
Analyses Sets: 
Primary Analysis Set:  The primary efficacy set will include all randomized subjects with a baseline 
measurement and at least one post-baseline measurement.  Each subject will be included in the 
treatment group assigned at randomization, regardless of the treatment received.  This set will be used 
for the primary analyses of all efficacy endpoints. 
Safety Analysis Set:  The safety analysis set consists of all randomized 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 or urine SA levels. 
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, 6MWT, sit-to-stand, and 
weighted arm lift 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 Primary Analysis Set and will be stratified by gender.  
GEE analysis will be performed to compare the two treatment groups with respect to the changes from 
baseline for the primary endpoint, and all secondary and tertiary efficacy endpoints. Baseline will be 
included as a covariate in the model.  This method will be the primary analysis method for all repeated 
measures endpoints. 
The statistical analyses will be reported using summary tables, figures, and data listings.  
Statistical tests will be 2-sided at the alpha=0.05 significance level.  Continuous variables will be 
summarized with means, standard deviations, medians, minimums, and maximums.  Categorical 
variables will be summarized by counts and by percentages of subjects in corresponding categories.  
The final analyses will be conducted at Week 48. 
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 by treatment group. A by-subject listing will be provided for those 
subjects who experience a SAE, including death, or experience an AE associated with early 
withdrawal from the study or study drug treatment. 
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. 
A review of blinded safety data will be conducted by the DMC at least two times a year.   
Ad hoc meetings will be held if indicated based on observed events. 


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Table 2.1: 
Schedule of Events 
ASSESSMENTS AND EVENTS* 
SCREENING
 a 
BASELINE
 a 
TREATMENT PERIOD
 b 
SAFETY 
FOLLOW-UP
 c 
WEEK 
-4 to -1 
0 
4 (TC) 
8 
16 
24 
32 
40 
48/ETa 
52 (TC) 
INFORMED CONSENT  
X 
 
 
 
 
 
 
 
 
 
MEDICAL HISTORY, HEIGHT AND WEIGHT  d 
X 
 
 
 
 
 
 
 
 
 
DYNAMOMETRY  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
6-MINUTE WALK TEST (6MWT)  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
SIT-TO-STAND TEST  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
WEIGHTED ARM LIFT TEST  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
GNE MYOPATHY FUNCTIONAL 
ACTIVITIES SCALE (GNEM-FAS) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
INDIVIDUAL NEUROMUSCULAR 
QUALITY OF LIFE QUESTIONNAIRE  
(INQOL) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
CREATINE KINASE 
 
X 
 
X 
X 
X 
X 
X 
X 
 
CLINICAL GLOBAL IMPRESSION SCALE (CGI) e 
 
X 
 
 
 
X 
 
 
X 
 
FREE SERUM SA LEVELS f 
 
X 
 
X 
X 
X 
X 
X 
X 
 
FREE, TOTAL AND BOUND URINE SA LEVELS f 
 
X 
 
 
X 
 
X 
 
X 
 
URINE TEST FOR MANNACg 
X 
X 
 
 
X 
 
X 
 
X 
 
INTERVAL HISTORY h 
 
X 
 
X 
X 
X 
X 
X 
X 
 
PHYSICAL EXAMINATION  
X 
X i 
 
X 
X 
X i 
X 
X 
X i 
 
VITAL SIGNS  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
HEMATOLOGY, CHEMISTRY PANEL, URINALYSIS 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
PREGNANCY TEST 
X 
X 
 
 
X 
 
X 
 
X 
 
CONCOMITANT MEDICATIONS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
SUICIDAL IDEATION AND BEHAVIOR  j 
X 
X 
 
X 
X 
X 
X 
X 
X 
 


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ASSESSMENTS AND EVENTS* 
SCREENING
 a 
BASELINE
 a 
TREATMENT PERIOD
 b 
SAFETY 
FOLLOW-UP
 c 
WEEK 
-4 to -1 
0 
4 (TC) 
8 
16 
24 
32 
40 
48/ETa 
52 (TC) 
ADVERSE EVENTS  
X 
X  
Xb 
X 
X 
X 
X 
X 
X 
X 
TREATMENT DISPENSED  k 
 
X 
 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE 
 
 
 
X 
X 
X 
X 
X 
X 
 
*     Refer to Study Reference Manual for recommended timing and order of assessments to be administered at each study visit 
a. 
Potential subjects will be screened approximately seven days (up to 28 days) before the Baseline Visit. Study drug will be dispensed only after all study 
procedures at the Baseline Visit have been performed. For subjects who discontinue prior to completing the study, every reasonable effort should be made to 
perform the Early Termination (ET) procedures within four weeks of discontinuation. 
b. Visits occur every 8 weeks ± 5 days; subjects will be contacted by telephone call (TC) at Week 4 for abbreviated safety assessment. Additional unscheduled 
telephone calls may also occur for subject follow up. Unscheduled visits are allowed for safety or administrative purposes. Notify the medical monitor before 
an unscheduled visit. 
c. 
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 the extension study, UX001-CL302. The site personnel will initiate a 
safety follow-up telephone call 28 days (+5 days) after a subject’s last dose of study drug to collect information on any ongoing or new AEs, serious adverse 
events (SAEs), and concomitant medications. Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, are resolved.  
d. Medical history will include a detailed GNEM disease-specific medical history. 
e. 
CGI-Severity scale will be assessed at Baseline (Week 0) along with identification of 3 target areas for disease improvement; CGI-Improvement scale will 
be assessed at each subsequent visit using 3 target areas identified at Baseline. 
f. 
Pre-dose blood samples and first-morning void urine will be collected to assess trough SA levels; record volume of urine collected.  
g. An aliquot from the urine sample provided for the standard urinalysis will be used for assessment of ManNAc. 
h. Interval history will include any signs, symptoms, or events (i.e. falls) experienced by the subject since the prior study visit that are not related to study 
procedure(s) performed at prior study visits or study drug.  Interval history may include exacerbation or improvement in existing medical conditions 
(including the clinical manifestations of GNEM) that might interfere with study participation, safety, and/or positively or negatively impact performance of 
functional assessments. 
i. 
The physical examinations at Baseline and Weeks 24 and 48 will be complete, including a neurological examination; all others will be brief physical 
examinations. 
j. 
Baseline/Screening C-SSRS administered at Screening and Baseline visits.  Since Last Visit C-SSRS administered at all subsequent visits. 
k. Subjects should be instructed to return unused study drug and packaging to every visit. 


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................4 
3 TABLE OF CONTENTS ...................................................................................................14 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................19 
5 INTRODUCTION .............................................................................................................22 
5.1 Overview of GNE Myopathy ....................................................................................23 
5.2 Brief Overview of SA-ER Development ..................................................................24 
5.2.1 
Brief Description of SA-ER ........................................................................24 
5.2.1.1 
Mechanism of Action in GNE Myopathy ....................................25 
5.2.2 
Nonclinical Studies ......................................................................................26 
5.2.3 
Previous Clinical Studies .............................................................................27 
5.2.4 
Summary of Overall Risks and Potential Benefits ......................................29 
5.3 Study Rationale .........................................................................................................30 
5.4 Primary Efficacy Hypothesis ....................................................................................30 
6 STUDY OBJECTIVES ......................................................................................................31 
7 INVESTIGATIONAL PLAN ............................................................................................32 
7.1 Overall Study Design and Plan .................................................................................32 
7.2 Discussion of Study Design, Including Choice of Control Group ............................33 
7.3 Selection of Study Population ...................................................................................34 
7.3.1 
Inclusion Criteria .........................................................................................34 
7.3.2 
Exclusion Criteria ........................................................................................35 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................36 
7.3.3.1 
Stopping Rules .............................................................................37 
7.4 Treatments .................................................................................................................37 
7.4.1 
Investigational Product ................................................................................37 
7.4.2 
Reference Therapy ......................................................................................37 


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7.4.3 
Selection of Doses and Study Duration .......................................................38 
7.4.4 
Method of Assigning Subjects to Treatment Groups ..................................39 
7.4.5 
Blinding .......................................................................................................39 
7.4.6 
Prior and Concomitant Therapy ..................................................................39 
7.4.6.1 
Prohibited Medications ................................................................39 
7.4.6.2 
Permitted Medications .................................................................40 
7.4.7 
Treatment Compliance ................................................................................40 
7.5 Study Procedures and Assessments ..........................................................................40 
7.5.1 
Study Schedule ............................................................................................41 
7.5.1.1 
Screening Period ..........................................................................41 
7.5.1.2 
Baseline Visit ...............................................................................41 
7.5.1.3 
Treatment Period ..........................................................................41 
7.5.1.4 
End of Study/Early Termination Visit (Week 48/ET) .................41 
7.5.1.5 
Safety Follow-up Period ..............................................................41 
7.5.2 
Efficacy Measures .......................................................................................42 
7.5.2.1 
Dynamometry ..............................................................................42 
7.5.2.2 
Knee Extensor Muscle Strength ...................................................43 
7.5.2.3 
GNEM Functional Activities Scale .............................................44 
7.5.2.4 
Sit-to-Stand Test ..........................................................................44 
7.5.2.5 
Weighted Arm Lift Test ...............................................................44 
7.5.2.6 
Six Minute Walk Test ..................................................................45 
7.5.2.7 
Individual Neuromuscular Quality of Life Questionnaire ...........45 
7.5.2.8 
Clinical Global Impression Scale.................................................45 
7.5.2.9 
Creatine Kinase Levels ................................................................46 
7.5.3 
Drug Concentration Measurements .............................................................46 
7.5.4 
Urine Testing for ManNAc .........................................................................46 
7.5.5 
Safety Measures & General Assessments ...................................................47 


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7.5.5.1 
Medical History ...........................................................................47 
7.5.5.2 
Height and Weight .......................................................................47 
7.5.5.3 
Interval History ............................................................................47 
7.5.5.4 
Physical Examination...................................................................47 
7.5.5.5 
Vital Signs ....................................................................................48 
7.5.5.6 
Clinical Laboratory Tests for Safety ............................................48 
7.5.5.7 
Pregnancy Testing ........................................................................50 
7.5.5.8 
Suicidal Ideation and Behavior ....................................................51 
7.5.5.9 
Concomitant Medications ............................................................51 
7.5.5.10 
Adverse Events ............................................................................51 
7.5.6 
Appropriateness of Measures ......................................................................52 
7.6 Statistical Methods and Determination of Sample Size ............................................52 
7.6.1 
Determination of Sample Size .....................................................................53 
7.6.2 
Subject Information .....................................................................................53 
7.6.3 
Populations Analyzed ..................................................................................53 
7.6.4 
Efficacy Analysis ........................................................................................53 
7.6.4.1 
Primary Efficacy Endpoint and Analysis .....................................54 
7.6.4.2 
Secondary Endpoints and Analyses .............................................54 
7.6.4.3 
Tertiary Endpoints and Analysis ..................................................55 
7.6.5 
Analyses of Drug Concentration Measurements .........................................56 
7.6.6 
Safety Analyses ...........................................................................................56 
7.6.7 
Data Monitoring Committee .......................................................................57 
8 STUDY CONDUCT ..........................................................................................................58 
8.1 Ethics .........................................................................................................................58 
8.1.1 
Institutional Review Board or Ethics Committee ........................................58 
8.1.2 
Ethical Conduct of Study ............................................................................58 
8.1.3 
Subject Information and Consent ................................................................58 


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8.2 Investigators and Study Administrative Structure ....................................................59 
8.3 Investigational Product Accountability .....................................................................59 
8.4 Data Handling and Record Keeping .........................................................................60 
8.4.1 
Case Report Forms and Source Documents ................................................60 
8.4.2 
Data Quality Assurance ...............................................................................60 
8.4.3 
Record Retention .........................................................................................61 
8.5 Reporting and Follow-up of Adverse Events ............................................................61 
8.5.1 
Definition of Adverse Events ......................................................................61 
8.5.2 
Severity of Adverse Events .........................................................................62 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................63 
8.5.4 
Adverse Event Reporting ............................................................................63 
8.5.4.1 
General .........................................................................................63 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................64 
8.5.4.3 
Pregnancy Reports .......................................................................64 
8.5.5 
Communication Plan ...................................................................................64 
8.5.5.1 
Review of Safety Data .................................................................64 
8.5.5.2 
Adverse Drug Reaction Reporting ...............................................65 
8.5.6 
Urgent Safety Measures ..............................................................................65 
8.5.7 
Safety Contact Information .........................................................................66 
8.6 Financing and Insurance ...........................................................................................66 
8.7 Publication Policy .....................................................................................................66 
9 REFERENCES ..................................................................................................................67 
10 SIGNATURE PAGE .........................................................................................................70 
 
 
 


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List of Tables 
Table 2.1: 
Schedule of Events ...............................................................................12 
Table 7.5.5.6.1: 
Clinical Laboratory Assessments for Safety ........................................49 
Table 7.5.5.6.1.1: 
Volume of Blood to Be Drawn From Each Subject ............................50 
 
List of Figures 
Figure 2.1: 
Study Schema.........................................................................................6 
Figure 5.2.1.1.1: 
The Biosynthetic Pathway of Sialic Acid in its Subcellular 
Locations ..............................................................................................26 
Figure 7.1.1: 
Study Schema.......................................................................................32 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
AFO 
ankle foot orthosis/orthoses  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
cGMP 
Current Good Manufacturing Practices 
CK 
creatine kinase 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
DMRV 
EC 
distal myopathy with rimmed vacuoles 
Ethics Committee 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
GI 
gastrointestinal 
GlcNAc 
N acetyl-glucosamine  
GNE 
glucosamine (UDP-N-acetyl)-2-epimerase 
GNE-DMP 
GNE Myopathy Disease Monitoring Program 
GNE/MNK 
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase 
GNEM 
GNE Myopathy 
GNEM-FAS 
GNE Myopathy Functional Activities Scale 
hERG 
human ether-à-go-go-related gene 
HIBM 
hereditary inclusion body myopathy 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 


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ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
INQoL 
Individual Neuromuscular Quality of Life Questionnaire 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
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 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
qHS 
at the time of sleep (i.e., at bedtime) 
QSM 
quadriceps sparing myopathy 
RBC 
red blood cell 
RSI 
Reference Safety Information  
SA 
sialic acid 
SAE 
serious adverse event 
SA-ER 
Sialic Acid-Extended Release 
SA-IR 
Sialic Acid Immediate Release 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions  


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TC 
TEAE 
Telephone call 
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 
 
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 
The product under investigation is sialic acid (SA) administered in extended release (SA-ER) 
tablets.  SA-ER is intended for use as a substrate replacement therapy for the treatment of 
GNE myopathy (GNEM), also known as Hereditary Inclusion Body Myopathy (HIBM), 
Quadriceps Sparing Myopathy (QSM), Inclusion Body Myopathy type 2, Distal Myopathy 
with Rimmed Vacuoles (DMRV), and Nonaka myopathy (Huizing et al. 2009);  
(Jay et al. 2009); (Malicdan et al. 2008).  Currently there are no approved treatments for 
GNEM.  
SA is an essential, naturally occurring amino sugar found in humans and most organisms.  
Defects in the SA biosynthetic pathway cause GNEM, a severe progressive myopathy.  
By replacing SA substrate, sialylation should be restored on key target glycoproteins and 
glycolipids, leading to restoration of biochemical function, improved muscle physiology and 
improved clinical function.  The scientific rationale is primarily based on the nature of the 
underlying genetic defect supported by proof of concept work in a knockout mouse that 
models the muscle disease and pathology of HIBM (Malicdan et al. 2009).  The safety of SA 
has been studied in chronic treatment studies in HIBM mice and toxicology studies in 
multiple species of normal animals.  These data demonstrated reasonable safety for SA and 
established a no adverse effect level (NOAEL) of 2,000 mg/kg in rats and dogs, enabling 
clinical studies in GNEM patients.   
Ultragenyx has developed SA-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).  SA-ER was developed to 
improve the stability of exposure to SA and allow more appropriate dosing and efficient 
substrate replacement. The SA-ER formulation was evaluated in an initial Phase 1 study to 
establish the safety and pharmacokinetic (PK) profile of a single dose and 7 days of repeat 
dosing in SA-deficient GNEM patients.  The study drug was well tolerated at all dose levels. 
There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to 
moderate with no dose relationship or pattern. 
A Phase 2 randomized, placebo-controlled study evaluated chronic dosing of SA-ER at 
two dose levels to establish the pharmacodynamic (PD) effects of SA on sialylation, identify 
the appropriate dose level, and provide insight into clinical efficacy and safety.  Data from 
the Phase 2 study demonstrated efficacy and acceptable safety profile at the higher 6 g/day 
SA-ER dose level.  The degree of effect observed was dependent on serum SA levels 
suggesting the potential to optimize the therapeutic index by increasing SA exposure.   
An extension of the Phase 2 study was designed in two parts to provide additional long-term 
safety and clinical efficacy data 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 SA ER 
tablets with an immediate-release capsule formulation of SA (SA-IR[Part II]). (Refer to the 
Investigator’s Brochure (IB) for additional details on SA-IR.) Data on combination 
SA-ER/SA-IR treatment at 12 g/day suggest a modest further improvement in UEC strength 
over the 6 g/day dose, although the result was not dramatically better, and there was an 


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increase in AEs related to gastrointestinal (GI) tolerability at the higher 12 g/day dose. 
Based on the totality of the data the 6 g/day dose demonstrated the optimal benefit to risk 
profile and thus will be tested in Phase 3. 
Ultragenyx is also sponsoring a GNEM Disease Monitoring Program (GNEM-DMP) which 
includes a disease registry (a longitudinal patient reported disease outcome survey) and a 
natural history study (a physician-reported protocol-driven formal study).  The GNEM-DMP 
is being conducted in parallel with the SA clinical development program to collect data on 
disease characteristics and progression. 
This Phase 3 randomized, placebo-controlled study is designed to confirm the long-term 
safety and efficacy of 6 g/day SA-ER tablets in GNEM patients. 
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.  Since that time, patients have been identified 
worldwide, including those of Italian, Japanese, Thai, Indian, American and African origin 
(Huizing et al. 2009).  GNEM is a rare disease; the incidence and prevalence is low but exact 
numbers are not available.  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 is similar and includes an onset usually after age 20 (mean 26 years, 
range 15–40 years) though it 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 some fatty replacement infiltration 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.  The ocular, pharyngeal and 
respiratory muscles are relatively spared clinically though they may show some abnormal 


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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. 1987); (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.  
Electromyography in GNEM is abnormal with spontaneous fibrillations consistent with 
denervation, however nerve conduction is generally normal (Sadeh et al. 1993);  
(Mizusawa et al. 1987).  Imaging studies of the muscle by computed tomography  
(Sadeh et al. 1993); (Mizusawa et al. 1987) 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. 
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 SA-ER Development 
SA-ER tablets are in development as a treatment for GNEM.  The scientific rationale for SA 
substrate replacement therapy is primarily based on the nature of the underlying genetic 
defect supported by proof of concept work in a knockout mouse which models the muscle 
disease and pathology of HIBM (Malicdan et al. 2009).  Nonclinical studies have been 
conducted in HIBM mice and multiple species of normal animals.  Three clinical studies 
have been conducted to characterize the PK, tolerability, safety and efficacy of SA 
replacement in GNEM patients. 
A brief overview of existing information on SA-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 SA-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 


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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 SA-ER tablets using United 
States Pharmacopoeia (USP)/National Formulary (NF) excipients commonly used for this 
purpose.  
SA-ER 500 mg tablets are white to off-white, film-coated, extended-release, oval tablets that 
are designed for oral administration. The tablet formulation contains approximately 41.6% 
active pharmaceutical ingredient in a mixed polymer matrix developed for extended release 
of SA. Tablets are manufactured by a formulation process using wet aqueous granulation; the 
blend is then dried and compressed into tablet cores. The tablet cores are coated with 
Opadry II, a non-functional aqueous film coating. SA-ER 500 mg tablets are 1200 mg in total 
weight. 
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 SA-ER, sialylation should be restored on key 
target glycoproteins and glycolipids, and lead to restoration of biochemical function, 
improved muscle physiology and improved clinical function. 


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Figure 5.2.1.1.1: 
The Biosynthetic Pathway of Sialic Acid in its Subcellular 
Locations 
 
5.2.2 
Nonclinical Studies 
Published studies in the HIBM mouse model have shown that SA replacement can reduce 
muscle weakness and atrophy, improve muscle pathology and function, and restore 
sialylation in muscle (Malicdan et al. 2009).  The rational basis for the use of SA as a therapy 
in GNEM is primarily dependent on these results.  Key safety pharmacology, PK, and 
toxicology studies to support the use of SA in treating GNEM are summarized below; 
additional details may be found in the IB.   
Safety pharmacology:  Ultragenyx conducted the core battery of safety pharmacology 
studies of 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 


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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 SA 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 SA-ER tablets was conducted in GNEM 
subjects.  Twenty-seven (27) subjects were assigned to treatment; 26 were dosed with SA-ER 
and completed dosing.  Subjects received SA-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 SA-ER showed that trough levels could be 
maintained above the pre-dose baseline level, as expected for a sustained release formulation.  
SA-ER was well tolerated in this group of GNEM patients 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. 


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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 dose and PD of SA-ER tablets in 47 GNEM patients (Argov et al. 2014).  
Subjects were randomized to receive placebo or 3 g/day or 6 g/day SA-ER. After 24 weeks, 
placebo subjects crossed over (blinded) to either 3 g/day or 6 g/day SA-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; 5.5% relative difference from baseline; 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 (+3.44 kg; 8.5% relative difference from baseline; 
p=0.0033). 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 (+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; a positive trend in total (p=0.086), mobility (p=0.087), and upper extremity scores 
(p=0.096) in the combined 6 g/day vs 3 g/day groups was observed at Week 48 when 
analyzed by the pre-specified ANCOVA analysis. Changes in total, mobility, and upper 
extremity scores were significant in the combined 6 g/day vs 3 g/day groups when analyzed 
in a post-hoc analysis. 
SA-ER appeared to be well tolerated with no SAEs reported in either dose group and no 
dose-dependent TEAEs identified. Common TEAEs included headache, arthralgia, back 
pain, fatigue, diarrhea, 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 SA-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 SA-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, the majority of 
subjects will have their dose reduced from 12 g/day to 6 g/day.  The treatment-naïve group 
and a small subset of rollover subjects who showed potential clinical benefit at 12 g/day will 
have the option to remain on the higher dose. 


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Evaluations include safety, changes in clinical endpoints such as muscle strength, mobility, 
and function, and changes in exploratory serum biomarkers.  Data from a 24-week 
assessment in Part II suggest that the 12 g/day dose does not convey dramatically better 
efficacy than the 6 g/day dose in muscle strength or clinical endpoints. 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. 
5.2.4 
Summary of Overall Risks and Potential Benefits 
Since SA is a normal body compound with native pathways for degradative metabolism and 
rapid renal clearance, there is no evidence or expectation of a significant safety issue with SA 
replacement therapy.  Data from nonclinical and clinical studies to date suggest SA-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 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 other SAEs. 
The majority of subjects had TEAEs that were graded as mild to moderate severity. A single 
subject in the 3 g/day SA-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 SA-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 SA-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 patients with GNEM, replacement of the substrate SA has the potential to restore normal 
sialylation of muscle glycoproteins and glycolipids, which could improve the function of 
muscle and limit the loss of muscle strength.  It is not clear how much the effects of 
GNEM are reversible or if and how fast reversal of muscle disease might occur.  The data in 


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the HIBM mouse model suggest that over a one-year period, substantial beneficial effects on 
the pathology of the disease are possible.  However, the extent to which advanced disease 
can be improved, or prevention of disease progression is unknown.   
In clinical studies conducted to date, 6 g/day SA-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 severe, progressive myopathy caused by a defect in the biosynthetic 
pathway for sialic acid (SA).  Substrate replacement is a potential therapeutic strategy based 
on the success of replacing missing SA and reducing muscle disease in a relevant mouse 
model of the human disease.  A Phase 2, placebo-controlled study evaluating SA extended 
release (SA-ER) at 2 doses for 48 weeks found that the higher dose of 6 g/day SA-ER 
stabilized the UEC score compared with placebo or the lower 3 g/day dose; this finding was 
supported by measurements of functional outcome on the GNEM-FAS. This Phase 3 study is 
being conducted to further evaluate and confirm the efficacy of 6 g/day SA-ER tablets to 
preserve upper extremity muscle strength and function. The study will also assess the effects 
of SA-ER on lower extremity muscle strength and function; patient-reported ability and 
health-related quality of life; and safety.   
5.4 
Primary Efficacy Hypothesis 
Treatment with 6 g/day SA-ER tablets is more effective than placebo at maintaining the UEC 
score based on changes from baseline in bilateral strength recorded in the following muscle 
groups using dynamometry: gross grip, shoulder abductors, elbow flexors, and elbow 
extensors.   


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6 STUDY OBJECTIVES 
Primary Objective: Evaluate the effect of 6 g/day SA-ER treatment of subjects with GNEM 
on upper extremity muscle strength (UEC score) as measured by dynamometry. 
Key Secondary Objectives: Evaluate the effect of 6 g/day of SA-ER treatment of subjects 
with GNEM on: 
• Lower extremity composite muscle strength score (LEC score) as measured by 
dynamometry 
• Muscle strength in the knee extensors as measured by dynamometry 
• Physical functioning as measured using the GNEM-FAS mobility domain score 
Secondary Objectives:  Evaluate the effect of 6 g/day of SA-ER treatment of subjects with 
GNEM on: 
• Physical functioning as measured using the GNEM-FAS upper extremity domain score 
• Lower extremity function as measured by a timed sit-to-stand test 
• Upper extremity function as measured by a timed weighted arm lift test 
• Lower extremity function as measured by distance walked in the 6MWT 
Tertiary Objectives: To evaluate the effect of 6 g/day SA-ER treatment of subjects with 
GNEM on: 
• Percent predicted UEC and LEC muscle strength scores as measured by dynamometry 
• Muscle strength  total force for each individual muscle group comprising the UEC and 
LEC muscle strength scores, as measured by dynamometry 
• Percent predicted in each individual muscle group comprising the UEC and LEC muscle 
strength scores, as measured by dynamometry 
• Percent predicted strength in the knee extensors, as measured by dynamometry 
• Physical functioning as measured using the GNEM-FAS total score 
• Physical functioning as measured using the GNEM-FAS self-care domain score  
• Health-related quality of life as measured by the Individual Neuromuscular Quality of 
Life Questionnaire (INQoL) 
• Investigator-assessed symptom severity as measured by the Clinical Global Impression 
(CGI) Scale 
• Changes in CK as a marker of muscle injury 
Drug Concentration Measurements 
• Free SA levels in serum  
• Free, total, and bound SA levels in urine  
Safety Objective: Evaluate the safety of 6 g/day SA-ER treatment of subjects with GNEM. 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multicenter study to assess the 
clinical effect of 6 g/day SA-ER treatment as compared with placebo in subjects with 
GNEM.  Approximately 80 subjects will be randomized in a 1:1 ratio to receive 6 g/day of 
SA-ER or matching placebo for 48 weeks. Randomization of subjects will be stratified by 
gender with a planned enrollment of no more than 60% of subjects of either gender.  
Subjects will take 4 tablets (500 mg SA-ER each for 2 g per dose), or matching placebo, 
orally 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 8 weeks 
during the Treatment Period with assessments as outlined in the Schedule of Events 
(Table 2.1). Subjects who complete the study may be eligible to participate in an open-label 
extension study. 
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, and concomitant medications.  Figure 7.1.1 provides a 
schematic of the study design. 
Figure 7.1.1: Study Schema 
 
  


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7.2 
Discussion of Study Design, Including Choice of Control Group 
This Phase 3 study is designed to confirm the long-term safety and efficacy of 6 g/day 
SA-ER in GNEM patients.  The study will be conducted as a randomized, double-blind, 
placebo-controlled study to assure objectivity and maximize validity in the assessment of 
changes related to efficacy.  The control group will be a parallel group receiving a placebo 
tablet formulated comparably to the SA-ER active investigational product. 
The study will assess long-term effects of SA-ER on clinical measures of muscle strength, 
mobility, function, ability and health-related quality of life. The primary efficacy endpoint in 
the study, change in UEC score over 48 weeks as measured by dynamometry, is 
representative of muscle strength and relevant to the clinical pathology and disease 
progression in GNEM.  In the UX001-CL201 Phase 2 study, the UEC for the combined 
6 g/day group showed a modest increase and a statistically significant difference relative to 
the decline in strength observed in the combined 3 g/day group. The 6MWT has been a 
useful measurement of lower extremity function in certain neuromuscular diseases and is 
included in this study as a secondary endpoint. For GNEM, the 6MWT was not chosen as the 
primary endpoint because of limitations of its use and interpretation in this disease.  This is 
due to the pattern of muscle weakness in GNEM. The ankle muscles including dorsiflexors 
and plantarflexors are typically severely atrophied in patients with GNEM and these muscles 
are critical in allowing the foot to spring forward and propel the patient while walking. 
Furthermore, the lack of strength in these muscles drives patients to use ankle-foot orthoses 
(AFOs), but these rigid devices also limit the ability to increase ambulatory speed. Lastly, 
data from the UX001-CL201 study indicates that hip flexors are nearly absent at the time of 
enrollment. These muscles are critical in swinging the entire leg forward to initiate walking, 
again limiting speed of ambulation. This lack of ability to increase speed is supported by the 
baseline data in the UX001-CL201 study where the comfortable walking speed was 61% of 
predicted normal whereas the maximum pace was only 46% predicted normal.  
Another reason for the lack of ability to increase speed may be the fear of falling. In the 
UX001-CL201 study, more than 70% of patients who were able to walk more than 200m 
reported frequent falls prior to enrollment. Thus, walking tests such as the 6MWT, based on 
the biology and clinical characteristics of the disease, may lack the sensitivity or specificity 
to properly quantify any potential treatment effect. 
The study population comprises adult GNEM patients since the onset of disease usually 
occurs after age 20.  The study seeks to balance gender effects by stratifying randomization 
based on gender, and targeting enrollment of no more than 60% of one gender. 
Enrolled subjects will be have a confirmed diagnosis of GNEM, however the study 
population is inherently limited to only those subjects able to reliably perform dynamometry 
and walk a minimum of 200 meters without the use of assistive devices in a 6MWT.  While 
these inclusion criteria ensure reproducible data, the study population may represent a less 
severe GNEM disease state due to these restrictions. 


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The 48-week treatment duration is intended to confirm whether the 6 g/day dose level is safe 
for long-term use and provide sufficient characterization of sustained clinical effects. In prior 
studies of comparable muscle diseases such as late-onset Pompe disease, the maximum 
treatment effect for the 6MWT was achieved in the first six months, with a plateau observed 
over the remaining 12 months of the study.  The amount of time required to obtain reversal of 
GNEM disease in humans is unknown, but it would be unlikely to observe such changes after 
6-12 months of treatment.  In a previous Phase 2 study in GNEM, results after 48 weeks of 
treatment were similar to those observed at the 24-week interim analysis. 
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 are unable 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. 
To provide reliable data on the efficacy of SA-ER treatment in improving muscle strength 
and function, eligible subjects must be able to provide reproducible dynamometry results in 
the dominant elbow flexor. As an indicator of lower muscle group disease involvement, 
subjects must also independently walk a minimum of 200 meters without the use of assistive 
devices during the 6MWT.  To avoid imbalance in the study population, the study will seek 
to enroll no more than 60% of either gender, and will stratify randomization based on gender.  
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.  For safety purposes, individuals with impaired 
liver and renal function are not eligible to participate in the study. 
7.3.1 
Inclusion Criteria 
The criteria below should be applied to all patients who are screened for the study.   
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Male or female, aged 18 − 55 years, inclusive 
2) Willing and able to provide written, signed informed consent after the nature of the 
study has been explained, and before any research-related procedures are conducted 
3) 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) 


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4) Able to provide reproducible force in elbow flexors (i.e. two dynamometry force 
values with no more than 15% variability in the dominant arm) at Screening  
5) Able to walk a minimum of 200 meters during the 6MWT at Screening without the 
use of assistive devices, including a cane, crutch(es), walker, wheelchair or scooter 
(AFOs are permitted) 
6) Willing and able to comply with all study procedures 
7) 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 (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 3 months after last dose of study drug 
8) 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) History of more than 30 days treatment with SA-ER and/or SA-IR in prior clinical 
trials in the past year 
3) Has had any hypersensitivity to SA or its excipients that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects 
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 


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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 within 
the defined follow-up period stated in Section 7.5.1.5, their etiology should be identified and 
Ultragenyx should be notified.  All unscheduled tests must be reported to Ultragenyx 
immediately. 


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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 
A Data Monitoring Committee (DMC) will be constituted for Study UX001-CL301 and will 
act in an advisory capacity to monitor the safety of SA-ER on a routine basis throughout the 
trial (Section 7.6.7).  The DMC may provide advice to Ultragenyx in any determination of 
whether study enrollment should be paused or if the study should be stopped.  
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 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 80 subjects will be randomized 1:1 to one of two treatment groups:   
• SA-ER tablets, 6 g/day divided TID 
• Matched placebo tablets, divided TID   
7.4.1 
Investigational Product 
Each SA-ER tablet contains 500 mg of SA in an extended release formulation for a total 
weight of 1200 mg/tablet. The 6000 mg (6 g) total daily SA dose will be administered by the 
oral route and will be divided into a TID regimen: 4 tablets taken in the morning, early 
evening, and before bedtime (qHS). The dose should be administered with food (i.e. within 
30 minutes of a meal or snack). 
The study drug is manufactured, packaged, and labeled according to current Good 
Manufacturing Practice (cGMP) regulations.   
7.4.2 
Reference Therapy 
Placebo is matched in appearance and overall size to the SA-ER tablet. Both placebo and 
SA-ER have a white coating to assure matched color/appearance. The placebo daily dose will 
be given orally TID as 4 tablets taken in the morning, early evening, and qHS. The dose 
should be administered with food (i.e. within 30 minutes of a meal or snack). 


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7.4.3 
Selection of Doses and Study Duration 
Selection of Doses: 
Successful use of SA replacement therapy in humans is believed to depend upon optimized 
exposure to the compound in the bloodstream to drive uptake of SA into the muscle.  
The 6 g/day SA-ER dose was selected based on biochemical and clinical data collected to 
date showing that 6 g/day is an efficacious dose, that 3 g/day is not efficacious, and that a 
higher dose of 12 g/day did not result in a significant improvement in effect over 6 g/day. 
These data derive from a randomized, placebo-controlled Phase 2 study and a corresponding 
extension study.   
The Phase 2, randomized, placebo-controlled study (UX001-CL201) evaluated treatment 
with SA-ER at two dose levels of 3 g/day and 6 g/day for 48 weeks.  In this study, the higher 
dose of 6 g/day stabilized upper extremity muscle strength compared with placebo or the 
lower 3 g/day dose; this finding was 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 SA-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 
SA treatment at 12 g/day. No substantial or dramatic 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 SA-ER dose has been selected for 
further study as the minimum effective dose with a maximal or near maximal 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 56 weeks, including up to 
4 weeks between Screening and Baseline visits, a treatment duration of 48 weeks, and a 
Safety Follow-up Call occurring approximately 4 weeks after last study drug administration. 
Subjects who complete the study may be eligible to participate in an open-label extension 
study. 
All subjects will be randomized to receive 6 g/day SA-ER or placebo during the 48-week 
Treatment Period. The 48-week treatment duration is also intended for collection of safety 
data on the SA-ER tablets for long-term use and to provide sufficient insight on sustained 
clinical effects and improvements in adult GNEM patients.   


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7.4.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be enrolled in the study and sequentially assigned an identification number.  
Approximately 80 eligible subjects will be randomized via an Interactive Web 
Randomization System (IWRS) and assigned in a 1:1 ratio to receive 6 g/day of SA-ER or 
matching placebo for 48 weeks.  Randomization of subjects will be stratified by gender with 
a planned enrollment of no more than 60% of subjects of either gender. 
7.4.5 
Blinding 
The study will be conducted as a randomized, double-blind, placebo-controlled study.  
Double-blind conditions will be established so that neither the sponsor, subject, or site 
personnel involved in study conduct will know the identity of a subject’s treatment.  
Study parameters to achieve and maintain the double-blind status of the study include: 
• Sequential assignment of subject numbers 
• Management of subject treatment assignment via an IWRS 
• Labeling of study drug with the study number and a unique kit number 
• Packaging and delivery of study drug supplies to sites in a manner that maintains blinding 
of site personnel 
• Matched appearance of investigational product and placebo 
The Investigator and site personnel will remain blinded to the randomization code during the 
study.  Treatment assignment for an individual subject should be unblinded by the 
Investigator only in an emergency, and only if knowledge of the treatment assignment is 
urgently needed for the clinical management or welfare of the subject.  Treatment should be 
provided in accordance with the medical condition and with regard to the information 
provided in the IB.  The Investigator should contact the medical monitor or project manager 
before unblinding, when possible, but priority should be given to treatment of the subject.   
The Investigator must record the date and reason for revealing the blinded treatment 
assignment for that subject in the IWRS and in the source documents.  Treatment assignment 
may be unblinded by the Sponsor to satisfy expedited safety reporting requirements of 
regulatory authorities.  The system to unblind an assignment will be maintained and executed 
through an IWRS which will be available 24 hours a day, 7 days a week. 
7.4.6 
Prior and Concomitant Therapy 
7.4.6.1 
Prohibited Medications 
Patients may not be enrolled if they have a history of more than 30 days treatment with SA 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 


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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. 
7.4.6.2 
Permitted Medications 
Other than medications specifically prohibited in this study, subjects may receive 
concomitant medications as required.  Medications (prescription, over-the-counter, and 
herbal) and nutritional supplements taken during the 30 days prior to Screening will be 
reviewed and recorded at the Screening visit.  At the Baseline visit, current medications will 
be recorded.  At each visit, any concomitant medications added or discontinued during the 
study should be recorded on the CRF. 
The site personnel should record the following in the CRF: date and time the medication was 
taken, the name of the medication, and the reason the medication was taken. 
7.4.7 
Treatment Compliance 
Site personnel will maintain a record of all medication dispensed to each subject.  
Subjects will be instructed to bring all unused study drug and product packaging to every 
visit.  Drug accountability will be assessed by site personnel and recorded.  All used 
containers and unused study drug must be returned at in-clinic visits.  Measurements of 
trough free SA levels in the serum and urine 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 
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-CL301, along with timing of assessments, are 
provided in the Schedule of Events (Table 2.1). Refer to the Study Reference Manual for 
additional details on specific assessments and the suggested order of administration. 


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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 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. 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 within 7 to 28 days of the Screening visit.  
Subjects will be randomized only after inclusion/exclusion criteria have been confirmed.  
Baseline visit (Week 0) assessments must be completed prior to first dose of study drug.   
7.5.1.3 
Treatment Period 
Subjects will be contacted by telephone four weeks after the Baseline Visit for an abbreviated 
safety follow-up.  Subjects will return to the clinic at 8-week intervals (± 5 days) throughout 
the Treatment Period (Weeks 0 – 48).   
7.5.1.4 
End of Study/Early Termination Visit (Week 48/ET) 
All randomized subjects who complete the study or discontinue early should complete the 
Week 48/ET visit.  
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. 
7.5.1.5 
Safety Follow-up Period 
A safety follow-up call should be initiated by the site personnel 28 days (+5 days) after a 
subject’s last dose of study drug to collect information on any ongoing or new AEs, serious 
adverse events (SAEs), and concomitant medications. Appropriate follow-up should continue 
until all safety concerns, in the Investigator’s opinion, are resolved.  
This call should 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.   


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Subjects who have completed the Week 48 Visit of this study, meet the requirements of the 
extension study, and choose to enroll in the open-label extension study, UX001-CL302, will 
not be required complete the follow-call. 
7.5.2 
Efficacy Measures 
Efficacy will be evaluated by changes in upper and lower extremity muscle strength and 
function, and self-reported physical functioning.  Results from baseline assessments will be 
compared with those of post-treatment assessments listed in the Schedule of Events 
(Table 2.1), with efficacy conclusions based on change from baseline over the treatment 
period for the SA-ER treatment group compared to placebo.   
The primary efficacy endpoint in this study, UEC as derived from dynamometry, will 
provide a clinical measure of muscle function and strength.  The primary efficacy endpoint 
will be the change from baseline in UEC score for the SA-ER group compared with placebo 
based on the overall trend over the treatment period (Section 7.6.4).  The primary efficacy 
measure will be supported by multiple secondary and tertiary endpoints, including 
GNEM-FAS mobility and upper extremity domain scores, LEC, multiple measures of lower 
extremity strength and function, clinical performance tests to assess mobility and functional 
abilities, health-related quality of life assessments, and biochemical markers.  Secondary and 
tertiary endpoints and associated analyses are described in Sections 7.6.4.2 and 7.6.4.3, 
respectively.  The following section describes the assessments that will be performed 
throughout the study to derive primary, secondary, and tertiary endpoints. 
7.5.2.1 
Dynamometry 
Dynamometry of multiple muscle groups will be used to derive the primary efficacy endpoint 
as well as multiple secondary and tertiary efficacy endpoints.  Dynamometry sessions will 
occur at each visit beginning with the Screening Visit to serve as training and ensure the 
subject meets eligibility criteria.   
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, elbow flexors, 
elbow extensors, hip abductors, hip adductors, hip flexors, hip extensors, knee flexors and 
knee extensors.  A hand dynamometer will be used to assess gross grip strength.   
Each effort will last approximately three seconds with a slow build to a maximum voluntary 
force.  Strength in the elbow flexors and elbow extensors will be measured with the subject 
lying in a supine position on an examination table.  Strength in the hip extensors will be 
measured with the subject leaning over an examination table in a prone position.  All other 
muscle groups will be tested with the subject in a sitting position.  All measurements will be 
taken bilaterally; the dominant side will be noted in the CRF.  Three tests will be 
administered in an attempt to obtain two force values within approximately 15% of each 
other for each muscle group.  The total force (in kg) will be recorded at the time of test 


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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 as secondary or tertiary endpoints (Section 7.6.4). 
7.5.2.1.1 
Primary Efficacy Endpoint:  Upper Extremity Composite Score 
Muscle strength based on the MVIC against a dynamometer will be measured bilaterally in 
the following upper extremity muscle groups: gross grip, shoulder abductors, elbow flexors, 
and elbow extensors.  The UEC is derived from the sum of the average of the right and left 
total force values (measured in kg) for each muscle group. The comparison of the two 
treatment groups will be based on the change from baseline in mean UEC score between 
SA-ER and placebo using generalized estimating equation (GEE) repeated measures with 
baseline as a covariate.   
Additional UEC-related parameters will serve as tertiary efficacy endpoints. The percent 
predicted total force values will be determined based on reference equations adjusting for 
age, gender, height, and weight. The percent predicted force will be calculated for each side 
and the bilateral percent predicted values will be averaged for each upper extremity muscle 
group (gross grip, shoulder abductors, elbow flexors, and elbow extensors).  The mean of the 
four averages in percent predicted scores will be calculated to create a percent predicted UEC 
score, and analyzed relative to baseline to create a UEC mean change in percent predicted 
score.  The change in mean percent predicted UEC score between SA-ER and placebo will be 
compared using the GEE repeated measures analysis. 
7.5.2.1.2 
Lower Extremity Composite Score 
Muscle strength based on MVIC against a dynamometer will be measured bilaterally in the 
following lower extremity muscle groups: knee flexors, hip flexors, hip extensors, hip 
abductors and hip adductors.  Each muscle group is the average of the right and left total 
values (measured in kg). The LEC score is derived from the sum of all muscle groups and is 
a key secondary endpoint. The percent predicted total force values for the LEC will also be 
determined and analyzed as a tertiary endpoint. The percent predicted force will be calculated 
for each side and the bilateral percent predicted values will be averaged for each lower 
extremity muscle group (knee flexors, hip flexors, hip extensors, hip abductors and hip 
adductors).  The mean of the five averages in percent predicted scores will be calculated to 
create a percent predicted LEC score, and analyzed relative to baseline to create a LEC mean 
change in percent predicted score.   
7.5.2.2 
Knee Extensor Muscle Strength 
The knee extensors (quadriceps) are widely recognized to be spared in GNEM relative to 
other lower extremity muscle groups, making it a defining feature of the disease and 
instrumental in making a differential diagnosis. Knee extensor strength based on MVIC 


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against a dynamometer will be measured bilaterally as described in Section 7.5.2.1 and is a 
key secondary endpoint. The percent predicted total force values for the knee extensors will 
also be determined and analyzed as a tertiary endpoint. 
7.5.2.3 
GNEM Functional Activities Scale 
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:  mobility (a key secondary endpoint), upper extremity (secondary 
endpoint), and self-care (tertiary endpoint); scores for each domain and a total score (tertiary 
endpoint) will be obtained.  The GNEM-FAS will be administered at the Baseline Visit and 
Weeks 8, 16, 24, 32, 40 and 48 (or Early Termination) to evaluate physical functioning.  
The scale has been developed specifically for patients with GNEM based on feedback 
received from affected individuals on the impact of the disease on their function.  Items in 
the scale assess the subject’s ability to independently perform various activities of living that 
involve self-care, mobility and use of the upper and lower extremities.  The scale will be 
administered in an interview format by a trained clinician (preferably a licensed physical 
therapist) and scored after the testing.  The physical therapists’ role is a combination of 
observing subjects conducting activities and asking subjects questions to assess performance 
of these activities. 
7.5.2.4 
Sit-to-Stand Test 
The sit-to-stand test (Agarwal et al. 2006); (Ozalevli et al. 2007) will be administered at 
Screening for training purposes, and each subsequent scheduled study visit through Week 48 
(or Early Termination), to assess lower extremity function.  The test will be administered by 
a trained clinician (preferably a licensed physical therapist).  The subject will be asked to 
stand upright from a seated position in a chair, return to a seated position, and then repeat the 
sequence at a comfortable pace according to their own rhythm for the 30 second duration of 
the test.  Use of an arm chair or a stationary object for leverage will be permitted if preferred 
by the subject.  The number of times the subject can rise from a seated to a standing position 
in a 30-second period will be recorded as a secondary endpoint. 
7.5.2.5 
Weighted Arm Lift Test 
Upper extremity function will be assessed using a weighted arm lift test.  The weighted arm 
lift test (Agarwal et al. 2006) will be administered at the Screening Visit for training 
purposes, then at each subsequent scheduled visit through Week 48 (or Early Termination).  
The subject will be asked to sit in a chair holding a 1 kg barbell with the shoulder adducted, 
the elbow in full flexion, and the forearm in supination.  On command, the subject will be 
asked to lift the arm above the head until the elbow is fully extended, then to lower the arm 
back to the starting position.  The subject will be asked to repeat the action at a comfortable 
pace according to their own rhythm for the 30 second duration of the test.  The test will be 
performed bilaterally and the final score will be the mean of the total number of completed 


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repetitions from both arms.  The number of times the subject can raise the 1 kg weight above 
the head in the 30-second test period will be recorded as a secondary endpoint. 
7.5.2.6 
Six Minute Walk Test 
The 6MWT will be administered at the Screening visit to determine eligibility.  The 6MWT 
will be administered once per test day at each subsequent scheduled study visit through 
Week 48 (or Early Termination).  Refer to the Study Reference Manual for detailed 
instructions on conducting the 6MWT. 
The 6MWT will be conducted based on American Thoracic Society guidelines  
(ATS/ERS 2002).  The course length has been modified to 20 meters to allow consistency 
across testing sites and the BORG scale will not be utilized.  Subjects will be instructed to 
walk the length of a pre-measured course for 6 consecutive minutes.  If applicable, the use of 
any AFOs in the performance of the 6MWT will be noted.  Devices other than AFOs may not 
be used during the baseline assessment; if a subject’s disease progresses substantially during 
the study and there are safety concerns with performing the 6MWT, then additional devices 
may be used and must be noted on the CRF. The total distance walked (meters) following the 
six minute period will be recorded as a secondary endpoint.  As an additional secondary 
endpoint, the percent predicted distance walked (for age and gender) will also be determined 
based on published normative data (Gibbons et al. 2001). 
7.5.2.7 
Individual Neuromuscular Quality of Life Questionnaire 
The INQoL (Vincent et al. 2007), a tertiary endpoint, is an individualized self-report measure 
of health-related quality of life designed specifically for adults with muscle disease.  
The INQoL will be administered at the Baseline Visit and Weeks 8, 16, 24, 32, 40, and 48 (or 
Early Termination).  The INQoL will be presented to the subject in paper format for 
completion prior to the administration of the performance tests.  The INQoL is a 45-item 
measure consisting of ten subscales; four measure the impact of muscle disease symptoms, 
including weakness, locking (seizing), pain and fatigue of muscles. Five additional subscales 
evaluate the degree of symptom impact on particular areas of life, including activities, 
independence, social, emotional, and body image. The final domain assesses perceived and 
expected treatment effects and will not be administered due to the blinded nature of the 
study.  All responses are given in a seven-point Likert scale, with higher scores indicating 
greater impact.   
The INQoL will only be completed for subjects when a validated version of the scale is 
available in the subject’s native language.  
7.5.2.8 
Clinical Global Impression Scale 
The CGI (a tertiary endpoint) was developed for use in National Institute of Mental Health-
sponsored clinical trials to provide a brief, stand-alone assessment of the clinician's view of 
the patient's global functioning prior to and after initiating a study medication (Guy 1976). 


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The CGI provides an overall clinician-determined summary measure that takes into account 
all available information, including knowledge of the patient's history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability 
to function. 
The Investigator will perform the CGI-Severity scale (CGI-S) at the Baseline Visit to rate the 
severity of a subject’s condition on a 7-point scale ranging from 1 (normal, not at all ill) to 
7 (among the most extremely ill subjects).  The Investigator will also identify 3 target areas 
of improvement with the subject, which will be recorded in the source documents.  
To generate the targets, an open-ended question should be asked, such as “If this program of 
treatment works for you, what things do you hope you will be doing better?”  
At Weeks 24 and 48 (or Early Termination), the Investigator will administer the 
CGI-Improvement (CGI-I) scale to assess the subject’s overall improvement in the 3 target 
areas recorded at the Baseline Visit, using a 7 point scale ranging from 1 (very much 
improved) to 7 (very much worse). The CGI-S and CGI-I should be completed by a clinician 
experienced in the evaluation of patients with GNEM.  
7.5.2.9 
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 (a tertiary 
endpoint) will be measured as indicated in the Schedule of Events (Table 2.1) to assess the 
degree of reduction associated with treatment. 
7.5.3 
Drug Concentration Measurements 
The concentration of free SA in serum will be measured.  At the Baseline Visit and each 
subsequent visit a serum sample will be collected prior to the morning dose of study 
medication (pre-dose) to assess trough levels of free SA.   
The free, total, and bound urine SA levels (corrected for creatinine) will be measured.  At the 
Baseline, and Week 16, 32, and 48 (or Early Termination) visits, first-morning void urine 
will be collected (pre-dose) to assess trough levels; the volume obtained will be recorded.   
Collection and processing instructions can be found in the Laboratory Manual. 
7.5.4 
Urine Testing for ManNAc 
An aliquot from the urine sample provided for the standard urinalysis testing will be analyzed 
for the presence of ManNAc at Screening, Baseline, and Week 16, 32, and 48 (or Early 
Termination) visits to detect noncompliance with prohibited medication restrictions.  
Collection and processing instructions can be found in the Laboratory Manual. 


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7.5.5 
Safety Measures & General Assessments 
General assessments include medical history, demographics, height and weight.  Safety will 
be evaluated by the incidence, frequency and severity of AEs and SAEs, including clinically 
significant changes from study baseline to scheduled time points in interval history, physical 
examinations, vital signs, clinical laboratory evaluations, suicidal ideation and behavior, and 
concomitant medications.  Pregnancy testing (or pregnancy of partner, if needed) will also be 
conducted as appropriate.  Refer to the Study Reference Manual for additional details on 
safety measures and general assessments. 
7.5.5.1 
Medical History 
A detailed medical history will be obtained at the Screening 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. 
7.5.5.2 
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.  Height should be measured in inches or centimeters 
without shoes with the subject standing on a flat surface. A calibrated scale must be used for 
all weight measurements. Weight should be measured in pounds or kilograms without shoes. 
Height and weight data will be used to evaluate each subject’s muscle strength and function 
using published normative data where available.  The measurement obtained at the Screening 
Visit will be used for all derivations of percent predicted. 
7.5.5.3 
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). 
7.5.5.4 
Physical Examination 
Complete physical examinations will be performed at Baseline, and the Week 24 and 
48 study visits (or Early Termination).  Physical examinations will include assessments 


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of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, 
lymphatic, respiratory, GI, genitourinary, musculoskeletal, and neurologic systems. 
The neurologic system examination will include assessments of cognition, cranial nerves, 
motor function, coordination and gait, reflexes, and sensory function.  Brief physical 
examinations will be conducted at all other study visits and will include assessments of 
general appearance, cardiovascular and respiratory systems, and a focus on any presenting 
complaints. Clinically significant changes from baseline will be recorded as AEs. 
7.5.5.5 
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 before any additional assessments are completed. 
7.5.5.6 
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 7.5.5.6.1.  Clinical laboratory testing will be performed at every visit.  Blood and urine 
samples will be collected prior to administration of study drug; fasting is not required.  Refer 
to the Laboratory Manual for additional details. 


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Table 7.5.5.6.1: 
Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Hematocrit 
Appearance 
Alkaline phosphatase 
Hemoglobin 
Bilirubin  
Amylase 
Mean corpuscular hemoglobin (MCH) 
Blood pH 
Aspartate aminotransferase (AST) 
MCH concentration (MCHC) 
Color  
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
Creatinine 2 
Blood urea nitrogen (BUN) 
Platelet count 
Glucose  
Calcium 
Red blood cell (RBC) count 
Hemoglobin  
Chloride 
Reticulocyte count 
Ketones  
Cholesterol (total) 
Neutrophil count (absolute and %) 
Leukoycte Esterase 
Creatine kinase 1 
Lymphocyte count (absolute and %) 
ManNAc 3 
Creatinine 
Monocyte count (absolute and %) 
Nitrite  
Gamma-glutamyl transpeptidase (GGT) 
Eosinophil count (absolute and %) 
Protein  
Glucose 
Basophil count (absolute and %) 
Specific gravity  
Lactate dehydrogenase (LDH) 
White blood cell (WBC) count 
Urobilinogen 
Lipase 
WBC differential 
 
Phosphorus 
 
Pregnancy test 
(if applicable) 
Potassium 
 
 
Protein (albumin and total) 
 
*Special assessment 
Sodium 
 
Serum pregnancy  test 
if a positive urine 
pregnancy test 
Triglycerides 
 
 
1  Also designated as PD variable (Section 7.5.2.9)  
2  Relevant to Drug Concentration Measurements (Section 7.5.3) 
3  To screen for use of prohibited medications (Section 7.4.6.1) 
If urinalysis detects protein, leukocyte esterase, blood or nitrite, microscopic examination 
will be conducted. The microscopic examination will consist of White Blood Cell (WBC), 
Red Blood Cell (RBC), Epithelial Cells: Squamous , Epithelial Cells: Transitional, Epithelial 
Cells: Renal Tubular, Hyaline Casts, WBC Casts, RBC Casts, Waxy Casts, Granular Casts, 
Calcium Oxalate Crystals, Uric Acid Crystals, Triphosphate Crystals, Yeast, Bacteria, 
Amorphous Urates, and Amorphous Phosphates.  
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.  


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7.5.5.6.1 
Volume of Blood to Be Drawn from Each Subject 
During this study, it is expected that approximately 16 mL of blood will be drawn from each 
subject, at each required time point, regardless of gender or age. The amount of blood 
required for each sample type is presented in Table 7.5.5.6.1.1.  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 7.5.5.6.1.1: 
Volume of Blood to Be Drawn From Each Subject 
Assessment 
Sample Volume (mL) 
Number of 
Samples 
Total Volume (mL) 
Safety 
Chemistry 1 
7.5 
8 
60 
Hematology 
3 
8 
24 
PK 
Sialic Acid  
5 
7 
35 
Total mL through study completion 
119 
1  Includes CK, an efficacy variable 
7.5.5.7 
Pregnancy Testing 
Female subjects of childbearing potential with a positive pregnancy test at Screening will not 
be enrolled in the study.  Female subjects will have urine pregnancy tests at the Baseline 
visit, at 16-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 3 months 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.  


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7.5.5.7.1 
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 
female partner’s consent for release of protected health information.  Refer to the Study 
Reference Manual for details on the reporting procedures to follow in the event of pregnancy. 
7.5.5.8 
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.  
7.5.5.9 
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 7.4.6. 
7.5.5.10 Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent until 30 days 
after the last dose of study drug, or, if applicable, until the date the subjects signs the 
informed consent for the open-label 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. 


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Clinically significant changes from study baseline in interval history, physical and 
neurological examination findings, vital signs, weight, clinical laboratory parameters, and 
concomitant medications will be recorded as AEs or SAEs, if appropriate. 
7.5.6 
Appropriateness of Measures 
The efficacy parameters to be evaluated in this study include clinical changes in muscle 
strength, subject mobility and function.  The clinical assessments in the study employ 
standard performance measures used in other neuromuscular diseases and conditions that 
cause muscle weakness and impaired function.  Based on results from Phase 2 studies 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).  An interview-based measure designed to 
evaluate ability in GNEM patients (GNEM-FAS) will be administered in this study to 
support the clinical meaningfulness of changes in muscle strength. In addition, walking 
ability will be assessed using the 6MWT test, a test of endurance commonly used in clinical 
trials for various indications that has served as the basis for many product approvals.    
The level of free SA in serum will reflect the absorption of and exposure of the muscles to 
SA during treatment. Serum CK level will be assessed as a measure of muscle injury 
throughout the study; a positive dose-dependent decrease in serum CK levels was observed 
in the UX001-CL201 Week 24 analysis.  Unlike other myopathies, CK activities are mildly 
elevated or in the normal range for these patients.  The mouse model of HIBM showed 
elevated CK levels that improved substantially on treatment (Malicdan et al. 2009).   
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, neurological 
examination, vital signs, serum chemistry, and other routine clinical and laboratory 
procedures.  In addition, symptoms of increasing muscle weakness and pain which are 
characteristic of myopathy will be recorded in interval histories. Suicidal ideation and 
behavior will be assessed using C-SSRS, a standardized rating instrument recommended in 
clinical trials of any investigational drug with potential neurological activity (FDA Draft 
Guidance, 2012). 
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 endpoint will be presented in the 
Statistical Analysis Plan (SAP); the information below is intended as a guide to planned 
analyses. 


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7.6.1 
Determination of Sample Size 
Based on the results of the Phase 2 study (UX001-CL201), approximately 80 subjects will be 
randomized in this Phase 3 study. This sample size will provide 90% power to detect a 
difference of about 5 kg in the UEC score change from baseline between the SA-ER 
treatment and the placebo groups, assuming a standard deviation of 6, and a two-sided alpha 
of 0.05. 
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 
Primary Analysis Set:  The primary efficacy set will include all randomized subjects with a 
baseline measurement and at least one post-baseline measurement.  Each subject will be 
included in the treatment group assigned at randomization, regardless of the treatment 
received.  This set will be used for the primary analyses of all efficacy endpoints. 
Safety Analysis Set:  The safety analysis set consists of all randomized subjects who receive 
at least one dose of study drug. This set will be used for the analyses of all safety endpoints. 
Sialic Acid Analysis Set:  The SA analysis set will consist of all randomized subjects with 
evaluable free serum SA levels or urine 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, sit-to-stand test, weighted arm lift test, and 6MWT 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 primary analysis set and will be stratified by gender.  
GEE analysis will be performed to compare the two treatment groups with respect to the 
changes from baseline of primary endpoint, secondary endpoints, and all tertiary efficacy 
endpoints. Baseline, gender, and geographic region will be included as covariates in the 
model. In general, randomly missing data for an individual subject will be treated as missing. 
The GEE method handles these cases appropriately.  If a subject drops out following a 
decline in function, regardless of whether that is the reason listed for withdrawal, then it will 
be assumed that missing data are not missing at random and a single imputation rule will be 
used. This method will be the primary analysis method for all repeated measures endpoints. 


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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® or SPLUS.  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. 
7.6.4.1 
Primary Efficacy Endpoint and Analysis 
The primary clinical efficacy analysis will be the change from baseline in UEC score for the 
SA-ER group compared with placebo based on bilateral strength recorded in the following 
muscle groups using a dynamometer: gross grip, shoulder abductors, elbow flexors, and 
elbow extensors.  The UEC is derived from the sum of the muscle groups.  Each muscle 
group value will represent the average of the right and left total values (measured in kg). 
The comparison of the two treatment groups will be based on the change from baseline in 
mean UEC score between SA-ER and placebo using GEE repeated measures analysis with 
baseline, gender, and geographic region as covariates. Region is considered as a covariate to 
account for the heterogeneity of the disease observed in some European countries and Israel 
relative to North American patients.   
For missing assessments for an individual subject, these data would remain as missing or will 
be imputed based on the rules provided in the SAP. For those subjects who are in the study 
for some period of time but decline in function and leave the study, regardless of whether 
that is the reason listed for withdrawal, the GEE method might not adequately cover the 
projected decline for these subjects and may not be appropriately conservative.  In such cases 
a single imputation method will be used to estimate the change in strength over the remaining 
time of the study using the existing subject’s data and these imputed values will be used for 
the GEE analysis. 
Details on primary endpoint analysis will be fully delineated in the SAP. 
7.6.4.2 
Secondary Endpoints and Analyses 
Analyses of secondary efficacy endpoints will follow the same methods as the primary 
analyses of the primary endpoint, where data are available. Additional details on the analysis 
of secondary endpoints will be described in the SAP. 
7.6.4.2.1 
Key Secondary Endpoints 
The key secondary clinical efficacy analyses will assess the change from baseline for the 
SA-ER group compared with the placebo group using GEE for the following variables:  
• LEC score based on a sum of the mean bilateral strength recorded in the following 
muscle groups: knee flexors, hip flexors, hip extensors, hip abductors and hip adductors 


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• Muscle strength in the knee extensors: bilateral total force (measured in kg)  
• GNEM-FAS mobility domain score 
Hochberg’s adjustment for multiplicity (Hochberg 1988) will be used for the key secondary 
endpoints, specifically LEC score, knee extensor strength, and GNEM-FAS mobility domain 
score.  
7.6.4.2.2 
Other Secondary Endpoints 
The analysis of other secondary endpoints will assess the change from baseline for the 
SA-ER group compared to the placebo group using GEE for the following variables:  
• GNEM-FAS upper extremity domain score 
• Sit-to-stand score calculated as the number of times a subject can rise from a sitting to a 
standing position in a 30-second period 
• Weighted arm lift score calculated as the number of times a subject can raise a 1 kg 
weight overhead in a 30-second period 
• Walking ability as measured by the 6MWT, which will be reported as distance in meters 
and percent predicted based on normative data for age and gender.  
7.6.4.3 
Tertiary Endpoints and Analysis 
Analyses of tertiary endpoints will follow the same methods as the primary analyses of the 
primary endpoint, where data are available.  The tertiary clinical efficacy analyses will assess 
the change from baseline for the SA-ER group compared to the placebo group using GEE for 
the following endpoints:  
• UEC score based on percent predicted bilateral strength recorded in the upper extremity 
muscle groups 
• LEC score based on percent predicted bilateral strength recorded in the upper extremity 
muscle groups 
• Muscle strength (total force in kg) for each individual muscle group comprising the UEC 
and LEC 
• Percent predicted muscle strength for each individual muscle group comprising the UEC 
and LEC using published normative data adjusted for age, gender, and weight 
• Percent of predicted muscle strength in the knee extensors using published normative 
data adjusted for age, gender, and weight 
• GNEM-FAS total score 
• GNEM-FAS self-care domain score 


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• Health-related quality of life as measured by the INQoL, which will be reported as 
subscale scores with higher scores associated with more significantly diminished quality 
of life  
• CGI-I scores 
• CK levels in serum 
• Trough (pre-dose) SA levels in serum (free) and urine (free, total, and bound; corrected 
for creatinine) 
Additional details on the analysis of tertiary endpoints will be described in the SAP.  
7.6.5 
Analyses of Drug Concentration Measurements 
The SA analysis set will be used to evaluate free serum SA levels and urine SA levels (free, 
bound and total; corrected for creatinine) at trough (pre-dose). Changes from baseline will be 
analyzed using repeated measures analysis. The comparison will be between the SA-ER 
treatment group and placebo group using GEE. 
7.6.6 
Safety Analyses 
The safety analysis set will be used for the analyses of all safety endpoints (Section 7.6.3).  
Safety will be evaluated by the incidence, frequency and severity of AEs and SAEs, 
including clinically significant changes from study baseline to scheduled time points in: 
• Interval history 
• Vital signs 
• Physical examination findings 
• Clinical laboratory evaluations 
• Suicidal ideation and behavior assessments 
• Concomitant medications 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), 
Preferred Term (PT), severity, and relationship to treatment.  The numbers (frequency) and 
incidence rates of AEs and SAEs will be summarized by treatment group. A by-subject 
listing will be provided for those subjects who experience a SAE, including death, or 
experience an AE associated with early withdrawal from the study or study drug treatment. 
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 


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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. 
7.6.7 
Data Monitoring Committee 
An independent DMC with appropriate expertise in the conduct of clinical trials will act in an 
advisory capacity to monitor subject safety on a routine basis throughout the trial.  A review 
of blinded safety data will be conducted by the DMC at least two times a year, with the first 
meeting scheduled once the first subject has been enrolled. Ad hoc meetings will be held if 
indicated based on observed events.  The responsibilities of the DMC will be fully defined in 
a DMC charter. 


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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 15 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 15 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 15 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. 


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


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the informed consent for the open-label extension study, UX001-CL302, whichever occurs 
sooner. In addition for those subjects choosing not to enroll in UX001-CL302, the 
Investigator should report any AE that occurs more than 30 days following the last dose of 
study drug that is believed to have a reasonable possibility of being associated with study 
drug.  
AEs ongoing after the defined follow-up period stated in the paragraph above 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 through 
the defined follow-up period stated in Section 8.5.4.1 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 8.5.5.2. 
8.5.5 
Communication Plan 
8.5.5.1 
Review of Safety Data 
An independent DMC will act in an advisory capacity to monitor subject safety on a routine 
basis throughout the course of the study. The DMC will meet at least two times a year, or as 
needed, to review aggregate safety data and provide advice regarding the safety of subjects 
and the continuing scientific validity of the study. The DMC may also be asked to review 
SUSARs that represent changes in the nature or an increase in the frequency of events and 
may provide recommendations regarding continued subject participation. 
Potential safety signals identified during the DMC reviews or any other process during the 
conduct of the study will be escalated to the appropriate internal Ultragenyx safety governing 


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bodies. Any action indicated by Ultragenyx safety governing bodies will be communicated 
accordingly to all stakeholders, e.g. Regulatory Authorities, ECs, IRBs, and Investigators. 
8.5.5.2 
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 SA, major safety 
findings) that may occur during the clinical trial that do not fall within the definition of a 
SUSAR but may affect the safety of subjects participating in the clinical trials, as required, in 
accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from the signing of the informed consent through the defined follow-up 
period stated in Section 8.5.4.1. The Investigator will notify the IRBs/Research Ethics Boards 
(REB)/ECs of SAEs and urgent safety matters, in accordance with IRB/REB/EC 
requirements and local laws and regulations. A copy of this notification must be provided to 
Ultragenyx or its designee. 
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and ECs, as per local laws and regulations. 
8.5.6 
Urgent Safety Measures 
The regulations governing clinical studies state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations.  According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard.  The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
EC is notified at the same time.”  The reporting period for urgent safety measures is the 
period from the signing of the informed consent through the defined follow-up period stated 
in Section 8.5.4.1.   Investigators are required to report any urgent safety measures to 
Ultragenyx within 24 hours. 


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8.5.7 
Safety Contact Information 
Drug Safety 
Medical Monitor 
PrimeVigilance 
Fax:     1 (415) 930-4033 
e-mail: ultragenyx@primevigilance.com 
 
Telephone:   
 
e-mail:         
 
 
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 
Agarwal, S, and Kiely, PD. 2006. "Two simple, reliable and valid tests of proximal muscle 
function, and their application to the management of idiopathic inflammatory myositis." 
Rheumatology (Oxford) 45 (7):874-9. 
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. 
ATS/ERS. 2002. "American Thoracic Society Statement: Guidelines for the six-minute walk 
test." Am.J.Respir, Crit.Care Med 166 (1):111-117. 
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. 
Gibbons, WJ, Fruchter, N, Sloan, S, and Levy, RD. 2001. "Reference values for a multiple 
repetition 6-minute walk test in healthy adults older than 20 years." J Cardiopulm.Rehabil. 
21 (2):87-93. 
Guy, W. 1976. "The Clinical Global Impression Scale." In Handbook of Psychiatric 
Measures, 2008, edited by A. John Rush Jr, M.B First and D Blacker, 90-92. Washington, 
DC: American Psychiatric Publishing, Inc. 
Hochberg, Y. 1988. "A sharper Bonferroni procedure for multiple tests of significance." 
Biometrika 75 (4):800-802. 
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. 


Protocol Number:  UX001-CL301 
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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. 
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. 
Mizusawa, H, Kurisaki, H, Takatsu, M, Inoue, K, Mannen, T, Toyokura, Y, and Nakanishi, 
T. 1987. "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. 
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. 
Ozalevli, S, Ozden, A, Itil, O, and Akkoclu, A. 2007. "Comparison of the Sit-to-Stand Test 
with 6 min walk test in patients with chronic obstructive pulmonary disease." Respir Med 
101 (2):286-93. 
Peters, MJ, van Nes, SI, Vanhoutte, EK, Bakkers, M, van Doorn, PA, Merkies, IS, Faber, 
CG, and PeriNom, SSg. 2011. "Revised normative values for grip strength with the Jamar 
dynamometer." J Peripher Nerv Syst 16 (1):47-50. 
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, 
Melvin, GA, Greenhill, L, Shen, S, and Mann, JJ. 2011. "The Columbia-Suicide Severity 
Rating Scale: initial validity and internal consistency findings from three multisite studies 
with adolescents and adults." Am J Psychiatry 168 (12):1266-77. 
Sadeh, M, Gadoth, N, Hadar, H, and Ben-David, E. 1993. "Vacuolar myopathy sparing the 
quadriceps." Brain 116 ( Pt 1):217-232. 


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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. 
Vincent, KA, Carr, AJ, Walburn, J, Scott, DL, and Rose, MR. 2007. "Construction and 
validation of a quality of life questionnaire for neuromuscular disease (INQoL)." Neurology 
68 (13):1051-7. 
 


Protocol Number: UX001-CL301 
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10 SIGNATURE PAGE 
Protocol Title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Sialic Acid Extended-Release Tablets in Patients with 
GNE Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM) 
Protocol Number: UX001-CL301 
I have read Protocol UX001-CL301 Amendment 5. I agree to conduct the study as detailed 
in this protocol and in compliance with the Declaration of Helsinki, Good Clinical Practices 
(GCP), and all applicable regulatory requirements and guidelines. 
Investigator Signature 
Date 
Printed Name: ------------------------------------------------------
Accepted for the Sponsor: 
As the Sponsor representative, I confi1m that Ultragenyx will comply with all Sponsor 
obligations as detailed in all applicable regulations and guidelines. I will ensure the 
Investigator is infmmed of all relevant infmmation that becomes available during the conduct 
ofthis study. 
 
Senior Medical Director 
Ultragenyx Pharmaceutical Inc. 
Proprietary and Confidential 
Date 
Page 70 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
Title: 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Sialic Acid Extended Release 
Tablets in Patients with GNE Myopathy (GNEM) or Hereditary 
Inclusion Body Myopathy (HIBM) 
Protocol: 
UX001-CL301, Amendment 5, May 25, 2017 
Compound: 
Aceneuramic Acid (Sialic Acid) Extended-Release  
(Ace-ER; SA-ER) Tablets 
Phase: 
3 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Author: 
 
Date: 
May 26, 2017 
Status: 
Amendment 1, V2.0 
 
 
 


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STATISTICAL ANALYSIS PLAN AMENDMENT VERSION 2.0 
SUMMARY OF CHANGES AND RATIONALE 
 
The major statistical analysis plan changes are summarized below: 
 
1. FAS Upper Extremity domain is moved from a Key secondary endpoint to 
“Other secondary” endpoints (Section 4.3) 
 
Rationale: The original validation of the GNEM-FAS was performed using data from 
patients from the UX001-CL201 Phase 2 and the UX001-CL401 observational studies with 
no restrictions related to the functional status of the subjects.  Given the entry criterion in the 
UX001-CL301 study to enroll only patients  able to walk at least 200 meters in the 6-minute 
walk test (6MWT) without the use of an assistive device, the validation exercise was 
repeated using baseline data from a subset of patients meeting this criteria from 
UX001-CL201 and UX001-CL401 (n=50) studies.  Response distributions for the 
GNEM-FAS items from this pooled data suggest a ceiling effect for all items in the upper 
extremity domain. 
2. Hochberg method for multiplicity is added to Section 8.8.1 for three key secondary 
endpoints 
 
Rationale:  There was no statistical method for multiplicity adjustment for the key secondary 
endpoints included in the original version of the SAP.


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TABLE OF CONTENTS 
ABBREVIATIONS ...................................................................................................................6 
1 INTRODUCTION ...............................................................................................................7 
2 STUDY OBJECTIVES ........................................................................................................8 
2.1 Primary Objective .......................................................................................................8 
2.2 Key Secondary Objectives:  Evaluate the effect of 6 g/day of SA-ER 
treatment of subjects with GNEM on: ........................................................................8 
2.3 Other Secondary Objectives: Evaluate the effect of 6 g/day of SA-ER 
treatment of subjects with GNEM on: ........................................................................8 
2.4 Tertiary Objectives ......................................................................................................8 
2.5 Drug Concentration Measurements: ...........................................................................9 
2.6 Safety Objective ..........................................................................................................9 
3 STUDY DESIGN...............................................................................................................10 
3.1 Overall Study Design and Plan .................................................................................10 
3.2 Discussion of Study Design, Including Choice of Control Group ............................11 
3.3 UX001-CL301 Justification of Endpoint Selection and Prioritization .....................12 
3.4 Study Duration ..........................................................................................................15 
3.5 Stratification Factors .................................................................................................16 
3.6 Randomization, Blinding ..........................................................................................16 
3.7 Determination of Sample Size ..................................................................................16 
3.8 Interim Analysis ........................................................................................................17 
3.9 Data Monitoring Committee .....................................................................................17 
4 STUDY CLINICAL OUTCOMES AND COVARIATES ................................................18 
4.1 Primary Clinical Efficacy Endpoint ..........................................................................18 
4.2 Key Secondary Clinical Efficacy Endpoints .............................................................18 
4.3 Other Secondary Clinical Efficacy Endpoints ..........................................................18 
4.4 Tertiary Efficacy Endpoints ......................................................................................19 
4.5 Drug Concentration Measurements ..........................................................................20 


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4.6 Urine Testing for ManNAc: ......................................................................................20 
4.7 Safety Endpoints .......................................................................................................20 
4.8 Potential Covariates ..................................................................................................20 
5 DEFINITIONS ...................................................................................................................21 
5.1 Baseline .....................................................................................................................21 
5.2 Drug Compliance ......................................................................................................21 
5.3 Muscle Strength ........................................................................................................21 
5.4 Patient Reported Outcomes .......................................................................................22 
6 ANALYSIS POPULATIONS ...........................................................................................23 
6.1 Primary Analysis Set .................................................................................................23 
6.2 Per Protocol Set .........................................................................................................23 
6.3 Safety Analysis Set ...................................................................................................23 
6.4 Sialic Acid (SA) Analysis Set ...................................................................................23 
7 DATA SCREENING AND ACCEPTANCE ....................................................................24 
7.1 Handling of Missing and Incomplete Data ...............................................................24 
7.2 Partial or Missing Dates Imputation Rules ...............................................................25 
7.3 Software ....................................................................................................................26 
8 STATISTICAL METHODS OF ANALYSIS ...................................................................27 
8.1 General Principles .....................................................................................................27 
8.2 Visit Window Definition ...........................................................................................27 
8.3 Demographics ...........................................................................................................28 
8.4 Disease Characteristics and Medical History............................................................28 
8.5 Patient Accountability ...............................................................................................28 
8.6 Extent of Exposure ....................................................................................................29 
8.7 Primary Efficacy Endpoint and Analysis ..................................................................29 
8.8 Analyses of Secondary and Tertiary Endpoints ........................................................29 
8.8.1 
Analyses of Key Secondary Endpoints .......................................................29 


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8.8.2 
Analyses of Other Secondary Endpoints .....................................................30 
8.8.3 
Analyses of Tertiary Endpoints ...................................................................31 
8.8.4 
Analyses of Sialic Acid, Creatine Kinase and Free ManNAc .....................32 
8.9 Safety Analyses .........................................................................................................33 
8.9.1 
Adverse Events to Monitor ..........................................................................35 
9 REFERENCES ..................................................................................................................36 
10 APPENDICES ...................................................................................................................38 
10.1 Schedule of Events ....................................................................................................38 
10.2 Missing Observation in Hand Held Dynamometry and GNEM-FAS ......................40 
10.3 Computation Formula for Derived HHD Variables ..................................................43 
10.4 Percent Predicted Derived Variables ........................................................................44 
10.5 Patient-reported Outcomes ........................................................................................48 
10.6 Adverse Events to Monitor .......................................................................................52 
10.6.1 Gastrointestinal MedDRA Query ................................................................52 
10.6.2 Liver-Related Investigations .......................................................................53 
10.7 Summary of Efficacy Endpoint and Analysis ...........................................................54 
 
List of Tables 
Table 7.1.1: 
An example of the imputation method for a subject with only 2 
values ...................................................................................................25 
Table 8.2.1: 
Visit Window Definition......................................................................28 
 
List of Figures 
Figure 3.1: 
Study Schema.......................................................................................10 
 


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ABBREVIATIONS 
6MWT 
Six Minute Walk Test 
CRF  
Case Report Form 
DMC   
Data Monitoring Committee 
GNE  
glucosamine (UDP-N-acetyl)-2-epimerase 
GNEM 
GNE Myopathy 
GNEM-FAS GNE Myopathy Functional Activities Scale 
HHD  
Hand-held dynamometer 
HIBM  
hereditary inclusion body myopathy 
GEE  
Generalized Estimating Equation  
 
INQoL 
Individual Neuromuscular Quality of life Questionnaire 
IWRS  
Interactive Web Randomization System  
Kg 
 
Kilogram 
LEC  
lower extremity composite  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
 
Milligram 
MMRM 
Mixed effect Model Repeat Measurement  
PD 
 
pharmacodynamic 
PK 
 
Pharmacokinetic  
SA 
 
sialic acid 
SAE  
serious adverse event 
SA-ER 
Sialic Acid-Extended Release 
SAP 
 
Statistical Analysis Plan 
SOC  
System Organ Class 
TEAE  
treatment-emergent adverse event 
UEC  
upper extremity composite 


Study Number:  UX001-CL301  
Statistical Analysis Plan 
26 May 2017, Amendment 1, Version 2.0 
 
 
Proprietary and Confidential 
Page 7 
1 INTRODUCTION 
The purpose of this statistical analysis plan is to provide details of the statistical analyses that 
have been outlined within the original UX001-CL301 and Protocol Amendment 5 dated May 
25, 2017.  The data collected in this study will be used to evaluate the efficacy and safety of 
aceneuramic acid (sialic acid) extended release (SA-ER) tablets in patients with GNE 
Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM). Should there be a 
difference between the SAP and the protocol with respect to analysis methods, the SAP will 
take precedence over the protocol. 


Study Number:  UX001-CL301  
Statistical Analysis Plan 
26 May 2017, Amendment 1, Version 2.0 
 
 
Proprietary and Confidential 
Page 8 
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
Evaluate the effect of 6 g/day SA-ER treatment in subjects with GNEM on upper extremity 
muscle strength (UEC score) as measured by dynamometry. 
2.2 
Key Secondary Objectives:  Evaluate the effect of 6 g/day of SA-ER treatment of 
subjects with GNEM on: 
• Lower extremity composite muscle strength score (LEC score) as measured by 
dynamometry 
• Muscle strength in the knee extensors as measured by dynamometry 
• Physical functioning as measured using the GNEM-FAS mobility domain score 
2.3 
Other Secondary Objectives: Evaluate the effect of 6 g/day of SA-ER treatment of 
subjects with GNEM on: 
• Physical functioning as measured using the GNEM-FAS upper extremity domain score 
• Lower extremity function as measured by a timed sit-to-stand test 
• Upper extremity function as measured by a timed weighted arm lift test 
• Lower extremity function as measured by distance walked in the 6MWT 
2.4 
Tertiary Objectives 
To evaluate the effect of 6 g/day SA-ER treatment of subjects with GNEM on: 
• Percent predicted UEC and LEC muscle strength scores as measured by dynamometry 
• Muscle strength total force for each individual muscle group comprising the UEC and 
LEC muscle strength scores, as measured by dynamometry 
• Percent predicted strength in each individual muscle group comprising the UEC and 
LEC scores, as measured by dynamometry 
• Percent predicted strength in the knee extensors, as measured by dynamometry 
• Physical functioning as measured using the GNEM-FAS total score 
• Physical functioning as measured using the GNEM-FAS self-care domain score 
• Health-related quality of life as measured by the Individual Neuromuscular Quality of 
Life Questionnaire (INQoL) 
• Investigator-assessed symptom severity as measured by the Clinical Global Impression 
(CGI) Scale 
• Changes in CK as a marker of muscle injury 


Study Number:  UX001-CL301  
Statistical Analysis Plan 
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Page 9 
2.5 
Drug Concentration Measurements: 
• Free SA levels in serum  
• Free, total, and bound SA levels in urine 
2.6 
Safety Objective 
• Evaluate the safety of 6 g/day SA-ER treatment of subjects with GNEM. 


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Study Number:  UX001-CL301  
Statistical Analysis Plan 
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Page 11 
3.2 
Discussion of Study Design, Including Choice of Control Group 
This Phase 3 study is designed to confirm the long-term safety and efficacy of 6 g/day 
SA-ER in GNEM patients.  The study will be conducted as a randomized, double-blind, 
placebo-controlled study to assure objectivity and maximize validity in the assessment of 
changes related to efficacy.  The control group will be a parallel group receiving a placebo 
tablet formulated comparably to the SA-ER active investigational product. 
The study will assess long-term effects of SA-ER on clinical measures of muscle strength, 
mobility, function, ability and health-related quality of life. The primary efficacy endpoint in 
the study, change in UEC score over 48 weeks as measured by dynamometry, is 
representative of muscle strength and relevant to the clinical pathology and disease 
progression in GNEM.  In the UX001-CL201 Phase 2 study, the UEC for the combined 
6 g/day group showed a statistically significant improvement relative to the combined 
3 g/day group. 
The study population comprises adult GNEM patients since the onset of disease usually 
occurs after age 20.  The study seeks to balance gender effects by stratifying randomization 
based on gender, and targeting enrollment of no more than 60% of one gender. 
Enrolled subjects will have a confirmed diagnosis of GNEM and are able to reliably perform 
dynamometry and walk a minimum of 200 meters without the use of assistive devices in a 
6MWT. These inclusion criteria were selected to identify patients with sufficient intact 
muscle to be able to response to replacement therapy. As GNE myopathy is a rare disease, 
the diagnosis is often delayed. By the time of diagnosis, patients have substantial muscle 
replaced with fat and fibrosis which is unlikely to respond to replacement therapy.  
The 48-week treatment duration is intended to confirm whether the 6 g/day dose level is safe 
for long-term use and provide sufficient characterization of sustained clinical effects.   
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.  These patients are unable 
to synthesize normal levels of 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.  For safety purposes, individuals with impaired 
liver and renal function are not eligible to participate in the study. 


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3.3 
UX001-CL301 Justification of Endpoint Selection and Prioritization 
HHD UEC Score 
GNEM is a muscle disease characterized by a progressive loss of muscle strength in the 
upper and lower extremities. Although the disease presents and progresses more rapidly in 
the lower extremities, there is evidence of weakness in the upper extremities early in the 
disease course.  The presenting symptom in most patients is a foot drop caused by extensive 
muscle tissue damage in the lower leg, particularly the tibialis anterior, which leads to 
tripping and falling.  AFOs (ankle-foot orthoses) are often prescribed at the time of diagnosis 
to keep the ankle and foot at a 90 degree angle to allow the patients to walk without falling.   
In clinical practice, the most common technique for the identification of muscle weakness or 
impairment is manual muscle testing, which relies on a single clinician to assign a grade 
based on a subjective estimate of the amount of force exerted by a patient.  In research 
practice, it is more common to use techniques that allow for the objective quantification of 
muscle strength.  A dynamometer is a device that has been used to document muscle 
weakness, disease progression and treatment outcomes in various neuromuscular diseases, 
including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Duchenne 
muscular dystrophy (DMD), myotonic dystrophy and Pompe disease, and has been suggested 
as a surrogate measure of motor function, including ambulation. (Febrer et al. 2010), , 
(Merlini et al. 2002), (Stuberg et al. 1988), (van der Ploeg et al. 2010), (Hebert et al. 2010), 
HHD devices are also highly reliable and sensitive; the MicroFet2 model utilized in the 
Phase 2 study can detect a minimum of 0.8 pounds of force in an individual muscle group. 
This allows for the measurement of strength even in more severely affected muscle groups 
with limited residual healthy muscle tissue, which is commonly observed in GNE Myopathy.  
The UX001-CL102 study allowed for the pilot testing of measures of muscle strength and 
function, including HHD, prior to the initiation of the Phase 2 study.  Dynamometry results 
from the pilot study suggested that the MicroFet2 and Jamar devices were capable of 
accurately and reliably quantifying force in several muscle groups, although it was clear there 
was less variability and more residual strength among upper extremity muscle groups.  
This same pattern of weakness was observed in the UX001-CL201 Phase 2 study with more 
variability in lower extremity strength among patients than upper extremity strength.  
Although GNE Myopathy affects muscles in both the lower and upper extremities, the lower 
extremity muscles are more profoundly impacted early in the disease course and may have a 
more rapid rate of progression than the upper extremity muscles.  Given the typical delay 
between disease onset, symptom onset and diagnosis, muscle groups in the hips and legs may 
have sustained irreparable damage before an intervention, such as a clinical trial, can take 
place.  Dynamometry data collected during the pilot and Phase 2 studies revealed that nearly 
all tested patients had residual strength in the upper extremity muscle groups tested, although 
they were considerably weaker than their peers based on normative data that adjusts for age, 
gender and body size.  To discern a treatment response in a relatively small sample of 
clinically heterogeneous patients, an endpoint comprised of strength values from upper 
extremity muscle groups that still have residual strength and healthy muscle tissue will 


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provide the most objective measure of treatment-related changes in muscle strength.  Hence, 
a composite score of upper extremity strength (UEC) in the shoulder abductors, gross grip, 
elbow flexors and elbow extensors is proposed as the primary endpoint for the 
UX001-CL301 study.  
GNEM-FAS Mobility Domain Score 
The GNEM-FAS is a disease-specific disability measure developed and validated by the 
Sponsor to characterize the impact of GNE Myopathy on the daily activity of affected 
individuals and to determine the clinically meaningful benefit of any observed changes in 
physiological outcome measures, such as dynamometry, biopsy, etc.  The GNEM-FAS is a 
clinician-reported measure that evaluates mobility, upper extremity function and self-care 
skills by clinical observation and patient report. Development of this novel instrument was 
based on interviews and assessments of HIBM patients in parallel with the Phase 1 Study 
(UX001-CL102).  Validation work was completed using data from the Phase 2 study 
(UX001-CL201).  
Given the extent of the muscle damage observed in the lower extremity on MRI and biopsy, 
the difficulty in obtaining the minimum strength requirements for HHD measurement in 
various LE muscle groups and the confounding role of orthoses in the performance of gross 
motor functional tests, the GNEM-FAS Mobility score provides the best opportunity to 
evaluate change in lower extremity movement and function based on clinical observation and 
patient self-report.  The items included in the Mobility domain of the GNEM-FAS focus on 
gross motor activities that require strength and integrated movement of the muscles of the 
trunk, hips and legs, such as transferring from a lying position to a sitting position (i.e., 
sitting up from bed), transferring from a sitting position to a standing position (i.e. getting out 
of bed), bending to the floor and returning to an upright position, walking and climbing 
stairs.  Changes in GNEM-FAS Mobility domain scores could be used to provide evidence of 
treatment-related changes in lower extremity function even in patients for whom lower 
extremity strength can no longer be quantified in some of the individual lower extremity 
muscle groups that comprise the LEC.  
GNEM-FAS Upper Extremity Domain Score 
The GNEM-FAS Upper Extremity domain allows for changes in upper extremity muscle 
strength, as measured by the UEC, to be translated into clinically meaningful outcomes by 
evaluating the performance of upper extremity functional activities based on clinical 
observation and patient report.  The items included in the Upper Extremity domain include 
flexing the fingers, writing, eating with utensils, opening doors and bottles, reaching 
overhead and carrying objects while walking, such as groceries.  Performance of these 
various activities requires the use of the muscle groups that comprise the UEC (i.e., gross 
grip for opening doors, shoulder abductors for reaching overhead, elbow flexors/extensors 
for carrying groceries) and can therefore help to put observed changes into context. 


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HHD LEC Score 
Dynamometry data collected during the Phase 2 UX001-CL201 study revealed extensive 
weakness in various muscle groups of the hip and leg despite the fact that all enrolled 
patients remained ambulatory.  Pilot study data revealed no muscle groups in the lower leg, 
including the tibialis anterior and gastrocnemius, where strength could be quantified using 
the MicroFet2 dynamometer despite the sensitivity of the device. In the Phase 2 study, a wide 
range of lower extremity weakness was observed despite all patients being ambulatory.  
All muscle groups tested were considerably weaker than their peers based on normative data 
adjusting for age, gender and body size.  In fact, some patients were not able to assume the 
standardized testing positions for individual muscle groups due to weakness and could not 
provide any measurable resistance against the device even when alternate testing positions 
were used.  The amount of variability observed in the lower extremity strength of ambulatory 
patients and the magnitude of the weakness observed in certain muscle groups makes it 
difficult to identify an endpoint that can be used to quantify treatment-related changes in 
lower extremity strength in a rare disease such as GNE Myopathy where trials enroll a 
relatively small sample of clinically heterogeneous patients.  Given these concerns, the LEC 
will be evaluated as a secondary endpoint but will focus on the UEC as a primary endpoint to 
evaluate the efficacy of SA-ER.   
Sit-to Stand Test (STS) 
The STS test is a performance test that requires an individual to rise from a seated position as 
many times as possible in a 30-second period with the score recorded as the number of 
repetitions completed.  Performance of this test requires the use of various lower extremity 
muscle groups, including the hip extensors, knee extensors, hip adductors, hip flexors and 
knee flexors.  Each of these muscle groups makes a different contribution depending on the 
stage of the maneuver. Given that all of the muscle groups required to rise from a seated 
position are being tested using HHD, improved performance on this measure could be used 
to translate any observed changes in LEC or the individual lower extremity muscle groups 
into clinically meaningful benefit to the patient. The ability to rise from a seated position is 
critical to performance of various daily activities, including toileting and getting out of a car, 
and is necessary to maintain functional independence. 
Weighted Arm Lift Test (WAL) 
The WAL test is a performance test that requires an individual to raise a 1 kg dumbbell over 
the head from a seated position as many times as possible in a 30-second period with the 
score recorded as the number of repetitions completed.  Performance of this test requires the 
use of various upper extremity muscle groups, including grip, specifically finger flexors and 
wrist flexors/extensors, to hold the dumbbell, elbow extensors (and to a lesser extent elbow 
flexors) to raise the dumbbell and shoulder flexors, deltoids and pectoral muscles to assume 
and maintain the position of the shoulder during the maneuver.  Muscle groups in the trunk 
and neck are also required for stabilization in the seated position.  Improved performance on 
this measure could be used to translate any observed changes in the UEC into clinically 
meaningful benefit to the patient since reaching ability is critical to the performance of 
various activities of daily living and the maintenance of functional independence. 


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Knee Extensors  
The knee extensors (quadriceps) are widely recognized to be spared in GNE Myopathy 
relative to other lower extremity muscle groups making it a defining feature of the disease 
and instrumental in making a differential diagnosis.  Dynamometry data from the Phase 2 
study showed significant weakness in this muscle group relative to normative data although 
the magnitude of the weakness was considerably less than in the other lower extremity 
muscle groups tested.  Biopsy data from the Phase 2 study revealed limited pathology 
suggesting that there was considerable viable muscle tissue remaining in this group.  For this 
reason, strength in the knee extensors, as measured by dynamometry, is included as an 
endpoint to assess the effect of SA-ER on a relative intact lower extremity muscle group.  
It should be noted, however, that there can be considerable variability in dynamometry 
results for this large, intact muscle group, particularly among stronger patients who can 
overpower the strength of the test administrator during the maneuver. 
Six Minute Walk Test (6MWT) 
A comprehensive analysis of the 6MWT data from the UX001-CL201 study suggests that the 
test may not be appropriate for the assessment of lower extremity function in GNE 
Myopathy.  The majority of the subjects begin wearing AFOs (ankle-foot orthoses) shortly 
after diagnosis to compensate for the “foot drop” resulting from weakness in the tibialis 
anterior, the most common presenting symptom.  The AFOs, which hold the foot and ankle at 
a 90 degree angle, limit the flexibility of the foot and ankle while walking.  Specifically, they 
prevent the generation of power during the stepping process that is necessary to propel the 
body forward.  The impact this has on the ability to take longer, more frequent steps could 
interfere with the ability to detect changes in 6MWT distance even if lower extremity 
strength is improved.  In addition, stability issues resulting from extensive weakness in the 
hip and knee flexors make patients fearful of falling during walking which can compromise 
performance on this volitional test.  Supportive evidence for this includes two findings. 
First, while patients were able to walk at 61.0% predicted comfortable walking speed, they 
were only able to walk at 45.7% predicted during the rapid walking test. Second, 72.7% of 
patients able to walk ≥ 200m (70% of the patients enrolled) reported frequent falls prior to 
enrollment. Given these findings that patients may be unwilling or unable to increase walk 
distance even with improved strength, the 6MWT is not appropriate for use as a key 
secondary endpoint in this study.  
3.4 
Study Duration 
Individual subject participation in this study will be a maximum of 56 weeks, including up to 
4 weeks between Screening and Baseline visits, a treatment duration of 48 weeks, and a 
Safety Follow-up Visit occurring 4 weeks after last study drug administration. Subjects who 
complete the study may be eligible to participate in an open-label extension study. 
All subjects will be randomized to receive 6 g/day SA-ER or placebo during the 48-week 
Treatment Period. The 48-week treatment duration is also intended for collection of safety 


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data on the SA-ER tablets for long-term use and to provide sufficient insight on sustained 
clinical effects and improvements in adult GNEM patients. 
3.5 
Stratification Factors 
Subjects will be enrolled in the study and sequentially assigned an identification number.  
Approximately 80 eligible subjects will be randomized via an Interactive Web 
Randomization System (IWRS) and assigned in a 1:1 ratio to receive 6 g/day of SA-ER or 
matching placebo for 48 weeks.  Randomization of subjects will be stratified by gender with 
a planned enrollment of no more than 60% of subjects of either gender.  
3.6 
Randomization, Blinding 
The study will be conducted as a randomized, double-blind, placebo-controlled study.  
Double-blind conditions will be established so that neither the study team, subject, or site 
personnel involved in study conduct will know the identity of a subject’s treatment.  
Study parameters to achieve and maintain the double-blind status of the study include: 
• Sequential assignment of subject numbers  
• Management of subject treatment assignment via an IWRS 
• Labeling of study drug with the study number and a unique kit number 
• Packaging and delivery of study drug supplies to sites in a manner that maintains blinding 
of site personnel 
• Matched appearance of investigational product and placebo 
The Investigator and site personnel will remain blinded to the randomization treatment 
assignment during the study.  Treatment assignment for an individual subject should be 
unblinded by the Investigator only in an emergency, and only if knowledge of the treatment 
assignment is urgently needed for the clinical management or welfare of the subject.  
Treatment should be provided in accordance with the medical condition and with regard to 
the information provided in the IB.  The Investigator should contact the medical monitor or 
project manager before unblinding, when possible, but priority should be given to treatment 
of the subject.   
The Investigator must record the date and reason for revealing the blinded treatment 
assignment for that subject in the IWRS and in the source documents.  Treatment assignment 
may be unblinded by the Sponsor to satisfy expedited safety reporting requirements of 
regulatory authorities.  The system to unblind an assignment will be maintained and executed 
through an IWRS which will be available 24 hours a day, 7 days a week. 
3.7 
Determination of Sample Size 
The design and analysis of this study is intended to provide sufficient data to evaluate clinical 
efficacy of SA-ER. 


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Based on the results of the Phase 2 study (UX001-CL201), approximately 80 subjects will be 
randomized in this Phase 3 study. This sample size will provide 90% power to detect a 
difference of 5 kg in the UEC score change from baseline using a t-test between the SA-ER 
treatment and the placebo group, assuming a standard deviation of 6, and a two-sided alpha 
of 0.05. 
3.8 
Interim Analysis 
No interim analysis is planned. 
3.9 
Data Monitoring Committee 
An independent DMC with appropriate expertise in the conduct of clinical trials will act in an 
advisory capacity to monitor subject safety on a routine basis throughout the trial.  A review 
of blinded safety data will be conducted by the DMC at least twice per year, with the first 
meeting scheduled once the first subject has been enrolled. Ad hoc meetings will be held if 
indicated based on observed events.  The DMC may also provide advice to Ultragenyx in any 
determination of whether study enrollment should be paused or if the study should be halted.  
The responsibilities of the DMC will be defined in a DMC charter. 


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4 STUDY CLINICAL OUTCOMES AND COVARIATES 
All data are collected according to the schedule of assessments included in the protocol. 
Efficacy will be evaluated by changes in upper and lower extremity muscle strength and 
function, and self-reported physical functioning.  Results from baseline assessments will be 
compared with those of post-treatment assessments, with efficacy conclusions based on 
change from baseline over the treatment period in comparison with placebo. 
4.1 
Primary Clinical Efficacy Endpoint 
Upper Extremity Composite Score:  Muscle strength based on the maximum voluntary 
isometric contraction (MVIC) against a dynamometer will be measured bilaterally in the 
following upper extremity muscle groups: gross grip, shoulder abductors, elbow flexors, and 
elbow extensors.  The UEC is derived from the sum of the average of the right and left total 
force values (measured in kg). 
4.2 
Key Secondary Clinical Efficacy Endpoints 
• Lower Extremity Composite Score:  Muscle strength based on MVIC against a 
dynamometer will be measured bilaterally in the following lower extremity muscle 
groups: knee flexors, hip flexors, hip extensors, hip abductors and hip adductors. 
The LEC is derived from the sum of the average of the right and left total force values 
(measured in kg).  
• Muscle strength in knee extensors: bilateral total force defined as the average of the right 
and left force values (measured in kg).  
• GNEM Functional Activities Scale Mobility:  Lower extremity use and function will be 
assessed using the Mobility domain of the GNEM-FAS instrument a disease-specific 
measure developed to assess the functional impact of changes in muscle strength on 
mobility (reflective of the lower extremities). 
4.3 
Other Secondary Clinical Efficacy Endpoints 
• GNEM Functional Activities Scale Upper Extremity Score:  Upper extremity use and 
function will be assessed using the Upper Extremity domain of the GNEM-FAS 
instrument, a disease-specific measure developed to assess the functional impact of 
changes in upper extremity muscle strength. 
• Number of Stands in the Sit-to-Stand Test:  Lower extremity function will be assessed 
using a sit-to-stand test.  The number of times the subject can rise from a seated to a 
standing position in a 30-second period will be recorded. 
• Number of Lifts in the 30 second Weighted Arm Lift Test:  Upper extremity function will 
be assessed using a weighted arm lift test performed bilaterally.  The number of times the 
subject can raise a 1 kg weight above the head in a 30-second period will be recorded.  


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• Meters Walked in the Six-Minute Walk Test:  The total distance walked (meters) in a six 
minute period (6MWT) will be measured as well as the percent predicted distance based 
on normative data for age and gender.  
4.4 
Tertiary Efficacy Endpoints 
• Upper Extremity Composite Percent Predicted:  The percent predicted total force values 
will be determined based on reference equations adjusting for age, gender, height, and 
weight. The percent predicted force will be calculated for each side and the bilateral 
percent predicted values will be averaged for each upper extremity muscle group.  
The mean of the four averages in percent predicted scores will be calculated for each 
subject to create a percent predicted UEC score, and analyzed relative to baseline to 
create a UEC mean change in percent predicted score.     
• Lower Extremity Composite Percent Predicted:  The percent predicted total force values 
will be determined based on reference equations adjusting for age, gender, height, and 
weight. The percent predicted force will be calculated for each side and the bilateral 
percent predicted values will be averaged for each lower extremity muscle group.  
The mean of the five averages in percent predicted scores will be calculated for each 
subject to create a percent predicted LEC score, and analyzed relative to baseline to 
create a LEC mean change in percent predicted score.  
• Muscle strength (Total Force in kg)) for Each Individual Muscle Group: Bilateral total 
force for each individual muscle group included in the UEC and LEC will be reported.  
• Percent Predicted in Each Individual Muscle Group: Bilateral total force for each 
individual muscle group included in the UEC and LEC. 
• Percent of Predicted Muscle Strength in Each Individual Muscle Group: Bilateral percent 
predicted total force for each individual muscle group included in the UEC and LEC. 
• Percent Predicted in knee extensors: Bilateral percent predicted total force of knee 
extensors. 
• Total Score on the GNEM-FAS 
• Self-Care Domain Score on the GNEM-FAS 
• Individual Neuromuscular Quality of Life Questionnaire:  A 45-item self-report 
questionnaire with 4 domains on the impact of key muscle disease symptoms on the 
ability to perform basic activities of daily living, functional independence, relationships 
and overall well-being will be administered. The individual domain scores will be 
calculated. 
• Clinical Global Impression Scale:  Investigator assessment of severity of subject’s 
GNEM using the CGI-improvement scale (CGI-I) during treatment, in 3 target areas.  
• 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. 


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4.5 
Drug Concentration Measurements 
• Serum Free Sialic Acid: The change in free SA level.  
• Urine Sialic Acid - Free, Total and Bound: Changes from baseline in urine free, total and 
bound SA levels. 
4.6 
Urine Testing for ManNAc:  
Urine will be tested for the presence of ManNAc to detect compliance with prohibited 
medication restrictions.  
• Changes from baseline in Free ManNAc levels in urine will be analyzed. 
4.7 
Safety Endpoints 
Safety will be evaluated by the incidence and frequency of adverse events (AEs) and serious 
adverse events (SAEs), including clinically significant changes from study baseline to 
scheduled time points in the following: 
• Interval history 
• Vital signs 
• Physical examination results 
• Clinical laboratory results  
• Suicidal ideation and behavior 
• Concomitant medications 
4.8 
Potential Covariates 
All models used for each individual clinical endpoint will incorporate the baseline value, 
gender and region as covariates. Region is comprised of two levels, one that combine all sites 
in North America, and the other one combines all sites in the rest of the world. Additional 
covariates may be used and the details will be included in the analysis model. 


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5 DEFINITIONS 
5.1 
Baseline 
Baseline is defined as the last assessments prior to or on the date of first dose of 
investigational product administration. Analyses will indicate if a different baseline value is 
used.  
5.2 
Drug Compliance 
Compliance = total dosage received / total dosage planned * 100%. Total dose planned is 
calculated for the period a subject is on investigational product, which is either 48 weeks if a 
subject completes the study, or the period up to early withdrawal.  
5.3 
Muscle Strength  
The highest value of the three measurements collected for each muscle will be used for all 
HHD endpoints. 
• 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.  
• HHD Upper Extremity (UE) Composite Score is calculated as the sum of the 
individual muscle strength average scores for the following muscle groups: gross grip, 
shoulder abductors, elbow flexors and elbow extensors. If a component individual muscle 
strength raw score is missing, the composite score will not be computed.  
• HHD Lower Extremity (LE) Composite Score is calculated as the sum of the 
individual muscle strength average scores for the following muscle groups: hip flexors, 
hip extensors, hip abductors, hip adductors and knee flexors.  Knee extensors will not be 
included in the calculation of the LE HHD composite score.  If a component individual 
muscle strength raw score is missing, the composite score will not be computed. 
• HHD Total Composite Score is calculated as the sum of the HHD UE composite score 
and the HHD LE composite score. If the UE or LE composite scores are missing, the 
HHD Total Composite Score will not be computed. 
• Predicted Normal HHD Values will be derived for the raw right/left strength values 
from bilateral pinch, gross grip, shoulder abductors, elbow flexors, elbow extensors, hip 
flexors, hip extensors, hip abductors, hip adductors, knee flexors and knee extensors 
collected at Baseline using the regression equations outlined in Appendix 10.4. Predicted 
normal HHD scores for derived variables such as individual muscle raw score, UE/LE 
composite score, and total composite score will use the same computation method for raw 


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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.  
• % of predicted Total HHD UE and LE values will be calculated as follows:  (Raw 
strength value/Predicted normal strength value) *100%. Percent predicted total normal 
strength value is the sum of percent predicted values of individual muscle groups. 
5.4 
Patient Reported Outcomes 
• GNEM Functional Activities Scale (GNEM-FAS) Total Score will be calculated as the 
sum of the Total Scores range from 0 to 100 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 range from 
0 to 40 with higher scores representing greater mobility.  Upper Extremity subscale 
scores range from 0 to 32 with higher scores representing more skilled, independent use 
of the arms during functional activity performance.  Self-Care subscale scores range from 
0 to 28 with higher scores representing greater independence with functional care 
activities.  
• Individual Neuromuscular Quality of Life Scale (INQoL) Subscale and QoL: The 
individual domain scores will be calculated using the scoring algorithms outlined in 
Appendix 10.5 Derived Variables. 
• Number of doses administered will be calculated for each subject by summing the 
number of doses administered over all visits. 
• Prior medications include all medications taken by the subject from 30 days prior to the 
signing of the informed consent until the first dose of study medication is administered.  
• Concomitant medications include all medications that are taken after the first dose of 
study medication is administered. 


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6 ANALYSIS POPULATIONS 
6.1 
Primary Analysis Set 
The Primary Analysis Set will include all randomized subjects with a baseline measurement 
and at least one post-baseline measurement. Each subject will be included in the treatment 
group assigned at randomization, regardless of the treatment received. This set will be used 
for the primary analyses of all efficacy endpoints. 
6.2 
Per Protocol Set 
The per protocol analysis set consists of all subjects in the Primary Analysis Set who have a 
dosing compliance rate ≥ 80%.  
6.3 
Safety Analysis Set 
The safety analysis set consists of all subjects randomized and received at least one dose of 
investigational product. This analysis set will be used for the analyses of all safety endpoints. 
6.4 
Sialic Acid (SA) Analysis Set  
The SA analysis set will consist of all randomized subjects with evaluable free serum SA 
levels at any time point. 


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7 DATA SCREENING AND ACCEPTANCE 
7.1 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed patient 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 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. For UEC and 
LEC, if measurements are missing for both sides while patients are still in study, the 
composite score will not be computed. Such cases are expected to be limited. Details of 
missing observation handling in HHD for individual muscle group are provided in  
Appendix 10.2. The handling of missing data in individual questions in GNEM-FAS can also 
be found in Appendix 10.2. 
In general, randomly missing assessments for an individual subject would remain as missing. 
The important case for imputation will be those subjects who are in the study for some period 
of time but decline in function and leave the study, regardless of whether this decline is the 
reason listed for withdrawal. The GEE method might not adequately cover the projected 
decline for these subjects and may not be appropriately conservative. In such cases a single 
imputation method will be used to estimate the change in strength over the remaining time of 
the study and these imputed values will be used for the GEE analysis. 
For those early-withdraw subjects who are in the study for some period of time (defined as at 
least one non- missing post-baseline visit) but decline (defined as negative change from 
baseline to the last non-missing post-baseline visit), all missing post-baseline data will be 
imputed for the HHD efficacy endpoints such as UE, LE, and Knee extensors. The imputed 
values are calculated using the subject’s average change at previous time points adjusted by 
the timing of missing data.  For example, for a subject with only the first 2 data values the 
average of the existing values is taken and the rest are imputed by multiplying the average  
by the (duration of each missing)/(duration of last non missing). See Table 7.1.1 for an upper 
extremity example. 


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Table 7.1.1: An example of the imputation method for a subject with only 2 values 
Week 
Change from 
baseline 
Average of existing 
data 
Imputed values 
8 
-1 
 
 
16 
-2 
 
 
 
 
-1.5 
 
24 
Missing 
 
-1.5x(24/16) =-2.25 
32 
Missing 
 
-1.5x (32/16)=-3.00 
40 
Missing  
 
-1.5x (40/16)=-3.75 
48 
Missing 
 
-1.5x (48/16)=-4.50 
 
In order to avoid extreme cases of imputed values that would not reflect the clinical course of 
the disease, if any of the imputed values for a subject obtained using the proposed method 
yields values greater (in magnitude) than the worst observed decline of all other subjects at 
the imputed time point, then the worst observed decline of the other subjects at that time 
point will be used. This will be done separately for each treatment group.  
7.2 
Partial or Missing Dates Imputation Rules 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.  In those circumstances, the imputed value may 
be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will be assigned 
a missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute the month and day 
of the first dose date. 
ii) Otherwise, assign ‘January.‘  
3) 
If the day is unknown, then: 
i) If the month and year match the first dose date month and year, then impute 
the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 


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B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will be assigned 
a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
7.3 
Software 
SAS® software version 9.2 or higher will be used to perform all statistical analyses. 


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8 STATISTICAL METHODS OF ANALYSIS 
8.1 
General Principles 
Efficacy analyses will be based on the primary analysis set.  GEE analysis  
(Hanley et al. 2003) for repeated measures will be performed to compare the two treatment 
groups with respect to the changes from baseline of primary endpoint, secondary endpoints, 
and all tertiary efficacy endpoints, using an exchangeable working covariance structure 
among time points. Baseline, gender and region will be included as covariates in the model. 
Compound symmetry may be used if convergence is not achieved or if the AIC is larger than 
the one from the exchangeable covariance structure. 
In general, randomly missing efficacy data for an individual subject will be treated as 
missing. The GEE method might not adequately cover the projected decline for these 
subjects and may not be appropriately conservative. In such cases a single imputation method  
will be used to estimate the change in strength over the remaining time of the study as 
described in Section 7.1 and these imputed values will be used for the GEE analysis. 
This method of imputation will be the primary analysis method for all repeated measures 
endpoints.  
A sensitivity analysis without use of the single imputation method for dropouts will be also 
be performed using the same GEE 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, standard errors, 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. 
8.2 
Visit Window Definition 
Unscheduled visit occurring prior to or on the date of initiation of the first dose will be 
mapped to the baseline visit if it is the latest assessment prior to or on the date of initiation of 
the first dose; otherwise no mapping will be performed.  
Unscheduled visit and early termination visits occurring after the date of initiation of the first 
dose will be mapped to the closest post-baseline scheduled visit according to Table 8.2.1. If 
the unscheduled visit is in the middle of two scheduled visits, map to the later one. 
When there are more than one measurements mapped to the same scheduled visit (including 
the original measurement taken from the scheduled visit), the measurement taken on the 
scheduled visit will be used if it is not missing, otherwise the one closest to the target day 
will be used. If more than one visit has the equal distance to the target day then the later one 


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Page 28 
will be used. If more than one measurement collected on the same day, use the time or the 
sequence number to select the latest record.  
Table 8.2.1: Visit Window Definition 
Visit 
Target Day 
Window 
Screening 
Day -4 to -1 
Days < 0 
Baseline 
Day 1 
Days = 1 
Week 8 
Day 57 
Days [1, 85] 
Week 16 
Day 113 
Days [86, 141] 
Week 24 
Day 169 
Days [142, 197] 
Week 32 
Day 225 
Days [198, 253] 
Week 40 
Day 281 
Days [254, 309] 
Week 48 
Day 337 
Days >= 310 
 
8.3 
Demographics 
Summary statistics will be presented for the following variables by treatment group: 
• Gender 
• Ethnicity 
• Race 
• Age at diagnosis  
• Age at start of treatment 
• Height (cm)   
• Weight (kg)   
8.4 
Disease Characteristics and Medical History 
Summary statistics will be presented for disease characteristics and medical history by 
treatment group.  
8.5 
Patient Accountability 
The number of subjects randomized to each treatment group, included in the primary and 
safety analysis sets, will be summarized. The reason for treatment discontinuation and study 
discontinuation will also be summarized by treatment group. 


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8.6 
Extent of Exposure 
The number of doses, total dose and duration of treatment per patient administered, and 
dosing compliance will be summarized overall and by treatment group for the Safety 
Population. Study medication dispensing and treatment compliance will also be listed. 
Compliance = total dosage received / total dosage planned * 100% 
8.7 
Primary Efficacy Endpoint and Analysis 
The primary clinical efficacy analysis will be the changes from baseline in UEC score over 
time for the SA-ER group compared with placebo based on bilateral strength recorded in the 
following muscle groups using a dynamometer: gross grip, shoulder abductors, elbow 
flexors, and elbow extensors.  The UEC is derived from the sum of the muscle groups.  
Each muscle group value will represent the average of the right and left total values 
(measured in kg).  
The comparison of the two treatment groups will be based on the changes from baseline over 
time in mean UEC score between SA-ER and placebo using the week 48 ls-means from GEE 
repeated measures analysis with baseline, gender, and region as covariates. Region is 
considered as a covariate to account for the heterogeneity of the disease observed in some 
European countries and Israel relative to North American patients. 
The imputations method described in Section 7.1 will be used to estimate the change in 
strength for dropouts. Sensitivity analyses will also be performed as described in Section 8.1. 
In addition, the primary analysis will be repeated in the Per Protocol population.   
8.8 
Analyses of Secondary and Tertiary Endpoints 
Analyses of the secondary and tertiary efficacy variables will follow the same methods as the 
primary analysis of the primary endpoint.  The key and other secondary clinical efficacy 
analyses will assess the change from baseline to week 48 for the SA-ER group compared 
with the placebo group using the same methodology as the one for the primary endpoint. 
Sensitivity analysis will be conducted only for the key secondary endpoints as described in 
Section 8.1. 
8.8.1 
Analyses of Key Secondary Endpoints 
Key secondary endpoints include the following: 
• Lower Extremity Composite Score:  Muscle strength based on MVIC against a 
dynamometer will be measured bilaterally in the following lower extremity muscle 
groups: knee flexors, hip flexors, hip extensors, hip abductors and hip adductors. 
The LEC is derived from the sum of the average of the right and left raw scores 
(measured in kg) at each time point through week 48. 


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• GNEM Functional Activities Scale Upper Extremity Domain score: this is a domain of 
the GNEM Functional Activities Scale reflective of upper extremity muscle strength 
• Number of Stands in the Sit-to-Stand Test:  Lower extremity function will be assessed 
using a sit-to-stand test.  The number of times the subject can rise from a seated to a 
standing position in a 30-second period will be recorded. 
• Number of Lifts in the 30 second Weighted Arm Lift Test:  Upper extremity function will 
be assessed using a weighted arm lift test performed bilaterally.  The number of times the 
subject can raise a 1 kg weight above the head in a 30-second period will be recorded.  
• Meters Walked in the Six-Minute Walk Test:  The total distance walked (meters) in a 
six minute period (6MWT) will be measured as well as the percent predicted distance 
based on normative data for age and gender.  
No adjustment for multiplicity will be performed for these endpoints. Each endpoint will be 
tested at the 0.05 two sided level of significance and nominal p-values will be reported using 
the same GEE model as the one for the primary analysis.  
Two sets of analyses will be conducted on Functional Activities Scale of upper extremity: 
one will be on the primary analysis set, and the other will be on the subset of subjects that 
excludes those subjects with the maximum score at baseline. For example, subjects with a 
baseline score of 32 in upper extremity will be excluded from the analysis of the upper 
extremity scale. The same method of analysis model (GEE) as the one for the analysis of the 
primary endpoints will be used. 
In addition, in the subjects with a baseline score less than the maximum of 32 on the GNEM-
FAS upper extremity scale, the proportion of subjects in each treatment group who achieve 
the MID as defined by an increase in UE domain score of at least 1.47 points (GNEM-FAS 
Dossier) indicating an improvement in UE function or a decrease of at least 1.47 points in 
UE domain score indicating a decline in UE function or changes between -1.47 and 1.47 will 
be summarized descriptively as a supportive analysis. 
In addition, the cumulative distribution Curve based on change from baseline to Week 48 in 
FAS UE will be provided separately in each treatment group. 
8.8.3 
Analyses of Tertiary Endpoints 
Analyses of the tertiary efficacy endpoints will follow the same methods as the primary 
analysis of the primary endpoint unless otherwise stated. No sensitivity analysis will be 
performed for tertiary efficacy endpoints. 
Tertiary efficacy endpoints include the following: 
• Upper Extremity Composite and Lower Extremity Composite Percent Predicted:  
The percent predicted total force values will be determined based on reference equations 
adjusting for age, gender, height, and weight (APPENDIX 10.2). The percent predicted 
force will be calculated for each side and the bilateral percent predicted values will be 


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averaged for each upper extremity muscle group.  The mean of the four averages in 
percent predicted scores will be calculated to create a percent predicted UEC score for 
each subject, and analyzed relative to baseline to create a UEC mean change in percent 
predicted score.  Similar methodology will be used to determine the percent predicted 
total force values for the LEC. Summary statistics on the changes from baseline will only 
be presented.   
• Muscle Strength Total Force (kg) and Percent Predicted in Each Individual Muscle 
Group: Bilateral total force and percent predicted total force for each individual muscle 
group included in the UEC and LEC and percent predicted for the knee extensors will be 
reported. Summary statistics on the changes from baseline will only be presented. 
• Total Score on the GNEM-FAS 
• Self-Care Domain Score on the GNEM-FAS 
• Individual Neuromuscular Quality of Life Questionnaire:  The individual domain scores, 
a 45-item self-report questionnaire on the impact of key muscle disease symptoms on the 
ability to perform basic activities of daily living, functional independence, relationships 
and overall well-being will be recorded.  
• Clinical Global Impression Scale:  Investigator assessment of severity of subject’s 
GNEM using the CGI-Severity scale (CGI-S) and improvement (CGI-I) during treatment. 
Physicians caring for each subject will provide a global assessment of change using a 
seven point scale ranging from 1 (normal) to 7 (extremely affected) for CGI-S at Baseline 
and -3 (severe worsening) to +3 (significant improvement) for CGI-I at Week 24 and 
Week 48. Descriptive statistics and number and percentage of subjects will be reported 
for CGI-S. The CGI-I score will be analyzed using GEE as well as a shift table 
conditional on the CGI-S categories at baseline.  
No adjustment for multiplicity will be performed for these endpoints. Each endpoint will be 
tested at the 0.05 two sided level of significance and nominal p-values will be reported. 
8.8.4 
Analyses of Sialic Acid, Creatine Kinase and Free ManNAc 
The following clinical lab outcomes will be analyzed using GEE using the SA analysis set. 
No imputation will be performed for missing data. Free, total, and bound urine SA and urine 
ManNAc are collected at Baseline, Week 24, and Week 48. All other labs are collected every 
8 weeks up to Week 48.  
• 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 
• Free SA in urine: Free SA levels in urine will be assessed to determine the overall 
absorption of SA-ER over time.  Free SA levels in urine will be expressed in micrograms 
of SA per ml of urine. 


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• Total SA in urine: Total SA levels in urine will be assessed to determine the accumulated 
excretion of sialic acid from dosing. Total SA levels in urine will be expressed in 
micrograms of SA per ml of urine. 
• Bound Sialic Acid in urine: Bound SA levels in urine is calculated as the difference 
between each subject’s total sialic acid and free sialic acid in urine corrected for total 
protein.  Bound sialic acid in urine may also be corrected for creatine and calculated as 
the difference between each subject’s total sialic acid and free sialic acid corrected for 
creatine.  The primary correction for SA  will be total protein with creatine correction 
only used when an alternate method is required 
• 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. 
• Free ManNAc in urine: Free ManNAc levels in urine will be assessed to determine the 
amount of naturally occurring ManNAc in the urine of study subjects and the stability of 
these levels over time.  Free ManNAc levels in urine will be expressed in micrograms of 
SA per ml of urine. Changes from baseline in Free ManNAc levels in urine will be 
analyzed. 
• Free ManNAc/Free SA in urine: The ratio of free ManNAc to free SA levels in urine will 
be assessed to ensure compliance with the restriction placed on ManNAc consumption 
during the study period.   
8.9 
Safety Analyses 
Analysis of safety will be performed on the safety analysis set.  Blinded study data will be 
monitored on an ongoing basis by the clinical study team including the medical monitor and 
the clinical drug safety team to ensure patients’ safety.  
Safety will be evaluated by the incidence, frequency and severity of AEs and SAEs, 
including clinically significant changes from study baseline to scheduled time points in: 
• Interval history 
• Vital signs and weight 
• Physical examination findings 
• Clinical laboratory evaluations 
• Suicidal ideation and behavior assessments 
• Concomitant medications 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
17.1 or beyond). The incidence and frequency of treatment emergent AEs (occurred after the 
first dose of study drug) will be summarized by System Organ Class (SOC), Preferred Term 
(PT), severity, and relationship to treatment.  The numbers (frequency) and incidence rates of 
AEs and SAEs will be summarized by treatment group. A by-subject listing will be provided 


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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. Each of these outputs will 
include tabulation by maximum severity for each SOC and preferred term.  Summaries of 
AEs will be provided in descending order of frequency by SOC and preferred term. 
Additional tables summarizing patient incidence (by preferred term) of the following will be 
generated: 
• All AEs; 
• SAEs; 
• Treatment-related AEs; 
• Treatment-related SAEs; 
• AEs leading to the discontinuation of study drug  or discontinuation of study; 
• Deaths. 
Separate outputs maybe be provided for subgroups defined by gender, and race (if feasible).  
Detailed listings for all AEs and listings and/or narratives will be provided for serious and 
significant AEs, deaths (with “on-study” deaths [deaths that occur before the end of safety 
follow-up period] identified). 
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 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. 
Interval history for all subjects in the safety population will be reported in a listing.   
Clinical Laboratory Parameters 
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 or shifts of normal/abnormal status from study baseline to the post-treatment 
visits will be provided. 
Concomitant Medications 
The number and proportion of patients receiving each reported medication will be 
summarized by Anatomical Therapeutic Chemical (ATC) code (WHO Drug version 


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December 2014 or beyond) and preferred term for each treatment group as coded by the 
World Health Organization Drug (WHODRUG) dictionary.  A listing of all concomitant 
medications by patient will also be provided. 
Physical Exam  
Complete physical examinations, including a neurological examination, will be performed at 
Baseline, Weeks 24 and. Brief physical examinations will be performed at Week 8, 16, 32, 
and 40. The full physical examination results will be reported in a shift table, if appropriate, 
by examination category. The physical examinations will also be listed. 
Vital Signs  
Vital signs are collected every 8 weeks including 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 reported descriptively at each time point.  
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. 
Results for all subjects in the safety population will be reported in listing format. 
8.9.1 
Adverse Events to Monitor 
Appendix 10.6 includes certain adverse events and liver related investigations.  
Tables summarizing patient incidence of the following will be generated: 
• All AEs; 
• SAEs; 
• Treatment-related AEs; 
• Treatment Related SAEs 
• Liver-related Investigations  


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9 REFERENCES 
Bohannon, RW. 1997a. "Comfortable and maximum walking speed of adults aged 20-79 
years: reference values and determinants." Age Ageing 26 (1):15-9. 
Bohannon, RW. 1997b. "Reference values for extremity muscle strength obtained by hand-
held dynamometry from adults aged 20 to 79 years." Arch.Phys.Med.Rehabil. 78 (1):26-32. 
Febrer, A, Rodriguex, N, Alias, L, and Tizzano, E. 2010. "Measurement of Muscle Strength 
with a Handheld Dynamometer in Patients with Chronic Spinal Muscular Atrophy." J 
Rehabil Med 42:228-231. 
Hanley, JA, Negassa, A, Edwardes, MD, and Forrester, JE. 2003. "Statistical analysis of 
correlated data using generalized estimating equations: an orientation." Am J Epidemiol 157 
(4):364-75. 
Hebert, L, Remec, J, Saulnier, J, Vial, C, and Puymirat, J. 2010. "The use of muscle strength 
assessed with handheld dynamometers as a non-invasive biological marker in myotonic 
dystrophy type 1 patients: a multicenter study." BMC Musculoskelet Dosord 11 (72):1-9. 
Hochberg, Y. 1988. "A sharper Bonferroni procedure for multiple tests of significance." 
Biometrika 75 (4):800-802. 
Merlini, L, Mazzone, ES, Solari, A, and Morandi, L. 2002. "Reliability of hand-held 
dynamometry in spinal muscular atrophy." Muscle Nerve 26 (1):64-70. 
NIMS. 1996. "Muscular weakness assessment: use of normal isometric strength data. The 
National Isometric Muscle Strength (NIMS) Database Consortium." Arch Phys Med Rehabil 
77 (12):1251-5. 
Peters, MJ, van Nes, SI, Vanhoutte, EK, Bakkers, M, van Doorn, PA, Merkies, IS, Faber, 
CG, and PeriNom, SSg. 2011. "Revised normative values for grip strength with the Jamar 
dynamometer." J Peripher Nerv Syst 16 (1):47-50. 
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, 
Melvin, GA, Greenhill, L, Shen, S, and Mann, JJ. 2011. "The Columbia-Suicide Severity 
Rating Scale: initial validity and internal consistency findings from three multisite studies 
with adolescents and adults." Am J Psychiatry 168 (12):1266-77. 
Stoll, T, Huber, E, Seifert, B, Michel, BA, and Stucki, G. 2000. "Maximal isometric muscle 
strength: normative values and gender-specific relation to age." Clin Rheumatol 19 (2):105-
13. 
Stuberg, WA, and Metcalf, WK. 1988. "Reliability of quantitative muscle testing in healthy 
children and in children with Duchenne muscular dystrophy using a hand-held 
dynamometer." Phys Ther 68 (6):977-82. 


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van der Ploeg, AT, Clemens, PR, Corzo, D, Escolar, DM, Florence, J, Groeneveld, GJ, 
Herson, S, Kishnani, PS, Laforet, P, Lake, SL, Lange, DJ, Leshner, RT, Mayhew, JE, 
Morgan, C, Nozaki, K, Park, DJ, Pestronk, A, Rosenbloom, B, Skrinar, A, van Capelle, CI, 
van der Beek, NA, Wasserstein, M, and Zivkovic, SA. 2010. "A Randomized Study of 
Alglucosidase Alfa in Late-Onset Pompe's Disease." N Engl J Med 362 (15):1396-1406. 
Vincent, KA, Carr, AJ, Walburn, J, Scott, DL, and Rose, MR. 2007. "Construction and 
validation of a quality of life questionnaire for neuromuscular disease (INQoL)." Neurology 
68 (13):1051-7. 
Visser, J, Mans, E, de Visser, M, van den Berg-Vos, RM, Franssen, H, de Jong, JM, van den 
Berg, LH, Wokke, JH, and de Haan, RJ. 2003. "Comparison of maximal voluntary isometric 
contraction and hand-held dynamometry in measuring muscle strength of patients with 
progressive lower motor neuron syndrome." Neuromuscul Disord 13 (9):744-50. 
 


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10 APPENDICES 
10.1 Schedule of Events 
ASSESSMENTS AND EVENTS* 
SCREENING
 a 
BASELINE
 a 
TREATMENT PERIOD
 b 
SAFETY 
FOLLOW-UP
 c 
WEEK 
-4 to -1 
0 
4 (TC) 
8 
16 
24 
32 
40 
48/ETa 
52 
INFORMED CONSENT  
X 
 
 
 
 
 
 
 
 
 
MEDICAL HISTORY, HEIGHT AND WEIGHT  d 
X 
 
 
 
 
 
 
 
 
 
DYNAMOMETRY  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
6-MINUTE WALK TEST (6MWT)  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
SIT-TO-STAND TEST  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
WEIGHTED ARM LIFT TEST  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
GNE MYOPATHY FUNCTIONAL 
ACTIVITIES SCALE (GNEM-FAS) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
INDIVIDUAL NEUROMUSCULAR 
QUALITY OF LIFE QUESTIONNAIRE  
(INQOL) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
CREATINE KINASE 
 
X 
 
X 
X 
X 
X 
X 
X 
 
CLINICAL GLOBAL IMPRESSION SCALE (CGI) e 
 
X 
 
 
 
X 
 
 
X 
 
FREE SERUM SA LEVELS f 
 
X 
 
X 
X 
X 
X 
X 
X 
 
FREE, TOTAL AND BOUND URINE SA LEVELS f 
X 
X 
 
 
X 
 
X 
 
X 
 
URINE TEST FOR MANNACg 
X 
X 
 
 
X 
 
X 
 
X 
 
INTERVAL HISTORY h 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PHYSICAL EXAMINATION  
X 
X i 
 
X 
X 
X i 
X 
X 
X i 
X 
VITAL SIGNS  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
HEMATOLOGY, CHEMISTRY PANEL, 
URINALYSIS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PREGNANCY TEST 
X 
X 
 
 
X 
 
X 
 
X 
X 


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ASSESSMENTS AND EVENTS* 
SCREENING
 a 
BASELINE
 a 
TREATMENT PERIOD
 b 
SAFETY 
FOLLOW-UP
 c 
WEEK 
-4 to -1 
0 
4 (TC) 
8 
16 
24 
32 
40 
48/ETa 
52 
CONCOMITANT MEDICATIONS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
SUICIDAL IDEATION AND BEHAVIOR  j 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ADVERSE EVENTS  
X 
X  
Xb 
X 
X 
X 
X 
X 
X 
X 
TREATMENT DISPENSED  k 
 
X 
 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE 
 
 
 
X 
X 
X 
X 
X 
X 
 
* 
Refer to Study Reference Manual for recommended timing and order of assessments to be administered at each study visit 
a 
Potential subjects will be screened approximately seven days (up to 28 days) before the Baseline Visit. Study drug will be dispensed only after all study 
procedures at the Baseline Visit have been performed. For subjects who discontinue prior to completing the study, every reasonable effort should be made to 
perform the Early Termination (ET) procedures within four weeks of discontinuation. 
b 
Visits occur every 8 weeks ± 5 days; subjects will be contacted by telephone call (TC) at Week 4 for abbreviated safety assessment. Additional unscheduled 
telephone calls may also occur for subject follow up. Unscheduled visits are allowed for safety or administrative purposes. Notify the medical monitor before 
an unscheduled visit.  
c 
The Safety Follow-up visit occurs four weeks (± 5 days) after a subject receives the last dose of study medication (i.e. Week 52).   
d 
Medical history will include a detailed GNEM disease-specific medical history. 
e 
CGI-Severity scale will be assessed at Baseline (Week 0) along with identification of 3 target areas for disease improvement; CGI-Improvement scale will 
be assessed at each subsequent visit using 3 target areas identified at Baseline. 
f 
Pre-dose blood samples and first-morning void urine will be collected to assess trough SA levels; record volume of urine collected.  
g 
An aliquot from first morning void urine will be used for assessment of ManNAc; record volume of urine collected. 
h 
Interval history will include any signs, symptoms, or events (i.e. falls) experienced by the subject since the prior study visit that are not related to study 
procedure(s) performed at prior study visits or study drug.  Interval history may include exacerbation or improvement in existing medical conditions 
(including the clinical manifestations of GNEM) that might interfere with study participation, safety, and/or positively or negatively impact performance of 
functional assessments. 
i 
The physical examinations at Baseline and Weeks 24 and 48 will be complete, including a neurological examination; all others will be brief physical 
examinations. 
j 
Baseline/Screening C-SSRS administered at Screening and Baseline visits.  Since Last Visit C-SSRS administered at all subsequent visits. 
k 
Subjects should be instructed to return unused study drug and packaging to every visit. 


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


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


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


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10.3 Computation Formula for Derived HHD Variables 
Individual Muscle Strength Average Score = (left-side measurement + right-side 
measurement) / 2 
UE Composite Score = sum( Individual Muscle Strength Average Score for muscle group 
gross grip, shoulder abductors, elbow flexors and elbow extensors) 
LE Composite Score = sum(Individual Muscle Strength Average Score for muscle group 
hip flexors, hip extensors, hip adductors and knee flexors) 
Total Composite Score = sum(UE score + LE score) 
Predicted Normal for Individual Muscle Strength Average Score = (left-side predicted 
normal + right-side predicted normal) / 2 
Predicted Normal for UE Composite Score = sum(Predicted Normal for Individual Muscle 
Strength Average Score for muscle group gross grip, shoulder abductors, elbow flexors and 
elbow extensors) 
Predicted Normal for LE Composite Score = sum(Predicted Normal for Individual Muscle 
Strength Average Score for muscle group hip flexors, hip extensors, hip adductors and knee 
flexors) 
Predicted Normal for Total Composite Score = sum(Predicted Normal for UE + Predicted 
Normal for LE) 
% of predicted normal HHD values = (Observed strength value/  Predicted normal strength 
value) *100%.  
Predicted Normal HHD Values can be derived using the regression equations outlined in 
Appendix 10.4.  


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


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


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Gross Grip 
Normative grip strength values for the Jamar dynamometer for clinical use (in pounds) 
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. 
Walking Ability 
Calculation of Predicted Six-Minute Walk Test Distance 
6MWT Distance (meters) = 868.8 - (2.99*Age) – (74.7*Gender) 
Age in years. Men = 0 and Women = 1.  
Gibbons WJ,  Fruchter N,  Sloan S, Levy RD. Reference Values for a Multiple Repetition 
6-Minute Walk Test in Healthy Adults Older than 20 Years. J Cardpulm Rehabil. 2001 
Mar/Apr; 21(2):87-93 
Note: The age of a subject at the Baseline visit will be used for the calculation of 6MWT 
predicted values for all study time points. 


Study Number:  UX001-CL301  
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Gait Speed Tests 
Mean (X) and Standard Deviation (SD) of Comfortable and Maximum Gait Speed 
Presented by Gender and Decade of Age 
COMFORTABLE GAIT SPEED (cm/sec) 
MAXIMUM GAIT SPEED (cm/sec) 
 
Actual 
Height 
Normalized* 
Actual 
Height 
Normalized* 
Sex/decade 
X 
SD 
X 
SD 
X 
SD 
X 
SD 
Men 
 
 
 
 
 
 
 
 
20s 
139.3 
15.3 
0.788 
0.093 
253.3 
29.1 
1.431 
0.162 
30s 
145.8 
9.4 
0.828 
0.052 
245.6 
31.5 
1.396 
0.177 
40s 
146.2 
16.4 
0.829 
0.090 
246.2 
36.3 
1.395 
0.197 
50s 
139.3 
22.9 
0.794 
0.119 
206.9 
44.8 
1.182 
0.259 
60s 
135.9 
20.5 
0.777 
0.116 
193.3 
36.4 
1.104 
0.198 
70s 
133.0 
19.6 
0.762 
0.105 
207.9 
36.3 
1.192 
0.201 
Women 
 
 
 
 
 
 
 
 
20s 
140.7 
17.5 
0.856 
0.098 
246.7 
25.3 
1.502 
0.142 
30s 
141.5 
12.7 
0.864 
0.087 
234.2 
34.4 
1.428 
0.206 
40s 
139.1 
15.8 
0.856 
0.098 
212.3 
27.5 
1.304 
0.160 
50s 
139.5 
15.1 
0.863 
0.104 
201.0 
25.8 
1.243 
0.158 
60s 
129.6 
21.3 
0.808 
0.131 
177.4 
25.4 
1.107 
0.157 
70s 
127.2 
21.1 
0.807 
0.131 
174.9 
28.1 
1.110 
0.176 
(Bohannon 1997a) 
* actual speed (cm/s)/height (cm). 
Note: Height normalized values will be used for the calculation of predicted comfortable and 
maximum gait speeds.  The age category (in decades) of a subject at the Baseline visit will be 
used for the calculation of comfortable and maximum gait speed predicted values for all 
study time points. 


Study Number:  UX001-CL301  
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10.5 Patient-reported Outcomes 
Individual Neuromuscular Quality of Life Questionnaire (INQoL) 
Dimensions 
Subscales 
Number 
of Items 
Cluster of 
Items 
Item 
Reversion 
Direction of 
Dimensions 
Symptoms 
Weakness 
3 
1 a, b, c 
No 
 
Locking 
3 
2 a, b, c 
Pain 
3 
3 a, b, c 
Fatigue 
3 
4 a, b, c 
Life domains 
Activities 
5 
5 AI, II, III 
5 BI, II 
No 
Higher scores = 
higher impact 
Independence 
3 
6A, 6BI, 6BII 
Social 
relationships 
10 
7AI, II, III, IV 
7 BI, II, III, IV, 
V, VI 
Emotions 
6 
8AI, II, III, IV, 
BI, II 
Body image 
3 
9A, 9BI, II 
Treatment 
effects (not 
included in this 
study) 
Perceived 
treatment effects 
3 
10AI, III 
10BI, III 
No 
 
Expected 
treatment effects 
3 
10AII, AIII, 
10BII, III 
Quality of life 
NA 
14 
Items from 
section B for 
questions 5 to 9 
No 
 
 


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SCORING OF DIMENSIONS: 
Item Scaling 
7-point Likert scale from 1 to 7 for items 1a, 2a, 3a, 4a 
7-point Likert scales from 0 to 6: for all other items 
Weighting of 
items 
Yes. Please see the scoring procedure below 
Extension of the 
scoring scale 
0-100 
Scoring 
Procedure 
1. Weakness score = (a+b+c) / 19 X 100 
 
2. Muscle ‘locking’ score = (a+b+c) / 19 X 100 
3. Pain score = (a+b+c) / 19 X 100 
4. Fatigue score = (a+b+c) / 19 X 100 
5. Activities score = [4 X (AI+AII+AIII)] + [3 X (BI+BII)] / 108 X 100 
     If not working due to condition item  AIII=6 
     If retired/unemployed/work in home (not as a result of condition) 
      [6 X (AI+AII)] + [3 X (BI+BII)] / 108 X 100 
6. Independence score = [12 X A] + [3 X (BI+BII)] / 108 X 100 
7. Social relationships = [3 X (AI+AII+AIII+AIV)] + [BI+II+III+IV+V+VI] / 108 X 100 
     If partner/spouse item (AI) not applicable: 
      [4 X (AII+AIII+AIV)] + [BI+II+III+IV+V+VI] / 108 X 100 
8. Emotions score = [3 X (AI+AII+AIII+AIV)] + [3 X (BI+BII)] / 108 X 100 
9. Body Image score = [12 X (A)] + [3 X (BI+BII)] / 108 X 100 
10. Qol score: Add scores of items in section B for questions 5-9 (with correction i.e. 3X 
(BI + B2) for Quns 5,6,8&9 and BI+II+III+IV+V+VI for Qun 7), divide total score by 180 
and multiply by 100 (to achieve percentage score) 


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Interpretation 
and Analysis of 
missing data 
Quns 1-4 
1A-4A If missing and rest of symptom qun missing (i.e. part B)  score zero 
     1B-4B a. If missing, score “1” 
                b. If missing, impute previous value (part a) 
                c. If missing, score “0” 
Qun 5 
5 
A. If an item missing, sum completed items, and multiply by 6 if two items completed 
and 12 if only one item has been completed (to get score out of 72) 
(N.B. “Work activities” item: if not working due to condition score “6” and count as a 
completed item). 
     EXAMPLE: If “Leisure activities” is missing, add values of “Daily activities” & “Work 
Activities”. Multiply this by 6. 
     BI. If missing, impute average of completed “activities” items (from 5A) 
     BII. If missing, score as “0” 
Qun 6 
6     A. if missing, score as “0” 
       BI. If missing, impute value from 6A 
       BII. If missing, score as “0” 
Qun 7 
7     A. If item missing, sum the completed items and multiply by 4 if three completed 
items, 6 if two completed items & 12 if one completed item 
      BI. If missing, impute average of 7a items 
i) 
Relationship with spouse/partner & 
ii) 
Relationship with other family members 
      BII. If missing, score as “0” 
      BIII. If missing, impute value from “Friends” (7AII) item 
      BIV. If missing, score as “0” 
      BV. If missing, impute value from “Other people” (7AIV) item 
      BVI. If missing, score as “0” 


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Qun 8 
8 
A. If item missing, sum the completed items and multiply by 4 if three completed 
items, 6 if two completed items and 12 if one completed item 
      BI. If missing, impute average of items completed in 8A 
      BII. If missing, score as “0” 
Qun 9 
      A. If missing, score as “0” 
      BI. If missing, impute value from 9a 
      BII. If missing, score as “0” 
Qun 10 (not included in this study) 
10A     I. If missing, score as “0” 
           II. If missing, score as “0” 
           III. If missing, score as “0” 
10B     I. If missing, score as “0” 
           II. If missing, score as “0” 
           III. If missing, score as “0” 
 
(Vincent et al. 2007). 
Note: Question #10 dealing with treatment effects was not administered or scored as part of 
this study due to the double-blind study design. 


Study Number:  UX001-CL301  
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10.6 Adverse Events to Monitor 
10.6.1 Gastrointestinal MedDRA Query 
The following MedDRA PTs are included in the gastrointestinal SMQ version 17.1. 
Narrow Scope 
Broad Scope 
Abdominal discomfort 
Anorectal swelling 
Abdominal distension 
Antacid therapy 
Abdominal pain 
Antidiarrhoeal supportive care 
Abdominal pain lower 
Antiemetic supportive care 
Abdominal pain upper 
Breath odour 
Abdominal symptom 
Chest pain 
Abdominal tenderness 
Colonic lavage 
Abnormal faeces 
Dysphagia 
Aerophagia 
Early satiety 
Anorectal discomfort 
Gastritis prophylaxis 
Bowel movement irregularity 
Gastrointestinal disorder therapy 
Change of bowel habit 
Gastrointestinal tract irritation 
Constipation 
Gastrooesophageal reflux prophylaxis 
Defaecation urgency 
Glycogenic acanthosis 
Diarrhoea 
Hypovolaemia 
Epigastric discomfort 
Laxative supportive care 
Eructation 
Malabsorption 
Faecal volume decreased 
Mucous stools 
Faecal volume increased 
Oesophageal polymer implantation 
Faeces hard 
Pernicious anaemia 
Faeces soft 
Post procedural constipation 
Flatulence 
Post procedural diarrhea 
Frequent bowel movements 
Post-tussive vomiting 
Gastrointestinal pain 
Probiotic therapy 
Gastrointestinal sounds abnormal 
Procedural nausea 
Gastrointestinal toxicity 
Procedural vomiting 
Infrequent bowel movements 
Prophylaxis against diarrhoea 
Nausea 
Prophylaxis of nausea and vomiting 
Non-cardiac chest pain 
Regurgitation 
Oesophageal discomfort 
Retching 
Oesophageal pain 
Steatorrhoea 
Premenstrual cramps 
Vomiting projectile 
Vomiting 
 
 


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


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10.7 Summary of Efficacy Endpoint and Analysis 
Test / 
Instrument 
Endpoint 
Type of 
analysis 
Time points for 
Assessment 
Statistical 
approach at 
week 48/ET 
analysis 
Physical therapy 
– Hand-held 
Dynamometry 
(HHD) 
The changes from baseline in 
Upper Extremity Composite 
(UEC) Score over time based on 
bilateral strength recorded in the 
following muscle groups: gross 
grip, shoulder abductors, elbow 
flexors, and elbow extensors 
Primary analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
GNEM 
Functional 
Activities Scale 
(GNEM-FAS) 
Changes in muscle strength on 
mobility domain score (reflective 
of the lower extremities) 
Key secondary 
efficacy analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Physical therapy 
– Hand-held 
Dynamometry 
(HHD) 
The change from baseline in 
Lower Extremity Composite 
(LEC) Score over time based on 
bilateral strength recorded in the 
following muscle groups: knee 
flexors, hip flexors, hip extensors, 
hip abductors and hip adductors. 
Key secondary 
efficacy analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model  
Changes in muscle strength  in 
knee extensor over time based on 
bilateral total force (kg)  
GNEM 
Functional 
Activities Scale 
(GNEM-FAS) 
Changes in muscle strength on 
upper extremity domain score 
(reflective of the upper 
extremities) 
Other secondary 
efficacy analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Sit to Stand 
Changes from baseline on the 
number of times the subject can 
rise from a seated to a standing 
position in a 30-second period will 
be recorded. 
Other secondary 
efficacy analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Weighed Arm 
Lift Test 
Changes from baseline on the 
number of times the subject can 
raise a 1 kg weight above the head 
in a 30-second period will be 
recorded. 
Other secondary 
efficacy analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 


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Test / 
Instrument 
Endpoint 
Type of 
analysis 
Time points for 
Assessment 
Statistical 
approach at 
week 48/ET 
analysis 
6-Minute Walk 
Test 
Change from baseline in distance 
walked (meters) during a six 
minute period. 
Other secondary 
efficacy analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Change from baseline in percent 
predicted of the distance walked 
(meters) during a six minute 
period. 
Physical therapy 
– Hand-held 
Dynamometry 
(HHD) 
Changes from baseline on Upper 
Extremity Composite and Lower 
Extremity Composite Percent 
Predicted: The percent predicted 
total force values will be 
determined based on reference 
equations adjusting for age, 
gender, height, and weight. 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Changes from baseline on actual 
and percent predicted in each 
Individual Muscle Group: 
Bilateral total force for each 
individual muscle group included 
in the UEC and LEC, and Percent 
Predicted of knee extensors.  
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
GNEM 
Functional 
Activities Scale 
(GNEM-FAS) 
Changes from baseline on the total 
score on the GNEM-FAS 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Changes from baseline on the 
Self-Care Domain Score on the 
GNEM-FAS 
Individual 
Neuromuscular 
Quality of Life 
Questionnaire 
(INQoL) 
Changes from baseline on the total 
score on a 45-item self-report 
questionnaire on the impact of key 
muscle disease symptoms on the 
ability to perform basic activities 
of daily living, functional 
independence, relationships and 
overall well-being 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model 
Clinical Global 
Impression scale 
(CGI)  
The CGI-Severity scale (CGI-S), 
and improvement (CGI-I) during 
treatment 
Tertiary efficacy 
analysis 
Baseline (CGI-S 
only), Weeks 24 
and 48 
GEE Model 
The proportions of patients with 
reported degrees of change from 
baseline to week 48 
Descriptive 
statistics 
Creatine Kinase 
Changes from baseline over time 
Tertiary efficacy 
analysis 
Weeks 8, 16, 24, 
32, 40, and 48 
GEE Model