Conditions: GNE Myopathy Hereditary Inclusion Body Myopathy (HIBM)
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 59
Healthy volunteers: no

Brief summary:
The safety objectives of the study are to: evaluate additional long-term safety of SA-ER treatment of participants with GNE myopathy previously treated with SA-ER at dose of 6g/day (Part I); evaluate the safety of 12g /day SA (delivered by 1.5g of SA-ER tablets and 1.5g of SA-IR capsules 4 times per day) in the treatment of participants with GNE myopathy (Part II) over a 6 month treatment period; evaluate the safety of SA treatment at both 6g/day and 12 g/day (Part III \[SA-ER/SA-IR\] and Part IV \[SA-ER\]).

Detailed description:

Arms:
arm 1: Participants completing the 48-week study (UX001-CL201; NCT01517880) were enrolled into Part I of the study:

* Part I: participants continued on 6 g/day SA-ER for 12 weeks
* Part II: 12 g/day SA (1.5 g of SA-ER and 1.5 g of SA-IR treatment 4 times per day \[QID\]) for 36 months
* Part III: 6 g/day or 12 g/day SA (both SA-ER and SA-IR)
* Part IV: 6 g/day or 12 g/day SA (SA-ER only) arm 2: Treatment naïve participants with GNE myopathy were enrolled into Part II of the study:

* Part II: 12 g/day SA (1.5 g of SA-ER and 1.5 g of SA-IR treatment QID) for 36 months
* Part III: 6 g/day or 12 g/day SA (both SA-ER and SA-IR)
* Part IV: 6 g/day or 12 g/day SA (SA-ER only)

Interventions: intervention 1: SA-ER 500 mg intervention 2: SA-IR 500 mg
Intervention descriptions: intervention 1: oral tablets intervention 2: oral capsules

Protocol document:
Prot_000.pdf: 
 
An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of 
Sialic Acid-Extended Release (SA-ER) Tablets and Sialic Acid-Immediate Release (SA-IR) 
Capsules in Patients with GNE Myopathy or Hereditary Inclusion Body Myopathy 
                                    
                                    Protocol Number: 
 
UX001-CL202 
                                    Original Protocol: 
 
01 March 2013 
                                    Amendment 1: 
 
02 October 2013 
                                    Amendment 2: 
 
17 December 2014 
                                    Amendment 3: 
 
07 October 2015 
                                    Amendment 4: 
 
17 June 2016  
 
Investigational Product: 
Sialic Acid-Extended Release Tablets (SA-ER)/Sialic Acid-
Immediate Release Capsules (SA-IR) 
Indication: 
GNE myopathy, also known as Hereditary Inclusion Body 
Myopathy (HIBM), Distal Myopathy with Rimmed Vacuoles 
(DMRV), or Nonaka Disease 
IND/EudraCT Number: 
109,334 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA  94949 
Sponsor’s Responsible 
Medical Officer: 
 MD 
Vice President, Clinical Sciences  
 
 
Coordinating Investigator: Professor Yoseph Caraco, MD  
 
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. 


Protocol Number:  UX001-CL202 
Protocol Amendment 4 
17 June 2016 
 
 
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Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 4 
17 June 2016 
 
 
The Protocol Amendment 3 of UX001-CL202 (dated 07 October 2015) has been modified by 
Amendment 4 to incorporate a number of changes based on additional information acquired 
since the beginning of the study.  The major changes to the protocol impacting the conduct of 
the study are summarized below.  Additional changes have also been made to provide 
supportive background information and rationale for the proposed changes (along with minor 
edits for consistency and clarity) but are not detailed in this summary. 
1. The Month 36 visit was defined as the end of study visit. In addition, this amendment 
now provides subjects the opportunity to enroll in the UX001-CL302, an ongoing 
extension study. These changes affected the synopsis, Table 2.2, and Sections 7.1 and 
7.5.1. This amendment also clarifies that the Termination Visit is not required for 
subjects who are rolling over to the UX001-CL302 extension study, but is required 
for subjects who terminate study participation early or who decide not to participate 
in the UX001-CL302 extension study. 
Rationale: The changes were made to clarify the end of study visit, clarify which 
subjects are required to complete the Termination Visit, and to provide subjects in the 
current study the opportunity to enroll in the UX001-CL302 extension study.  
2. Record Retention: Section 8.4.3 has been updated to state that all study records must 
be retained for at least 25 years after the end of the clinical trial or in accordance with 
national law. 
Rationale: This administrative change has been made to reflect upcoming changes to 
EU clinical trial regulations and current regulations by other health authorities. 
3. Updates were made to Section 7.4.2, Identity of Study Drug.  
Rationale: These changes were made for clarification. 
4. A change was made to Section 8.5.4, Adverse Event Reporting to Ultragenyx.  
Rationale: This change was made to be consistent with the current Ultragenyx 
template language regarding this topic. 
 


Protocol Number:  UX001-CL202 
Protocol Amendment 3 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 3 
07 October 2015 
 
 
The Protocol Amendment 2 of UX001-CL202 (dated 17 December 2014) has been modified 
by Amendment 3 to incorporate a number of changes based on additional information 
acquired since the beginning of the study.  The major changes to the protocol impacting the 
conduct of the study are summarized below.  Additional changes have also been made to 
provide supportive background information and rationale for the proposed changes (along 
with minor edits for consistency and clarity) but are not detailed in this summary. 
1. Part IV was added to change the formulation from sialic acid immediate release 
(SA-IR) to SA extended release (SA-ER). The SA-IR dose formulation has been 
removed. This change affects multiple sections of the protocol synopsis and body of 
the protocol, including the Schedule of Events (Table 2.2), Study Rationale 
(Section 5.4), Study Objectives (Section 6), Investigational Plan (Section 7), and 
Treatments (Section 7.4). 
Rationale: By the 4th day of dosing in a nonclinical study conducted in dogs, AUC for 
free SA was similar between the immediate and extended release formulations. In 
addition, a review of population data for Month 12 of Part III in the current study 
confirmed that 12g/day SA-IR did not appear to provide any additional benefit 
compared with 6g/day SA-ER, although some individual patients may have improved. 
Therefore, no further SA-IR will be administered after the initiation of Part IV; 
patients currently on 12g/day may continue receiving the 12g/day dose, if desired, by 
taking SA-ER.  
2. Updated Section 8.5.1 (Definition of Adverse Events) with the following text: “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.” 
Rationale: Updated for clarification of the SAE definition. 
3. Updated Sections 8.5.4 with new text related to reporting of adverse events. 
Rationale: Updated to align with other Ultragenyx protocols. 
4. Updated safety contact information (Section 8.5.5). 
Rationale: Updated to inform proper reporting of serious adverse events. 


Protocol Number:  UX001-CL202  
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 2 
17 December 2014 
 
 
The Protocol Amendment 1 of UX001-CL202 (dated 02 October 2013) has been modified by 
Amendment 2 to incorporate a number of changes based on additional information acquired 
since the beginning of the study.  The major changes to the protocol impacting the conduct of the 
study are summarized below.  Additional changes have also been made to provide supportive 
background information and rationale for the proposed changes (along with minor edits for 
consistency and clarity) but are not detailed in this summary. 
1. Sponsor’s Responsible Medical Officer and associated Medical Monitor contact 
information (Section 8.5.6) have been updated to: 
, MD 
2. Part III was added to the study design to allow for the reduction of the dose from 12g/day 
to 6g/day for a majority of participating subjects. This change affects multiple sections of 
the protocol synopsis and body of the protocol, including the Schedule of Events 
(Table 2.2), Study Rationale (Section 5.4), Study Objectives (Section 6), Investigational 
Plan (Section 7), and Treatments (Section 7.4). 
Rationale: This change is based on a review of the data for the rollover subjects from the 
parent study UX001-CL201 who had been receiving 12g/day in Part II of this extension 
study.  The data analysis suggests that an improvement of at least 15% in either the UEC 
or the LEC after 6 months of treatment with 12g/day SA represents a response that is 
suggestive of an added benefit from the higher dose.  The small subset of rollover 
subjects who meet these criteria, along with the ongoing naïve subjects, will have the 
option to remain on the 12g/day dose for the remainder of the study. 
3. The statistical methods were updated (synopsis and Section 7.6). 
Rationale: The statistical methods were updated to reflect the changes to the study design 
described in change #2 and to clarify which analyses populations were used for the Part 
II interim analyses. 
4. The protocol was updated to include a coordinating investigator. The coordinating 
investigator was identified on the cover page of the protocol and the selection process and 
responsibilities of the coordinating investigator are discussed in Investigators and Study 
Administrative Structure (Section 8.2).  


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Rationale: Identification of a coordinating investigator is required by the European 
Union.   
5. Prohibited Medications (Section 7.4.4.1) was updated by removing the text stating that 
urine will be analyzed to detect the presence of ManNAc.  
Rationale: This text was removed for clarification as this study procedure was only 
performed in Part I. 
6. Updated pregnancy text in Section 7.5.4.10. 
 
Rationale: This text was updated to match the current protocol template text. 
 
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 1 
02 October 2013 
 
 
The Original Protocol 01 version of UX001-CL202 (dated 01 March 2013) has been 
modified by Amendment 1 to incorporate a number of changes based on additional 
information acquired since the beginning of the study.  The majority of changes were 
predicated by a complete analysis and review of pharmacokinetic (PK), pharmacodynamic 
(PD), clinical efficacy, and safety results from the 24-week placebo-controlled, double-blind 
Treatment Period of the UX001-CL201 Phase 2 clinical trial.  The major changes to the 
protocol impacting the conduct of the study are summarized below.  Additional changes have 
also been made to provide supportive background information and rationale for the proposed 
changes (along with minor edits for consistency and clarity) but are not detailed in this 
summary.  
1. Indication:  GNE Myopathy is now the preferred term used in the protocol for the 
indication.  The majority of references to HIBM have been replaced with GNE 
Myopathy. 
2. Sponsor’s Responsible Medical Officer and associated contact information has been 
changed to 
 MD PhD. 
3. Overall Study Design and Plan. 
The study will now be conducted in two parts.  Part I of the study will provide additional 
information on the long-term safety and efficacy of 6g/day dose of SA-ER as initially 
designed, except the maximum treatment duration on 6g SA-ER has been shortened to 
approximately 12 weeks.  The Part I Termination Visit will also serve as the Baseline 
Visit for Part II of the study. 
Part II of the study will assess the long-term safety and efficacy of an increased SA dose 
(12g/day).  In this phase, SA treatment will be administered in the form of SA-ER tablets 
and sialic acid immediate release (SA-IR) capsules.  Beginning with the Part II-Baseline 
Visit, all subjects currently enrolled in Part I will crossover to the SA-ER/SA-IR dosing 
regimen.  An additional 10 GNE Myopathy subjects will be enrolled into Part II of the 
study.  The additional subjects will provide an assessment of 12g/day SA-ER/SA-IR 
treatment in treatment-naïve subjects able to walk at least 200 meters (and < 80% 
predicted) in a screening 6 Minute Walk Test (6MWT).   Throughout the Part II 
Treatment Period, all subjects will be administered three 500 mg SA-ER tablets and three 


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500 mg SA-IR capsules orally four times per day (QID), in the morning, afternoon, early 
evening, and at bedtime (qHS), for a total dose of 12g/day.   
Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, 
and function, and changes in exploratory serum biomarkers will be performed according 
to the Schedule of Events specific to each phase of the study (Table 2.1 and Table 2.2).  
If reasonable efficacy and safety are demonstrated during an interim analysis following 6 
months of treatment, the subjects will continue treatment for up to 36 months.  A Part II 
Termination Visit will be conducted 4 weeks after subjects receive their last dose of study 
drug. 
Rationale:  The modification of study design was predicated on results of planned PK, 
PD, clinical efficacy, and safety analyses following the 24-week placebo-controlled 
Treatment Period in the UX001-CL201 Phase 2 clinical study, wherein SA-ER treatment 
was administered at two dose levels, 3g and 6g SA-ER/day.  The goal of the Week 24 
interim analysis was to identify the dose that provides the best risk-benefit profile.  
The results show that the highest dose (6g/day SA-ER) provided sustained exposure, a 
modest clinical efficacy signal, and acceptable safety profile.   
The clinical efficacy data showed dose-dependent improvement in muscle strength 
relative to placebo in some muscle groups, particularly in the upper extremities at the 
6g/day SA-ER dose. These changes were statistically significant or trended towards 
significance, and were more pronounced in subjects that had greater walking ability at 
baseline, a predefined subset.  Other clinical endpoints (e.g. weighted arm lift test) did 
not reveal measureable changes at the Week 24 interim assessment.  Creatine kinase 
(CK) levels showed a trend to improvement in the 6g/day SA-ER dose group compared 
with placebo.  Overall, SA-ER appeared to be well tolerated with no serious adverse 
events observed in either dose group. 
Based on data from the Week 24 analysis following the placebo-controlled Treatment 
Period, the 6g/day SA-ER dose level appears to be at the lower end of the effective range, 
while 3g/day SA-ER had almost no effect.  An additional analysis of safety and efficacy 
data will be conducted at the end of the Treatment Continuation Period in UX001-CL201 
Phase 2 clinical study to evaluate whether the observed treatment effect is sustained or 
increased over a longer 48-week period. However, additional clinical benefit is not 
expected.   
In summary, the Week 24 interim data show a modest positive clinical efficacy signal 
and acceptable safety profile at the 6g/day dose suggesting the potential to optimize the 
therapeutic index by increasing SA exposure.  Therefore, investigation into optimizing 
the risk-benefit profile of SA substrate replacement by examining higher SA doses is 
warranted. 
 


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4. Investigational Product and Treatment.   
Part II of the study will assess the safety and efficacy of 12g/day SA-ER/SA-IR treatment 
for 6 months.  If reasonable efficacy and safety are demonstrated, the subjects will 
continue SA-ER/SA-IR treatment for up to 36 months. 
The SA-ER/SA-IR study drugs administered in Part II of the study will consist of SA-ER 
tablets, each containing 500 mg of SA active ingredient in an extended release 
formulation, and SA-IR capsules, each containing 500 mg of SA active ingredient.  
During the Part II Treatment Period, the 12g total daily SA-ER/SA-IR dose will be 
administered by the oral route and will be divided into a QID regimen: three SA-ER 
tablets (1.5g SA-ER) and three SA-IR capsules (1.5g SA-IR) taken in the morning, 
afternoon, early evening, and qHS.  If tolerability issues arise, the dose may be 
temporarily stepped down until symptoms resolve. 
Rationale:  Since successful use of SA replacement therapy in humans is believed to 
depend upon optimized exposure to the compound, an increased dose will be examined in 
Part II of the study.  Although administration of more extended release tablets could be 
utilized, data in canines suggests that administration of immediate release SA in 
combination with the SA-ER will maximize absorption in the GI tract. Therefore, Part II 
will examine safety and efficacy of an increased dose level combining immediate release 
SA (SA-IR) with SA-ER. 
The SA-ER/SA-IR dose and regimen for Study UX001-CL202 was selected based on the 
apparent detectable treatment effect at the highest dose and the association of higher SA 
serum levels with better improvement in strength, suggesting that a higher dose might be 
useful.  PK data from canine studies suggest that adding immediate release SA was the 
most effective way to increase SA, and higher doses of SA should be safe.  Supportive 
information is summarized below: 
• Dose effect at 6g only.  Interim results from UX001-CL201 suggest the 6g SA-ER 
dose level appears to be at the lower end of the effective range since a clinical 
efficacy signal was observed but 3g SA-ER had almost no effect.   
• The SA level correlates with treatment effect based on HHD.  The Week 24 
interim data imply a positive PD signal and acceptable safety profile suggesting the 
potential to optimize the therapeutic index by increasing SA exposure.   
• Canine studies show that immediate release most effective way to increase SA.  
Studies in normal canines showed that more than proportional increases in absorption 
of SA are possible if an immediate release formulation was mixed with an extended 
release formulation.  The concept is that the immediate release product enhances 
stomach absorption which is not well utilized by extended release formulated tablets. 
• QID therapy should support higher SA levels.  Since SA-IR is rapidly cleared, a 
QID dosing regimen is predicted to provide optimized continuous exposure to SA.  


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Administration of a 12g total daily dose of SA would therefore be divided into 4 
equal doses of 3g each (1.5g SA-ER + 1.5g SA-IR), representing only a 50% increase 
for each dose. 
• Safety of very high SA doses.  In a chronic toxicology study in rats, the NOAEL was 
2000 mg/kg SA, which provides a safety margin of approximately 1.4-fold for the 
proposed 12g/day dose level.  In a 6 month oral toxicity study in dogs, the NOAEL 
was 2000 mg/kg SA, which provides a safety margin of approximately 5-fold for the 
human 12g/day dose level.   
• Single doses of 6g SA-ER given in one dose, were well tolerated.  In the Phase 1 
PK and tolerability study, 6g SA-ER was administered to GNE Myopathy subjects in 
a single oral dose and was well tolerated with no SAEs observed. 
5. Study Objectives. 
The safety objectives in Part II of the study have been modified to evaluate the safety of 
12g/day SA in the treatment of GNE Myopathy subjects over a 6 month period.  
The clinical efficacy objectives of the study remain unchanged, except to reflect the 
change in investigational product to SA-ER/SA-IR.  An additional exploratory objective 
has been added to determine whether 12g /day of SA-ER/SA-IR administered as 
1.5g/1.5g four times per day is superior to prior treatment with 6g/day of SA-ER therapy 
administered as 2g three times per day in GNE Myopathy subjects.  
Rationale:  The objectives of the study have been revised to delineate specific aims for 
Part I and Part II of the study.  The change is in agreement with the overall study design 
and treatment regimens. 
6. Selection of Study Population and Sample Size. 
The sample size has been increased to enroll an additional 10 treatment naïve GNE 
Myopathy subjects into Part II of the study. 
Rationale:  Approximately 46 subjects currently enrolled in the study have completed a 
minimum of 48-weeks SA-ER treatment as part of study UX001-CL201 and Part I of this 
study.  Part II of the study will be the first time GNE Myopathy subjects will be treated 
with 12g/day SA-ER/SA-IR.  Therefore, 10 additional subjects will be enrolled to assess 
safety and clinical efficacy of the higher 12 g/day dose level in a treatment naïve 
population.  


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7. Inclusion Criteria. 
The first inclusion criterion was modified to: 
• Enrollment in, and successful completion of the UX001-CL201 protocol OR 
(for 10 treatment naïve subjects): 
o Have a confirmed diagnosis of GNE Myopathy 
o Aged 18 -65 years of age, inclusive 
o Able to walk ≥ 200 meters and < 80% of predicted normal during the 6MWT 
(orthotics and assistive devices allowed) 
o No prior history of treatment with SA or MaNAc 
Rationale:   The modified criterion aids in defining the study population, which consists 
primarily of GNE Myopathy subjects who completed the UX001-CL201 Phase 2 clinical 
study, but also defines requirements for the enrollment of additional treatment naïve 
subjects.  The diagnosis and age range for the treatment naïve subjects are the same as 
requirements for continuing subjects.  The ability to walk at least 200 meters during the 
6MWT was an enrollment target for 60% of subjects in the UX001-CL201 protocol.  
Since the strongest clinical efficacy signal in the Week 24 interim analysis was observed 
in this subset of GNE Myopathy subjects, Part II of this study will seek to enroll 
additional subjects most likely to obtain clinical benefit from treatment.  
8. Schedule of Events.   
For clarity, the Schedule of Events has been separated into two distinct tables.  The visit 
schedule and assessments to be conducted during Part I of the study are presented in 
Table 2.1.  The visit schedule and assessments to be conducted during Part II of the study 
are presented in Table 2.2.   
Rationale:  Specific assessments may differ depending on the phase of the study (i.e. Part 
I or Part II).  Evaluations of safety, changes in clinical endpoints such as muscle strength, 
mobility, and function, PK, and changes in exploratory serum biomarkers will be 
performed according to the Schedule of Events specific to each phase of the study.   
9. Exploratory Efficacy Measures.    
Exploratory efficacy assessments will be conducted as indicated in the Schedule of 
Events for Parts I and II of the study (Table 2.1 and Table 2.2, respectively).  However, 
samples to assess serum protein biomarkers (other than CK) will not be obtained in Part 
II of the study. 
Rationale:  Results from a panel of serum biomarkers at the Week 24 interim analysis of 
the Phase 2 study (UX001-CL201) were ambiguous.  Therefore, serum protein 
biomarkers will not be assessed in Part II of the study to avoid subjecting study 
participants to unnecessary procedures.  CK levels in serum will be assessed in both Parts 


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I and II of the study since a positive, dose-dependent decrease in serum CK levels was 
observed in UX001-CL201. 
10. Safety Measures & Procedures.   
A detailed medical history, including a GNE Myopathy-specific medical history will be 
obtained at the Part II Screening/Baseline Visit for newly enrolled subjects only.  
There are no changes to safety measures, only revised timing of assessments.  
Safety assessments will be conducted as indicated in the Schedule of Events for Parts I 
and II of the study (Table 2.1 and Table 2.2, respectively). 
Rationale:  For continuing subjects, the Medical History information obtained during the 
UX001-CL201 study will carry over to the current treatment extension study.  
Similar information must be obtained for the treatment naïve subjects who will enroll 
directly into Part II of the study. 
Stopping Rules. 
Specific language regarding stopping rules (Section 7.3.3.1) has been modified as 
follows: 
“If two subjects develop the same unexpected Grade 3 AE that is possibly or probably 
related to study drug or any subject develops an unexpected Grade 4 AE that is possibly 
or probably related to study drug, enrollment of new subjects will may be suspended until 
a thorough evaluation can be performed.”  
Rationale:  Interim results following a 24-week Treatment Period with SA-ER are now 
available and provide a profile of expected AEs; no SAEs have been reported to date in 
the ongoing study.   Should unexpected Grade 3 and 4 AEs occur as detailed above, a full 
clinical evaluation will performed by the medical monitor, principal investigators, and the 
Data Monitoring Committee (DMC) as detailed in the protocol.  Following the full 
evaluation, an informed decision can be made whether to suspend enrollment or stop the 
study. 


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Safety Contact Information. 
The safety contact information for Ultragenyx (Biosoteria/Dohmen Safety) has been 
updated. 
11. Drug Concentration Measurements. 
Free SA in the urine will be measured in Part I of the study only.  Free SA trough levels 
will be assessed in serum during Parts I and II of the study.  There will be no assessments 
of free SA in the urine during Part II of the study. 
Rationale:  Results of PK assessments at the Week 24 interim analysis of the Phase 2 
study (UX001-CL201) suggest serum SA measurement is more reliable than urine for 
characterizing trough levels of SA.  Therefore, urine PK parameters will not be assessed 
in Part II of the study to avoid subjecting study participants to unnecessary procedures.   
12. Statistical Methods. 
An interim analysis will be conducted when the last subject has completed the Month 6 
Visit of the Part II Treatment Period.  For Part II efficacy evaluation of the continuing 
subjects, change from baseline of Part II to Month 6 assessment at 12g/day SA-ER/SA-IR 
dose will be determined and compared with the improvement observed during the first 
6 months of treatment with 6g/day SA-ER dose and to the rate of change observed with 
placebo or 3g treatments during the first 6 months of the study.  The 10 additional 
treatment naïve subjects will be evaluated for change from their baseline visit to Month 6 
assessment at 12g/day SA-ER/SA-IR dose compared with placebo, 3 g and 6 g treatments 
for 24 weeks in subjects that walk more than 200m at baseline in the 6MWT.  
Rationale:  Changes to the planned statistical analysis are consistent with the modified 
study design to assess the efficacy and tolerability of the higher dose of sialic acid.  
The planned interim analysis following 6-months treatment with SA-ER/SA-IR will 
provide an initial assessment of safety and efficacy.  If reasonable safety and efficacy are 
demonstrated, subjects will continue therapy for up to 36 months.  Full details of planned 
analysis will be presented in the Statistical Analysis Plan for UX001-CL202. 


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2 SYNOPSIS 
TITLE OF STUDY: 
An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of Sialic 
Acid-Extended Release (SA-ER) Tablets and Sialic Acid-Immediate Release (SA-IR) Capsules in 
Patients with GNE Myopathy or Hereditary Inclusion Body Myopathy 
PROTOCOL NUMBER: 
UX001-CL202 
STUDY SITES: 
Four sites, globally 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
GNE myopathy or hereditary inclusion body myopathy (HIBM) is a rare and severely debilitating 
disease caused by a defect in the biosynthetic pathway for sialic acid (SA).  Substrate replacement of 
SA in an extended release formulation (SA-ER; also termed Ace-ER) is a potential therapeutic 
strategy based on evidence from relevant in vivo models, supported by pharmacokinetic (PK) 
characterization in a Phase 1 clinical study, and stabilization in muscle strength in a Phase 2 
randomized controlled trial (UX001-CL201).  The interim data from the Phase 2 study implied a 
positive clinical efficacy signal and acceptable safety profile suggesting the potential to optimize the 
therapeutic index by increasing SA exposure.  Since successful use of SA replacement therapy in 
humans is believed to depend upon optimized exposure to the compound, an increased dose was 
suggested.  Although administration of more extended release tablets could be utilized, data in canines 
suggest that administration of immediate release SA (SA-IR) in combination with the SA-ER will 
maximize absorption in the GI tract. Therefore a study testing an increased dose level combining 
SA-IR with SA-ER was proposed.   
Subjects completing the 48-week study (UX001-CL201) were eligible to continue treatment under this 
open-label extension protocol.  Additional GNE Myopathy subjects have been enrolled to assess the 
safety and efficacy of SA-ER/SA-IR in a treatment naïve population. 
Ultragenyx is conducting this study (UX001-CL202) in four parts:  Part I of the study will provide 
additional information on the long-term safety and efficacy of 6g/day SA-ER; Part II of the study will 
assess the long-term safety and efficacy of 12g/day SA (comprised of 1.5g of SA-ER and 1.5g of 
SA-IR treatment 4 times per day). Parts III and IV will provide long-term safety and efficacy data on 
both 6 and 12g/day SA (both SA-ER/SA-IR [Part III] and SA-ER [Part IV]).  Part III was added based 
on a review of individual subject data for the rollover subjects from the parent study UX001-CL201 at 
Month 6. The data analysis suggested that a small subset of subjects received an added benefit from 
the higher dose (defined as at least a 15% increase in either the UEC or LEC).  The rollover subjects 
who met these criteria, along with the ongoing naïve subjects, had the option to remain on the 12g/day 
dose for the remainder of the study. Part IV was added to change the formulation from SA-IR to 
SA-ER. The SA-IR dose formulation has been removed based on data showing that by the 4th day of 
dosing in a nonclinical study conducted in dogs, AUC for free SA was similar between the immediate 


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and extended release formulations. In addition, a review of population data for Month 12 of Part III in 
the current study confirmed that 12g/day SA-IR did not appear to provide any additional benefit 
compared with 6g/day SA-ER, although some individual patients may have improved. Therefore, no 
further SA-IR will be administered after the initiation of Part IV; patients currently on 12g/day may 
continue receiving the 12g/day dose, if desired, by taking SA-ER. 
Patients who elect to decrease from 12g/day to 6g/day may be allowed to do so upon Sponsor 
approval. 
OBJECTIVES: 
 
The safety objectives of the study are to: 
• Evaluate additional long-term safety of SA-ER treatment of GNE Myopathy subjects previously 
treated with SA-ER at dose of 6g/day (Part I) 
• Evaluate the safety of 12g/day SA (delivered by 1.5g of SA-ER tablets and 1.5g of SA-IR 
capsules 4 times per day) in the treatment of GNE Myopathy subjects (Part II) over a 6 month 
treatment period. 
• Evaluate the safety of SA treatment at both 6g/day and 12g/day (Part III [SA-ER/SA-IR] and 
Part IV [SA-ER]). 
 
The clinical objectives of the study are to: 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on muscle strength as 
measured by hand-held dynamometry (HHD) 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on mobility, strength, 
and function using a series of physical performance measures 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on functional disability 
using an interview-based questionnaire.  
 
The exploratory objectives of the study are to: 
• Evaluate the effect of SA treatment on serum biomarkers of sialylation in GNE Myopathy 
subjects (Part I) 
• Determine whether 12g /day SA-ER/SA-IR administered 1.5g/1.5g four times per day is superior 
to prior treatment with SA-ER in GNE Myopathy subjects (Part II) 
o Determine whether a subset of subjects have additional benefit on the higher dose 
treatment. 
STUDY DESIGN AND METHODOLOGY: 
This open-label extension study of will assess the long-term safety and efficacy of SA treatment over a 
period of approximately 36 months, or until marketing approval or program termination by 
Ultragenyx. Subjects who complete the study will be eligible to enroll into UX001-CL302 open-label 
extension study.  In Part I of the study, approximately 46 subjects will be enrolled following 
successful completion of the UX001-CL201 study.  The Baseline visit will be conducted in 
conjunction with the UX001-CL201 Week 48 study visit to avoid treatment disruption.  Enrollment 
will take place after all UX001-CL201 Week 48 study assessments have been completed and the 
investigator has determined the subject meets all eligibility criteria.  Data collected at the 


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UX001-CL201 Week 48 visit will serve as the Baseline data for Part I of this protocol.  Following the 
signing of informed consent at the Baseline visit, each subject will be dispensed a 6-week supply of 
study drug.  Throughout the Part I Treatment Period of the study, all subjects will continue to take four 
500 mg SA-ER tablets orally three times per day (TID), in the morning, early evening, and at bedtime 
(qHS), for a total dose of 6g/day.  The Part I Termination Visit will also serve as the Baseline Visit for 
Part II of the study. 
Beginning with the Part II-Baseline Visit, all subjects currently enrolled in Part I will crossover to the 
SA-ER/SA-IR dosing regimen.  Approximately 10 GNE Myopathy subjects will be enrolled into Part 
II of the study.  The additional subjects will provide an assessment of SA-ER/SA-IR treatment in SA 
naïve subjects able to walk at least 200 meters (and < 80% predicted) in a screening 6 Minute Walk 
Test (6MWT).   
Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, and function, 
and changes in exploratory serum biomarkers will be performed according to the Schedule of Events 
specific to each phase of the study (Table 2.1 and Table 2.2).  A Termination Visit will be conducted 
4 weeks after subjects receive their last dose of study drug (last dose of study drug received at Month 
36). For subjects who are eligible and choose to participate in the UX001-CL302 open-label extension 
study, the Month 36 Visit is considered the end of study visit and the Termination Visit is not required. 
Any subject who discontinues the current study early or is ineligible or decides not to participate in the 
UX001-CL302 open-label extension study is required to have a Termination Visit 4 weeks after their 
last dose of study drug, as per Schedule of Events. Efficacy data analyses will be conducted at the end 
of the Treatment Period, although interim analyses may be performed at the discretion of Ultragenyx. 
Safety will be monitored throughout the study based on physical examinations, clinical laboratory 
analyses, and reporting of adverse events (AEs) and Serious Adverse Events (SAEs).  An independent 
Data Monitoring Committee (DMC) will review safety information periodically an on an ad hoc basis 
as outlined in the DMC charter, which is maintained separately from this protocol. 
NUMBER OF SUBJECTS PLANNED: 
Up to 46 subjects previously treated in the UX001-CL201 study will be enrolled.  Approximately 
10 subjects, naïve to SA and MaNAc treatment, will be enrolled directly into Part II of the study. 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
 
Individuals eligible to participate in this study must meet all of the following criteria: 
• 
Enrollment in, and successful completion of the UX001-CL201 protocol OR  
(for 10 treatment naïve subjects): 
O Have a confirmed diagnosis of GNE Myopathy 
O Aged 18 -65 years of age, inclusive 
o Able to walk ≥ 200 meters and < 80% of predicted normal during the 6MWT (orthotics 
and assistive devices allowed)  
o No prior history of treatment with SA or MaNAc  
• 
Must be willing and able to provide written, signed informed consent after the nature of the study 
has been explained, and prior to any research-related procedures 
• 
Must be willing and able to comply with all study procedures  
• 
Sexually active subjects must be willing to use an acceptable method of contraception while 


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participating in the study 
• 
Females of childbearing potential must have a negative pregnancy test at Baseline 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, or have had tubal 
ligation at least one year prior to Baseline, or who have had total hysterectomy. 
 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
• 
Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at any time 
during the study 
• 
Use of any investigational product (other than SA-ER tablets) to treat GNE Myopathy 
• 
Ingestion of N-acetyl-D-mannosamine (ManNAc) or similar SA-producing compounds  
• 
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 
• 
Have any co-morbid conditions, including unstable major organ-system disease(s) that in the 
opinion of the investigator, places the subject at increased risk of complications, interferes with 
study participation or compliance, or confounds study objectives.  
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: 
Part I:  The investigational product will consist of SA-ER tablets, each containing 500 mg of SA active 
ingredient in an extended release formulation.  During the Part I Treatment Period, the 6000 mg (6g) 
total daily SA-ER dose will be administered by the oral route and will be divided into a TID regimen:  
four tablets in the morning, four tablets in the early evening, and four SA-ER tablets qHS.  
Part II:  Each dose of SA-ER/SA-IR will consist of SA-ER tablets, each containing 500 mg of SA 
active ingredient in an extended release formulation and SA-IR capsules, each containing 500 mg of 
SA active ingredient.  During the Part II Treatment Period, the 12,000 mg (12g) total daily SA dose 
will be administered by the oral route and will be divided into a QID regimen:  three SA-ER tablets 
(1.5g SA-ER) and three SA-IR capsules (1.5g SA-IR) taken in the morning, afternoon, early evening, 
and qHS.  If tolerability issues arise, the dose may be temporarily stepped down until symptoms 
resolve. 
Part III:  12g/day dose – Each dose of SA-ER/SA-IR will consist of SA-ER tablets, each containing 
500 mg of SA active ingredient in an extended release formulation and SA-IR capsules, each 
containing 500 mg of SA active ingredient.  During the Part III Treatment Period, the 12,000 mg (12g) 
total daily SA dose will be administered by the oral route and will be divided into a TID or QID 
regimen. If tolerability issues arise, the dose may be temporarily stepped down until symptoms 
resolve.  
6g/day dose – Each dose of SA-ER will consists of tablets, each containing 500 mg of SA active 
ingredient in an extended release formulation.  During the Treatment Period, the 6000 mg (6g) total 
daily SA-ER dose will be administered by the oral route and will be divided into a TID regimen. 
Part IV: 6g/day dose and 12g/day dose – Each dose of SA-ER will consists of tablets, each containing 
500 mg of SA active ingredient in an extended release formulation.  During the Treatment Period, the 
6g total daily SA-ER dose will be administered by the oral route and will be divided into a TID 


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regimen. The 12g total daily SA-ER dose will be administered by the oral route and will be divided 
into a TID or QID regimen. 
All doses should be taken with food (i.e. within 30 minutes following a meal or snack). 
DURATION OF TREATMENT: 
The Part I Treatment Period will be up to approximately 12 weeks (3 months) in duration.  The Part II, 
Part III, and Part IV Treatment periods will be up to 36 months in duration.  The total duration of the 
study will be up to 40 months.  
CRITERIA FOR EVALUATION: 
Efficacy: 
Efficacy will be evaluated by continued improvement in clinical assessments.  Efficacy assessments 
may differ depending on the phase of the study (i.e. Part I, Part II, Part III, or Part IV).   For Part I 
efficacy evaluation, results from the last pre-treatment assessment from UX001-CL201 will be 
compared with the last post-treatment assessment for the Part I Treatment Period as listed in the 
Schedule of Events (Table 2.1), with efficacy conclusions based on change since SA-ER treatment 
initiation.   
An interim analysis will be conducted when a majority of subjects have completed the Month 6 Visit 
of the Part II Treatment Period.  For Part II efficacy evaluation of the continuing subjects, change from 
baseline of Part II to Month 6 assessment at 12g/day SA-ER/SA-IR dose will be determined and 
compared with the improvement observed during the first 6 months of treatment with 6 g/day SA-ER 
dose, and to the rate of change observed with placebo or 3g treatments during the first 6 months of the 
study.  The changes from baseline of the treatment-naïve subjects will be evaluated over time.   
In addition, changes in muscle strength over the entire treatment period of subjects who started with 
6g/day and 3g/day will be evaluated and compared to the projected values of subjects who received 
placebo for the first 24 weeks of treatment in UX001-CL201. 
Clinical Efficacy Measures: 
• 
Hand-Held Dynamometry:  Muscle strength based on the maximum voluntary isometric 
contraction (MVIC) against a hand-held dynamometer will be measured in the following muscle 
groups: gross grip, pinch, shoulder abductors, elbow flexors, elbow extensors, hip abductors, hip 
adductors, hip flexors, hip extensors, knee flexors and knee extensors.  The total force (kg) will be 
measured as well as the percent of predicted normal force based on age, gender, height and weight 
(where applicable). 
• 
Six-Minute Walk Test:  The total distance walked (meters) in a six minute period will be 
measured as well as the percent of predicted normal distance based on age and gender.   
• 
Walking Speed Test:  The time required to walk 25 feet (7.62 meters) will be assessed at a 
comfortable and a maximum gait speed.  The total number of seconds required for each speed will 
be recorded.  Individual subject performance will also be compared to healthy peers based on 
normative data. 
• 
Weighted Arm Lift Test:  The number of times the subject can raise a 1 kg weight above the head 
in a 30-second period will be recorded.  The test will be performed bilaterally. 
• 
HIBM Functional Activities Scale:  The total score, as well as subscale scores for mobility, 
self-care, and upper extremity function on an interview-administered functional disability measure 
will be recorded. 


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Exploratory Efficacy Measures: 
• 
Serum protein markers:  Serum specimens will be evaluated to assess potential use as biomarkers 
of sialylation.  
• 
Creatine kinase levels in serum will be assessed as a potential biomarker for muscle injury 
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:  
• 
Vital signs 
• 
Neurological and physical examination results 
• 
Laboratory evaluations 
• 
Interval history:  reported symptoms of increasing muscle weakness or pain, incidence of falls 
STATISTICAL METHODS: 
Details of the planned interim analysis, safety and efficacy analyses will be provided in a statistical 
analysis plan maintained separately from this protocol. 
Interim Analysis: 
An Interim analysis will be conducted when a majority of subjects have completed the Month 6 Visit 
during the Part II Treatment period. 
Efficacy Analyses: 
Efficacy data analyses will be conducted at the end of the 6-month Treatment Period with 
SA-ER/SA-IR, when all subjects have completed 12 months of participation, and at the end of the 
36 month Treatment Period.  The treatment naïve subjects will be studied as a separate subgroup. 
Clinical efficacy analyses will include:  1) Muscle strength as measured by HHD, and reported as 
force in kg and percent of predicted normal, 2) Walking ability as measured by the 6MWT, and 
reported as distance in meters and percent of predicted normal, 3) Walking speed as measured by the 
walking speed test, which will be reported in seconds and percent of predicted normal for each 
walking speed, 4) Arm raising ability as measured by the weighted arm lift test, which will be 
reported as the total number of completed repetitions, and 5) Functional disability as measured by the 
HIBM-FAS, which will be reported as a total score and subscale scores for mobility, self-care, and 
upper extremity function with lower scores associated with greater disability.   
For those clinical evaluations with repeated assessments (i.e., HHD, 6MWT, and the walking speed 
and weighted arm lift tests), the analysis will be performed using a repeated measures analysis. 
A full accounting of the analyses for Parts III and IV of the study will be provided in the Statistical 
Analysis Plan.   
Safety Analyses: 
All subjects who receive study drug will be included in the safety analysis.  Safety will be evaluated 
on the incidence and frequency of AEs and SAEs, and clinically significant change in vital signs, 
laboratory test results, or physical examinations.  Safety data will be periodically reviewed by the 
DMC.  


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Table 2.1: 
Schedule of Events (Part I) 
a Potential subjects for the Part I Treatment Period will be baselined at the UX001-CL201 Week 48 study visit. Study drug 
will be dispensed only after UX001-CL202 consent has been signed and all study procedures have been performed. 
b For Week 6 and 12 visits, the window is ± 0 days. 
c The Part I Termination Visit will also serve as the Part II Baseline Visit.  For subjects who discontinue prior to completing 
the study, the Termination Visit will be considered an Early Termination Visit; every reasonable effort should be made to 
perform the Termination Visit procedures within four weeks of discontinuation.  
d Interval history will include 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 GNE Myopathy) that 
might interfere with study participation, safety, and/or positively or negatively impact performance of functional 
assessments. 
e The physical examinations at all study visits will be complete. 
f Portions of the HHD, 6MWT, walking speed and weighted arm lift testing sessions may be videotaped to monitor 
administration technique and assess qualitative changes in function.  Subject identity will be protected by blurring out the 
facial area in the video.  
g Trough levels of free SA in serum and free and total SA in urine. 
h Adverse Events will be collected after subject signs Informed Consent form. 
ASSESSMENTS AND EVENTS 
PART I TREATMENT PERIOD b 
(weeks) 
PART I TERM 
VISIT c 
 
BASELINE a 
6 
12 
 
INFORMED CONSENT 
X 
 
 
 
INTERVAL HISTORY d 
X 
 
 
X 
VITAL SIGNS 
X 
 
 
X 
HEIGHT AND WEIGHT 
X 
 
 
X 
PHYSICAL EXAM e 
X  
 
 
X 
NEUROLOGICAL EXAM 
X 
 
 
X 
EFFICACY MEASURES 
HAND-HELD DYNAMOMETRY (HHD) f 
X 
 
 
X 
6 MINUTE WALK TEST  
(6MWT) f 
X 
 
 
X 
WALKING SPEED TEST f 
X 
 
 
X 
WEIGHTED ARM LIFT TEST f 
X 
 
 
X 
HIBM-FAS 
X 
 
 
X 
CLINICAL LABORATORY TESTS 
CREATINE KINASE 
X 
 
 
X 
SERUM PROTEIN MARKERS 
X 
 
 
X 
FREE SERUM SA LEVELS g 
X 
 
 
X 
FREE AND TOTAL URINE SA LEVELS g 
X 
 
 
X 
CBC, CHEMISTRY, URINALYSIS 
X 
 
 
X 
PREGNANCY TEST 
X 
 
 
X 
ADVERSE EVENTS 
Xh 
X 
X 
X 
CONCOMITANT MEDICATIONS 
X 
X 
X 
X 
TREATMENT DISPENSED 
X 
X 
X 
 


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Table 2.2: 
Schedule of Events (Parts II, III, and IV) 
ASSESSMENTS AND EVENTS 
PARTS II, III, AND IV TREATMENT PERIOD b 
(months) 
TERM 
VISIT c 
 
SCREENING/
BASELINE a 
1 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36k 
 
INFORMED CONSENT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL/INTERVAL HISTORYd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
VITAL SIGNS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HEIGHT AND WEIGHT 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PHYSICAL EXAM e 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
NEUROLOGICAL EXAM 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
EFFICACY MEASURES 
HAND-HELD DYNAMOMETRY 
(HHD) f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
6 MINUTE WALK TEST 
(6MWT) f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
WALKING SPEED TEST f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
WEIGHTED ARM LIFT TEST f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HIBM-FAS 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
CLINICAL LABORATORY TESTS 
CREATINE KINASE 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
FREE SERUM SA LEVELS g 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
CBC, CHEMISTRY 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
PREGNANCY TEST 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
ADVERSE EVENTS 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CONCOMITANT MEDICATIONS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DISPENSE STUDY DRUG i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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a The Part I Termination Visit also serves as the Parts II, III, and IV Baseline Visit for continuing subjects.  SA naïve subjects enter directly into Part II of the study 
(Screening/Baseline Visit for these subjects). Study drug will be dispensed only after UX001-CL202 (Parts II, and III, and IV) consent has been signed. 
b The Month 1 Visit window is ± 1 week.  For all other Visits the window is ± 14 days. For Part III and Part IV transitions, subjects will be asked to return to the clinic (may be an 
unscheduled visit) within 5 weeks from IRB/EC approval, to discuss their dosing and to consent.  
c The Termination Visit occurs four weeks after subjects receive their last dose.  For subjects who discontinue prior to completing the study, the Termination Visit will be 
considered an Early Termination Visit; every reasonable effort should be made to perform the Termination Visit procedures within four weeks of discontinuation.  The 
Termination Visit is not required for subjects who are eligible and choose to participate in the UX001-CL302 open-label extension study, but must be completed for any subject 
who terminates study participation early or is ineligible or decides not to participate in the extension study.  
d For SA naïve subjects, medical history (including a detailed GNE Myopathy disease-specific history) will be reviewed at the Screening/Baseline visit.  Interval history for all 
subjects will include 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 GNE Myopathy) that 
might interfere with study participation, safety, and/or positively or negatively impact performance of functional assessments. 
e The physical examinations at all study visits will be complete. 
f Portions of the HHD, 6MWT, walking speed and weighted arm lift testing sessions may be videotaped to monitor administration technique and assess qualitative changes in 
function.  Subject identity will be protected by blurring out the facial area in the video.  
g Trough levels of free SA in serum. 
h Adverse Events will be collected after subject signs Informed Consent form. 
i Study drug will be dispensed at scheduled treatment visits; additional study drug will be shipped directly to subjects between visits on a monthly basis.  
j Phone calls will be placed to each subject at least once between each study visit to assess treatment compliance with the dosing regimen.  Additional telephone contacts with the 
subject may be placed as needed. 
k Subjects who complete this study and are eligible may enroll in the UX001-CL302 open-label extension study. The Month 36 Visit is considered the end of study visit for 
subjects who are eligible and chose to participate in the open label extension study.  


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................12 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................16 
5 INTRODUCTION .............................................................................................................19 
5.1 Overview of the Disease ...........................................................................................20 
5.2 Brief Overview of the Development of the Product .................................................22 
5.2.1 
Brief Description of the Investigational Product .........................................23 
5.2.2 
Nonclinical Studies ......................................................................................24 
5.2.3 
Previous Clinical Studies .............................................................................25 
5.3 Summary of Overall Risks and Potential Benefits ....................................................26 
5.4 Study Rationale .........................................................................................................27 
6 STUDY OBJECTIVES ......................................................................................................28 
7 INVESTIGATIONAL PLAN ............................................................................................29 
7.1 Overall Study Design and Plan .................................................................................29 
7.2 Discussion of Study Design, Including Choice of Control Group ............................30 
7.3 Selection of Study Population ...................................................................................31 
7.3.1 
Inclusion Criteria .........................................................................................32 
7.3.2 
Exclusion Criteria ........................................................................................33 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................33 
7.3.3.1 
Stopping Rules .............................................................................34 
7.4 Treatments .................................................................................................................34 
7.4.1 
Treatments Administered ............................................................................34 
7.4.2 
Identity of Study Drugs ...............................................................................35 
7.4.2.1 
Investigational Product ................................................................35 
7.4.3 
Selection of Doses and Study Duration .......................................................36 


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7.4.4 
Prior and Concomitant Therapy ..................................................................38 
7.4.4.1 
Prohibited Medications ................................................................38 
7.4.4.2 
Permitted Medications .................................................................38 
7.4.5 
Treatment Compliance ................................................................................39 
7.5 Study Procedures and Assessments ..........................................................................39 
7.5.1 
Schedule of Events ......................................................................................39 
7.5.2 
Clinical Efficacy Measures .........................................................................40 
7.5.2.1 
Hand-held dynamometry .............................................................40 
7.5.2.2 
Six Minute Walk Test ..................................................................40 
7.5.2.3 
Walking Speed Test .....................................................................41 
7.5.2.4 
Weighted Arm Lift Test ...............................................................41 
7.5.2.5 
HIBM Functional Activities Scale ...............................................42 
7.5.3 
Exploratory Efficacy Measures ...................................................................42 
7.5.4 
Safety Measures & General Assessments ...................................................42 
7.5.4.1 
Medical History ...........................................................................42 
7.5.4.2 
Interval History ............................................................................42 
7.5.4.3 
Vital Signs ....................................................................................43 
7.5.4.4 
Height and Weight Evaluations ...................................................43 
7.5.4.5 
Physical Examination...................................................................43 
7.5.4.6 
Neurological Examination ...........................................................43 
7.5.4.7 
Clinical Laboratory Tests .............................................................44 
7.5.4.8 
Adverse Events ............................................................................45 
7.5.4.9 
Concomitant Medications ............................................................45 
7.5.4.10 
Pregnancy Testing ........................................................................45 
7.5.4.11 
Pregnancy in Subject or Partner ...................................................45 
7.5.5 
Drug Concentration Measurements .............................................................46 
7.5.6 
Appropriateness of Measures ......................................................................46 


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7.6 Statistical Methods and Determination of Sample Size ............................................47 
7.6.1 
Clinical and Exploratory Efficacy Measures ...............................................47 
7.6.1.1 
Clinical Efficacy Analyses ...........................................................47 
7.6.2 
Safety Measures ..........................................................................................49 
7.6.3 
Data Monitoring Committee .......................................................................50 
7.6.4 
Determination of Sample Size .....................................................................50 
8 STUDY CONDUCT ..........................................................................................................51 
8.1 Ethics .........................................................................................................................51 
8.1.1 
Institutional Review Board or Ethics Committee ........................................51 
8.1.2 
Ethical Conduct of Study ............................................................................51 
8.1.3 
Subject Information and Consent ................................................................51 
8.2 Investigators and Study Administrative Structure ....................................................52 
8.3 Investigational Product Accountability .....................................................................52 
8.4 Data Handling and Record Keeping .........................................................................53 
8.4.1 
Case Report Forms and Source Documents ................................................53 
8.4.2 
Data Quality Assurance ...............................................................................53 
8.4.3 
Record Retention .........................................................................................54 
8.5 Reporting and Follow-up of Adverse Events ............................................................54 
8.5.1 
Definition of Adverse Events ......................................................................54 
8.5.2 
Severity of Adverse Events .........................................................................55 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................56 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................56 
8.5.4.1 
General .........................................................................................56 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................57 
8.5.4.3 
Urgent Safety Reporting ..............................................................57 
8.5.4.4 
Adverse Drug Reaction Reporting ...............................................58 
8.5.4.5 
Pregnancy in Subject or Partner ...................................................58 


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8.5.5 
Safety Contact Information .........................................................................59 
8.6 Financing and Insurance ...........................................................................................59 
8.7 Publication Policy .....................................................................................................59 
9 REFERENCES ..................................................................................................................60 
10 SIGNATURE PAGE .........................................................................................................63 
 
List of Tables 
Table 2.1: 
Schedule of Events (Part I) ....................................................................9 
Table 2.2: 
Schedule of Events (Parts II, III, and IV) ............................................10 
Table 7.5.4.7.1: 
Clinical Laboratory Assessments .........................................................44 
 
List of Figures 
Figure 5.1.1: 
The Sialic Acid Biosynthetic Pathway ................................................22 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CMP-SA 
cytosine monophosphate-sialic acid 
CRF 
Case Report Form 
CSR 
clinical study report 
CT 
computed tomography 
DMC 
Data Monitoring Committee 
DMRV 
EC 
distal myopathy with rimmed vacuoles 
Ethics Committee 
ELISA 
enzyme-linked immunosorbent assay 
EMG 
electromyography 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
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 
hERG 
human ether-à-go-go-related gene 
HHD 
hand-held dynamometry 
HIBM 
hereditary inclusion body myopathy 
HIBM-FAS 
HIBM Functional Activities Scale 
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) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IVIG 
intravenous immune globulin 
LDH 
lactate dehydrogenase 
ManNAc 
N-acetyl-D-mannosamine 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP9 
matrix metallopeptidase 9 
MRC 
Medical Research Council 
MUAP 
polyphasic muscle unit action potential 
MVIC 
maximum voluntary isometric contraction 
NANA 
N-acetylneuraminic acid 
NCAM 
neural cell adhesion molecule 
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) 
QID 
four times per day 
RBC 
red blood cell 
SA 
sialic acid 
SAE 
serious adverse event 
SA-ER 
Sialic Acid-Extended Release 
SA-IR 
Sialic Acid Immediate Release 
SAP 
Statistical Analysis Plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
TID 
three times per day 
US 
United States 
WBC 
white blood cell 


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


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5 INTRODUCTION 
Sialic Acid-Extended Release (SA-ER, UX001; also termed Ace-ER) is an extended release 
formulation of sialic acid (SA, also known as N-acetylneuraminic acid or NANA) intended 
as a substrate replacement therapy for GNE myopathies.  GNE myopathy, hereditary 
inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), and 
Nonaka disease are all different names of the same disorder, which is caused by a defect in 
the biosynthetic pathway for SA.  For the purposes of this protocol, GNE Myopathy will be 
used as the term for this disorder. 
Patients with GNE Myopathy cannot produce sufficient SA in muscle tissues; consequently 
glycoproteins and glycolipids in affected patients are not appropriately sialylated.  
In humans, GNE Myopathy is a severe progressive myopathy with onset usually in affected 
patients 18-30 years of age.  Initial diagnosis is followed by progressive loss of muscle 
strength, distal to proximal, which ultimately leads to loss of ambulation in 10-20 years.  
By replacing SA substrate, sialylation should be restored on key target glycoproteins and 
glycolipids and should lead to restoration of biochemical function, improved muscle 
physiology, and improved clinical function.   
The scientific rationale for this substrate replacement therapy is primarily based on the nature 
of the underlying genetic disease and on the work of Malicdan and colleagues, who 
demonstrated oral SA replacement therapy can be effective in restoring biochemical function 
with higher levels of sialylation in a relevant HIBM mouse model (Malicdan et al. 2009).  
The improved biochemical function in treated mice resulted in reduced or absent HIBM 
pathology, prevented clinical signs of muscle disease, and improved survival (Malicdan et al. 
2009). 
SA has a short half-life in the circulation.  Rapid clearance makes it difficult to use as a 
therapeutic replacement substrate in which a steady and constant supply of SA is required for 
use in glycoprotein and glycolipid synthesis.  The SA-ER formulation is expected to provide 
more stable blood levels of SA without spikes or troughs over the 24 hour cycle in humans 
when dosed three or four times per day (TID or QID).  Continuous exposure is likely an 
important step in assuring adequate sialylation during peak periods of synthesis, particularly 
during the night when maximal muscle growth and repair occur. 
The safety of SA has been evaluated in studies of chronic treatment of HIBM mice and in 
toxicology studies in multiple species of normal animals.  Data from these studies, 
summarized in the Investigator’s Brochure (IB), established a reasonable safety profile for 
SA and allow the determination of a no observed adverse effect level (NOAEL), setting the 
stage for the translation of this work to human GNE Myopathy patients.   
The SA-ER formulation was evaluated in a Phase 1 pharmacokinetic (PK) study to assess 
safety and exposure after a single dose and seven days of repeat dosing in SA-deficient GNE 
Myopathy subjects.  Data from this study suggests SA-ER is well tolerated by subjects with 
GNE Myopathy at single and multiple doses up to 6g/day, and sustained levels of SA in 


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blood and urine are achieved.  The TID dosing interval is sufficient to maintain trough levels 
of SA above background. 
A Phase 2 randomized, double-blind study has been performed to evaluate the safety and 
pharmacodynamic (PD) effects of SA-ER at two dose levels (6g/day and 3g/day) over 
48 weeks, including a 24-week placebo-controlled Treatment Period followed by a 24-week 
Treatment Continuation period on SA-ER.  Interim results from the 24-week placebo 
controlled Treatment Period implied a clinical efficacy signal and acceptable safety profile 
suggesting the potential to optimize the therapeutic index by increasing SA exposure.   
Part I of the study will provide treatment continuation for subjects completing the 
aforementioned Phase 2 study and elicit additional information on the long-term safety and 
efficacy of 6g/day SA-ER.  Parts II, III, and IV of the study will assess the long-term safety 
and efficacy of 12g/day SA-ER/SA-IR or SA-ER treatment (1.5g/1.5g TID or QID) and the 
long-term safety and efficacy of 6g/day SA-ER treatment (1.5g TID) for up to 36 months.   
Ultragenyx is also sponsoring a GNE Myopathy-Disease Monitoring Program 
(GNEM-DMP), a novel registry/natural history study to obtain data on the disease 
characteristics of GNE Myopathy and its progression.   
5.1 
Overview of the Disease 
GNE Myopathy was first described by Argov and Yarom in 1984 in a group of affected 
Iranian Jews in Israel (Argov et al. 1984).  The patients showed progressive muscle weakness 
and atrophy, and rimmed vacuoles on biopsy.  Since that time, a variety of GNE Myopathy 
patients have been identified worldwide, including those of Italian, Japanese, Thai, Indian, 
American and African origin (Huizing et al. 2009).  The clinical course is similar among 
these populations, and includes disease onset usually after age 20  years (mean 26 years, 
range 15–40 years; (Nalini et al. 2010); (Nonaka et al. 2005); (Sadeh et al. 1993); (Sunohara 
et al. 1989) though it can be symptomatic earlier. 
Patients often have foot drop due to tibialis anterior weakness as a first sign of GNE 
Myopathy; general weakness is usually more pronounced peripherally, 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 curious 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 leading to a wheelchair-bound state in a mean of 
12 years (Nonaka et al. 2005).  The ocular, pharyngeal and respiratory muscles are relatively 
spared clinically though they may show some abnormal pathology in some patients (Argov et 
al. 1984).  A representative example of disease progression was chronicled in Japanese 
patients over a decade (Sunohara et al. 1989) and showed the Medical Research Council 
(MRC) scale of manual motor assessment scores on a five point scale declining over a 
decade or so in three patients.  Disease progression is not rapid compared with some 


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myopathies but ultimately the level of function becomes severely compromised and 
equivalent to quadriplegia.  
Other clinical or physiological evaluations of GNE Myopathy patients show a variable 
number of abnormalities, all consistent with the myopathic pathologic process.  Unlike other 
myopathies, blood creatine kinase (CK) activities are only mildly elevated or remain in the 
normal range (22/58 patients reported by three publications had two-times or higher 
elevations; (Sadeh et al. 1993); (Mizusawa et al. 1987); (Sunohara et al. 1989) but evaluation 
of CK may still be useful as a marker for GNE Myopathy.  The mouse model of HIBM 
showed elevated CK levels that improve substantially 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, such as 
Duchenne muscular dystrophy. 
Electromyography (EMG) in GNE Myopathy patients is abnormal, with spontaneous 
fibrillations consistent with denervation.  A myopathic pattern (polyphasic muscle unit action 
potentials [MUAPs]) consistent with denervation is observed, however nerve conduction is 
generally normal (Sadeh et al. 1993); (Mizusawa et al. 1987).  Conducting EMG in clinical 
programs is very difficult as there are substantial difficulties with differences in operators 
and inconsistencies of findings. 
Imaging studies of the muscle by computed tomography (CT) scan (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 more normal appearance (Huizing et al. 2009).  Many 
muscles have limited muscle tissue left, which could impact the potential for optimal 
treatment and substantial disease reversal in advanced patients.  
All GNE myopathies (HIBM, DMRV and Nonaka disease) are caused by defects in the 
GNE gene encoding the enzyme for the first step of the SA biosynthetic pathway 
(Figure 5.1.1).  The GNE gene codes 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 the SA that is required for the complete glycosylation of many glycoproteins 
and glycolipids. 
Studies in tissues and mouse models have shown that the deficiency of SA production in 
GNE Myopathy is a key factor in the disease state, though the exact pathophysiologic effect 
of decreased sialylation on glycoproteins or glycolipids is still debated.  Sialylation is 
decreased in the most credible experiments and effects on proteins like neural cell adhesion 
molecule (NCAM) or on proteases like neprilysin, have been proposed (Malicdan et al. 
2008); (Broccolini et al. 2009).  NCAM is essential for muscle enervation and is 
hyposialylated in GNE Myopathy (Ricci et al. 2006).  The pattern of spontaneous fibrillation 
of denervation in GNE Myopathy may be consistent with a pathophysiological role for 
NCAM hyposialylation (Broccolini et al. 2009).  NCAM hyposialylation was used recently 


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to identify atypical GNE Myopathy patients with GNE mutations among a cohort of 
myopathy patients (Broccolini et al. 2010).  Another model involves a hyposialylation effect 
on neprilysin, an endopeptidase for hydrophobic proteins.  The accumulation of unfolded 
proteins and amyloid is consistent with neprilysin being deficient (Malicdan et al. 2008).  
When hyposialylated, neprilysin is less stable and less active, potentially leading to the 
accumulation of unfolded, undigested proteins in vacuoles (Broccolini et al. 2008).  
Among glycolipids, GM3 is also decreased in GNE Myopathy but the role this glycolipid 
plays in the biology of the disease is not clear (Paccalet et al. 2010).  Even with these 
limitations as to the specific pathophysiological role of sialylation, analyses of sialylation of 
these muscle components should still be useful in assessing the PD effects of substrate 
replacement therapy. 
Figure 5.1.1: The Sialic Acid Biosynthetic Pathway 
 
Although no proven pathway for the effect of hyposialylation in GNE Myopathy has been 
demonstrated conclusively, the pathology and data suggest that some combination of 
pathophysiologies is likely and that human skeletal muscle is prone to these problems 
because of normally lower expression levels of GNE/MNK.  In any case, replacement with 
either N-acetyl-D-mannosamine (ManNAc), which is located downstream of the block in 
GNE/MNK, or SA itself can restore CMP-SA synthesis and subsequent sialylation of 
proteins and lipids (Figure 5.1.1).  The GNE/MNK protein may have other functions, but the 
substrate replacement work to date shows that its role in the synthesis of SA is its dominant 
role in the muscle cell and SA deficiency is at the core of the cause of this disease. 
5.2 
Brief Overview of the Development of the Product 
A brief overview of existing information is provided below; a comprehensive review of the 
data is contained in the IB provided by Ultragenyx Pharmaceutical Inc. (Ultragenyx), which 
should be reviewed prior to initiating the study. 


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SA as an active ingredient was produced from N-acetylglucosamine using an enzyme 
catalyzed process.  The active ingredient was subjected to a series of nonclinical 
pharmacology and toxicology studies conducted by Ultragenyx; evaluation of the active 
ingredient also included some data from prior published work on SA toxicology.  
The NOAEL for the product was determined to be 2000 mg/kg in dogs and rats.  SA-ER, the 
extended release formulation of SA to be used in the study, was developed to enhance the PK 
of the product due to its rapid clearance from the body.   
Following clearance of an Investigational New Drug (IND) submission by the United States 
(US) Food and Drug Administration (FDA), a Phase 1 study of SA-ER was conducted.  
Over a range of single or multiple day doses from 650 - 6,000 mg/day no safety problems 
were identified, and PK analysis showed acceptable absorption of the product with a PK 
curve that covered about 8-16 hours.  Repeat dosing for one week with dose levels from 
1,950-6000 mg/day showed that trough levels could be maintained above the background 
level, as expected for a sustained release formulation.  
A Phase 2 randomized, placebo-controlled study has been performed to evaluate the safety 
and PD effects of SA-ER at two dose levels (6g/day and 3g/day).  The study consisted of a 
24-week placebo-controlled Treatment Period, followed by an additional 24-week Treatment 
Extension period with all subjects on the investigational product.  The interim 24-week data 
from the Phase 2 study suggested a positive clinical efficacy signal and acceptable safety 
profile indicating the potential to optimize the therapeutic index by increasing SA exposure.   
5.2.1 
Brief Description of the Investigational Product 
SA (also known as N-acetylneuraminic acid or NANA) intended as a substrate replacement 
therapy for GNE Myopathy, which is caused by a defect in the de novo biosynthesis of sialic 
acid.  The choice of an extended release formulation is based on the fact that SA has a short 
half-life in the circulation and its rapid clearance makes it difficult to use as a therapeutic 
replacement substrate in which a steady and constant supply of SA is needed.  SA-ER was 
developed to improve the stability of exposure to SA and allow more appropriate dosing and 
efficient substrate replacement. 
SA-ER 500 mg tablets are white to off-white, uncoated or film-coated, extended release, oval 
tablets that are designed for oral administration.  The tablet formulation contains 
approximately 43.3% active pharmaceutical ingredient in a mixed polymer matrix developed 
for extended release of SA over 24 hours.  Tablets are manufactured by a formulation process 
using wet aqueous granulation; the blend is then dried and compressed into tablets.  
Film-coated tablets are coated with Opadry II, a non-functional aqueous film coating.  
SA-ER 500 mg tablets are 1,150 mg in total weight. 
Since successful use of SA replacement therapy in humans is believed to depend upon 
optimized exposure to the compound, an increased dose was examined in Part II of this 
extension study.  Although administration of more extended release tablets could have been 
utilized, data in canines suggested that administration of immediate release SA in 


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combination with the SA-ER would maximize absorption in the GI tract. Therefore a study 
testing an increased dose level combining immediate release SA (SA-IR) with SA-ER was 
proposed in Amendment 1. Amendment 2 allows for subjects to receive either 6g/day or 
12g/day based on the data collected and analyzed from Part II. Refer to Section 7.2 for 
additional details and rationale for the dose reduction in Part III.  
SA-IR 500mg capsules are naturally colored, size 000, immediate release, hard gelatin 
capsules designed for oral administration.  The capsule formulation contains approximately 
93.5% active pharmaceutical ingredient.  Manufacturing consists of dry blending followed by 
filling into capsules.  SA-IR capsules have a fill weight of approximately 535 mg and a total 
weight of approximately 698 mg. 
5.2.2 
Nonclinical Studies 
Published in vivo studies in the HIBM mouse model have shown that replacement by SA 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 GNE Myopathy is primarily dependent on these results.  Key safety pharmacology, PK, 
and toxicology studies to support the use of SA in treating GNE Myopathy 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.  There were no adverse effects on neurobehavior in rats or on respiratory 
and cardiovascular function in dogs at oral SA doses as high as 2000 mg/kg. 
PK study in dogs:  Ultragenyx conducted a multiple-dose, cumulative dosing, PK study in 
dogs to assess exposure following administration of SA-ER and the SA-ER/SA-IR treatment 
combination.  Each dog was administered SA-ER (200 mg/kg/day; human dose equivalent 
100 mg/kg/day) TID throughout the study duration (12 days).  Following 4 days of SA-ER 
treatment, SA-IR (100 mg/kg/day) TID was added to SA-ER treatment.  Following 4 days of 
SA-ER/SA-IR treatment, the SA-IR dose was increased to 200 mg/kg/day.  The highest dose 
level of SA-ER/SA-IR was equivalent to a human dose of 200 mg/kg/day.  The area under 
the curve (AUC) during the 8-hr dosing window increased proportionally to the dose of 
SA-IR, suggesting the administration of SA in extended-release and immediate-release forms 
can improve overall absorption of SA-ER and increase free SA levels up to 3X in the serum.   
Overall SA-ER/SA-IR was well tolerated in this study.        
Chronic toxicology studies in rats and dogs:  In an oral 6-month rat study, there were no 
treatment-related effects on clinical condition, body weight, food consumption, 
ophthalmology, clinical pathology (hematology, blood chemistry, and urinalysis) and in 
pathologic evaluations (gross, organ weight, and histopathology).  The no observed adverse 


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effect level (NOAEL) in this study was 2000 mg/kg which is equivalent to approximately a 
17 g daily human dose.  This provides a safety margin of approximately 1.4–fold over the 
proposed highest dose (12g/day) in the Phase 2 UX001-CL201 Study.  The 9-month oral 
toxicity study in dogs did not show any adverse effects on clinical condition, body weight, 
food consumption ophthalmology, electrocardiography, clinical pathology (hematology, 
blood chemistry, and urinalysis) and in pathologic evaluations (gross, organ weight, and 
histopathology). The NOAEL in this study was 2000 mg/kg which is equivalent to a 60 g 
daily human dose. This provides a safety margin of approximately 5–fold over the proposed 
highest dose (12g/day) proposed in the Phase 2 UX001-CL201 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 GNE Myopathy are summarized 
below; additional details may be found in the IB.   
Phase 1 PK and Safety (UX001-CL101):  “A Phase 1 Study to Evaluate the Safety and 
Pharmacokinetics of Single and Repeat Doses of Sialic Acid Extended-Release (SA-ER) 
Tablets in Patients with Hereditary Inclusion Body Myopathy (HIBM)”.   
The study was conducted in 28 subjects who received single and multiple doses to assess 
the PK and safety of SA-ER.  Subjects received SA-ER tablets orally at one of five dose 
levels in the single dose phase, and one of four levels in the repeat dose phase.  Each of the 
28 enrolled subjects were sequentially assigned to a specific dose level and received two 
single-dose exposures at that same dose level (fasted and fed).  The low dose cohorts were 
filled before assigning higher dose cohorts.  The subjects were then assigned to receive one 
repeat-dose regimen.  The lower dose repeat-dose cohorts are being filled before proceeding 
to higher repeat-dose levels.   Dose levels are as follows: 
• single doses:  650 mg (n = 6), 1,950 mg (n = 6), 2,925 mg (n = 6), 4,875 mg (n = 4), 
6000 mg (n=6). 
• multiple dosing:  650 mg TID (1,950 mg/day; n = 8), 975 mg TID (2,925 mg/day; n = 8), 
1,625 mg TID (4,875 mg/day; n = 6), 2000 mg TID (6000 mg/day; n = 6). 
Safety evaluations have not shown any significant drug-associated safety problems.  
Preliminary PK analyses show that the drug is absorbed with some variation in humans.  
Multi-day dosing has shown increased and sustained blood levels of free SA over a 24 hour 
cycle, consistent with expectations for an extended release formulation.   


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Phase 2 PK, PD and Safety (UX001-CL201):  “A Phase 2 Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group Study to Evaluate the Dose and Pharmacodynamic 
Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients with GNE Myopathy or 
Hereditary Inclusion Body Myopathy”. 
A Phase 2 randomized, placebo-controlled study has been performed to evaluate the safety 
and PD effects of SA-ER at two dose levels (3g and 6g/day).  The study consists of a 
24-week placebo-controlled Treatment Period, followed by an additional 24-week Treatment 
Continuation Period whereby all subjects receive active treatment.  A planned analysis was 
conducted following completion of the 24-week placebo-controlled Treatment Period; the 
goal was to identify the dose that provides the best risk-benefit profile.   
Results of planned PK, PD, clinical efficacy, and safety analyses following the 24-week 
placebo-controlled Treatment Period showed dose-dependent improvement in muscle 
strength relative to placebo, particularly in the upper extremities at the 6g SA-ER dose. 
These changes were statistically significant or trended towards significance, and were more 
pronounced in subjects that had greater walking ability at baseline, a predefined subset.  
Other clinical endpoints did not reveal changes at this Week 24 interim assessment.  
CK levels showed a trend to improvement in the 6g SA-ER dose group compared with 
placebo.  SA-ER appeared to be well tolerated with no serious adverse events (SAEs) 
observed in either dose group.  As expected, the highest dose (6g/day SA-ER) provided a 
sustained exposure, a clinical efficacy signal, and acceptable safety profile.   
GNE Myopathy-Disease Monitoring Program:  A natural history study collecting data on 
the disease characteristics and its progression is also in progress.   
5.3 
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 at this time.  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.  
Interim safety results following a 24-week Treatment Period in a completed Phase 2 study 
(UX001-CL201), suggested an increase in diarrhea and GI symptoms relative to placebo.  
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.    
In patients with GNE Myopathy, 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 GNE Myopathy are reversible or if and how fast reversal of muscle disease might occur.  
The data in the HIBM mouse model suggest that over a one year period, substantial 
beneficial effects on the pathology of the disease are possible.  However, it is not clear 


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whether advanced disease can improve, as opposed to preventing progression of existing 
disease.  If the therapy has an effect comparable to that observed by Sparks and colleagues 
using intravenous immune globulin (IVIG) as a source of SA (Sparks et al. 2007), then the 
benefit to GNE Myopathy patients in improving muscle strength and function might be 
substantial.  In clinical studies conducted to date, the highest dose (6g/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. 
5.4 
Study Rationale 
GNE myopathy or HIBM is a severe progressive metabolic myopathy caused by a defect in 
the biosynthetic pathway for sialic acid (SA).  Substrate replacement of SA is a potential 
therapeutic strategy based on evidence from relevant in vivo models, supported by PK 
characterization in a Phase 1 clinical study, and improvement in muscle strength from a 
Phase 2 randomized controlled trial.  The first study showed some efficacy at the 6g dose 
level but not at 3g, indicating the dose level may be at the low end of the dose response 
curve.  The interim data implied a clinical efficacy signal and acceptable safety profile 
suggesting the potential to optimize the therapeutic index by increasing SA exposure.  
Since successful use of SA replacement therapy in humans is believed to depend upon 
optimized exposure to the compound, an increased dose was suggested.  Although 
administration of more extended release tablets could be utilized, data in canines suggests 
that administration of immediate release SA (SA-IR) in combination with the SA-ER will 
maximize absorption in the GI tract. Therefore a study testing an increased dose level 
combining SA-IR with SA-ER is proposed. 
Subjects completing the 48-week UX001-CL201 study are eligible to continue treatment 
under this open-label extension protocol testing an increased dose of SA.  Additional GNE 
Myopathy subjects will be enrolled to assess the safety and efficacy of SA-ER/SA-IR in a 
treatment-naïve population.  Ultragenyx is conducting this study in four parts:  Part I of the 
study will provide additional information on the long-term safety and efficacy of 6g/day 
SA-ER; Part II of the study will assess the safety and efficacy of 12g/day of SA (comprised 
of 1.5 g of SA-ER / 1.5 g of SA-IR treatment QID).  Part III of the study reduces the dose 
from 12g/day to 6g/day for subjects who did not show additional benefit at 12g/day; 
however, treatment-naïve subjects and a small subset of rollover subjects will be invited to 
remain on the higher dose of 12g/day (described in Section 7.2).  Part IV was added to 
change the formulation from SA-IR to SA-ER. The SA-IR dose formulation has been 
removed based on data showing that by the 4th day of dosing in a nonclinical study conducted 
in dogs, AUC for free SA was similar between the immediate and extended release 
formulations. In addition, a review of population data for Month 12 of Part III in the current 
study confirmed that 12g/day SA-IR did not appear to provide any additional benefit 
compared with 6g/day SA-ER, although some individual patients may have improved. 
Therefore, no further SA-IR will be administered after the initiation of Part IV; patients 
currently on 12g/day may continue receiving the 12g/day dose, if desired, by taking SA-ER. 


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6 STUDY OBJECTIVES 
The safety objectives of the study are to: 
• Evaluate additional long-term safety of SA-ER treatment of GNE Myopathy subjects 
previously treated with SA-ER at dose of 6g/day (Part I) 
• Evaluate the safety of 12g /day SA (delivered by 1.5g of SA-ER tablets and 1.5g of 
SA-IR capsules 4 times per day) in the treatment of GNE Myopathy subjects (Part II) 
over a 6 month treatment period 
• Evaluate the safety of SA treatment at both 6g/day and 12 g/day (Part III [SA-ER/SA-IR] 
and Part IV [SA-ER]).   
The clinical objectives of the study are to: 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on muscle 
strength as measured by hand-held dynamometry (HHD) 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on mobility, 
strength, and function using a series of physical performance measures 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on functional 
disability using an interview-based questionnaire.  
The exploratory objectives of the study are to: 
• Evaluate the effect of SA-ER treatment on serum biomarkers of sialylation in GNE 
Myopathy subjects (Part I)  
• Determine whether 12g/day SA-ER/SA-IR administered 1.5g/1.5g four times per day is 
superior to prior treatment with SA-ER in GNE Myopathy subjects (Part II) 
o Determine whether a subset of subjects has additional benefit on the higher dose 
treatment. 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
This open-label extension study of will assess the long term safety and efficacy of SA 
treatment over a period of approximately 36 months, or until marketing approval or program 
termination by Ultragenyx.  In Part I of the study, approximately 46 subjects will be enrolled 
following successful completion of the UX001-CL201 study.  The Baseline visit will be 
conducted in conjunction with the UX001-CL201 Week 48 study visit to avoid treatment 
disruption.  Enrollment will take place after all UX001-CL201 Week 48 study assessments 
have been completed and the investigator has determined the subject meets all eligibility 
criteria.  Data collected at the UX001-CL201 Week 48 visit will serve as the Baseline data 
for Part I of this protocol.  Following the signing of informed consent at the Baseline visit, 
each subject will be dispensed a 6-week supply of study drug.  Throughout the Part I 
Treatment Period of the study, all subjects will continue to take four 500 mg SA-ER tablets 
orally three times per day (TID), in the morning, early evening, and at bedtime (qHS), for a 
total dose of 6g/day.  The Part I Termination Visit will also serve as the Baseline Visit for 
Part II of the study. 
Beginning with the Part II-Baseline Visit, all subjects currently enrolled in Part I will 
crossover to the SA-ER/SA-IR dosing regimen.  Approximately 10 treatment naïve GNE 
Myopathy subjects will be enrolled into Part II of the study.  The additional subjects will 
provide an assessment of SA-ER/SA-IR treatment in SA naïve subjects able to walk at 
least 200 meters (and < 80% predicted) in a screening 6 Minute Walk Test (6MWT).   
Throughout the 36-month Part II Treatment Period, all subjects will be administered 1.5g 
SA-ER and 1.5g SA-IR orally four times per day (QID), in the morning, afternoon, early 
evening, and qHS, for a total SA dose of 12g/day.  
Part III of the study reduces the SA dose from 12g/day to 6g/day for subjects who did not 
show additional benefit at 12g/day at the interim analysis; however, treatment naïve subjects 
and a small subset of rollover subjects who showed a potential efficacy benefit will be 
invited to remain on the higher dose of 12g/day. Part III will assess the long-term safety 
and efficacy of 12g/day SA-ER/SA-IR treatment for the duration of the study for the subjects 
who stay on the higher dose in Part III and will provide additional information on the 
long-term safety and efficacy of 6g/day SA-ER for the remaining subjects.  
Part IV was added to change the formulation from SA-IR to SA-ER. The SA-IR dose 
formulation has been removed based on data showing that by the 4th day of dosing in a 
nonclinical study conducted in dogs, AUC for free SA was similar between the immediate 
and extended release formulations. In addition, a review of population data for Month 12 of 
Part III in the current study confirmed that 12g/day SA-IR did not appear to provide any 
additional benefit compared with 6g/day SA-ER, although some individual patients may have 
improved. Therefore, no further SA-IR will be administered after the initiation of Part IV; 
patients currently on 12g/day may continue receiving the 12g/day dose, if desired, by taking 
SA-ER.   


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Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, and 
function, and changes in exploratory serum biomarkers will be performed according to 
the Schedule of Events specific to each phase of the study (Table 2.1 and Table 2.2).  
A Termination Visit will be conducted 4 weeks after subjects receive their last dose of study 
drug (last dose of study drug received at Month 36).  For subjects who are eligible and 
choose to participate in the UX001-CL302 open-label extension study, the Month 36 Visit is 
considered the end of study visit and the Termination Visit is not required. Any subject who 
discontinues the current study early or is ineligible or decides not to participate in the 
UX001-CL302 extension study is required to have a Termination Visit 4 weeks after their 
last dose of study drug, as per Schedule of Events. Efficacy data analyses will be conducted 
at the end of the 36-month Treatment Period, although interim analyses may be performed at 
the discretion of Ultragenyx. 
Safety will be monitored throughout the study based on physical examinations, clinical 
laboratory analyses, and reporting of adverse events (AEs) and SAEs.  An independent Data 
Monitoring Committee (DMC) will review safety information periodically an on an ad hoc 
basis as outlined in the DMC charter, which is maintained separately from this protocol. 
7.2 
Discussion of Study Design, Including Choice of Control Group 
Part I of the study will focus on evaluating the long-term safety of 6g/day SA-ER treatment 
in GNE Myopathy subjects continuing SA-ER treatment as an extension of the 48-week, 
Phase 2 UX001-CL201 clinical study.  Part I of the study will also explore long-term effects 
of SA-ER on clinical measures of muscle strength, mobility, function, disability and 
health-related quality of life.  Exploratory evaluations of the effects of SA-ER on serum 
biomarkers will be performed in Part I of the study only.  
Since Part I of the study is designed as an open-label extension designed to continue SA-ER 
treatment for subjects successfully completing the Phase 2 UX001-CL201 study, the study 
size and population are therefore restricted to said individuals.  In UX001-CL201, safety and 
efficacy of SA-ER was examined in a randomized, double-blind study at two dose levels and 
compared to placebo treatment control.  The current study design is not powered to assess 
statistically significant comparisons between treatment groups.  Instead, the study population 
for Part I is intended to provide additional long-term safety data following maintenance 
treatment with 6g/day SA-ER.   Since all subjects will receive the same treatment, 
randomization or blinding of study drug is not necessary.  
The Week 24 interim data from the Phase 2 UX001-CL201 study implied a positive PD 
signal and acceptable safety profile suggesting the potential to optimize the therapeutic index 
by increasing SA exposure.  Therefore, investigation into optimizing the risk-benefit profile 
of SA substrate replacement by examining higher SA doses is warranted.  Part II of the study 
will assess the long-term safety and efficacy of an increased SA dose (total 12g/day) for up to 
12 months.  In this phase, SA treatment will be in the form of SA-ER tablets and immediate 
release capsules (SA-IR) to maximize absorption from the GI tract based on data obtained 
from nonclinical studies in canines.  Continuing subjects will terminate Part I of the study 


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following approximately 12 weeks of treatment with 6g/day SA-ER and continue on to 
Part II of the study by crossing over to an increased daily SA dose of 12g/day.  Since Part II 
of the study will be the first time GNE Myopathy subjects will be treated with the 
SA-ER/SA-IR investigational product, approximately 10 GNE Myopathy subjects will be 
enrolled to assess long-term safety and clinical efficacy of SA-ER/SA-IR in a treatment naïve 
population. 
An interim analysis was conducted after 6 months of treatment with SA-ER/SA-IR; the 
results of this interim analysis have led to the establishment of Part III of the study.  Part III 
will provide long-term safety and efficacy data on both 6 and 12g/day SA.  This change is 
based on a review of individual subject data for the rollover subjects from the parent study 
UX001-CL201. The data analysis suggests that a small subset of subjects received an added 
benefit from the higher dose (defined as at least a 15% increase in either the UEC or LEC).  
The rollover subjects who met these criteria, along with the ongoing naïve subjects, had the 
option to remain on the 12g/day dose for the remainder of the study. 
Part IV was added to change the formulation from SA-IR to SA-ER. The SA-IR dose 
formulation has been removed based on data showing that by the 4th day of dosing in a 
nonclinical study conducted in dogs, AUC for free SA was similar between the immediate 
and extended release formulations. In addition, a review of population data for Month 12 of 
Part III in the current study confirmed that 12g/day SA-IR did not appear to provide any 
additional benefit compared with 6g/day SA-ER, although some individual patients may have 
improved. Therefore, no further SA-IR will be administered after the initiation of Part IV; 
patients currently on 12g/day may continue receiving the 12g/day dose, if desired, by taking 
SA-ER.  
Patients who elect to decrease from 12 g/day to 6 g/day may be allowed to do so upon 
Sponsor approval.  
The 36-month treatment duration is intended to evaluate the long-term safety and efficacy of 
SA.  While the lack of a control group may introduce difficulties in discerning natural disease 
progression from treatment effectiveness, due to the progressive debilitative nature of the 
disease, a placebo-controlled study of this duration is not feasible 
7.3 
Selection of Study Population 
The study will be conducted in adult patients who have previously demonstrated mutations in 
the gene for the GNE/MNK enzyme leading to a diagnosis of GNE myopathy (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 to determine if exogenous SA leads 
to improved protein and lipid sialylation and stabilized or improved muscle structure and 
performance.  The majority of the study population will consist of approximately 46 GNE 
Myopathy subjects who successfully completed UX001-CL201 and may or may not have 


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been previously exposed to SA-ER.  Approximately 10 GNE Myopathy subjects who are SA 
and MaNAc-treatment naïve will be enrolled into Part II of the study. 
The inclusion/exclusion criteria from the UX001-CL201 study inherently define the study 
population for subjects in Part I of the study, since successful completion of UX001-CL201 
is requisite for enrollment in this study.   The previous study was designed to allow for the 
enrollment of patients with a broad spectrum of physical disability, with at least 60% of 
enrolled subjects having residual lower extremity strength and function sufficient to walk 
≥ 200 meters in the 6MWT.  Enrolling patients across the spectrum of disease severity as 
subjects allowed the study to fully explore the safety and efficacy profile of SA-ER and 
inform the design of future studies.  However, it should be noted that subjects unable to 
complete UX001-CL201 would not be eligible for this extension study, potentially 
introducing population bias toward subjects experiencing favorable safety and efficacy 
following up to 48 weeks treatment with SA-ER. 
For the additional treatment naïve subjects enrolled into Part II of the study, the diagnosis 
and age range are the same as requirements for continuing subjects.  This subgroup will be 
restricted to GNE Myopathy subjects with the ability to walk at least 200 meters during the 
6MWT.  Since the strongest clinical efficacy signal was observed in this subset of GNE 
Myopathy subjects participating in the UX001-CL201 study, this protocol was designed to 
enroll those subjects most likely to obtain clinical benefit from study treatment. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
• Enrollment in and successful completion of the UX001-CL201 protocol OR 
(for 10 treatment naïve subjects): 
o Have a confirmed diagnosis of GNE Myopathy 
o Aged 18 -65 years of age, inclusive 
o Able to walk ≥ 200 meters and < 80% of predicted normal during the 6MWT 
(orthotics and assistive devices allowed) 
o No prior history of treatment with SA or MaNAc 
• Must be willing and able to provide written, signed informed consent after the nature of 
the study has been explained, and prior to any research-related procedures 
• Must be willing and able to comply with all study procedures  
• Sexually active subjects must be willing to use an acceptable method of contraception 
while participating in the study 
• Females of childbearing potential must have a negative pregnancy test at Baseline 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, 


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or have had tubal ligation at least one year prior to Baseline, or who have had total 
hysterectomy. 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
• Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at 
any time during the study 
• Use of any investigational product (other than SA-ER tablets) to treat GNE Myopathy 
• Ingestion of ManNAc or similar SA producing compounds  
• 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 
• Have any co-morbid conditions, including unstable major organ-system disease(s) that in 
the opinion of the Investigator, places the subject at increased risk of complications, 
interferes with study participation or compliance, or confounds study objectives. 
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 principal investigators and Ultragenyx also have the 
right to remove subjects from the study.  Subjects may be removed from the study for the 
following reasons: 
• Occurrence of an unacceptable AE 
• An illness that, in the judgment of the principal investigator or Ultragenyx, might 
invalidate the study or place the subject at risk 
• At the request of the subject, principal investigator, or Ultragenyx, whether for 
administrative or other reasons 
• Protocol deviation or unreliable behavior 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the Case 
Report Form (CRF).  Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve.  If such abnormalities do not return to normal within 
30 days after the last dose given, their etiology should be identified and Ultragenyx should be 
notified.  All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the (Early) Termination Visit procedures within four weeks of discontinuation. 


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Subjects who withdraw or are removed from the study after receiving study drug may not 
re-enter the study. 
7.3.3.1 
Stopping Rules 
A DMC will be constituted for Study UX001-CL202 and will act in an advisory capacity to 
Ultragenyx to monitor the safety of SA-ER/SA-IR in subjects who participate in the study 
(see Section 7.6.3).  The DMC may provide advice to Ultragenyx in any determination of 
whether study enrollment should be paused or if the study should be halted. 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE).  If two subjects develop the same unexpected Grade 3 
AE that is possibly or probably related to study drug or any subject develops an unexpected 
Grade 4 AE that is possibly or probably related to study drug, enrollment of new subjects 
may be suspended until a thorough evaluation can be performed.  Should these AEs occur, a 
full clinical evaluation will be performed by the medical monitor, principal investigators, and 
DMC in order to make a decision regarding what actions to take, including whether to 
suspend or resume enrollment, or recommend stopping the study after Institutional Review 
Board (IRB)/Ethics Committee (EC) review.  The recommendations from the medical 
monitor and investigators will be forwarded to the IRB/EC for review and approval. 
7.4 
Treatments 
7.4.1 
Treatments Administered 
The SA-ER investigational product will consist of tablets containing 500 mg of SA active 
ingredient in an extended release formulation.  In Part I of the study, the 6000 mg (6g) total 
daily SA-ER dose will be self-administered by the oral route and will be divided into a three 
TID regimen; all subjects will self-administer four 500 mg tablets in the morning, four tablets 
in the early evening, and four SA-ER tablets qHS.  
The SA-IR investigational product will consist of capsules containing 500 mg of SA active 
ingredient in an immediate release formulation.  In Part II of the study, the 12,000 mg (12g) 
total daily SA dose will be self-administered by the oral route and will be divided into a QID 
regimen; all subjects will self-administer three 500 mg tablets (1.5g SA-ER) and three 
500 mg capsules (1.5g SA-IR) in the morning, afternoon, early evening, and qHS.  
In Part III of the study, for those subjects on the 12g/day dose, each dose of SA-ER/SA-IR 
will consist of SA-ER tablets, each containing 500 mg of SA active ingredient in an extended 
release formulation and SA-IR capsules, each containing 500 mg of SA active ingredient.  
During the Treatment Period, the 12,000 mg (12g) total daily SA dose will be administered 
by the oral route and will be divided into a TID or QID regimen. If tolerability issues arise, 
the dose may be temporarily stepped down until symptoms resolve.  
In Part III of the study, for those subjects on the 6g/day dose, each dose of SA-ER will 
consists of tablets, each containing 500 mg of SA active ingredient in an extended release 


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formulation.  During the Treatment Period, the 6000 mg (6g) total daily SA-ER dose will be 
administered by the oral route and will be divided into a TID regimen. 
Part IV: 6g/day dose and 12g/day dose – Each dose of SA-ER will consists of tablets, each 
containing 500 mg of SA active ingredient in an extended release formulation.  During the 
Treatment Period, the 6g total daily SA-ER dose will be administered by the oral route and 
will be divided into a TID regimen. The 12g total daily SA-ER dose will be administered by 
the oral route and will be divided into a TID or QID regimen. 
Subjects will be instructed to take all study medication with food in the morning, the 
afternoon, early evening, and/or qHS (i.e. within 30 minutes following a meal or snack).   
7.4.2 
Identity of Study Drugs 
The study drugs for protocol UX001-CL202 are white, oval, SA-ER tablets and naturally 
colored, size 000, hard gelatin SA-IR capsules for oral administration.  No animal-derived 
products are used in the manufacture of the tablets.  Where bovine gelatin is used for 
production of gelatin capsules, it is in compliance with pharmaceutical regulatory statutes. 
The study drugs were manufactured, packaged, and labeled according to Good 
Manufacturing Practice (GMP) regulations. 
Study drug tablets will be packaged in bottles.  Each bottle will contain 168 tablets or 
capsules, equivalent to 2 weeks of study drug supply.  During Part I, subjects will receive an 
approximate 6 week supply at the Baseline and Week 6 visits.  For Week 6 and Week 12 
visits, the visit window is ± 0 days.  For the duration of the study, subjects will be instructed 
to return all unused study drug to the next visit.   
Study drug will be dispensed at in-clinic visit. Additional drug may be shipped to subjects by 
the investigative site in between scheduled clinic visits.   
Bottles will be labeled with the study number (UX001-CL202).  The bottle will display the 
protocol number (UX001-CL202), the name and city, state, and zip code of the study sponsor 
(Ultragenyx Pharmaceutical Inc.), the storage conditions, expiration date, and the statement 
"Caution: New Drug – Limited by Federal (US) Law to Investigational Use".   
7.4.2.1 
Investigational Product 
SA-ER 500 mg tablets are white to off-white, extended release, oval tablets intended for oral 
administration.  The tablet formulation contains approximately 43.3% active pharmaceutical 
ingredient in a mixed polymer matrix developed for extended release of SA over 24 hours.  
Tablets are manufactured by a formulation process using wet aqueous granulation; the blend 
is then dried and compressed into tablets.  SA-ER 500 mg tablets are 1150 mg in total 
weight. 
SA-IR 500mg capsules are naturally colored, size 000, immediate release, hard gelatin 
capsules designed for oral administration.  The capsule formulation contains approximately 


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93.5% active pharmaceutical ingredient.  Manufacturing consists of dry blending followed by 
filling into capsules.  SA-IR capsules have a fill weight of approximately 535 mg and a total 
weight of approximately 698 mg. 
7.4.3 
Selection of Doses and Study Duration 
Part I - SA-ER Treatment Period:  In Part I of this Phase 2 open label extension study, 
SA-ER will be administered orally TID for a total dose of 6000 mg/day (6g SA-ER).  
The SA-ER dose and regimen for Study UX001-CL202 was selected based on the following 
information: 
• Analyses of SA PK in the Phase 1 study UX001-CL101 indicate that orally administered 
doses of SA-ER at 2000 - 6000 mg/day divided into TID dosing is effectively absorbed in 
humans, and multiple day dosing at doses up to 6000 mg/day achieves steady, increased 
levels of free SA in the serum with some individual variation. 
• In the Phase 1 study, single oral doses of SA-ER at up to 6g SA-ER and seven days of 
treatment at up to 6g/day have been administered without any significant drug-associated 
safety problems. 
• Malicdan and colleagues have demonstrated that 20 mg/kg/day SA given orally as 
replacement therapy effectively prevented disease in a mouse model of HIBM (Malicdan 
et al. 2009).  Using the allometric scaling method suggested by the US FDA (FDA 
Guidance for Industry 2005), the human equivalent dose is 12.5 times higher; a mouse 
dose of 20 mg/kg/day is equivalent to a human dose of 1.6 mg/kg/day. 
• Toxicology studies have identified the NOAEL to be 2000 mg/kg in dogs and rats, far 
above the proposed human dose level of 6g/day SA-ER in Part I of the study. 
• TID dosing in conjunction with an extended release formulation is able to achieve steady 
increased levels of SA over the 24 hour cycle. 
• To date, no SAEs have been observed from an ongoing Phase 2 randomized, 
placebo-controlled study evaluating the safety and PD effects of 3g/day and 6g/day 
SA-ER.   
Based on these data, the 6g/day total daily dose selected for Part I of the Phase 2 extension 
study is deemed reasonable.  The use of doses above that tested in preclinical mouse models 
accounts for species-specific differences in absorption and/or biological activity.  Based on 
Phase 1 clinical data, steady state SA levels are achieved with TID dosing:  in the morning, 
early evening, and qHS.  The qHS dose is particularly important to assure coverage during 
the night.   
Part II - SA-ER/SA-IR Treatment Period:  Successful use of SA replacement therapy in 
humans is believed to depend upon optimized exposure to the compound.  Interim results 
from the UX001-CL201 study suggest an increased dose of therapy is warranted.  In Part II 
of this Phase 2 open label extension study, 12g SA will be administered orally via 1.5g of 


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SA-ER tablets and 1.5g SA-IR capsules, QID.  The SA-ER/SA-IR dose and regimen for 
Study UX001-CL202 was selected based on the following additional information: 
• Dose effect at 6g only.  Interim results from UX001-CL201 suggest the 6g SA-ER dose 
level appears to be at the lower end of the effective range since a clinical efficacy signal 
was observed but 3g SA-ER had almost no effect.   
• The SA level correlates with treatment effect based on HHD.  The Week 24 interim 
data imply a positive PD signal and acceptable safety profile suggesting the potential to 
optimize the therapeutic index by increasing SA exposure.   
• Canine studies show that immediate release most effective way to increase SA.  
Studies in normal canines showed that more than proportional increases in absorption of 
SA are possible if an immediate release formulation was mixed with an extended release 
formulation.  The concept is that the immediate release product enhances stomach 
absorption which is not well utilized by extended release formulated tablets. 
• QID therapy should support higher SA levels.  Since SA-IR is rapidly cleared, a QID 
dosing regimen is predicted to provide optimized continuous exposure to SA.  
Administration of a 12g total daily dose of SA would therefore be divided into 4 equal 
doses of 3g each (1.5g SA-ER + 1.5g SA-IR), representing only a 50% increase for each 
dose. 
• Safety of very high SA doses.  In a chronic toxicology study in rats, the NOAEL was 
2000 mg/kg SA, which is provides a safety margin of approximately 1.4-fold for the 
proposed 12g/day dose level.  In a 6 month oral toxicity study in dogs, the NOAEL was 
2000 mg/kg SA, which provides a safety margin of approximately 5-fold for the human 
12g/day dose level.   
• Single doses of 6g SA-ER given in one dose were well tolerated.  In the Phase 1 PK 
and tolerability study, 6g SA-ER was administered to GNE Myopathy subjects in a single 
oral dose and was well tolerated with no SAEs observed. 
Based on these data, the 12g/day total daily dose selected for Part II of the Phase 2 extension 
study is deemed reasonable.  Results of nonclinical studies in canines suggest the 
administration of SA in extended-release and immediate-release form can improve overall 
absorption of SA-ER and increase free SA levels in the serum.  Although administration of 
more extended release tablets could be utilized, data in canines suggests that administration 
of SA-ER/SA-IR will maximize absorption in the GI tract. 
Part III – 12g/day SA-ER/SA-IR or 6g/day SA-ER Treatment Period:  This change is based 
on a review of individual subject data for the rollover subjects from the parent study 
UX001-CL201. The data analysis suggests that a small subset of subjects received an added 
benefit from the higher dose.  The rollover subjects who meet these criteria, along with the 
ongoing naïve subjects, will have the option to remain on the 12g/day dose for the remainder 
of the study. 


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Part IV – 12g/day SA-ER or 6g/day SA-ER Treatment Period: Part IV was added to change 
the formulation from SA-IR to SA-ER. The SA-IR dose formulation has been removed based 
on data showing that by the 4th day of dosing in a nonclinical study conducted in dogs, AUC 
for free SA was similar between the immediate and extended release formulations. 
In addition, a review of population data for Month 12 of Part III in the current study 
confirmed that 12g/day SA-IR did not appear to provide any additional benefit compared 
with 6g/day SA-ER, although some individual patients may have improved. Therefore, no 
further SA-IR will be administered after the initiation of Part IV; patients currently on 
12g/day may continue receiving the 12g/day dose, if desired, by taking SA-ER.  
Study Duration:  The maximum treatment duration for Part I of the study will be 12 weeks 
to allow crossover to Part II of the study.  The Parts II, III, and IV treatment durations of 
approximately 36 months enables a long-term assessment of the safety and efficacy of 
SA-ER/SA-IR and SA-ER in subjects with GNE Myopathy. 
7.4.4 
Prior and Concomitant Therapy 
7.4.4.1 
Prohibited Medications 
Patients may not be enrolled if they have used any investigational product (other than SA-ER 
tablets) or investigational medical device prior to Baseline, or if they require any 
investigational agent prior to completion of all scheduled study assessments.  Ingestion of 
ManNAc, SA, or related metabolites; IVIG; or anything that can be metabolized to produce 
SA in the body is prohibited during the 60 days prior to Baseline and throughout the study.  
If ManNAc, SA or other substrate was used more than 60 days prior to Baseline, the time 
period of use, the compound used, and the dose and dose regimen should be recorded in the 
subject’s history.  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 
RESULTS.   
7.4.4.2 
Permitted Medications 
Other than the medications specifically prohibited in this document, subjects may receive 
concomitant medications as required.  Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 60 days prior to 
Baseline will be reviewed and recorded.  At the Baseline visit, current medications will be 
recorded.  If a subject takes any medication other than SA-ER during study treatment, the 
subject should record the date and time the medication was taken, the name of the 
medication, and the reason the medication was taken in the drug administration diary; this 
data will be recorded in the subject’s CRF. 


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Any non-study therapies received during study participation will be similarly recorded in the 
subject’s medical record and CRF. 
7.4.5 
Treatment Compliance 
Subjects will be asked to maintain a record of self-administration in a drug accountability 
diary; the diary will be reviewed at each study visit.  Subjects will be instructed to return all 
unused study drug to the next visit.  Drug accountability diaries will be collected by site 
personnel at the clinic visits.  Site personnel will maintain a record of all medication 
dispensed to each subject and all unused medication returned to the site. In Parts II, III, and 
IV of the study, site personnel will make periodic calls to subjects to ensure treatment 
compliance. 
7.5 
Study Procedures and Assessments 
7.5.1 
Schedule of Events 
The Part I Baseline Visit will be conducted in conjunction with the UX001-CL201 Week 48 
study visit to avoid treatment disruption.  Enrollment will take place after all UX001-CL201 
Week 48 study assessments have been completed and the investigator has determined the 
subject meets all eligibility criteria.  Data collected at the UX001-CL201 Week 48 visit will 
serve as the Baseline data for Part I of this study.  Following the signing of informed consent 
at the Part I Baseline visit, each subject will be dispensed study drug and will return for 
assessments according to the Part I Schedule of Events (Table 2.1).   
For subjects continuing treatment during Part I, the Part II Baseline Visit will be conducted in 
conjunction with the Part I Termination Visit.  Additional treatment-naïve subjects will be 
enrolled directly into Part II of the study, with screening and baseline assessments taking 
place at the Part II Baseline Visit.  Following the signing of informed consent at the Part II 
Baseline visit, each subject will be dispensed study drug and will return for assessments 
according to the Schedule of Events (Table 2.2).   
The Termination Visit occurs four weeks after subjects receive their last dose of the study 
(last dose of study drug received at Month 36).  The Termination Visit is not required for 
subjects who are eligible and choose to participate in the extension study, but must be 
completed for any subject who terminates study participation early or decides not to 
participate in the UX001-CL302 open-label extension study. For subjects who discontinue 
prior to completing the study, the Termination Visit will be considered an Early Termination 
Visit; every reasonable effort should be made to perform the Termination Visit procedures 
within four weeks of discontinuation. 
The parameters to be assessed in Study UX001-CL202, along with timing of assessments for 
each part of the study, are provided in the Schedule of Events (Table 2.1 and Table 2.2).  


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7.5.2 
Clinical Efficacy Measures 
The clinical efficacy measures in this study will evaluate muscle strength, mobility and 
function using the evaluations detailed below.  Assessments will be conducted as indicated in 
the Schedule of Events (Table 2.1 and Table 2.2, respectively).  Portions of the tests may be 
videotaped to monitor test administration and assess for qualitative changes in function 
(e.g., gait).  Subject identity will be protected by blurring the facial area in the video(s).  
Refer to the Clinical Evaluator Manual for additional details on clinical efficacy measures. 
7.5.2.1 
Hand-held dynamometry 
In Part I of the study, HHD testing will be performed at the Baseline and Part I Termination 
Visits, to assess muscle strength.  For continuing subjects, the assessment at the Part I 
Termination Visit will serve as the baseline assessment for Part II of the study.  HHD testing 
in Parts II, III, and IV of the study will be performed at Baseline (for treatment naïve 
subjects), Months 3, 6, 12, 18, 24, 30, 36 and Termination Visits.  Formal training will be 
conducted with the licensed physical therapists administering the HHD testing 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 and a pinch dynamometer will be used to assess pinch 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 administrator will attempt to obtain two force values within 
approximately 15% of each other for each muscle group.  Testing positions may be altered 
at the discretion of the administrator to improve the reliability of the test.  The total force 
(in kg) will be recorded at the time of test administration.  The highest force value collected 
for each muscle group will be used for data analysis.  The percent of predicted normal values 
will be calculated after the testing using published normative data (Mathiowetz et al. 1985); 
(NIMS 1996); (Bohannon 1997b); (Bohannon et al. 2006); (Peters et al. 2011). 
7.5.2.2 
Six Minute Walk Test  
In Part I of the study, the 6MWT (Solway et al. 2001) will be administered at Baseline and 
the Part I Termination Visits to assess walking ability.  For continuing subjects, the 
assessment at the Part I Termination Visit will serve as the baseline assessment for Part II of 
the study.  In Parts II, III, and IV of the study, the 6MWT will be administered at Baseline 
(for treatment naïve subjects), Months 3, 6, 12, 18, 24, 30, 36 and Termination Visits.  
The 6MWT will be administered by a licensed physical therapist in accordance with 
American Thoracic Society (ATS) guidelines (ATS 2002).  Blood pressure, heart rate and 
self-reported Borg scale dyspnea and fatigue ratings will be recorded before and after the test 


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administration.  ATS guidelines require a subject to have a pre-test resting heart rate of less 
than 120 beats/minute, systolic blood pressure of less than 180 mm Hg and diastolic blood 
pressure of less than 100 mm Hg to ensure safety.  Subjects who meet the safety criteria will 
be instructed to walk the length of a pre-measured 20 meter course for six consecutive 
minutes.  Traffic cones will be used to standardize the distance in hallways longer than 
20 meters.  The subject will walk laps around the cones until the six minute time period has 
expired.  However, the test will not be interrupted and the subject will continue to walk for 
the 6-minute duration of the test.  Instructions and encouragement will be given according to 
the script provided in the ATS guidelines.  The distance walked at the end of six minutes 
will be recorded in meters at the time of test administration.  The percent of predicted 
normal values will be calculated after the testing using published normative data (Gibbons et 
al. 2001). 
7.5.2.3 
Walking Speed Test 
In Part I of the study, the walking speed test will be administered at Baseline and the Part I 
Termination Visits to assess gait speed.  In Parts II, III, and IV of the study, the walking 
speed test will be administered at Baseline (for treatment naïve subjects), Months 3, 6, 12, 
18, 24, 30, 36 and Termination Visits.  The test will be administered twice by a licensed 
physical therapist, once at a comfortable speed and once at a maximum speed.  Subjects will 
be instructed to walk the length of a pre-measured 25 foot (7.62 meter) course.  Traffic cones 
or tape on the floor will be used to standardize the distance.  Subjects will have a few feet at 
the beginning and the end of the 25 foot course to allow for acceleration and deceleration.  
For the comfortable speed test, subjects will be instructed to walk at their normal pace.  
For the maximum speed test, subjects will be instructed to walk as fast as they safely can 
without running.  The total number of seconds required to complete the test for each speed 
will be recorded in seconds at the time of test administration.  Subject performance relative to 
peers will be calculated after the testing using published normative data (Bohannon 1997a).  
7.5.2.4 
Weighted Arm Lift Test 
In Part I of the study, the weighted arm lift test (Agarwal et al. 2006) will be administered at 
Baseline and the Part I Termination Visits, to assess upper limb function.  In Parts II, III, and 
IV of the study, the weighted arm lift test will be administered at Baseline (for treatment 
naïve subjects), Months 3, 6, 12, 18, 24, 30, 36 and Termination Visits.  The test will be 
administered by a licensed physical therapist.  The subject will be asked to sit in a chair 
holding a 1 kg barbell with the shoulder adducted, the elbow in full flexion and the forearm 
in supination.  On command, the subject will be asked to lift the arm above the head until the 
elbow is fully extended, then to lower the arm back to the starting position.  The subject will 
be asked to repeat the action at a comfortable pace according to their own rhythm for the 
30 second duration of the test.  The test will be performed bilaterally and the final score will 
be the mean of the total number of completed repetitions from both arms.  The number of 
completed repetitions from each arm and the mean score will be recorded at the time of test 
administration.   


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7.5.2.5 
HIBM Functional Activities Scale 
In Part I of the study, the HIBM Functional Activities Scale (HIBM-FAS) will be 
administered at the Baseline and Part I Termination Visits, to assess functional disability.  
For continuing subjects, the assessment at the Part I Termination Visit will serve as the 
baseline assessment for Part II of the study.  Additional HIBM-FAS assessments in Parts II, 
III, and IV of the study will be performed at Baseline (for treatment naïve subjects), Months 
6, 18, 36 and Termination Visits.  The scale is being developed specifically for patients with 
GNE myopathy (HIBM) 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 
licensed physical therapist and scored after the testing. 
7.5.3 
Exploratory Efficacy Measures 
Additional novel exploratory biomarkers of sialylation and muscle injury may also be 
evaluated to explore the possible best methodology to monitor GNE Myopathy disease.  
Candidate biomarkers present in serum may include: 
• CK levels 
• Neural cell adhesion molecule (NCAM) measured using an ELISA assay and/or 
immunoblot assay to characterize the NCAM types present.  
• Other biomarkers of muscle injury and remodeling, including MMP9 and microRNAs 
Assessment of serum protein markers will only be conducted in Part I of the study.  In Parts 
II, III, and IV of the study, CK levels will be the only exploratory efficacy measure assessed.   
7.5.4 
Safety Measures & General Assessments 
7.5.4.1 
Medical History 
For continuing subjects, the medical history information obtained during the UX001-CL201 
study will carry over to this study.  A detailed medical history, including a GNE 
Myopathy-specific medical history, will be obtained at Screening/Baseline Visit for new 
subjects entering the study (i.e. treatment naïve individuals).  The medical history will solicit 
information on any prior or existing medical conditions that might interfere with study 
participation or safety.  This medical history should elicit all major illnesses, diagnoses, and 
surgeries to date.  
7.5.4.2 
Interval History 
Each 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 


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improvement in existing medical conditions (including the clinical manifestations of GNE 
Myopathy) 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 the study visits indicated in the Schedule of 
Events (Table 2.1 and Table 2.2). 
7.5.4.3 
Vital Signs 
Vital signs will include seated systolic blood pressure and diastolic blood pressure measured 
in millimeters of mercury (mm Hg), 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 study visits indicated in the Schedule of Events (Table 2.1 and Table 2.2).   
7.5.4.4 
Height and Weight Evaluations 
Measurements of height and weight will be collected on each subject using a stadiometer and 
a scale by the physical therapist administering the performance testing.  Height and weight 
data will be used to evaluate each subject’s muscle strength and function using published 
normative data where available. 
7.5.4.5 
Physical Examination 
In Part I of the study, complete physical examinations will be performed at the Baseline and 
Part I Termination Visits.  For continuing subjects, findings in the Part I Termination Visit 
will serve as the Part II baseline assessment.  In Parts II, III, and IV of the study, a complete 
physical examination will be performed at Baseline (for treatment naïve subjects), Months 6, 
18, 36 and the Termination Visits.  Physical examinations will include assessments of 
general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, 
lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, neurologic systems 
(at designated visits where a complete neurological examination is not performed).  
Other body systems may be examined and symptoms of increasing muscle weakness and 
pain will be recorded.  The presence of changes in muscle pain or weakness should be 
evaluated carefully by a complete neurologic exam when these changes are reported by 
subjects.  The specific muscle location and pain should be noted.  Clinically significant 
changes from Baseline will be recorded as AEs.   
7.5.4.6 
Neurological Examination 
In Part I of the study, a neurological examination will be performed at the Baseline and Part I 
Termination Visits.  For continuing subjects, findings in the Part I Termination Visit will 
serve as the Part II baseline assessment.  In Parts II, III, and IV of the study, a neurological 
examinations will be performed at Baseline (for treatment naïve subjects), Months 6, 18, 36 
and the Termination Visits.  The neurological examination will include assessments of 
cognition, cranial nerves, motor function, coordination and gait, reflexes, and sensory 
function.   


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7.5.4.7 
Clinical Laboratory Tests 
The clinical laboratory evaluations to be performed in this study are listed in Table 7.5.4.7.1; 
the time points for these evaluations are indicated in the Schedule of Events (Table 2.1 and 
Table 2.2).  Fasting is not required.  Refer to the central laboratory manual for additional 
details. 
Table 7.5.4.7.1: 
Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Special Assessments 
Alanine 
aminotransferase 
(ALT/SGPT) 
Hematocrit 
Appearance 
Free serum SA 
Alkaline phosphatase 
Hemoglobin 
Color 
Serum pregnancy test 
(if positive urine 
pregnancy test) 
Amylase 
MCH concentration (MCHC) 
pH 
 
Aspartate 
aminotransferase 
(AST/SGOT) 
Mean corpuscular hemoglobin 
(MCH) 
Specific 
gravity 
 
Bilirubin (direct and 
total) 
Mean corpuscular volume 
(MCV) 
Ketones 
 
Blood urea nitrogen 
(BUN) 
Platelet count 
Protein  
 
Calcium 
Red blood cell (RBC) count 
Glucose  
 
Chloride 
Reticulocyte count 
Bilirubin 
 
Cholesterol (total) 
WBC differential 
Nitrite 
 
Creatine kinase (CK) 
Neutrophil count (absolute and 
%) 
Urobilinogen 
 
Creatinine 
Lymphocyte count (absolute and 
%) 
Hemoglobin 
 
Gamma-glutamyl 
transpeptidase (GGT) 
Monocyte count (absolute and 
%) 
Creatinine 
 
Glucose, non-fasting 
Eosinophil count (absolute and 
%) 
 
 
Lactate dehydrogenase 
(LDH) 
Basophil count  
(absolute and %) 
 
 
Lipase 
White blood cell (WBC) count 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Protein (albumin and 
total) 
 
 
 
Sodium 
 
 
 
Triglycerides 
 
 
 
 
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. 


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7.5.4.8 
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 subject 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 every study visit. 
7.5.4.9 
Concomitant Medications 
Concomitant medications will be reviewed and recorded at each study visit.  A discussion of 
concomitant medications is provided in Section 7.4.4. 
7.5.4.10 Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests as specified in the 
Schedule of Events (Table 2.1 and Table 2.2).  Female patients with a positive pregnancy test 
at Baseline do not meet eligibility criteria for enrollment and will not be enrolled in the 
study.  Females considered not of childbearing potential include those who have had total 
hysterectomy, have been in menopause for at least two years, or have had tubal ligation at 
least one year prior to Baseline. 
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.  
Experience with UX001 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby which are currently unknown.  Participants of child‐bearing 
potential or with partners of child bearing potential who have not undergone a bilateral 
salpingo‐oophorectomy and are sexually active must consent to use a highly effective method 
of contraception as determined by the site investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug.  Examples of highly 
effective methods of contraception include oral hormonal contraceptives, patch hormonal 
contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical 
hysterectomy, vasectomy, tubal ligation or true abstinence (when this is in line with the 
preferred and usual lifestyle of the subject), which means not having sex for the duration 
specified above because the subject chooses not to.  
7.5.4.11 Pregnancy in Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee.  The investigator must make every effort to follow the 
pregnancy of either subject or partner through resolution of the pregnancy (delivery or 
termination) and report the resolution to Ultragenyx or its designee. In the event of a 
pregnancy in the partner of a subject, the investigator should make every effort to obtain the 


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female partner’s consent for release of protected health information.  Refer to the Study 
Reference Manual for details on the reporting procedures to follow in the event of pregnancy. 
7.5.5 
Drug Concentration Measurements 
Blood samples for the measurement of trough levels of free serum SA will be drawn at the 
time points shown in the Schedule of Events (Table 2.1 and Table 2.2); samples will be 
obtained from the subjects during blood draws for clinical laboratory samples.  
Urine samples for measurement of free serum SA will be collected during Part I of the study 
only.  The time elapsed from the last dose of study drug should be noted.  SA, the active 
study drug in UX001-CL202, occurs naturally in the human body, both through de novo 
synthesis and via the diet.  Consequently, the free serum SA level should reflect, but will not 
be a quantitative measure, of circulating study drug.  Refer to the central laboratory manual 
for details on the drug concentration measurements. 
7.5.6 
Appropriateness of Measures 
The efficacy parameters to be evaluated in this study include clinical changes in muscle 
strength, and 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 the work of Aitkens 
(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 HHD, a form of 
quantitative muscle testing that uses a device with a strain gauge to measure force during a 
MVIC (Sisto et al. 2007) .  Walking ability will be assessed using the 6MWT test, a 
commonly used test of endurance used in clinical trials for various indications that has served 
as the basis for many product approvals.   In addition, an interview-based measure designed 
to evaluate disability in GNE Myopathy patients (HIBM-FAS) will be administered in this 
study to further validate the instrument. 
Exploratory measures will attempt to identify changes in serum biomarkers in Part I of the 
study.  Serum NCAM may be evaluated to provide some estimate of the sialylation of 
NCAM in the regenerating muscle, albeit at low levels in the circulation.  Other biomarkers 
of muscle injury (e.g., MMP9 and microRNAs) may also be assessed.  However, interim data 
from the UX001-CL201 study suggests the results may be of limited value; therefore, 
exploratory serum protein markers will not be assessed in Parts II, III, and IV of the study.   
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; 22/58 patients reported by three publications had two-times 
or higher elevations (Sadeh et al. 1993); (Mizusawa et al. 1987); (Sunohara et al. 1989).  
The mouse model of HIBM showed elevated CK levels that improved substantially on 
treatment (Malicdan et al. 2009).  Given the modest CK levels in patients, it is unclear if this 


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is a universally evaluable endpoint in humans, however in the mouse model, the data on 
reduced CK levels during SA treatment was compelling (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. 
7.6 
Statistical Methods and Determination of Sample Size 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data.  In particular the endurance measures will be performed in 
duplicate using standard and consistent methodology.  The detailed method for analyses will 
be presented in the Statistical Analysis Plan (SAP); the information below is intended as a 
guide to planned analyses.  
7.6.1 
Clinical and Exploratory Efficacy Measures 
The clinical evaluation measures in this study are: 
• Improvement in quantitative muscle strength as measured by HHD. 
• Improvement in mobility, strength and gross motor function as measured by the 6MWT 
and walking speed and weighted arm lift tests. 
• Improvement in functional disability as measured by the HIBM-FAS. 
The exploratory efficacy measures in this study will involve evaluation of novel biomarkers 
of sialylation and muscle injury.  The exploratory efficacy measures may include: 
• Improvement in serum biomarkers of muscle injury, including CK. 
• Improvement in other serum biomarkers of muscle injury, sialylation, and remodeling, 
including MMP9 (metalloproteinase level) and specific microRNAs associated with 
muscle disease. 
Serum biomarkers of sialylation will be evaluated as exploratory analyses in Part I of the 
study only.  Serum CK levels will be evaluated in Parts I, II, III, and IV of the study.   
7.6.1.1 
Clinical Efficacy Analyses 
All subjects with any post-dose data will be included in the intent-to-treat (ITT) efficacy 
analysis.   
Efficacy will be evaluated by continued improvement in clinical assessments.  Efficacy 
assessments may differ depending on the phase of the study (i.e., Part I, Part II, Part III, or 


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Part IV). For Part I efficacy evaluation, results from the last pre-treatment assessment from 
UX001-CL201 will be compared with the last post-treatment assessment for the Part I 
Treatment Period as listed in the Schedule of Events (Table 2.1), with efficacy conclusions 
based on change since SA-ER treatment initiation.  An interim analysis will be conducted 
when a majority of subjects have completed the Month 6 Visit of the Part II Treatment 
Period.  For Part II efficacy evaluation of the continuing subjects, change from baseline of 
Part II to Month 6 assessment at 12g/day SA-ER/SA-IR dose will be determined and 
compared with the improvement observed during the first 6 months of treatment with 6 g/day 
SA-ER dose, and to the rate of change observed with placebo or 3g treatment during the first 
6 months of the study.   
The changes from baseline of the treatment-naïve subjects will be evaluated over time. 
Potential comparisons of the changes from baseline to Month 6 will be performed for the 
6MWT, UE, and LE between the naïve group versus the placebo and 6g/day treatment 
groups for the first 24 weeks of treatments in subjects able to walk more than 200m at 
baseline.  In addition, changes in muscle strength over the entire treatment period of subjects 
who started with 6g/day and 3g/day will be evaluated and compared to the projected values 
of subjects who received placebo for the first 24 weeks of treatment in UX001-CL201. 
A full accounting of the analyses for Parts III and IV of the study will be provided in the 
Statistical Analysis Plan.  
For those clinical evaluations with repeated assessments (i.e., HHD, 6 MWT, walking speed 
and weighted arm lift tests) the analysis will be performed using a repeated measures 
analysis.  An exchangeable variance-covariance structure will be used.  The final treatment 
effect estimate based on this model will be the estimated treatment difference at Month 36.  
The purpose of including data from assessments prior to Month 36 is to increase the 
precision of the estimated variance, while using categorical effects of time-by-treatment to 
avoid modeling assumptions.  
Muscle strength as measured by HHD will be reported as force in kg and percent of predicted 
normal force based on age, gender, height and weight (where applicable).  Changes in force 
and percent of predicted normal force will be assessed for gross grip, pinch, shoulder 
abductors, elbow flexors, elbow extensors, hip abductors, hip adductors, hip flexors, hip 
extensors, knee flexors, and knee extensors.  Individual muscle groups will also be compared 
to assess individual muscle changes. 
Walking ability as measured by the 6MWT will be reported as distance in meters and percent 
of predicted normal based on age and gender.  Changes in distance and percent of predicted 
normal will be assessed.  The proportion of subjects with a normal percent predicted distance 
walked (i.e., a percent predicted distance walked of ≥ 80%) at each time point may be 
tabulated.  The relationship between 6MWT results and other and efficacy outcomes may 
also be explored. 


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Walking speed as measured by the 25 feet walk test will be reported in seconds and percent 
of predicted normal for each walking speed.  Changes in the number of seconds and percent 
of predicted normal for each speed from Baseline will be assessed. 
Arm raising ability as measured by the weighted arm lift test will be reported as the total 
number of completed repetitions.  Changes from Baseline in repetitions between the 
treatment arms will be assessed. 
Functional disability as measured by the HIBM-FAS will be reported as a total score and 
subscale scores for mobility, self-care, and upper extremity function, with lower scores 
associated with greater disability.  Changes in the total score will be assessed. 
7.6.2 
Safety Measures 
The safety measures in this study are: 
• Incidence and frequency of AEs and SAEs 
• Clinically significant changes from baseline in vital signs, physical and neurological 
examination findings and laboratory evaluations 
• Interval history, including reported symptoms of increasing muscle weakness or pain, and 
incidence of falls 
The analyses of safety will include all subjects who receive any study drug at any time during 
the study and provide any post-treatment safety information.  Safety data will be periodically 
reviewed by the DMC.  
For the safety analysis, the incidence and frequency of AEs and SAEs will be evaluated.  
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), relationship to study drug, and severity for each 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. 
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 after study drug 
administration will be presented for each clinical laboratory measurement.  For each clinical 
laboratory measurement, descriptive statistics will be provided for Baseline and all 
subsequent post-treatment scheduled visits.  Changes from Baseline to the post-treatment 
visits will also be provided.  Descriptive statistics of vital signs, imaging assessments, and 
concomitant medications will also be provided in a similar manner. 
The SAP will provide additional details on the planned statistical analysis. 


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7.6.3 
Data Monitoring Committee 
A DMC will be constituted for Study UX001-CL202 and will act in an advisory capacity to 
Ultragenyx to monitor the safety of SA-ER/SA-IR in subjects who participate in the study.  
The DMC may: 
• Review plans for data monitoring. 
• Evaluate the progress of the trial, study data quality, timeliness, subject recruitment, 
accrual and retention, subjects’ risk versus potential benefit, and other factors that could 
affect the study outcome. 
• Consider relevant information that may have an impact on the safety of the participants or 
the ethics of the study 
• Make other recommendations to Ultragenyx concerning continuation, termination or 
other modifications of the study based on their observations of the study. 
7.6.4 
Determination of Sample Size  
Approximately 46 subjects may be enrolled in Part I of this open-label extension study.  
Sample size is limited to the number of subjects enrolled in the Phase 2 safety and efficacy 
study, UX001-CL201.  As Part I of the study is intended to evaluate of the long-term safety 
of 6g/day SA-ER in subjects with GNE Myopathy, and ascertain the long-term effect of 
SA-ER treatment on muscle strength, mobility, and functional disability, the sample size is 
deemed reasonable to satisfy Part I study objectives.   
Approximately 10 treatment-naïve subjects will be enrolled into Part II of the study.  
This subset of treatment naïve GNE Myopathy subjects will provide additional safety and 
efficacy information following treatment with SA-ER/SA-IR. 
The study design is open-label with all subjects receiving the same treatment.  Therefore, the 
study is not powered to assess statistically significant comparisons.  Instead, the sample size 
is intended to provide the maximum amount of long-term safety and efficacy data for the 
investigational product. 


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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee 
The IRB/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 


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to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements.  Subjects will be given a copy 
of the signed ICF and will be provided any new information during the course of the study 
that might affect their continued participation in the study.  The investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction.  If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
Receipt 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 has been identified for this trial.  The Coordinating Investigator 
is 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 reads and signs the Clinical Study Report (CSR). 
8.3 
Investigational Product Accountability 
While at the clinical site, study drug must be stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging.  
The storage facility must be available for inspection by the study monitor at any time during 
the study.   


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


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


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• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or 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.  
The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions.  
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and of a minor 
irritant type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death 
or are disabling. 
• Death (Grade 5): Events that result in death. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
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 


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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. 
• Not Related:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt.  That is, another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is inconsistent 
with the onset of the event and the exposure to study drug and/or a causal relationship is 
considered biologically implausible. 
• Possibly Related:  This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug, but that could readily have been produced 
by a number of other factors. 
• Probably Related:  This category applies to an AE that is likely related to the 
investigational agent/procedure.  That is, the AE has a temporal relationship to the 
administration of the investigational agent(s) or research intervention, follows a known or 
suspected pattern of response, and is strongly associated with study drug exposure. 
8.5.4 
Adverse Event Reporting to Ultragenyx 
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 AE eCRF via the EDC system. 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 
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.   


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8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Any SAE that occurs at any time during the study, including a clinically significantly 
abnormal laboratory test result that is considered serious, must be reported within 24 hours of 
knowledge of the event to Ultragenyx or its designee. These requirements apply equally to all 
subjects, regardless of the study phase or the at-risk subject's treatment assignment or dosage. 
The reporting requirement for SAEs is from the time of signing of the ICF through 30 days 
following the last study drug administration.  
SAEs will be reported by completing and submitting SAE report forms to Ultragenyx or its 
designee. Initial SAE reports must be followed by detailed descriptions. These should include 
copies of hospital case records and other documents when requested. 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. 
A death occurring during the study, during the per-protocol follow-up period, or within 
30 days after stopping treatment with the study drug must be reported to Ultragenyx or its 
designee within 24 hours of knowledge of the death whether or not it is considered 
treatment-related.  
The investigator also must notify the IRB/EC of the occurrence of the SAE, in writing, as 
soon as is practicable and in accordance with IRB/EC requirements and local law. A copy of 
this notification must be provided to Ultragenyx or its designee.    
8.5.4.3 
Urgent Safety Reporting 
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 
Ethics Committee (EC) is notified at the same time.”  The reporting period for urgent safety 
issues is the period from the signing of the ICF through 30 days following the last dose of 
study drug. Investigators are required to report any urgent safety measures to Ultragenyx 
within 24 hours. 


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8.5.4.4 
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), Ethics Committees, 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, 
Ethics Committees, and Investigators of any events (e.g. change to the safety profile of 
UX001, major safety findings) that may occur during the clinical trial that do not fall within 
the definition of a SUSAR but may affect the safety of subjects participating in the clinical 
trials, as required, in accordance with applicable laws and regulations. The reporting period 
for urgent safety issues is the period from the signing of the ICF through 30 days following 
the last dose of study drug. 
The investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs and urgent 
safety matters, in accordance with IRB/REB/EC requirements and local laws and regulations. 
A copy of this notification must be provided to Ultragenyx or its designee.  
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and Ethics Committees, as per local laws and regulations. 
8.5.4.5 
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 reporting period for pregnancies is the period from 
the signing of the ICF through 30 days following the last dose of study drug. 
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. 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. 
Pregnancy-associated SAEs will be processed and submitted, as necessary, as per the 
SUSAR reporting process (Section 8.5.4.4). 




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vacuole formation. A follow-up study." Brain 112 ( Pt 1):65-83. 
 



SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Title: 
An Open-label Phase 2 Extension Study to Evaluate the Long 
Term Safety and Efficacy of Sialic Acid-Extended Release (SA-
ER) Tablets and Sialic Acid-Immediate Release (SA-IR) 
Capsules in Patients with GNE Myopathy or Hereditary 
Inclusion Body Myopathy 
Protocol Number: 
UX001-CL202 
Phase: 
Phase 2 (Extension Study from UX001-CL201) 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA  94949 
Author: 
Summit Analytical, LLC 
 
SAP Date: 
2014-05-05 
Status: 
FINAL V1.1 
 
 
 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ......................................................................................................................................... 8 
2 
STUDY OBJECTIVES .................................................................................................................................. 9 
1.1. 
Safety Objectives .............................................................................................................................. 9 
1.2. 
Clinical Objectives ............................................................................................................................ 9 
1.3. 
Exploratory Objectives ..................................................................................................................... 9 
3 
STUDY DESIGN ........................................................................................................................................ 10 
4 
ANALYSIS POPULATIONS...................................................................................................................... 16 
5 
ANALYSIS VARIABLES .......................................................................................................................... 17 
5.1 
Study Drug Dosing.......................................................................................................................... 17 
5.2 
Demographics and Baseline Characteristics ................................................................................... 18 
5.3 
Safety Variables .............................................................................................................................. 19 
5.4 
Efficacy Variables ........................................................................................................................... 22 
5.5 
Exploratory Efficacy Variables ....................................................................................................... 25 
6 
STATISTICAL METHODOLOGY ............................................................................................................ 27 
6.1 
Sample Size ..................................................................................................................................... 27 
6.2 
Randomization ................................................................................................................................ 27 
6.3 
Analysis at 6-months (Part II) ......................................................................................................... 27 
6.4 
Final Analysis at end of Part II. ...................................................................................................... 28 
6.5 
General Considerations for Statistical Analysis .............................................................................. 28 
6.5.1 
Changes in Analysis in Comparison to Study Protocol ................................................. 29 
6.5.2 
Derived Efficacy Variables ........................................................................................... 29 
6.5.3 
Derived Safety, Dosing, and Medication Variables ...................................................... 30 
6.5.4 
Data Handling ............................................................................................................... 30 
6.5.5 
Handling of Early Termination Visits ........................................................................... 31 
6.5.6 
Handling of Missing Values .......................................................................................... 31 
6.5.7 
Pooling of Investigator Centers ..................................................................................... 32 
6.5.8 
Determination of Baseline Values ................................................................................. 32 
6.5.9 
Coding of Events and Medications ............................................................................... 33 
6.5.10 
Analysis Software ......................................................................................................... 33 
6.5.11 
Analysis Data Sets......................................................................................................... 33 
6.6 
Statistical Analysis: Disposition, Dosing, and Baseline Characteristics ......................................... 33 
6.6.1 
Subject Disposition ....................................................................................................... 33 
6.6.2 
Dosing Summary ........................................................................................................... 34 
6.6.3 
Demographics and Baseline Characteristics ................................................................. 34 
6.6.4 
Prior and Concomitant Medications .............................................................................. 34 
6.7 
Statistical Analysis: Clinical Efficacy ............................................................................................. 34 
6.7.1 
Planned Comparisons for Clinical Efficacy Parameters ................................................ 34 
6.7.2 
Statistical Modeling: Repeated Measure Model: General Estimating 
Equations (GEE) ........................................................................................................... 37 
6.7.3 
Statistical Modeling: Analysis of Covariance (ANCOVA)........................................... 38 
6.7.4 
Statistical Modeling: Graphic Displays of Study Results ............................................. 38 
6.7.5 
Efficacy Analysis: Muscle Strength - Hand Held Dynamometry 
(HHD) ........................................................................................................................... 39 
6.7.6 
Exploratory Efficacy Analysis: Hand Held Dynamometry (HHD) ............................... 40 
6.7.7 
Efficacy Analysis: Six-Minute Walk Test Distance ...................................................... 41 
6.7.8 
Exploratory Efficacy Analysis: 6MWT ........................................................................ 42 


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6.7.9 
Efficacy Analysis: Walking Speed Test ........................................................................ 42 
6.7.10 
Exploratory Efficacy Analysis: Walking Speed Test .................................................... 42 
6.7.11 
Efficacy Analysis: Weighted Arm Lift Test .................................................................. 43 
6.7.12 
Efficacy Analysis: HIBM Functional Activities Scale .................................................. 43 
6.7.13 
Exploratory Efficacy Analysis: Creatine Kinase ........................................................... 44 
6.8 
Statistical Analysis: Effect of Changes in Muscle Strength, PROs, and Physical Function ........... 44 
6.8.1 
Upper Extremity Muscle Strength vs. Weighted Arm Lift Test .................................... 44 
6.8.2 
Lower Extremity Muscle Strength vs. 6MWT Distance ............................................... 44 
6.8.3 
Lower Extremity Muscle Strength vs. Gait Speed Test ................................................ 45 
6.8.4 
HIBM-FAS Total and UE Subscale Score vs. HHD UE Composite 
Score ............................................................................................................................. 45 
6.8.5 
HIBM-FAS Total and Mobility Subscale Score vs. HHD LE 
Composite Score ........................................................................................................... 45 
6.8.6 
HIBM-FAS Total and Mobility Subscale Score vs. 6MWT Distance .......................... 45 
6.8.7 
HIBM-FAS Total and Mobility Subscale Score vs. Gait Speed Test ............................ 46 
6.8.8 
HIBM-FAS Total and UE Subscale Score vs. Weighted Arm Lift 
Test ................................................................................................................................ 46 
6.9 
Statistical Analysis: Pharmacokinetics ............................................................................................ 46 
6.9.1 
Free Serum Sialic Acid (SA) Levels ............................................................................. 46 
6.10 
Statistical Analysis: Safety .............................................................................................................. 47 
6.10.1 
Adverse Events.............................................................................................................. 47 
6.10.2 
Clinical Laboratory Parameters ..................................................................................... 49 
6.10.3 
Vital Signs ..................................................................................................................... 50 
6.10.4 
Medical History ............................................................................................................. 50 
6.10.5 
Interval History ............................................................................................................. 51 
6.10.6 
Physical Examination .................................................................................................... 51 
6.10.7 
Neurological Examination............................................................................................. 52 
6.10.8 
Pregnancy Testing ......................................................................................................... 52 
6.10.9 
Other Safety Parameters ................................................................................................ 52 
7 
REFERENCES ............................................................................................................................................ 53 
8 
APPENDICES ............................................................................................................................................. 54 
8.1 
List of Prospective Tables and Figures ........................................................................................... 55 
 
LIST OF TABLES 
 
Table 1 
Schedule of Events (Part I)............................................................................................ 12 
Table 2 
Schedule of Events (Part II) .......................................................................................... 13 
Table 3 
Study Drug Dosing Pathways: UX001-CL201 – UX001-CL202 ................................. 17 
Table 4 
Demographic and Baseline Characteristic Variables .................................................... 18 
Table 5 
Safety Analysis Variables ............................................................................................. 19 
Table 6 
Efficacy Analysis Variables .......................................................................................... 23 
Table 7 
Exploratory Efficacy Analysis Variables ...................................................................... 25 
Table 8 
Planned Comparisons .................................................................................................... 35 
Table 9 
NCI-CTCAE Common AE Grading Criteria ................................................................ 47 
Table 10 
Mapped AE Grading Criteria ........................................................................................ 48 
Table 11 
AE Relationship to Study Medication ........................................................................... 49 
 
 


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LIST OF FIGURES 
 
Figure 1 
UX001-CL202 Study Periods and Analysis Map ......................................................... 15 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation/Term 
Definition 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CMP-SA 
cytosine monophosphate-sialic acid 
CRF 
Case Report Form 
CT 
computed tomography 
DMC 
Data Monitoring Committee 
DMRV 
EC 
distal myopathy with rimmed vacuoles 
Ethics Committee 
ELISA 
enzyme-linked immunosorbent assay 
EMG 
electromyography 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
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 
hERG 
human ether-à-go-go-related gene 
HHD 
hand-held dynamometry 
HIBM 
hereditary inclusion body myopathy 
HIBM-FAS 
HIBM Functional Activities Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
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Abbreviation/Term 
Definition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat Population 
IVIG 
intravenous immune globulin 
LDH 
lactate dehydrogenase 
ManNAc 
N-acetyl-D-mannosamine 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP9 
matrix metallopeptidase 9 
MRC 
Medical Research Council 
MUAP 
polyphasic muscle unit action potential 
MVIC 
maximum voluntary isometric contraction 
NANA 
N-acetylneuraminic acid 
NCAM 
neural cell adhesion molecule 
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) 
QID 
four times per day 
QD 
one time per day 
RBC 
red blood cell 
SA 
sialic acid 
SAE 
serious adverse event 
SA-ER 
Sialic Acid-Extended Release 
SA-IR 
Sialic Acid Immediate Release 
SAP 
Statistical Analysis Plan 


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Abbreviation/Term 
Definition 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
TID 
three times per day 
TNP 
Treatment Niave Popultion 
US 
United States 
WBC 
white blood cell 
 
 
 


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1 INTRODUCTION 
This document presents a statistical analysis plan (SAP) for Ultragenyx Pharmaceutical, Inc. 
Protocol UX001-CL202 (An Open-label Phase 2 Extension Study to Evaluate the Long Term 
Safety and Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets and Sialic Acid-
Immediate Release (SA-IR) Capsules in Patients with GNE Myopathy or Hereditary 
Inclusion Body Myopathy. 
Reference materials for this statistical plan include the Protocol UX001-CL202 (Original: 01 
March 2013, Amendment #1: 02 October 2013), UX001-CL202 Case Report Forms (24 July 
2013), feeder study Protocol UX001-CL201 and the SAP for UX001-CL201 (05 November 
2013: Week 48 Analysis).  Study UX001-CL202 is an Open-Label extension study and 
treatment is not blinded. Subjects completing 48-week in study UX001-CL201 are eligible to 
continue treatment under this open-label extension protocol testing an increased dose of SA.  
Additional GNE Myopathy subjects will be enrolled to assess the safety and efficacy of SA-
ER/SA-IR in a treatment naïve population.  Ultragenyx Pharmaceutical is conducting 
UX001-CL202 in two parts: 
• Part I of the study will provide additional information on the long-term safety and 
efficacy of 6g/day SA ER;  
• Part II of the study will assess the safety and efficacy of 1.5 g of SA-ER / 1.5 g of SA-IR 
treatment 4 times per day (12g/day SA-ER/SA-IR total dose) for 6 months.  If reasonable 
efficacy and safety are demonstrated at the interim analysis at 6 months post initiation of 
part II, the subjects may continue therapy for up to 36 months.   
The statistical plan described hereafter is an a priori plan.  The SAP will be finalized and 
approved prior to completing inferential or descriptive analyses of data pertaining Ultragenyx 
Pharmaceutical, Inc. Protocol UX001-CL202.  Statistical Analysis programming may occur 
as study data accumulate in order to have analysis programs ready at the time the study 
finishes.  For the reasons stated herein the conduct of the study in the field is considered to be 
independent of any study outcome that might materialize upon enactment of the currently 
proposed statistical analysis plan. 


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2 STUDY OBJECTIVES 
Study objectives defined in the protocol and amendment include safety, clinical endpoints, 
and exploratory objectives for both Part I and Part II of the study. Objectives are specified as 
follows from the protocol: 
1.1. 
Safety Objectives 
• Evaluate additional long-term safety of SA-ER treatment of GNE Myopathy subjects 
previously treated with SA-ER at dose of 6g/day (Part I). 
• Evaluate the safety of 12g /day SA-ER/SA-IR (delivered by 1.5g of SA-ER tablets and 
1.5g of SA IR capsules 4 times per day) in the treatment of GNE Myopathy subjects over 
a 6 month treatment period (Part II). 
1.2. 
Clinical Objectives 
• Evaluate the long-term effect of SA-ER/SA-IR treatment of GNE Myopathy subjects on 
muscle strength as measured by hand-held dynamometry (HHD). 
• Evaluate the long-term effect of SA-ER/SA-IR treatment of GNE Myopathy subjects on 
mobility, strength, and function using a series of physical performance measures. 
• Evaluate the effect of SA-ER/SA-IR treatment of GNE Myopathy subjects on functional 
disability using an interview-based questionnaire. 
1.3. 
Exploratory Objectives 
• Evaluate the effect of SA-ER treatment on serum biomarkers of sialylation in GNE 
Myopathy subjects (Part I).  
• Determine whether 12g/day SA-ER/SA-IR administered 1.5g/1.5g four times per day is 
superior to prior treatment with SA-ER in GNE Myopathy subjects (Part II). 


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3 STUDY DESIGN 
As background for the statistical methods presented below, this section provides an overview 
of the study design and plan of study execution. The protocol (plus protocol amendment) is 
the definitive reference for all matters discussed in what follows. 
UX001-CL202 open-label extension study will assess the long term safety and efficacy of 
SA ER/SA-IR treatment over a period of approximately 36 months, or until marketing 
approval or program termination by Ultragenyx.  In Part I of the study, approximately 46 
subjects will be enrolled following successful completion of the UX001-CL201 study.  The 
Baseline visit will be conducted in conjunction with the UX001-CL201 Week 48 study visit 
to avoid treatment disruption.  Enrollment will take place after all UX001-CL201 Week 48 
study assessments have been completed and the investigator has determined the subject 
meets all eligibility criteria.  Data collected at the UX001-CL201 Week 48 visit will serve as 
the Baseline data for Part I of this protocol.  Following the signing of informed consent at the 
Baseline visit, each subject will be dispensed a 6-week supply of study drug.  Throughout the 
Part I Treatment Period of the study, all subjects will continue to take four 500 mg SA-ER 
tablets orally three times per day (TID), in the morning, early evening, and at bedtime (qHS), 
for a total dose of 6g/day.  The Part I Termination Visit will also serve as the Baseline Visit 
for Part II of the study. However, for completion of the analysis with integrated information 
from UX001-CL201 subjects the baseline may be defined as the week 48 visit from UX001-
CL201, or other such baselines from key time points in the UX001-CL201 study as may be 
defined for selected analyses to examine clinical endpoints. 
Beginning with the Part II-Baseline Visit, all subjects currently enrolled in Part I will 
crossover to the SA-ER/SA-IR dosing regimen.  An additional 10 treatment naive GNE 
Myopathy subjects will be enrolled into Part II of the study.  The additional subjects will 
provide an assessment of SA-ER/SA-IR treatment in SA naïve subjects able to walk at least 
200 meters (and < 80% predicted) in a screening 6 Minute Walk Test (6MWT).   Throughout 
the 36-month Part II Treatment Period, all subjects will be administered 1.5g SA-ER and 
1.5g SA-IR orally four times per day (QID), in the morning, afternoon, early evening, and 
qHS, for a total SA dose of 12g/day.  
Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, and 
function, and changes in exploratory serum biomarkers will be performed according to the 
Schedule of Events specific to each phase of the study.  A Part II Termination Visit will be 
conducted 4 weeks after subjects receive their last dose of study drug.  Efficacy data analyses 
will be conducted at the end of the 36-month Part II Treatment Period, although additional 
analyses may be performed and documented at the discretion of Ultragenyx. 
Safety will be monitored throughout the study based on physical examinations, clinical 
laboratory analyses, and reporting of adverse events (AEs) and SAEs.  An independent Data 
Monitoring Committee (DMC) will review safety information periodically an on an ad hoc 
basis as outlined in the DMC charter, which is maintained separately from this protocol. 


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A complete schedule of events specific for each part of the study is found in the protocol 
(Section 2, Tables 2.1 and 2.2) and repeated herein as Table 1 and Table 2. 
Subjects enrolled in UX001-CL201 will roll over into UX001-CL202. In addition SA naïve 
treated subjects will be enrolled into Part II of UX001-CL202. Figure 1 presents a summary 
of the time points and dosing expected for subjects participating in UX001-CL0202, as well 
as outlining the key analysis time points: Additional analysis at 6 months after initiating Part 
II and the final analysis. (Note that the protocol refers to the 6 months analysis in Part II as an 
interim analysis. This analysis is being referred to as an additional analysis since this is an 
open label single arm study, and no formal adjustments for alpha spending will be employed 
in the study analyses). 
 
 


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Table 1 
Schedule of Events (Part I) 
a Potential subjects for the Part I Treatment Period will be baselined at the UX001-CL201 Week 48 study visit. Study drug 
will be dispensed only after UX001-CL202 consent has been signed and all study procedures have been performed. 
b For Week 6 and 12 visits, the window is ± 0 days. 
c The Part I Termination Visit will also serve as the Part II Baseline Visit.  For subjects who discontinue prior to completing 
the study, the Termination Visit will be considered an Early Termination Visit; every reasonable effort should be made to 
perform the Termination Visit procedures within four weeks of discontinuation.  
d Interval history will include 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 GNE Myopathy) that 
might interfere with study participation, safety, and/or positively or negatively impact performance of functional 
assessments. 
e The physical examinations at all study visits will be complete. 
f Portions of the HHD, 6MWT, walking speed and weighted arm lift testing sessions may be videotaped to monitor 
administration technique and assess qualitative changes in function.  Subject identity will be protected by blurring out the 
facial area in the video.  
g Trough levels of free SA in serum and free and total SA in urine. 
h Adverse Events will be collected after subject signs Informed Consent form. 
ASSESSMENTS AND EVENTS 
PART I TREATMENT PERIOD b 
(weeks) 
PART I TERM 
VISIT c 
 
BASELINE a 
6 
12 
 
INFORMED CONSENT 
X 
 
 
 
INTERVAL HISTORY d 
X 
 
 
X 
VITAL SIGNS 
X 
 
 
X 
HEIGHT AND WEIGHT 
X 
 
 
X 
PHYSICAL EXAM e 
X  
 
 
X 
NEUROLOGICAL EXAM 
X 
 
 
X 
EFFICACY MEASURES 
HAND-HELD DYNAMOMETRY (HHD) f 
X 
 
 
X 
6 MINUTE WALK TEST  
(6MWT) f 
X 
 
 
X 
WALKING SPEED TEST f 
X 
 
 
X 
WEIGHTED ARM LIFT TEST f 
X 
 
 
X 
HIBM-FAS 
X 
 
 
X 
CLINICAL LABORATORY TESTS 
CREATINE KINASE 
X 
 
 
X 
SERUM PROTEIN MARKERS 
X 
 
 
X 
FREE SERUM SA LEVELS g 
X 
 
 
X 
FREE AND TOTAL URINE SA LEVELS g 
X 
 
 
X 
CBC, CHEMISTRY, URINALYSIS 
X 
 
 
X 
PREGNANCY TEST 
X 
 
 
X 
ADVERSE EVENTS 
Xh 
X 
X 
X 
CONCOMITANT MEDICATIONS 
X 
X 
X 
X 
TREATMENT DISPENSED 
X 
X 
X 
 


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Table 2 
Schedule of Events (Part II) 
 
 
ASSESSMENTS AND EVENTS 
PART II TREATMENT PERIOD b 
(months) 
TERM 
VISIT c 
 
SCREENING/
BASELINE a 
1 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
 
INFORMED CONSENT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL/INTERVAL HISTORYd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
VITAL SIGNS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HEIGHT AND WEIGHT 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PHYSICAL EXAM e 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
NEUROLOGICAL EXAM 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
EFFICACY MEASURES 
HAND-HELD DYNAMOMETRY 
(HHD) f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
6 MINUTE WALK TEST 
(6MWT) f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
WALKING SPEED TEST f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
WEIGHTED ARM LIFT TEST f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HIBM-FAS 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
CLINICAL LABORATORY TESTS 
CREATINE KINASE 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
FREE SERUM SA LEVELS g 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
CBC, CHEMISTRY 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
PREGNANCY TEST 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
ADVERSE EVENTS 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CONCOMITANT MEDICATIONS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DISPENSE STUDY DRUG i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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a The Part I Termination Visit will also serve as the Part II Baseline Visit for continuing subjects.  SA naïve subjects will enter directly into Part II of the study (Part II 
Screening/Baseline Visit). SA-ER/SA-IR study drug will be dispensed only after UX001-CL202 (Part II) consent has been signed and all study procedures have been 
performed. 
b The Month 1 Visit window is ± 1 week.  For all other Visits the window is ± 14 days. 
c The Part II Termination Visit occurs four weeks after subjects receive their last dose.  For subjects who discontinue prior to completing the study, the Termination Visit will 
be considered an Early Termination Visit; every reasonable effort should be made to perform the Termination Visit procedures within four weeks of discontinuation.  
d For SA naïve subjects, medical history (including a detailed GNE Myopathy disease-specific history) will be reviewed at the Screening/Baseline visit.  Interval history for 
all subjects will include 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 GNE 
Myopathy) that might interfere with study participation, safety, and/or positively or negatively impact performance of functional assessments. 
e The physical examinations at all study visits will be complete. 
f Portions of the HHD, 6MWT, walking speed and weighted arm lift testing sessions may be videotaped to monitor administration technique and assess qualitative changes in 
function.  Subject identity will be protected by blurring out the facial area in the video.  
g Trough levels of free SA in serum; record the time of last dose and sample collection. 
h Adverse Events will be collected after subject signs Informed Consent form. 
i A one month supply of study drug will be dispensed at scheduled treatment visits; additional study drug will be shipped directly to subjects between visits on a monthly 
basis.  
j Phone calls will be placed to each subject at least once between each study visit to assess treatment compliance with the dosing regimen.  Additional telephone contacts with 
the subject may be placed as needed. 
 
 


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Figure 1 
UX001-CL202 Study Periods and Analysis Map 
 
 


 
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4 ANALYSIS POPULATIONS 
The following analysis populations are defined for this study: 
Safety Population (SAFETY): All subjects who provide informed consent and receive at 
least one dose of planned study medication in either Part I or Part II of the study and provide 
any post-treatment safety information. The safety population may be further sub-divided into 
Part I-Safety Population and Part II-Safety Population where appropriate for planned 
summaries. Subjects included in the safety population will be analyzed as treated. The Safety 
Population will be the source for all planned safety endpoints and analyses. 
Intent-to-Treat Population (ITT): All subjects who are in the Safety Population and 
provide a least one (1) post-baseline clinical endpoint (efficacy) assessment over the course 
of the study will be included in the ITT Population. The ITT population may be further sub-
divided into Part I-ITT Population and Part II-ITT Population where appropriate for planned 
analyses. Subjects included in the ITT population will be analyzed as treated. The ITT 
population will be the source for all planned clinical endpoint (efficacy) assessments and 
analyses. 
Treatment Naïve Population (TNP): Subjects who are identified and enrolled into Part II of 
the study as treatment naïve subjects will be included in this analysis population and 
analyzed as a separate subgroup. 


 
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5 ANALYSIS VARIABLES 
Analysis variables will be required from both the UX001-CL201 study, carried over week 24 
and week 48 analysis variables, as well as from UX001-CL202 from both Part I and Part II.  
Additional variables may be added as this SAP is developed and/or as discussion unfolds 
concerning the usefulness of derived variables formulated using the information presented 
below. 
5.1 
Study Drug Dosing 
Study Drug Dosing for the UX001-CL201 feeder study and for this study UX001-CL202 are 
mapped to present all possible treatment combinations that a subject may participate in 
within these two studies (Table 3). 
 
Table 3 
Study Drug Dosing Pathways: UX001-CL201 – UX001-CL202 
 
UX001-CL201 
UX001-CL202 
Path 
Weeks 0-24 
Weeks 24-48 
Part I 
Part II 
1 
6g/day 
6g/day 
6g/day 
12g/day 
2 
3g/day 
3g/day 
6g/day 
12g/day 
3 
0g/day 
6g/day 
6g/day 
12g/day 
4 
0g/day 
3g/day 
6g/day 
12g/day 
5 
N/A 
N/A 
N/A 
12g/day 
The 0/6 and 0/3 treatment groups (pathways 3 and 4) may be combined during weeks 0-24 for UX001-CL201 subjects to 
form a placebo group for comparisons with pathway 5. 
 
The 0/6 and 6/6 treatment groups (pathways 1 and 3) and 0/3 and 3/3 treatment groups (pathways 2 and 4 may be 
combined to form 3g and 6g treatment groups for comparison with the 12g/day SA-ER/SA-IR dosing. 
 
A total of 5 separate treatment pathways are identified for evaluation. Subjects enrolled in 
UX001-CL202 who are members of the TNP will have no treatment pathway from the 
UX001-CL201 study. Subjects who roll over from UX001-CL201 into Part I of this study 
will continue on a dose of 6g/day SA-ER. These data will be used primarily for additional 
safety data. All subjects participating in Part II of this study will receive 12g/day SA-ER/SA-
IR. The focus of the safety analyses for the primary objective will be on safety at the 6g/day 
SA-ER and safety at the 12g/day SA-ER/SA-IR doses. 


 
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5.2 
Demographics and Baseline Characteristics 
Demographic and Baseline Characteristics for the study population in UX001-CL202 will 
include the parameters listed in Table 4. For Subjects who roll over from the UX001-CL201 
demographic parameters will be cross validated from the UX001-CL201 study into the 
UX001-CL202 study as the same variable.  
 
Table 4 
Demographic and Baseline Characteristic Variables 
Analysis 
Variable Name 
Analysis Variable 
Description 
Code List/ Variable Notes 
SEX 
Subject Gender 
M = Male, F = Female 
Will be carried over from UX001-
CL201 
AGE 
 
 
 
AGE1 
Subject Age at time of 
Informed Consent – 
UX001-CL201 
Subject Age at time of 
Informed Consent – 
UX001-CL202 
Computed as (Date of Informed 
Consent – Date of Birth / 365.25) +1 
 
For Subjects carried over from 
UX001-CL201 two ages will be 
reported: AGE and AGE1 
RACE 
Subject Race 
1 = White, 2 = Black or African 
American, 3 = Asian, 4 = Native 
Hawaiian or Other Pacific Islander, 5 
= American Indian or Alaska Native, 6 
= Other (Specified). 
Will be carried over from UX001-
CL201 
ETHNIC 
Subject Ethnicity 
1 = Hispanic or Latino, 2 = Not 
Hispanic or Latino 
Will be carried over from UX001-
CL201 
HT 
Subject Height at 
Baseline 
Height in CM, assessed at baseline 
visit in UX001-CL202 
WT 
Subject Weight at 
Baseline 
Weight in KG, assessed at baseline 
visit in UX001-CL202 


 
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Analysis 
Variable Name 
Analysis Variable 
Description 
Code List/ Variable Notes 
BMI 
Subject Body Mass 
Index (BMI) at baseline 
Derived from baseline HT and 
Weight. 
Computed as WT (kg) / HT (m2) 
BMICAT 
Subject BMI Category 
at baseline 
Derived from BMI and assigned as: 
1 = Underweight (<18.5) 
2 = Normal weight (18.5–24.9) 
3 = Overweight (25.0–29.9) 
4 = Obese (30.0-39.9) 
5 = Morbidly Obese (≥40.0) 
Interval History 
Analysis variables 
related to collection of 
HIBM interval history 
Interval History data will be reported 
as collected by category. 
5.3 
Safety Variables 
Safety analysis variables for the study population in UX001-CL202 will include the 
parameters listed in Table 5. Safety analysis variables will be summarized for Part I and Part 
II in this study. Baseline safety analysis variable values for subjects who roll over from 
UX001-CL201 will be the last safety variable assessment recorded in UX001-CL201. For 
subjects who are SA Naïve and enroll into Part II of this study the baseline value will be 
assigned as the screening visit for the subject.  
Table 5 
Safety Analysis Variables 
Analysis Variable Name 
Analysis Variable 
Description 
Code List/ Variable Notes 
Medical History: 
MHTERM 
MHDECOD 
MHPTCD 
MHBODSYS 
MHSOC 
MHSOCCD 
 
Verbatim MH Text 
Preferred MH Term 
Preferred Term Code 
Body System (SOC) 
Primary SOC 
Primary SOC Code 
Will be carried over from 
UX001-CL201 for roll 
over subjects 
SA Naïve subjects will 
have baseline Medical 
History recorded at the 
screening visit 
Medical History will be 
coded with MEDDRA 
medical dictionary SOC 
and Preferred term. 
Medical history will be 


 
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Analysis Variable Name 
Analysis Variable 
Description 
Code List/ Variable Notes 
listed for all subjects 
participating in UX001-
CL202 
Physical Examination 
PE TERM 
PEDECOD 
 
Verbatim PE Text 
Preferred PE Term 
 
Physical Examination data 
will be reported as 
collected by term. 
Neurological Examination 
NE TERM 
NEDECOD 
 
Verbatim NE Text 
Preferred NE Term 
 
Neurological Examination 
data will be reported as 
collected by term. 
Concomitant medications: 
CMTRT 
CMDECOD 
PREFCODE 
DCL2C 
 
 
Verbatim CM Text 
Preferred CM Term 
Preferred Code 
ATC Level 2 Code 
Concomitant Medications 
will be coded with 
WHODRUG medications 
dictionary to primary term 
and ATC Level 2 code.  
Concomitant Medications 
will be listed for all 
subjects participating in 
UX001-CL202 
Adverse Events 
AETERM 
AEDECOD 
AEPTCD 
AEBODSYS 
AESOC 
AESOCCD 
AESEV 
AECTCAE 
 
Verbatim  AE Text 
Preferred AE Term 
Preferred Term Code 
Body System (SOC) 
Primary SOC 
Primary SOC Code 
AE Severity Code 
CTCAE Severity Grade 
Adverse Events will be 
assessed on a continual 
basis during the conduct 
of the trial. Adverse 
Events will be coded with 
MEDDRA medical 
dictionary SOC and 
Preferred term 
Vital Signs: 
SYSBP 
DIABP 
HR 
RP 
TEMP 
 
Systolic BP(mmHg) 
Diastolic BP (mmHg) 
Heart Rate (bpm) 
Respiratory Rate (bpm) 
Temperature (°C) 
Vital Signs will be 
assessed at baseline and at 
subsequent visits over the 
course of the study. 
Baseline will be carried 
over for UX001-CL201 


 
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Analysis Variable Name 
Analysis Variable 
Description 
Code List/ Variable Notes 
roll-over subjects from the 
last visit in UX001-
CL201. 
Laboratory Studies: 
LBCAT=HEMA 
HB 
MCHC 
MCHB 
MCV 
PLATLET 
RBC 
RETIC 
WBCDIFF 
NEUTABS 
NEUTPCT 
LYMPABS 
LYMPPCT 
EOSINABS 
EOSINPCT 
BASOABS 
BASOPCT 
WBC 
 
Hemoglobin (Hb) 
MCH Concentration 
Mean Corpuscular Hb 
Mean Corpuscular Vol 
Platelet Count 
Red Blood Cell Count 
Reticulocyte Count 
WBC Differential 
Neutrophil count (abs) 
Neutrophil count (%) 
Lymphocyte count (abs) 
Lymphocyte count (%) 
Eosinophil count (abs) 
Eosinophil count (%) 
Basophil count (abs) 
Basophil count (%) 
White Blood Cell 
Laboratory data will be 
identified stored by 
category (LBCAT) and 
test code (LBTESTCD). 
Units standardized across 
the study. 
Laboratory Studies: 
LBCAT=CHEM 
ALTSGPT 
 
ALKP 
AMY 
ASTSGOT 
 
BILID 
BILIT 
BUN 
CALC 
CHLOR 
CHOLT 
CK 
 
 
Alanine 
aminotransferase 
Alkaline phosphatase 
Amylase 
Aspartate 
aminotransferase 
Bilirubin (direct) 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol (total) 
Creatine kinase (CK) 
Laboratory data will be 
identified stored by 
category (LBCAT) and 
test code (LBTESTCD). 
Units standardized across 
the study. 


 
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Analysis Variable Name 
Analysis Variable 
Description 
Code List/ Variable Notes 
CREAT 
GGT 
 
GLUC 
LDH 
LIP 
PHOS 
K 
ALB 
ALBT 
TRIG 
Creatinine 
Gamma-glutamyl 
transpeptidase 
Glucose 
Lactate dehydrogenase 
Lipase 
Phosphorus 
Potassium 
Protein (ALB) 
Protein (Total) 
Triglycerides 
Laboratory Studies: 
LBCAT=URINE 
COLOR 
PH 
SG 
KET 
PROTEIN 
GLUC 
BILI 
NIT 
UROB 
HEMO 
CREAT 
 
Color 
pH 
Specific Gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrate 
Urobilinogen 
Hemoglobin 
Creatinine 
Laboratory data will be 
identified stored by 
category (LBCAT) and 
test code (LBTESTCD). 
Units standardized across 
the study. 
Laboratory Studies: 
LBCAT=SPEC 
FSACID 
PREGS 
PREGU 
 
Free serum SA 
Serum Pregnancy 
Urine Pregnancy 
Laboratory data will be 
identified stored by 
category (LBCAT) and 
test code (LBTESTCD). 
Units standardized across 
the study. 
 
5.4 
Efficacy Variables 
Efficacy analysis variables for the study population in UX001-CL202 will include the 
parameters listed in Table 6. Efficacy analysis variables will be summarized for Part II in this 
study to gain a better understanding of the 12 g/day SA-IR dose. Baseline efficacy analysis 


 
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variable values for subjects who roll over from UX001-CL201 will be identified based on the 
requested analysis.  Multiple baselines will be used to evaluate the change in disease course 
over the treatment pathways (Table 3). The baseline value to be used for the change from 
baseline comparisons will be identified with the specific analyses described in this SAP. 
Clinical efficacy analyses to be completed may include the following for the analysis 
variables listed below: 
(1) Muscle strength as measured by HHD UE, LE and individual components, and reported 
as force in kg and percent of predicted normal, 
(2) Walking ability as measured by the 6MWT, and reported as distance in meters and 
percent of predicted normal, 
(3) Walking speed as measured by the walking speed test, which will be reported in seconds 
and percent of predicted normal for each walking speed, comfortable and maximum, 
(4) Arm raising ability as measured by the weighted arm lift test, which will be reported as 
the total number of completed repetitions. 
(5) Functional disability as measured by the HIBM-FAS, which will be reported as a total 
score and subscale scores for mobility, self-care, and upper extremity function with lower 
scores associated with greater disability. 
 
Table 6 
Efficacy Analysis Variables 
Analysis Variable Name Analysis Variable Description 
Code List/ Variable 
Notes 
Hand Held 
Dynamometry: 
LELBEXT 
LELBFLX 
LGRIP 
LHIPABD 
LHIPADD 
LHIPEXT 
LHIPFLX 
LKEY 
LKNEEXT 
LKNEFLX 
LPALMAR 
LSHLDABD 
 
 
Left Elbow Extension (kg) 
Left Elbow Flexion (kg) 
Left Grip (kg) 
Left Hip Abduction (kg) 
Left Hip Adduction 
Left Hip Extension (kg) 
Left Hip Flexion (kg) 
Left Key (kg) 
Left Knee Extension (kg) 
Left Knee Flexion (kg) 
Left Palmar (kg) 
Left Shoulder Abduction (kg) 
Muscle strength based 
on the maximum 
voluntary isometric 
contraction (MVIC) 
against a hand-held 
dynamometer will be 
measured in the 
following muscle 
groups: gross grip, 
pinch, shoulder 
abductors, elbow 
flexors, elbow 
extensors, hip 
abductors, hip 


 
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Analysis Variable Name Analysis Variable Description 
Code List/ Variable 
Notes 
LTIP 
RELBEXT 
RELBFLX 
RGRIP 
RHIPABD 
RHIPADD 
RHIPEXT 
RHIPFLX 
RKEY 
RKNEEXT 
RKNEFLX 
RPALMAR 
RSHLDABD 
RTIP 
HHDHECS 
HHDLECS 
Left Tip (kg) 
Right Elbow Extension (kg) 
Right Elbow Flexion (kg) 
Right Grip (kg) 
Right Hip Abduction (kg) 
Right Hip Adduction 
Right Hip Extension (kg) 
Right Hip Flexion (kg) 
Right Key (kg) 
Right Knee Extension (kg) 
Right Knee Flexion (kg) 
Right Palmar (kg) 
Right Shoulder Abduction (kg) 
Right Tip (kg) 
HHD Upper Extremity CS 
HHB Lower Extremity CS 
adductors, hip flexors, 
hip extensors, knee 
flexors and knee 
extensors.  The total 
force (kg) will be 
measured as well as 
the percent of 
predicted normal force 
based on age, gender, 
height and weight 
(where applicable). 
Six-Minute Walk Test: 
SXMWTDIS 
SXMWTPP 
 
6-Min Walk Test (meters) 
6-Min Walk Test (%pred) 
The total distance 
walked (meters) in a 
six minute period will 
be measured as well as 
the percent of 
predicted normal 
distance based on age 
and gender. 
Walking Speed Test: 
COMFWALK 
MAXWALK 
 
Comfortable Gait Speed (cm/s) 
Maximum Walk Speed (cm/s) 
The time required to 
walk 25 feet (7.62 
meters) will be 
assessed at a 
comfortable and a 
maximum gait speed.  
The total number of 
seconds required for 
each speed will be 
recorded.  Individual 
subject performance 
will also be compared 
to healthy peers based 


 
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Analysis Variable Name Analysis Variable Description 
Code List/ Variable 
Notes 
on normative data. 
Weighted Arm Lift Test 
LNUMLIFT 
RNUMLIFT 
 
Left Arm Number of Lifts 
Right Arm Number of Lifts 
The number of times 
the subject can raise a 
1 kg weight above the 
head in a 30-second 
period will be 
recorded.  The test 
will be performed 
bilaterally. 
HIBM Functional 
Activities Scale 
FATSCR 
MOBLSCR 
SCARESCR 
UESCR 
 
 
 
Functional Activity Total Score 
Mobility Score 
Self-Care Score 
Upper Extremity Score 
 
The total score, as 
well as subscale scores 
for mobility, self-care, 
and upper extremity 
function on an 
interview-
administered 
functional disability 
measure will be 
recorded. 
 
5.5 
Exploratory Efficacy Variables 
Exploratory Efficacy analysis variables for the study population in UX001-CL202 will 
include the parameters listed in Table 7. These Exploratory Efficacy analysis variables will 
be summarized for both Part I and Part II in this study to gain a better understanding of the 6 
g/day SA-ER and 12 g/day SA-IR doses. 
 
Table 7 
Exploratory Efficacy Analysis Variables 
Analysis Variable Name Analysis Variable Description 
Code List/ Variable 
Notes 
Laboratory Studies: 
LBCAT=CHEM 
CK 
SA 
 
 
Creatine Kinase (u/L) 
Sialic Acid 
Biomarkers 


 
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Analysis Variable Name Analysis Variable Description 
Code List/ Variable 
Notes 
 
 


 
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6 STATISTICAL METHODOLOGY 
6.1 
Sample Size 
Approximately 46 subjects may be enrolled in Part I of this open-label extension study.  
Sample size is limited to the number of subjects enrolled in the Phase 2 safety and efficacy 
study, UX001-CL201, who achieve at least 80% treatment compliance and study visit 
completion.  As Part I of the study is intended to evaluate the long-term safety of 6g/day SA-
ER in subjects with GNE Myopathy and ascertain the long-term effect of SA-ER treatment 
on muscle strength, mobility, and functional disability, the sample size is deemed reasonable 
to satisfy Part I study objectives. 
An additional 10 subjects will be enrolled into Part II of the study.  This subset of treatment 
naïve GNE Myopathy subjects will provide additional safety and efficacy information 
following treatment with SA-ER/SA-IR. Note that more than 10 planned subjects may be 
enrolled in this subset of treatment naïve GNE Myopathy subjects, as new subjects are 
identified at the study centers. These additional subjects will only add additional information 
and informative value to this treatment naïve GNE Myopathy population. No modifications 
of updates to the SAP are needed for additional subjects in this group. 
The study design is open-label with all subjects receiving the same treatment.  Therefore, the 
study is not powered to assess statistically significant comparisons.  Instead, the sample size 
is intended to provide the maximum amount of long-term safety and efficacy data for the 
investigational product. 
6.2 
Randomization 
This is an Open-Label Study where all subjects who roll over from study UX001-CL201 will 
receive 6g/day SA-ER in Part I and 12g/day SA-ER/SA-IR in Part II.  Subjects enrolled into 
this study who are treatment naïve GNE Myopathy subjects will be included in Part II and 
receive 12g/day SA-ER/SA-IR. Since all subjects will receive the same treatment in Part II, 
randomization or blinding of study drug is not necessary. No randomization schedule or 
stratification strategy at baseline was developed for this study. 
6.3 
Analysis at 6-months (Part II) 
An analysis will be conducted following 6 months of treatment with 12g/day SA-ER/SA-IR 
in Part II of the study.  This analysis will be the primary analysis for the study for clinical 
efficacy information and initial safety information. 


 
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This analysis will be completed with the SAFETY, ITT, and TNP populations.   
The independent DMC may review the safety information from the analysis to assess the 
impact on the safety of the participants or the ethics of the study. The DMC may also make 
other recommendations to Ultragenyx Pharmaceutical concerning continuation, termination 
or other modifications of the study based on their observations of the study at the analysis or 
other DMC scheduled review of study data. 
Ultragenyx Pharmaceutical may also at its discretion complete additional examinations at 
additional time points for trends in efficacy and safety parameters after the analysis at 6-
months (Part II) has been completed to monitor and assess the 12g/day SA-ER/SA-IR dose. 
6.4 
Final Analysis at end of Part II. 
After all subjects have completed Part II dosing and follow-up termination visit on the 
12g/day SA-ER/SA-IR dose at approximately 36 months, the database will be locked and 
final analyses will be completed.  
6.5 
General Considerations for Statistical Analysis 
All statistical tests will be two-sided and a difference resulting in a p-value of less than or 
equal to 0.05 will be considered statistically significant.  All p-values will be rounded to and 
displayed in four decimals.  If a p-value less than 0.0001 occurs it will be shown in tables as 
<0.0001. 
There will be no multiplicity adjustments, or adjustments for multiple comparisons. 
Descriptive summaries of variables will be provided where appropriate.  For continuous 
variables, the number of non-missing values (n) and the median, mean, standard deviation, 
minimum, and maximum will be tabulated by treatment.  For categorical variables, the 
counts and proportions of each value will be tabulated by treatment.  Expansion of 
descriptive table categories within each treatment may occur if such elaborations are thought 
to be useful.     
All collected data will be presented in listings.  Data not subject to analysis according to this 
plan will not appear in any tables or graphs but will be included in the data listings. 
Post-hoc exploratory analyses not identified in this SAP may be performed to further 
examine the study data.  These analyses will be clearly identified as such in the final clinical 
study report. The SAP will not be amended for post-hoc, additional analyses identified after 
planned analyses are completed. Likewise, the list of planned tables (Section 8.1) is the list of 
planned tables prospectively defined for the study analyses. Additional tables and figures 
may be defined to further evaluate study results and the SAP will not be amended to list these 
additional analysis tables. 


 
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6.5.1 Changes in Analysis in Comparison to Study Protocol 
The analyses described in this analysis plan are consistent with the intended analyses 
described in the study protocol. In addition results from the UX001-CL201 study, both the 
Week 24 and Week 48 analyses, will be utilized as baseline information to explore and 
compare the various dosing combinations and trends in efficacy parameters, between the 
UX001-CL201 randomized feeder study and the UX001-CL202 extension study. 
6.5.2 Derived Efficacy Variables 
Muscle Strength - Hand Held Dynamometry (HHD): 
HHD Upper Extremity (UE) composite score is calculated as the sum of the average of the 
right and left raw scores (as measured in kg) for the following muscle groups: grip, shoulder 
abductors, elbow flexors and elbow extensors.  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 Lower Extremity (LE) composite score is calculated as the sum of the average of the 
right and left raw scores (as measured in kg) 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 value from the right or left 
side of an individual muscle group is missing, the missing value will be imputed using the 
non-missing value from the other side. 
 
Predicted normal HHD values will be derived for the raw strength values from bilateral 
pinch (tip, key and palmar), 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 generated for the variables. Baseline 
predicted normal values will be used to derive % of predicted normal values for all future 
study time points throughout the study. 
 
% of predicted normal HHD values for the individual muscle groups will be calculated as 
follows:  [(Raw strength value/Predicted normal strength value) *100]. 
 
Patient Reported Outcomes: 
HIBM Functional Activities Scale (HIBM-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 


 
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activity performance.  Self-Care subscale scores range from 0 to 28 with higher scores 
representing greater independence with functional care activities. 
6.5.3 Derived Safety, Dosing, and Medication Variables 
Non Treatment Emergent Adverse Events (AEs) include all adverse events that stopped 
the day prior to the start of study medication, started prior to the start of study medication but 
did not increase in severity or relationship during treatment, or started more than 30 days 
after the final study medication dosing date.  In this study there is no expectation on non-
treatment emergent adverse events in any subjects who roll-over from UX0010-CL201. 
Subjects in the treatment naïve population may have non-treatment emergent adverse events 
recorded if an event occurs between screening (informed consent) and the first dose of 
planned study medication (12g.day SA-ER/SA-IR). 
 
Treatment Emergent Adverse Events (TEAE) include all adverse events that start on or 
after the first dose of study medication, or adverse events that are present prior to the first 
dose of study medication, but their severity or relationship increases after the first dose of 
study medication up to and including 30 days after the final study medication dosing date. 
 
Dosing: Number of doses administered will be calculated for each subject by summing the 
number of doses administered over all visits. 
 
Medications: 
Prior medications include all medications that are taken prior to the first dose of study 
medication date.  
 
Concomitant medications include all medications that are taken on or after the date of first 
dose of study medication. 
6.5.4 Data Handling 
Unscheduled or repeated laboratory results will not be analyzed for the summary of 
continuous values but may be included in any post-hoc laboratory shift tables as follows.  
Unscheduled tests will be included with the time of the nearest regularly scheduled test.  If 
there is a scheduled laboratory result and one or more unscheduled tests assigned to the same 
time point, the most conservative test (i.e., a test with low or high results) will be used.  
Repeated tests will be included only if they reflect abnormal (low or high) results and the 
corresponding original results are normal. 


 
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6.5.5 Handling of Early Termination Visits 
Early termination visit data for safety variables will be analyzed at the closest scheduled 
visit.  If the closest visit has valid data, the early termination data will be assigned to the next 
available visit.  
6.5.6 Handling of Missing Values 
Partial or Missing Dates 
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. 
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. 
 
Imputation of missing endpoint assessments: 
Observed cases with data missing at random will be assumed for all planned analyses. If 
missing endpoint assessments are observed then the last observed value, at the collected time 
point, will be included in planned analyses.  


 
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Following a data review at the 6-month interim analysis and at the completion of the study 
Ultragenyx Pharmaceutical may at their discretion define an imputation rule if missing data 
for efficacy assessment and endpoints is believed to be non-random, and has some aspect of 
systematic error associated with the missing data. If this is determined following data review 
then a Last Observation Carried Forward (LOCF), or Baseline Observation Carried Forward 
(BOCF) may be considered for imputation for missing endpoint efficacy data. 
Imputation of missing endpoint assessments for HHD measures: 
Missing values explained as “Too Weak” are to be converted to zero scores for all HHD 
measures including Grip, Tip Pinch, Key Pinch, Palmar Pinch, Shoulder Abduction, Elbow 
Flexion, Elbow Extension, Knee Flexion, Knee Extension, Hip Flexion, Hip Extension, Hip 
Abduction and Hip Adduction. 
6.5.7 Pooling of Investigator Centers 
The data from all study centers will be pooled together for the primary analyses.  No a priori 
pooling strategy will be defined for this study. If after review of study data prior to planned 
interim analyses and final analyses the data review meeting identifies cohorts of sites that 
warrant pooling then a pooling strategy will be defined and implemented, and presented in 
the final CSR.  
6.5.8 Determination of Baseline Values 
Multiple baseline values for efficacy endpoints will be considered for the planned analyses. 
Figure 1 presents an analysis map that highlights the various possible baselines for planned 
analyses. Table 3 presents a dosing pathway matrix for all subjects enrolled in the study. 
Each pathway can be associated with a different baseline for analysis summaries and 
comparisons.  
In order the examine the long term trends and changes in SA therapy for those subjects who 
roll-over from UX001-CL201 additional analyses will also be performed using baseline 
assessments obtained at the following time points (Figure 1): 
• UX001-CL201 6/6 and 3/3 rollover subjects: UX001-CL201 Week 0 Visit 
• UX001-CL201 0/6 and 0/3 rollover subjects: UX001-CL201 Week 24 Visit 
• UX001-CL201 0/6 + 6/6 rollover subjects: UX001-CL201 Week 48 Visit 
• UX001-CL201 0/3 + 3/3 rollover subjects: UX001-CL201 Week 48 Visit 
• UX001-CL201 All rollover subjects: UX001-CL201 Week 48 Visit 


 
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• UX001-CL201 All rollover subjects: UX001-CL202 Part I Termination Visit 
• UX001-CL202 Treatment Naïve Subjects: UX001-CL202 Part II Screening/Baseline 
Visit (Week 0: Note that protocol refers to this as week 12 on the T&E schedule.) 
6.5.9 Coding of Events and Medications 
Adverse events will be coded to standardize presentation of AEs and TEAEs.  AEs will be 
mapped to the Medical Dictionary for Regulatory Activities (MedDRA Version 11.1) system 
for reporting (preferred term and body system). 
Concomitant medications will be coded using WHO-DD (Drug Dictionary) (Version 
2009003). 
6.5.10 Analysis Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.1.3 or higher) for 
Windows.  If the use of other software is warranted, the final clinical study report will detail 
what software was used and for what purposes. 
6.5.11 Analysis Data Sets 
Analysis data sets will be developed for all study data in UX001-CL202. The analysis data 
sets will conform as close as possible to the CDISC Analysis Data Model (ADaM). Because 
this study also utilizes analysis data from the feeder study UX001-CL201 the final analysis 
data sets from this study will also be utilized to build, where appropriate, pooled analysis 
data sets with UX001-CL202. Subjects who roll over from the UX001-CL201 study into 
UX001-CL202 will carry with them the same USUBJID (Subject identifier) from UX001-
CL201 for continuity of analysis data between studies. 
6.6 
Statistical Analysis: Disposition, Dosing, and Baseline Characteristics 
6.6.1 Subject Disposition 
The tabulation of number of subjects in each treatment group in both Part I (6g/day SA-ER) 
and Part II (12g/day SA-ER/SA-IR) and overall will be displayed for all subjects who are 
screened (Treatment Naïve Subjects: Part II), roll-over from UX001-CL201, in the Safety 
Population, and in the ITT Population, respectively.  


 
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The number and percent of subjects who completed or discontinued the study (at both the 
interim analysis and final analysis) will be displayed for each treatment group and overall 
together with reasons for early termination, where the percent is with respect to the total 
number of randomized subjects in that treatment group. 
6.6.2 Dosing Summary 
The number of doses administered will be summarized by treatment group for both the 
Safety and ITT Populations. Study medication dispensing and treatment compliance will be 
summarized in individual subject listings. 
6.6.3 Demographics and Baseline Characteristics 
Subject demographic data and baseline characteristics will be summarized descriptively by 
treatment group and overall.  The demographic data and baseline characteristics will be 
summarized for both the Safety and ITT Populations.  
Inclusion and Exclusion criteria will be presented in a listing. 
6.6.4 Prior and Concomitant Medications 
Concomitant medications will be assessed at all visits and throughout the course of the study.  
Prior Medications: The number and percent of prior medications recorded for Treatment 
Naïve Subjects (enrolled directly into Part II) will be presented by the ATC class and 
preferred term as coded in the WHO-Drug dictionary (WHO-DD, version 200903).  Prior 
medications will not be summarized for subjects who roll-over from UX001-CL201. 
The number and percent of Concomitant Medications recorded for all subjects will be 
summarized by treatment group in Part I (6g/day SA-ER) and Part II (12g/day SA-ER/SA-
IR) by the ATC class and preferred term as coded in the WHO-Drug dictionary. 
Prior and concomitant medications will be summarized for the Safety Population. 
6.7 
Statistical Analysis: Clinical Efficacy 
6.7.1 Planned Comparisons for Clinical Efficacy Parameters 
The planned comparisons for UX001-CL202 are based on change from baseline assessments, 
where different baselines are utilized to evaluate treatment across a subject’s treatment in 


 
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both UX001-CL201 and UX001-CL202. Table 8 presents the planned comparisons for study 
data obtained in UX001-CL202 compared with study data from UX001-CL201 for roll-over 
subjects, as well as the treatment naïve subjects in UX001-CL202.   
Clinical efficacy data collected in Part I of UX001-CL202 (all roll-over subjects dosed with 
6g/day SA-ER) will not be included in planned comparisons for the clinical efficacy analysis.  
Additional comparisons not specified in this statistical analysis plan may be completed as 
prospective analyses are completed to better understand study results. These additional 
comparisons will be clearly identified in final reporting. 
 
Table 8 
Planned Comparisons 
Planned Comparison 
Description 
Primary Analysis #1: 
Week 24 12g/day SA/ER/SA-IR vs. 
Week 0 
All subjects who roll-over from UX001CL201 
will have their week 0 assigned as baseline (Part 
I termination visit of the 202 study) and the 
change from this score will be compared to the 
week 24 12g/day SA-ER/SA-IR treatment to 
assess the impact of the 12g/day SA-ER/SA-IR 
dose. 
 
Primary Analysis #2: 
Week 24 12g/day SA/ER/SA-IR vs. 
Week 48 UX001-CL201 for 6/6+0/6 
SA-ER  
 
All subjects who roll-over from UX001CL201 
will have their week 48 assigned as baseline and 
the change from this score will be compared to 
the week 24 12g/day SA-ER/SA-IR treatment to 
assess the impact of the 12g/day SA-ER/SA-IR 
dose across the combined 6/6+0/6 dose (UX001-
CL201 subjects treated with 0/6 or 6/6 SA-ER 
will be combined for comparison from dosing 
pathways 1 and 3 from Table 3). 
 
A second comparison will be with a 6 minute 
walk test at  Screening of >=200 m 
(6MWT>=200m)  
Primary Analysis #3: 
Week 24 12g/day SA/ER/SA-IR vs. 
Week 48 UX001-CL201 for 3/3+0/3 
 
All subjects who roll-over from UX001CL201 
will have their week 48 assigned as baseline and 


 
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Planned Comparison 
Description 
SA-ER 
the change from this score will be compared to 
the week 24 12g/day SA-ER/SA-IR treatment to 
assess the impact of the 12g/day SA-ER/SA-IR 
dose across the combined 3/3+0/3 dose (UX001-
CL201 subjects treated with 0/3 or 3/3 SA-ER 
will be combined for comparison from dosing 
pathways 2 and 4 from Table 3) 
 
A second comparison will be with a 6 minute 
walk test at Screening of >=200 m 
(6MWT>=200m) 
Secondary Analysis: 
Stability in endpoint over time and 
dose from Week 0 UX001-CL201 
through Week 24 UX001-CL202. 
(Trend over time) 
 
 
All subjects who roll-over from UX001CL201 
will have their week 0 assigned as baseline and 
the stability from this baseline score will be 
assessed over time through the week 24 12g/day 
SA-ER/SA-IR treatment to assess the impact of 
dose combinations over time. For this analysis 
the UX001-CL201 subjects treated with 0/6 or 
6/6 SA-ER will be combined for analysis from 
dosing pathways 1 and 3 and subjects treated 
with 0/3 or 3/3 SA-ER will be combined for 
analysis from dosing pathways 2 and 4 (Table 
3). Each dosing pathway combination will be a 
separate analysis to assess the trend in endpoint 
scores over time and dose. 
 
A second comparison will be with a 6 minute 
walk test at Screening of >=200 m 
(6MWT>=200m) 
Treatment Naïve Primary Analysis: 
Week 24 12g/day SA/ER/SA-IR vs. 
Week 0 Baseline (Week 12 on T&E) 
 
Treatment Naïve subjects who enroll in UX001-
CL202 will have a primary comparison of their 
change from baseline assessment for efficacy 
parameters.  
Treatment Naïve Secondary 
Analysis:    
Week 24 12g/day SA/ER/SA-IR vs. 
 
 
Treatment Naïve subjects in UX001-CL202 


 
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Planned Comparison 
Description 
Week 0-24 UX001-CL201 Placebo 
 
 
endpoint data from week 0 to 24 will be 
compared to the UX001-CL201 Placebo (for 
those patients with 6MWT >=200m) treated 
subjects’ endpoint data from week 0 to 24 for 
change from baseline assessments. 
 
Additional comparisons may be defined upon review of the data to examine trends 
throughout a subject’s treatment course through both UX001-CL201 and UX001-CL202, via 
the dosing pathways identified in Table 3 and Figure 1.  
6.7.2 Statistical Modeling: Repeated Measure Model: General Estimating Equations 
(GEE) 
The primary analysis method to be applied for all repeated measures efficacy parameters will 
be a general estimating equation (GEE) model (Hanley 2003, SAS Software 2010). A 
generalized estimating equation (GEE) procedure will be performed for the repeated 
measures associated with the clinical efficacy endpoints analysis and associated planned 
comparisons.   
 
The GEE regression model is of the general form: 
 
Yij = α + β1X1i + … + βnΧyi + βn1T1ij + … + βnxTxij Χxi + εij 
Where, we assume that the Yij follow a Normal distribution with var(Yij ) = σ2, and cov(Yij, 
Yik) = δ (exchangeable correlation).  It follows that the link function is the identity.  The 
model above has been parameterized with reference cell coding, where the coefficient 
estimates corresponding to the treatment variables (Χ2, Χ3) capture the mean differences in 
the change from baseline for the planned comparison. The model will provide that a test of 
change from baseline at the planned time points (identified in the comparisons in Table 8) is 
the linear estimate of β3 + β12.  The following general form and sample SAS Software 
program code provides an example of this type of GEE model implementation across the 
planned efficacy parameters described in Table 6 and Table 7:  
 
PROC GENMOD DATA=<data set name>; 
      CLASS <id variable>; 
      MODEL <efficacy parameter> = <trt1>  <trt2>  <baseline>  
                     <covariates> <vx_trt1>  <vx_trt2>  <interactions> / DIST=NORMAL; 
      REPEATED SUBJECT=<id> / CORR=CS; 
      ESTIMATE ‘<planned comparison>’  <trt1> 1 <trt2> 1  <vx_trt1>  1; 


 
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RUN; 
QUIT; 
 
where: 
<id variable> uniquely identifies the subject: A record for every visit for each subject, 
<efficacy parameter> identifies the clinical efficacy parameter of interest, 
<baseline> identifies the baseline for the efficacy parameter measure for the subject, 
<planned comparison> comparisons identified in Table 8, 
<trt1> is the 12g/day SA-ER/SA-IR variable (1,0), 
<trt2> is the defined dose for comparisons (1,0), 
<vx> are coded (0,1) visit variables, 
<vx_trt1>, <vx_trt2> are coded (0,1) visit x treatment interaction variables, 
<covariates> define any additional baseline covariates assessed for inclusion in the GEE 
model at p<0.05. 
In general, baseline value, gender, and age will be covariates in the GEE models for each 
planned analysis where appropriate. The final form of the GEE model for each clinical 
efficacy parameter and planned comparison will be described in the final study report. 
6.7.3 Statistical Modeling: Analysis of Covariance (ANCOVA) 
Where appropriate, supportive analyses of clinical efficacy parameters may be completed 
with Analysis of Covariance (ANCOVA) (Kutner 2005). ANCOVA combines features of 
both analysis of variance (ANOVA) and regression. It augments the ANOVA model with 
one or more additional quantitative covariates, which are related to the response variable. 
The covariates are included to reduce the variance in the error terms and provide more 
precise measurement of the treatment effects.  ANCOVA is used to test the main and 
interaction effects of the factors, while controlling for the effects of the covariate.  In the 
analyses of this study, ANCOVA will be used for the variables that were measured at the 
baselines identified in Figure 1.  ANCOVA may be implemented to assess treatment group 
differences in comparisons identified in Table 8 while controlling for the screening measure 
of the clinical efficacy variable being analyzed. ANCOVA may be utilized where repeated 
measures are not anticipated for a planned, supplemental analysis or in cases where further 
understanding of study results will benefit from the use of ANCOVA. 
6.7.4 Statistical Modeling: Graphic Displays of Study Results 
Graphical displays of study endpoints will be completed and include both observed study 
data and modeled analyses. Arithmetic means, Least Square Means (LS Means), LS means 
differences, and appropriate measure of dispersion (e.g. standard deviation, standard error) or 
confidence intervals may be display in figures to augment the modeled analysis. In general, 


 
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graphical displays will be accompany each planned analysis to present study results, utilizing 
companion numbering aligned with tabular numbering. 
Scatter points over the observation time intervals for UX001-CL201 through the 6-month (24 
week) time point for UX001-CL202 will be completed for each study endpoint, by treatment 
pathway (Table 3), to examine trends in results over time of treatments for subjects who roll-
over from UX001-CL201. Treatment Naïve subjects enrolled in Part II of UX001-CL202 
will have the scatter plots scaled for their participation with treatment 12g/day SA-ER/SA-
IR. In general the scatterplots will include, for any given endpoint, all observations for every 
subject presented in a single figure, color coded for treatment pathways. 
Bar charts will be completed for each endpoint where change from baseline is examined and 
treatment differences are evaluated. Either the mean change or LS Mean’s differences, 
whichever is appropriate for the endpoint, will be displayed to support the statistical analyses 
performed. 
Exploratory scatter plots, and correlations, will be completed to examine study endpoint 
means (or LS means) compared to Free Sialic Acid (SA), and other serum biomarkers of 
interest, to explore the treatment effects with the 12g/day SA-ER/SA-IR dose compared to 
previous doses subjects (Table 3).  
6.7.5 Efficacy Analysis: Muscle Strength - Hand Held Dynamometry (HHD) 
The hand held dynamometry (HHD) assessment is completed in UX001-CL202 at the Part II 
time points of Screening/Baseline (last visit in Part I), months 3, 6, 12, 18, 24, 30, 36, and the 
termination visit (Table 2).  The HHD parameters will be summarized into composite scores 
and GEE analyses will be performed.  
HHD Upper Extremity (UE) Composite Score 
HHD UE composite scores will be used to evaluate change in upper extremity muscle 
strength.  HHD UE composite scores achieved for the 12g/day SA-ER/SA-IR dosing group at 
each study time point will be evaluated using descriptive statistics.  
A GEE model (see Section 6.7.2) will be completed for the week 24 (6 month) analysis and 
will include the visits from Part II of UX001-CL202 (Months 1 to 6) accounting for time on 
the 12g/day SA-ER/SA-IR treatment with subjects who cross-over from treatment 
administered in UX001-CL201 (Table 3). The primary model will incorporate the treatment 
groups defined in the planned comparisons (Table 8).   
HHD Lower Extremity (LE) Composite Score 
HHD LE composite scores will be used to evaluate change in lower extremity muscle 
strength.  HHD LE composite scores achieved for the 12g/day SA-ER/SA-IR dosing group at 
each study time point will be evaluated using descriptive statistics. The same modelling 
strategy applied for the HHD UE will be applied for the HHD LE Composite score. 


 
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6.7.6 Exploratory Efficacy Analysis: Hand Held Dynamometry (HHD) 
HHD Individual Raw Strength Scores 
Strength in the individual muscle groups tested by HHD will be assessed using raw scores (as 
measured in kg) from the right and left sides. Individual muscle groups to be assessed in the 
upper extremities include pinch (key, tip and palmar), gross grip, shoulder abductors, elbow 
flexors and elbow extensors. Individual muscle groups to be assessed in the lower extremities 
include hip abductors, hip adductors, hip flexors, hip extensors, knee flexors and knee 
extensors.   
Raw strength scores achieved for the 12g/day SA-ER/SA-IR treatment group in UX001-
CL202 at the Part II time points of Screening/Baseline (last visit in Part I), months 3, 6, 12, 
18, 24, 30, 36, and the termination visit (Table 2) will be evaluated for the average of the 
right and left sides of the individual muscle groups using descriptive statistics.  If one side is 
missing, it will be imputed using the other side. 
A GEE model (see Section 6.7.2) will be completed for the week 24 (6 month) primary 
analysis and will include the visits from Part II of UX001-CL202 (Months 1 to 6) accounting 
for time on the 12g/day SA-ER/SA-IR treatment with subjects who cross-over from 
treatment administered in UX001-CL201 (Table 3). The GEE model will incorporate the 
treatment groups defined in the planned comparisons (Table 8) for raw strength scores.   
 
HHD % Predicted Normal Strength Scores 
Strength in the individual muscle groups tested by HHD will be assessed using % of 
predicted normal scores for the right and left sides.  Predicted normal values will be 
calculated as described in Section 6.5.2. Individual muscle groups to be assessed in the upper 
extremities include pinch (key, tip and palmar), gross grip, shoulder abductors, elbow flexors 
and elbow extensors. Individual muscle groups to be assessed in the lower extremities 
include hip abductors, hip adductors, hip flexors, hip extensors, knee flexors and knee 
extensors.   
Percent of predicted normal scores achieved for the 12g/day SA-ER/SA-IR treatment group 
in UX001-CL202 at the Part II time points of Screening/Baseline (last visit in Part I), months 
3, 6, 12, 18, 24, 30, 36, and the termination visit (Table 2) will be evaluated for the average 
of the right and left sides of the individual muscle groups using descriptive statistics. 
A GEE model (see Section 6.7.2) will be completed for the week 24 (6 month) primary 
analysis will include the visits from in Part II of UX001-CL202 (Months 1 to 6) accounting 
for time on the 12g/day SA-ER/SA-IR treatment with subjects who cross-over from 
treatment administered in UX001-CL201 (Table 3). The GEE model will incorporate the 
treatment groups defined in the planned comparisons (Table 8) for HHD % predicted normal 
strength scores. 
Additional Analyses: HHD UE, LE Scores 


 
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In addition to the above analyses, additional analyses will be conducted to help further assess 
both the degree of change over the time course of treatment in both UX001-CL201 and in 
UX001-CL202 and the effect of crossover from the dosing pathways (Table 3).  For each of 
the treatment pathway groups (or combinations thereof) the HHD UE and LE composite 
change over time will be evaluated to seek understanding on the various dosing pathways and 
the effect of the 12g/day SA-ER/SA-IR dosing. 
The cross-over treatment pathway groups may be compared with the change observed in 
prior treatment period HHD UE and LE scores. Trends in the change observed in each 
parameter will be displayed using graphical techniques. These latter analyses will help 
evaluate an effect of SA over an extended period of time from UX001-CL201 through 
UX001-CL202, as well as on the reversal of HHD change for subjects that may have 
declined during the placebo period (Weeks 0-24 in UX001-CL201).  These analyses will help 
to understand the long term impact of treatment over dosing pathways and assess whether the 
rate of change in individual subjects has changed significantly from before to after the 
various treatments received. 
Additional Analyses: Serum SA Levels and HHD UE, LE Scores 
An analysis of change in mean serum SA level impact on HHD UE, LE scores will be 
performed.  Changes in mean serum SA level observed during the cross-over treatment 
pathway groups may be compared with the change observed in prior treatment period HHD 
UE and LE scores. Trends in these changes in observed SA levels and HHD UE and LE 
scores will be displayed using graphical techniques. 
Subjects achieving a mean change in serum SA of 0.1 mg/dl or greater over their individual 
baseline over all visits may be compared to those subjects with <0.1 mg/dl mean change in 
SA level.  Subjects will be placed into either the 0.1 mg/dl or greater mean difference group 
or the less than 0.1 mg/dl mean difference group, and then the change in HHD UE and LE 
scores will be compared across these two groups using a GEE model. 
6.7.7 Efficacy Analysis: Six-Minute Walk Test Distance 
The Six Minute Walk Test (6MWT) will be used to evaluate change in walking capacity. 
6MWT distance observed for the 12 g/day SA-ER/SA-IR treatment group will be 
summarized using descriptive statistics at each time point from Part II of UX001-CL202 
(Table 2).  
A GEE analysis model will be developed to examine the change in 6MWT distance for the 6-
month part II analysis with study time points as categorical predictors and age, gender and 
Screening 6MWT distance as covariates. The defined baselines and planned comparisons to 
be examined in this analysis are identified in Table 8. 
In addition the cross-over treatment pathway groups may be compared with the change 
observed in prior treatment period for the 6MWT. Trends in the change observed in 6MWT 
will be displayed using graphical techniques. 


 
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6.7.8 Exploratory Efficacy Analysis: 6MWT 
% Predicted of Normal 6MWT Distance 
The 6MWT performance of subjects relative to peers will be evaluated as a sensitivity 
analysis using % of predicted normal 6MWT distance values. Predicted normal values will 
be calculated as described in section 6.5.2.  Percent of predicted normal 6MWT distance 
achieved for the 12g/day SA-ER/SA-IR treatment group at each study time point will be 
evaluated using descriptive statistics for Part II UX001-CL201. 
A GEE Model similar in construct to that performed for the 6MWT efficacy variable will be 
completed for the % predicted of Normal 6MWT.  
In addition the cross-over treatment pathway groups may be compared with the change 
observed in prior treatment period for the % predicted of normal 6MWT distance. Trends in 
the change observed in % predicted of normal 6MWT distance will be displayed using 
graphical techniques. 
6.7.9 Efficacy Analysis: Walking Speed Test 
Gait Speed – Comfortable and Maximum Pace: 
The gait speed test will be used to evaluate walking speed at a comfortable and maximum 
pace on a 7.62 meter (25 feet) course. The speed at which the subject can walk 7.62 meters 
will be measured in centimeters/second (cm/s) for the comfortable and maximum paces.  
Comfortable gait speed (CGS) and maximum gait speed (MGS) observed for the 12g/day 
SA-ER/SA-IR treatment group in Part II of UX001-CL202 will be evaluated using 
descriptive statistics. 
A GEE analysis model will be developed to examine the change in speed (cm/s) at the 
comfortable pace (CGS) for the 6-month Part II analysis with study time points as categorical 
predictors and age, height and Baseline CGS as covariates. The same GEE model will be 
used to assess change in speed (cm/s) at maximum pace (MGS). The defined baselines and 
planned comparisons to be examined in this analysis are identified in Table 8. 
In addition the cross-over treatment pathway groups may be compared with the change 
observed in prior treatment period for the CGS and MGS parameters. Trends in the change 
observed in the CGS and MGS parameters will be displayed using graphical techniques. 
6.7.10 Exploratory Efficacy Analysis: Walking Speed Test 
% Predicted of Normal Gait Speed – Comfortable and Maximum Pace 
The gait speed of subjects relative to peers will be evaluated as a sensitivity analysis using % 
of height-normalized predicted speed values for CGS and MGS parameters.  Predicted 
normal values will be calculated as described in section 6.5.2.  Percent of predicted normal 


 
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CGS and MGS observed for the 12g/day SA-ER/SA-IR treatment group in Part II of UX001-
CL202 at each study time point will be summarized using descriptive statistics.    
GEE models similar to those performed for the CGS and MGS parameters will be completed 
as sensitivity analyses. 
In addition the cross-over treatment pathway groups may be compared with the change 
observed in prior treatment period for the % predicted CGS and MGS parameters. Trends in 
the change observed in the % predicted CGS and MGS parameters will be displayed using 
graphical techniques. 
6.7.11 Efficacy Analysis: Weighted Arm Lift Test 
The weighted arm lift test will be used to assess the ability to raise a weighted object 
overhead with each arm.  Performance will be measured by the number of times that a 
subject can lift a 1 kg dumbbell overhead in a 30-second period.  The test will be performed 
twice, once with the left arm and once with the right arm.  The number of repetitions 
performed on each side for the 12g/day SA-ER/SA-IR treatment group at each study time 
point will be evaluated using descriptive statistics on the average result of the left and right 
side. 
A GEE analysis model will be developed to examine the change in weighted arm lift test for 
the 6-month Part II analysis with study time points as categorical predictors and gender, age,  
and baseline weighted arm lift as covariates. Baseline for these analysis will be the week 48 
observation (termination visit) from UX001-CL201. The comparisons to be examined are 
identified in Table 8. 
In addition the cross-over treatment pathway groups may be compared with the change 
observed in prior treatment period for weighted arm lift test. Trends in the change observed 
in the weighted arm lift test will be displayed using graphical techniques. 
6.7.12 Efficacy Analysis: HIBM Functional Activities Scale 
The HIBM-FAS will be administered to assess subject’s self-reported activity limitations 
resulting from HIBM. Activity limitation will be measured with a total score and 3 subscale 
scores for mobility, upper extremity function and self-care.  The individual HIBM variables 
are presented in Table 6.   Total and subscale scores will be calculated as described in 
Section 6.5.2.  Total and subscale scores will be evaluated for the 12g/day SA-ER/SA-IR 
dose at each study time point in Part II of UX001-CL202 using descriptive statistics. 
A GEE analysis model will be developed to examine the change in HIBM-FAS with study 
time points as categorical predictors and gender, age, and baseline as covariates. Baseline for 
these analysis will be the week 48 observation (termination visit) from UX001-CL201. The 
comparisons to be examined are identified in Table 8.  The GEE approach detailed above for 


 
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the analysis of the HIBM-FAS total score will be repeated for HIBM-FAS Mobility, Upper 
Extremity and Self-Care subscales.   
In addition the cross-over treatment pathway groups may be compared with the change 
observed in prior treatment period for HIBM-FAS total score, as well as the individual scores 
for HIBM-FAS Mobility, Upper Extremity and Self-Care subscales. Trends in the change 
observed in the HIBM-FAS will be displayed using graphical techniques. 
6.7.13 Exploratory Efficacy Analysis: Creatine Kinase 
Creatine kinase (CK) samples are being assessed at baseline and the Part I termination visit, 
and at months 1, 3, 6, 12, 24, 36, a nd the termination visit in Part II in UX001-Cl202 for 
subjects who roll-over from UX001-CL201. Treatment Naïve subjects who are enrolled in 
Part II of this study will have a baseline assessed at the screening visit.  
Changes in CK will be evaluated using descriptive and graphical summaries to evaluate 
change over time in CK levels after dosing with 12g/day SA-ER/SA-IR in Part II.  
A GEE analysis model will be developed to examine the change in creatine kinase for the 6-
month Part II analysis with study time points, dose, and baseline creatine kinase as 
covariates. Baseline for these analysis will be the week 48 observation (termination visit) 
from UX001-CL201. The comparisons to be examined are identified in Table 8. 
6.8 
Statistical Analysis: Effect of Changes in Muscle Strength, PROs, and Physical 
Function 
6.8.1 Upper Extremity Muscle Strength vs. Weighted Arm Lift Test 
GEE will be used to assess the relationship between changes in upper extremity muscle 
strength and changes in arm raising ability.  Changes in HHD UE composite scores will be 
compared to changes in the number of repetitions performed in the weighted arm lift test.  
The GEE will be performed with and without treatment in the model for Part II in UX001-
CL202. Additional comparisons may be made to explore the changes in these muscle 
strength parameters over the dosing pathways identified in Table 3 and in Table 8. 
6.8.2 Lower Extremity Muscle Strength vs. 6MWT Distance 
GEE will be used to assess the relationship between changes in lower extremity muscle 
strength and changes in the results for the 6-minute walk test (6MWT).  Changes in HHD LE 
composite scores will be compared to changes in the 6MWT distance (as measured in 
meters).  The GEE will be performed with and without treatment in the model for Part II in 


 
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UX001-CL202. Additional comparisons may be made to explore the changes in these muscle 
strength parameters over the dosing pathways identified in Table 3 and in Table 8. 
6.8.3 Lower Extremity Muscle Strength vs. Gait Speed Test 
GEE will be used to assess the relationship between changes in lower extremity muscle 
strength and changes in the results for the comfortable gait speed (CGS) and maximum gait 
speed (MGS) observed for the 12g/day SA-ER/SA-IR treatment group in Part II of UX001-
CL202.  The GEE will be performed with and without treatment in the model for Part II in 
UX001-CL202 to examine changes in HHD LE composite scores compared to changes in 
CGS and MGS (as measured in cm/s).  Additional comparisons may be made to explore the 
changes in these muscle strength parameters over the dosing pathways identified in Table 3 
and in Table 8. 
6.8.4 HIBM-FAS Total and UE Subscale Score vs. HHD UE Composite Score 
GEE will be used to assess the relationship between changes in self-reported functional 
disability and changes in upper extremity strength.  Changes in HIBM-FAS total and HIBM-
FAS UE subscale score will be compared to changes in HHD UE composite score. The GEE 
will be performed with and without treatment in the model for Part II in UX001-CL202. 
Additional comparisons may be made to explore the changes in these parameters over the 
dosing pathways identified in Table 3 and in Table 8. 
6.8.5 HIBM-FAS Total and Mobility Subscale Score vs. HHD LE Composite Score 
GEE will be used to assess the relationship between changes in self-reported functional 
disability and changes in lower extremity strength.  Changes in HIBM-FAS total and HIBM-
FAS Mobility subscale score will be compared to changes in HHD LE composite score.  The 
GEE will be performed with and without treatment in the model for Part II in UX001-CL202. 
Additional comparisons may be made to explore the changes in these parameters over the 
dosing pathways identified in Table 3 and in Table 8. 
6.8.6 HIBM-FAS Total and Mobility Subscale Score vs. 6MWT Distance 
GEE will be used to assess the relationship between changes in self-reported functional 
disability and changes in walking ability (6MWT).  Changes in HIBM-FAS total and HIBM-
FAS Mobility subscale score will be compared to changes in 6MWT distance.  The GEE will 
be performed with and without treatment in the model for Part II in UX001-CL202. 
Additional comparisons may be made to explore the changes in these parameters over the 
dosing pathways identified in Table 3 and in Table 8. 


 
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6.8.7 HIBM-FAS Total and Mobility Subscale Score vs. Gait Speed Test 
GEE will be used to assess the relationship between changes in self-reported functional 
disability and changes in comfortable gait speed (CGS) and maximum gait speed (MGS).  
Changes in HIBM-FAS total and HIBM-FAS Mobility subscale score will be compared to 
changes in CGS and MGS (as measured in cm/s).  The GEE will be performed with and 
without treatment in the model for Part II in UX001-CL202.  Additional comparisons may be 
made to explore the changes in these parameters over the dosing pathways identified in Table 
3 and in Table 8. 
6.8.8 HIBM-FAS Total and UE Subscale Score vs. Weighted Arm Lift Test 
GEE will be used to assess the relationship between changes in self-reported functional 
disability and weighted arm lift test.  Changes in HIBM-FAS total and HIBM-FAS Mobility 
subscale score will be compared to changes in weighted arm lift test scores.  The GEE will be 
performed with and without treatment in the model for Part II in UX001-CL202. Additional 
comparisons may be made to explore the changes in these parameters over the dosing 
pathways identified in Table 3 and in Table 8. 
6.9 
Statistical Analysis: Pharmacokinetics 
6.9.1 Free Serum Sialic Acid (SA) Levels 
Blood samples for the measurement of trough levels of free serum SA will be drawn during 
blood draws for clinical laboratory samples. Free serum SA samples are being assessed at 
baseline and the Part I termination visit, and at months 1, 3, 6, 12, 24, 36, and the termination 
visit in Part II in UX001-Cl202 for subjects who roll-over from UX001-CL201. Treatment 
Naïve subjects who are enrolled in Part II of this study will have a baseline assessed at the 
screening visit.  
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 serum SA levels 
observed for the 12g/day SA-ER/SA-IR dose will be evaluated at each study time point using 
descriptive statistics.  
The change in free serum SA level from Baseline to the 6-month Part II time point will be 
analysed using a GEE model with baseline free serum SA level as a covariate for the 12g/day 
SA-ER-SA-IR dose group in Part II. Comparisons identified in Table 8 will be implemented 
for this analysis.  


 
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6.10 Statistical Analysis: Safety 
In general all safety analyses will be completed using descriptive summaries, graphs, and 
subject listings. No planned inferential testing of safety endpoints is planned. If after the any 
planned analysis it is determined by the medical writer and study medical monitor that 
inferential tests of significance may help to provide context for safety information these tests 
may be performed and identified in the CSR. 
6.10.1 Adverse Events 
Adverse Events will be assessed at all visits and throughout the course of the study. The 
number and percent of subjects with any treatment-emergent adverse events (TEAEs) will be 
displayed by system organ class and preferred term for each treatment group (6g/day SA-ER, 
12g/day SA-ER/SA-IR).  Within each preferred term, subjects will be counted only once if 
they had more than one event reported during the treatment period.  The same summary will 
be performed for all serious TEAEs and all TEAEs causing discontinuation of study drug.  
The number and percent of subject TEAEs will also be summarized by greatest reported 
severity grade (Grades 1-5) for each event preferred term by treatment group.  Wherever 
possible, the severity of all AEs observed will be graded using the NCI CTCAE (V4.0) as 
follows in Table 9: 
Table 9 
NCI-CTCAE Common AE Grading Criteria 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Source: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, 
Published May 28, 2009 (v4.03, June 24, 2010); USHHS/NIH/NCI 
* ADL=Activities for Daily Living: Instrumental ADL refer to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 


 
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The majority of AEs and TEAEs can be graded using the NCI-CTCAE system. Wherever 
possible, the severity of all AEs will be graded using the NCI CTCAE.  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 definitions in 
Table 10.  
 
Table 10 
Mapped AE Grading Criteria 
Grade 
Description 
Mild (Grade 1) 
Awareness of signs or symptoms, but easily tolerated and 
of a minor irritant type, causing no l oss 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 
 
The number and percent of subjects reporting one or more TEAEs that map to the severity 
grade classification for each preferred term will be summarized by treatment group.  At each 
level of summarization (system organ class or event preferred term) subjects are only 
counted once. 
The number and percent of subjects experiencing Serious Adverse Events (SAE) for each 
preferred term will be summarized by treatment group. 
The number and percent of subjects who withdraw from the study or discontinue study 
medication due to a TEAE or SAE will be summarized by treatment group. 
The number and percent of subject TEAEs will be summarized by greatest reported 
relationship to study medication in as follows in Table 11.  
 


 
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Table 11 
AE Relationship to Study Medication 
Relationship 
Description 
Not-Related 
This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt.  
That is, another cause of the event is most plausible; and/or a 
clinically plausible temporal sequence is inconsistent with the 
onset of the event and the exposure to study drug and/or a 
causal relationship is considered biologically implausible. 
Possibly-Related 
This category applies to an AE that follows a r easonable 
temporal sequence from administration of the study drug and 
that follows a known or expected response pattern to the 
suspected study drug, but that could readily have been 
produced by a number of other factors. 
Probably-Related 
This category applies to an AE that is likely related to the 
investigational agent/procedure.  T hat is, the AE has a 
temporal 
relationship 
to 
the 
administration 
of 
the 
investigational agent(s) or research intervention, follows a 
known or suspected pattern of response, and is strongly 
associated with study drug exposure. 
 
A listing will be produced for all subjects who reported serious TEAEs or who discontinued 
study medication due to TEAEs. 
All TEAEs will be listed individually by subject.  In addition, a separate listing will be 
produced for AEs that are not treatment-emergent.  Separate individual subject listings for 
SAE and TEAE leading to Study Withdrawal or discontinuation of Study Medication will 
also be produced. 
6.10.2 Clinical Laboratory Parameters 
Clinical safety laboratories (CBC, Chemistries, Creatine Kinase, Free Serum SA Levels, and 
Pregnancy tests) will be assessed during Part I of this study at baseline and the Part I 
termination visit.  For subjects who roll-over from study UX001-CL201 the baseline clinical 
laboratory values may be derived from the last visit (week 48, or termination visit) in 
UX001-CL201, prior to participation in UX001-CL202. 
Clinical safety laboratories (CBC, Chemistries, Creatine Kinase, and Free Serum SA Levels) 
will be assessed during Part II of this study at the Screening/Baseline and Months 1, 3, 6, 12, 
18, 24, 30, 36, and termination visits. Pregnancy testing will be completed in Part II at the 
Screening/Baseline and Months 12, 24, and termination visits. For subjects who roll-over 


 
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from study UX001-CL201 and participate in Part I of this study the baseline clinical 
laboratory values may be derived from the last visit in Part I (Part I termination visit). For 
Treatment Naïve Subjects enrolled directly into Part II the baseline values will be the 
Screening/Baseline visit for these subjects. 
Laboratory data will be monitored for safety and will be listed by subject. No descriptive 
information will be compiled for clinical laboratory data. 
6.10.3 Vital Signs 
Vital signs (Blood Pressure, respiratory rate, heart rate) will be assessed during Part I of this 
study at baseline and the Part I termination visit.  For subjects who roll-over from study 
UX001-CL201 the baseline vital sign values may be derived from the last visit (week 48, or 
termination visit) in UX001-CL201, prior to participation in UX001-CL202. 
Vital signs (Blood Pressure, respiratory rate, heart rate) will be assessed during Part II of this 
study at the Screening/Baseline and Months 1, 6, 12, 18, 24, 30, 36, and termination visits. 
For subjects who roll-over from study UX001-CL201 and participate in Part I of this study 
the baseline vital sign values may be derived from the last visit in Part I (Part I termination 
visit). For Treatment Naïve Subjects enrolled directly into Part II the baseline values will be 
the Screening/Baseline visit for these subjects. 
Vital signs data will be monitored for safety and will be listed by subject. No descriptive 
information will be compiled for vital signs data. 
6.10.4 Medical History 
Medical History for subjects who roll-over from study UX001-CL201 will be carried forward 
from the UX001-CL201 study.  
Medical History (and Interval History) will be assessed during Part II of this study at the 
Screening/Baseline and Months 1, 6, 12, 18, 24, 30, 36, and termination visits. For Treatment 
Naïve Subjects enrolled directly into Part II medical history (and interval history) will be 
assessed at the Screening/Baseline visit for these subjects. 
A detailed medical history will be obtained at Screening and presented descriptively by 
treatment group. The medical history will solicit information on any prior or existing medical 
conditions that might interfere with study participation or safety. Medical History information 
from subjects who participate in Part I of this study and roll-over from UX001-CL201 will be 
carried forward from the UX001-CL201 study. For Treatment Naïve Subjects enrolled 
directly into Part II the medical history will be obtained at the Screening/Baseline visit for 
these subjects. 


 
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Medical history results for all subjects in the safety population will be reported in listing 
format, identifying those subjects carried over from UX001-CL201 and those Treatment 
Naïve Subjects enrolled into Part II. 
6.10.5 Interval History 
Interval History will be assessed during Part I of this study at baseline and the Part I 
termination visit.  For subjects who roll-over from study UX001-CL201 the baseline interval 
history values may be derived from the last visit (week 48, or termination visit) in UX001-
CL201, prior to participation in UX001-CL202. 
Interval History will be assessed during Part II of this study at the Screening/Baseline and 
Months 1, 6, 12, 18, 24, 30, 36, and termination visits. For subjects who roll-over from study 
UX001-CL201 and participate in Part I of this study the baseline interval values may be 
derived from the last visit in Part I (Part I termination visit). For Treatment Naïve Subjects 
enrolled directly into Part II the baseline values will be the Screening/Baseline visit for these 
subjects. 
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 HIBM) 
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 listing format, 
identifying those subjects carried over from UX001-CL201 and those Treatment Naïve 
Subjects enrolled into Part II.   
The number of falls experienced by subjects in Part I (6g/day SA-ER) and in Part II (12g/day 
SA-ER/SA-IR) treatment groups will be evaluated at each study time point using descriptive 
statistics.  
6.10.6 Physical Examination 
Physical Examinations will be assessed during Part I of this study at baseline and the Part I 
termination visit.  For subjects who roll-over from study UX001-CL201 the baseline 
physical examination values may be derived from the last visit (week 48, or termination 
visit) in UX001-CL201, prior to participation in UX001-CL202. 
Physical Examination will be assessed during Part II of this study at the Screening/Baseline 
and Months 1, 6, 18, 36, and termination visits. For subjects who roll-over from study 
UX001-CL201 and participate in Part I of this study the baseline physical examination 
values may be derived from the last visit in Part I (Part I termination visit). For Treatment 


 
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Naïve Subjects enrolled directly into Part II the baseline values will be the 
Screening/Baseline visit for these subjects. 
Physical exam results for all subjects in the safety population will be reported in listing 
format. Changes in physical examination will be reported as adverse events. 
6.10.7 Neurological Examination 
Neurological Examinations will be assessed during Part I of this study at baseline and the 
Part I termination visit.  For subjects who roll-over from study UX001-CL201 the baseline 
neurological examination values may be derived from the last visit (week 48, or termination 
visit) in UX001-CL201, prior to participation in UX001-CL202. 
Neurological Examination will be assessed during Part II of this study at the 
Screening/Baseline and Months 6, 18, and 36 visits. For subjects who roll-over from study 
UX001-CL201 and participate in Part I of this study the baseline neurological examination 
values may be derived from the last visit in Part I (Part I termination visit). For Treatment 
Naïve Subjects enrolled directly into Part II the baseline values will be the 
Screening/Baseline visit for these subjects.  
The neurological examination will include assessments of cognition, cranial nerves, motor 
function, coordination and gait, reflexes, and sensory function.  
Neurological exam results for all subjects in the safety population will be reported in listing 
format. Changes in neurological examination will be reported as adverse events. 
6.10.8 Pregnancy Testing 
Results of pregnancy testing for females of child bearing potential will be provided in 
listings. 
6.10.9 Other Safety Parameters 
In some cases inferential statistical comparisons may be requested by the medical report 
writer (e.g., analysis of variance comparing vital signs or laboratory values between 
treatment groups).  All such requests will be carried out by the statistician.  P-values in such 
instances will serve as measures of distance to facilitate the clinical review and screening of 
these numerous variables. 


 
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7 REFERENCES 
 
Hanley JA, Negassa A, deB.Edwardes MD, Forrester JE.  Statistical analysis 
of correlated data using generalized estimating equations: an orientation.  Am 
J Epidemiol 2003;157:364-375. 
Kutner MH, Nachtsheim CK, Neter J, and Li W. Applied Linear Statistical 
Models (5th ed). 2005. McGraw-Hill. New York, NY. 
Wallenstein S. and Wittes J. The Power of the Mantel-Haenszel Test. 
Biometrics 1993;49 (4):1077–1087. 
SAS Software. SAS/STAT 9.22 User’s Guide: PROC GENMOD. 2010. SAS 
Institute, Cary, NC. 


 
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8 APPENDICES 
 


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8.1 
List of Prospective Tables and Figures 
The following is a list of the planned Tables and Figures prospectively identified for the planned analyses described in this SAP. A 
separate document will be completed for programming specifications that provides details on the unique mock Tables, Figures, 
and Listings. The mock shells may be updated throughout the course of programming and review without amendment of this SAP. 
Included is a list of the planned tables for this Study. Corresponding figures will be developed for those efficacy endpoints to 
display trends, frequencies, and modeled output were appropriate to better facilitate the understanding of the data and results. Note 
that additional tables and figures, not listed herein, may be generated to better understand study results. These additional tables and 
figures will be identified in the final publication of study results. The SAP will not be amended to identify additional analyses. 
The final numbering and presentation order of the tables and figures completed to support the analyses conducted for UX001-
CL202 will be determined prior to final delivery of the analyses. In general, clinical efficacy tables and figures will be grouped 
first by analysis type (as identified in Table 8), and then by endpoint. 
 
Table 
ID(1) 
Table Description(2) 
1 
Subject Disposition 
2 
Demographics and Baseline Characteristics- Safety Population 
3 
Demographics and Baseline Characteristics- ITT Population 
4 
Number of Doses Administered- Safety Population 
5 
Number of Doses Administered- ITT Population 
6 
Prior Medication 
7 
Concomitant Medication 
8 
Interval History- Number of Falls 
9 
TEAE- Overall Summary 


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Table 
ID(1) 
Table Description(2) 
10 
TEAE- by SOC and PT  (including second table of TEAE by descending frequency of PT) 
11 
Serious TEAE- by SOC and PT 
12 
TEAE Causing Discontinuation- by SOC and PT 
13 
TEAE by Severity- by SOC and PT  
14 
TEAE by Relationship- by SOC and PT 
15 
Elbow Extension (kg)- Summary 
16 
Elbow Extension (kg)- Primary Analysis #1 
17 
Elbow Extension (kg)- Primary Analysis #1- 6MWT >= 200 
18 
Elbow Extension (kg)- Primary Analysis #2 
19 
Elbow Extension (kg)- Primary Analysis #2- 6MWT >= 200 
20 
Elbow Extension (kg)- Primary Analysis #3 
21 
Elbow Extension (kg)- Primary Analysis #3- 6MWT >= 200 
22 
Elbow Extension (kg)- Secondary Analysis 
23 
Elbow Extension (kg)- Secondary Analysis- 6MWT >= 200 
24 
Elbow Extension (kg)- Treatment Naïve Primary Analysis 
25 
Elbow Extension (kg)- Treatment Naïve Secondary Analysis 
26 
Elbow Extension (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
27 
Elbow Flexion (kg)- Summary 
28 
Elbow Flexion (kg)- Primary Analysis #1 
29 
Elbow Flexion (kg)- Primary Analysis #1- 6MWT >= 200 
30 
Elbow Flexion (kg)- Primary Analysis #2 
31 
Elbow Flexion (kg)- Primary Analysis #2- 6MWT >= 200 


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Table 
ID(1) 
Table Description(2) 
32 
Elbow Flexion (kg)- Primary Analysis #3 
33 
Elbow Flexion (kg)- Primary Analysis #3- 6MWT >= 200 
34 
Elbow Flexion (kg)- Secondary Analysis 
35 
Elbow Flexion (kg)- Secondary Analysis- 6MWT >= 200 
36 
Elbow Flexion (kg)- Treatment Naïve Primary Analysis 
37 
Elbow Flexion (kg)- Treatment Naïve Secondary Analysis 
38 
Elbow Flexion (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
39 
Grip (kg)- Summary 
40 
Grip (kg)- Primary Analysis #1 
41 
Grip (kg)- Primary Analysis #1- 6MWT >= 200 
42 
Grip (kg)- Primary Analysis #2 
43 
Grip (kg)- Primary Analysis #2- 6MWT >= 200 
44 
Grip (kg)- Primary Analysis #3 
45 
Grip (kg)- Primary Analysis #3- 6MWT >= 200 
46 
Grip (kg)- Secondary Analysis 
47 
Grip (kg)- Secondary Analysis- 6MWT >= 200 
48 
Grip (kg)- Treatment Naïve Primary Analysis 
49 
Grip (kg)- Treatment Naïve Secondary Analysis 
50 
Grip (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
51 
Hip Abduction (kg)- Summary 
52 
Hip Abduction (kg)- Primary Analysis #1 
53 
Hip Abduction (kg)- Primary Analysis #1- 6MWT >= 200 


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Table 
ID(1) 
Table Description(2) 
54 
Hip Abduction (kg)- Primary Analysis #2 
55 
Hip Abduction (kg)- Primary Analysis #2- 6MWT >= 200 
56 
Hip Abduction (kg)- Primary Analysis #3 
57 
Hip Abduction (kg)- Primary Analysis #3- 6MWT >= 200 
58 
Hip Abduction (kg)- Secondary Analysis 
59 
Hip Abduction (kg)- Secondary Analysis- 6MWT >= 200 
60 
Hip Abduction (kg)- Treatment Naïve Primary Analysis 
61 
Hip Abduction (kg)- Treatment Naïve Secondary Analysis 
62 
Hip Abduction (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
63 
Hip Adduction (kg)- Summary 
64 
Hip Adduction (kg)- Primary Analysis #1 
65 
Hip Adduction (kg)- Primary Analysis #1- 6MWT >= 200 
66 
Hip Adduction (kg)- Primary Analysis #2 
67 
Hip Adduction (kg)- Primary Analysis #2- 6MWT >= 200 
68 
Hip Adduction (kg)- Primary Analysis #3 
69 
Hip Adduction (kg)- Primary Analysis #3- 6MWT >= 200 
70 
Hip Adduction (kg)- Secondary Analysis 
71 
Hip Adduction (kg)- Secondary Analysis- 6MWT >= 200 
72 
Hip Adduction (kg)- Treatment Naïve Primary Analysis 
73 
Hip Adduction (kg)- Treatment Naïve Secondary Analysis 
74 
Hip Adduction (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
75 
Hip Extension (kg)- Summary 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 59 of 78 
Table 
ID(1) 
Table Description(2) 
76 
Hip Extension (kg)- Primary Analysis #1 
77 
Hip Extension (kg)- Primary Analysis #1- 6MWT >= 200 
78 
Hip Extension (kg)- Primary Analysis #2 
79 
Hip Extension (kg)- Primary Analysis #2- 6MWT >= 200 
80 
Hip Extension (kg)- Primary Analysis #3 
81 
Hip Extension (kg)- Primary Analysis #3- 6MWT >= 200 
82 
Hip Extension (kg)- Secondary Analysis 
83 
Hip Extension (kg)- Secondary Analysis- 6MWT >= 200 
84 
Hip Extension (kg)- Treatment Naïve Primary Analysis 
85 
Hip Extension (kg)- Treatment Naïve Secondary Analysis 
86 
Hip Extension (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
87 
Hip Flexion (kg)- Summary 
88 
Hip Flexion (kg)- Primary Analysis #1 
89 
Hip Flexion (kg)- Primary Analysis #1- 6MWT >= 200 
90 
Hip Flexion (kg)- Primary Analysis #2 
91 
Hip Flexion (kg)- Primary Analysis #2- 6MWT >= 200 
92 
Hip Flexion (kg)- Primary Analysis #3 
93 
Hip Flexion (kg)- Primary Analysis #3- 6MWT >= 200 
94 
Hip Flexion (kg)- Secondary Analysis 
95 
Hip Flexion (kg)- Secondary Analysis- 6MWT >= 200 
96 
Hip Flexion (kg)- Treatment Naïve Primary Analysis 
97 
Hip Flexion (kg)- Treatment Naïve Secondary Analysis 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 60 of 78 
Table 
ID(1) 
Table Description(2) 
98 
Hip Flexion (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
99 
Key (kg)- Summary 
100 
Key (kg)- Primary Analysis #1 
101 
Key (kg)- Primary Analysis #1- 6MWT >= 200 
102 
Key (kg)- Primary Analysis #2 
103 
Key (kg)- Primary Analysis #2- 6MWT >= 200 
104 
Key (kg)- Primary Analysis #3 
105 
Key (kg)- Primary Analysis #3- 6MWT >= 200 
106 
Key (kg)- Secondary Analysis 
107 
Key (kg)- Secondary Analysis- 6MWT >= 200 
108 
Key (kg)- Treatment Naïve Primary Analysis 
109 
Key (kg)- Treatment Naïve Secondary Analysis 
110 
Key (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
111 
Knee Extension (kg)- Summary 
112 
Knee Extension (kg)- Primary Analysis #1 
113 
Knee Extension (kg)- Primary Analysis #1- 6MWT >= 200 
114 
Knee Extension (kg)- Primary Analysis #2 
115 
Knee Extension (kg)- Primary Analysis #2- 6MWT >= 200 
116 
Knee Extension (kg)- Primary Analysis #3 
117 
Knee Extension (kg)- Primary Analysis #3- 6MWT >= 200 
118 
Knee Extension (kg)- Secondary Analysis 
119 
Knee Extension (kg)- Secondary Analysis- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 61 of 78 
Table 
ID(1) 
Table Description(2) 
120 
Knee Extension (kg)- Treatment Naïve Primary Analysis 
121 
Knee Extension (kg)- Treatment Naïve Secondary Analysis 
122 
Knee Extension (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
123 
Knee Flexion (kg)- Summary 
124 
Knee Flexion (kg)- Primary Analysis #1 
125 
Knee Flexion (kg)- Primary Analysis #1- 6MWT >= 200 
126 
Knee Flexion (kg)- Primary Analysis #2 
127 
Knee Flexion (kg)- Primary Analysis #2- 6MWT >= 200 
128 
Knee Flexion (kg)- Primary Analysis #3 
129 
Knee Flexion (kg)- Primary Analysis #3- 6MWT >= 200 
130 
Knee Flexion (kg)- Secondary Analysis 
131 
Knee Flexion (kg)- Secondary Analysis- 6MWT >= 200 
132 
Knee Flexion (kg)- Treatment Naïve Primary Analysis 
133 
Knee Flexion (kg)- Treatment Naïve Secondary Analysis 
134 
Knee Flexion (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
135 
Palmar (kg)- Summary 
136 
Palmar (kg)- Primary Analysis #1 
137 
Palmar (kg)- Primary Analysis #1- 6MWT >= 200 
138 
Palmar (kg)- Primary Analysis #2 
139 
Palmar (kg)- Primary Analysis #2- 6MWT >= 200 
140 
Palmar (kg)- Primary Analysis #3 
141 
Palmar (kg)- Primary Analysis #3- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 62 of 78 
Table 
ID(1) 
Table Description(2) 
142 
Palmar (kg)- Secondary Analysis 
143 
Palmar (kg)- Secondary Analysis- 6MWT >= 200 
144 
Palmar (kg)- Treatment Naïve Primary Analysis 
145 
Palmar (kg)- Treatment Naïve Secondary Analysis 
146 
Palmar (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
147 
Shoulder Abduction (kg)- Summary 
148 
Shoulder Abduction (kg)- Primary Analysis #1 
149 
Shoulder Abduction (kg)- Primary Analysis #1- 6MWT >= 200 
150 
Shoulder Abduction (kg)- Primary Analysis #2 
151 
Shoulder Abduction (kg)- Primary Analysis #2- 6MWT >= 200 
152 
Shoulder Abduction (kg)- Primary Analysis #3 
153 
Shoulder Abduction (kg)- Primary Analysis #3- 6MWT >= 200 
154 
Shoulder Abduction (kg)- Secondary Analysis 
155 
Shoulder Abduction (kg)- Secondary Analysis- 6MWT >= 200 
156 
Shoulder Abduction (kg)- Treatment Naïve Primary Analysis 
157 
Shoulder Abduction (kg)- Treatment Naïve Secondary Analysis 
158 
Shoulder Abduction (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
159 
Tip (kg)- Summary 
160 
Tip (kg)- Primary Analysis #1 
161 
Tip (kg)- Primary Analysis #1- 6MWT >= 200 
162 
Tip (kg)- Primary Analysis #2 
163 
Tip (kg)- Primary Analysis #2- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 63 of 78 
Table 
ID(1) 
Table Description(2) 
164 
Tip (kg)- Primary Analysis #3 
165 
Tip (kg)- Primary Analysis #3- 6MWT >= 200 
166 
Tip (kg)- Secondary Analysis 
167 
Tip (kg)- Secondary Analysis- 6MWT >= 200 
168 
Tip (kg)- Treatment Naïve Primary Analysis 
169 
Tip (kg)- Treatment Naïve Secondary Analysis 
170 
Tip (kg)- Treatment Naïve Secondary Analysis- 6MWT >= 200 
171 
HHD Upper Extremity CS- Summary 
172 
HHD Upper Extremity CS- Primary Analysis #1 
173 
HHD Upper Extremity CS- Primary Analysis #1- 6MWT >= 200 
174 
HHD Upper Extremity CS- Primary Analysis #2 
175 
HHD Upper Extremity CS- Primary Analysis #2- 6MWT >= 200 
176 
HHD Upper Extremity CS- Primary Analysis #3 
177 
HHD Upper Extremity CS- Primary Analysis #3- 6MWT >= 200 
178 
HHD Upper Extremity CS- Secondary Analysis 
179 
HHD Upper Extremity CS- Secondary Analysis- 6MWT >= 200 
180 
HHD Upper Extremity CS- Treatment Naïve Primary Analysis 
181 
HHD Upper Extremity CS- Treatment Naïve Secondary Analysis 
182 
HHD Upper Extremity CS- Treatment Naïve Secondary Analysis- 6MWT >= 200 
183 
HHD Lower Extremity CS- Summary 
184 
HHD Lower Extremity CS- Primary Analysis #1 
185 
HHD Lower Extremity CS- Primary Analysis #1- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 64 of 78 
Table 
ID(1) 
Table Description(2) 
186 
HHD Lower Extremity CS- Primary Analysis #2 
187 
HHD Lower Extremity CS- Primary Analysis #2- 6MWT >= 200 
188 
HHD Lower Extremity CS- Primary Analysis #3 
189 
HHD Lower Extremity CS- Primary Analysis #3- 6MWT >= 200 
190 
HHD Lower Extremity CS- Secondary Analysis 
191 
HHD Lower Extremity CS- Secondary Analysis- 6MWT >= 200 
192 
HHD Lower Extremity CS- Treatment Naïve Primary Analysis 
193 
HHD Lower Extremity CS- Treatment Naïve Secondary Analysis 
194 
HHD Lower Extremity CS- Treatment Naïve Secondary Analysis- 6MWT >= 200 
195 
6MWT- Summary 
196 
6MWT- Primary Analysis #1 
197 
6MWT- Primary Analysis #1- 6MWT >= 200 
198 
6MWT- Primary Analysis #2 
199 
6MWT- Primary Analysis #2- 6MWT >= 200 
200 
6MWT- Primary Analysis #3 
201 
6MWT- Primary Analysis #3- 6MWT >= 200 
202 
6MWT- Secondary Analysis 
203 
6MWT- Secondary Analysis- 6MWT >= 200 
204 
6MWT- Treatment Naïve Primary Analysis 
205 
6MWT- Treatment Naïve Secondary Analysis 
206 
6MWT- Treatment Naïve Secondary Analysis- 6MWT >= 200 
207 
Comfortable Gait Speed- Summary 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 65 of 78 
Table 
ID(1) 
Table Description(2) 
208 
Comfortable Gait Speed- Primary Analysis #1 
209 
Comfortable Gait Speed- Primary Analysis #1- 6MWT >= 200 
210 
Comfortable Gait Speed- Primary Analysis #2 
211 
Comfortable Gait Speed- Primary Analysis #2- 6MWT >= 200 
212 
Comfortable Gait Speed- Primary Analysis #3 
213 
Comfortable Gait Speed- Primary Analysis #3- 6MWT >= 200 
214 
Comfortable Gait Speed- Secondary Analysis 
215 
Comfortable Gait Speed- Secondary Analysis- 6MWT >= 200 
216 
Comfortable Gait Speed- Treatment Naïve Primary Analysis 
217 
Comfortable Gait Speed- Treatment Naïve Secondary Analysis 
218 
Comfortable Gait Speed- Treatment Naïve Secondary Analysis- 6MWT >= 200 
219 
Maximum Gait Speed- Summary 
220 
Maximum Gait Speed- Primary Analysis #1 
221 
Maximum Gait Speed- Primary Analysis #1- 6MWT >= 200 
222 
Maximum Gait Speed- Primary Analysis #2 
223 
Maximum Gait Speed- Primary Analysis #2- 6MWT >= 200 
224 
Maximum Gait Speed- Primary Analysis #3 
225 
Maximum Gait Speed- Primary Analysis #3- 6MWT >= 200 
226 
Maximum Gait Speed- Secondary Analysis 
227 
Maximum Gait Speed- Secondary Analysis- 6MWT >= 200 
228 
Maximum Gait Speed- Treatment Naïve Primary Analysis 
229 
Maximum Gait Speed- Treatment Naïve Secondary Analysis 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 66 of 78 
Table 
ID(1) 
Table Description(2) 
230 
Maximum Gait Speed- Treatment Naïve Secondary Analysis- 6MWT >= 200 
231 
Weighted Arm Lift- Summary 
232 
Weighted Arm Lift- Primary Analysis #1 
233 
Weighted Arm Lift- Primary Analysis #1- 6MWT >= 200 
234 
Weighted Arm Lift- Primary Analysis #2 
235 
Weighted Arm Lift- Primary Analysis #2- 6MWT >= 200 
236 
Weighted Arm Lift- Primary Analysis #3 
237 
Weighted Arm Lift- Primary Analysis #3- 6MWT >= 200 
238 
Weighted Arm Lift- Secondary Analysis 
239 
Weighted Arm Lift- Secondary Analysis- 6MWT >= 200 
240 
Weighted Arm Lift- Treatment Naïve Primary Analysis 
241 
Weighted Arm Lift- Treatment Naïve Secondary Analysis 
242 
Weighted Arm Lift- Treatment Naïve Secondary Analysis- 6MWT >= 200 
243 
Elbow Extension (kg)- % Predicted- Summary 
244 
Elbow Extension (kg)- % Predicted- Primary Analysis #1 
245 
Elbow Extension (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
246 
Elbow Extension (kg)- % Predicted- Primary Analysis #2 
247 
Elbow Extension (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
248 
Elbow Extension (kg)- % Predicted- Primary Analysis #3 
249 
Elbow Extension (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
250 
Elbow Extension (kg)- % Predicted- Secondary Analysis 
251 
Elbow Extension (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 67 of 78 
Table 
ID(1) 
Table Description(2) 
252 
Elbow Extension (kg)- % Predicted- Treatment Naïve Primary Analysis 
253 
Elbow Extension (kg)- % Predicted- Treatment Naïve Secondary Analysis 
254 
Elbow Extension (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
255 
Elbow Flexion (kg)- % Predicted- Summary 
256 
Elbow Flexion (kg)- % Predicted- Primary Analysis #1 
257 
Elbow Flexion (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
258 
Elbow Flexion (kg)- % Predicted- Primary Analysis #2 
259 
Elbow Flexion (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
260 
Elbow Flexion (kg)- % Predicted- Primary Analysis #3 
261 
Elbow Flexion (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
262 
Elbow Flexion (kg)- % Predicted- Secondary Analysis 
263 
Elbow Flexion (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
264 
Elbow Flexion (kg)- % Predicted- Treatment Naïve Primary Analysis 
265 
Elbow Flexion (kg)- % Predicted- Treatment Naïve Secondary Analysis 
266 
Elbow Flexion (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
267 
Grip (kg)- % Predicted- Summary 
268 
Grip (kg)- % Predicted- Primary Analysis #1 
269 
Grip (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
270 
Grip (kg)- % Predicted- Primary Analysis #2 
271 
Grip (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
272 
Grip (kg)- % Predicted- Primary Analysis #3 
273 
Grip (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 68 of 78 
Table 
ID(1) 
Table Description(2) 
274 
Grip (kg)- % Predicted- Secondary Analysis 
275 
Grip (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
276 
Grip (kg)- % Predicted- Treatment Naïve Primary Analysis 
277 
Grip (kg)- % Predicted- Treatment Naïve Secondary Analysis 
278 
Grip (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
279 
Hip Abduction (kg)- % Predicted- Summary 
280 
Hip Abduction (kg)- % Predicted- Primary Analysis #1 
281 
Hip Abduction (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
282 
Hip Abduction (kg)- % Predicted- Primary Analysis #2 
283 
Hip Abduction (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
284 
Hip Abduction (kg)- % Predicted- Primary Analysis #3 
285 
Hip Abduction (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
286 
Hip Abduction (kg)- % Predicted- Secondary Analysis 
287 
Hip Abduction (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
288 
Hip Abduction (kg)- % Predicted- Treatment Naïve Primary Analysis 
289 
Hip Abduction (kg)- % Predicted- Treatment Naïve Secondary Analysis 
290 
Hip Abduction (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
291 
Hip Adduction (kg)- % Predicted- Summary 
292 
Hip Adduction (kg)- % Predicted- Primary Analysis #1 
293 
Hip Adduction (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
294 
Hip Adduction (kg)- % Predicted- Primary Analysis #2 
295 
Hip Adduction (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 69 of 78 
Table 
ID(1) 
Table Description(2) 
296 
Hip Adduction (kg)- % Predicted- Primary Analysis #3 
297 
Hip Adduction (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
298 
Hip Adduction (kg)- % Predicted- Secondary Analysis 
299 
Hip Adduction (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
300 
Hip Adduction (kg)- % Predicted- Treatment Naïve Primary Analysis 
301 
Hip Adduction (kg)- % Predicted- Treatment Naïve Secondary Analysis 
302 
Hip Adduction (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
303 
Hip Extension (kg)- % Predicted- Summary 
304 
Hip Extension (kg)- % Predicted- Primary Analysis #1 
305 
Hip Extension (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
306 
Hip Extension (kg)- % Predicted- Primary Analysis #2 
307 
Hip Extension (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
308 
Hip Extension (kg)- % Predicted- Primary Analysis #3 
309 
Hip Extension (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
310 
Hip Extension (kg)- % Predicted- Secondary Analysis 
311 
Hip Extension (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
312 
Hip Extension (kg)- % Predicted- Treatment Naïve Primary Analysis 
313 
Hip Extension (kg)- % Predicted- Treatment Naïve Secondary Analysis 
314 
Hip Extension (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
315 
Hip Flexion (kg)- % Predicted- Summary 
316 
Hip Flexion (kg)- % Predicted- Primary Analysis #1 
317 
Hip Flexion (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 70 of 78 
Table 
ID(1) 
Table Description(2) 
318 
Hip Flexion (kg)- % Predicted- Primary Analysis #2 
319 
Hip Flexion (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
320 
Hip Flexion (kg)- % Predicted- Primary Analysis #3 
321 
Hip Flexion (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
322 
Hip Flexion (kg)- % Predicted- Secondary Analysis 
323 
Hip Flexion (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
324 
Hip Flexion (kg)- % Predicted- Treatment Naïve Primary Analysis 
325 
Hip Flexion (kg)- % Predicted- Treatment Naïve Secondary Analysis 
326 
Hip Flexion (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
327 
Key (kg)- % Predicted- Summary 
328 
Key (kg)- % Predicted- Primary Analysis #1 
329 
Key (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
330 
Key (kg)- % Predicted- Primary Analysis #2 
331 
Key (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
332 
Key (kg)- % Predicted- Primary Analysis #3 
333 
Key (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
334 
Key (kg)- % Predicted- Secondary Analysis 
335 
Key (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
336 
Key (kg)- % Predicted- Treatment Naïve Primary Analysis 
337 
Key (kg)- % Predicted- Treatment Naïve Secondary Analysis 
338 
Key (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
339 
Knee Extension (kg)- % Predicted- Summary 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 71 of 78 
Table 
ID(1) 
Table Description(2) 
340 
Knee Extension (kg)- % Predicted- Primary Analysis #1 
341 
Knee Extension (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
342 
Knee Extension (kg)- % Predicted- Primary Analysis #2 
343 
Knee Extension (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
344 
Knee Extension (kg)- % Predicted- Primary Analysis #3 
345 
Knee Extension (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
346 
Knee Extension (kg)- % Predicted- Secondary Analysis 
347 
Knee Extension (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
348 
Knee Extension (kg)- % Predicted- Treatment Naïve Primary Analysis 
349 
Knee Extension (kg)- % Predicted- Treatment Naïve Secondary Analysis 
350 
Knee Extension (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
351 
Knee Flexion (kg)- % Predicted- Summary 
352 
Knee Flexion (kg)- % Predicted- Primary Analysis #1 
353 
Knee Flexion (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
354 
Knee Flexion (kg)- % Predicted- Primary Analysis #2 
355 
Knee Flexion (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
356 
Knee Flexion (kg)- % Predicted- Primary Analysis #3 
357 
Knee Flexion (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
358 
Knee Flexion (kg)- % Predicted- Secondary Analysis 
359 
Knee Flexion (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
360 
Knee Flexion (kg)- % Predicted- Treatment Naïve Primary Analysis 
361 
Knee Flexion (kg)- % Predicted- Treatment Naïve Secondary Analysis 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 72 of 78 
Table 
ID(1) 
Table Description(2) 
362 
Knee Flexion (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
363 
Palmar (kg)- % Predicted- Summary 
364 
Palmar (kg)- % Predicted- Primary Analysis #1 
365 
Palmar (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
366 
Palmar (kg)- % Predicted- Primary Analysis #2 
367 
Palmar (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
368 
Palmar (kg)- % Predicted- Primary Analysis #3 
369 
Palmar (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
370 
Palmar (kg)- % Predicted- Secondary Analysis 
371 
Palmar (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
372 
Palmar (kg)- % Predicted- Treatment Naïve Primary Analysis 
373 
Palmar (kg)- % Predicted- Treatment Naïve Secondary Analysis 
374 
Palmar (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
375 
Shoulder Abduction (kg)- % Predicted- Summary 
376 
Shoulder Abduction (kg)- % Predicted- Primary Analysis #1 
377 
Shoulder Abduction (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
378 
Shoulder Abduction (kg)- % Predicted- Primary Analysis #2 
379 
Shoulder Abduction (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
380 
Shoulder Abduction (kg)- % Predicted- Primary Analysis #3 
381 
Shoulder Abduction (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
382 
Shoulder Abduction (kg)- % Predicted- Secondary Analysis 
383 
Shoulder Abduction (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 73 of 78 
Table 
ID(1) 
Table Description(2) 
384 
Shoulder Abduction (kg)- % Predicted- Treatment Naïve Primary Analysis 
385 
Shoulder Abduction (kg)- % Predicted- Treatment Naïve Secondary Analysis 
386 
Shoulder Abduction (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
387 
Tip (kg)- % Predicted- Summary 
388 
Tip (kg)- % Predicted- Primary Analysis #1 
389 
Tip (kg)- % Predicted- Primary Analysis #1- 6MWT >= 200 
390 
Tip (kg)- % Predicted- Primary Analysis #2 
391 
Tip (kg)- % Predicted- Primary Analysis #2- 6MWT >= 200 
392 
Tip (kg)- % Predicted- Primary Analysis #3 
393 
Tip (kg)- % Predicted- Primary Analysis #3- 6MWT >= 200 
394 
Tip (kg)- % Predicted- Secondary Analysis 
395 
Tip (kg)- % Predicted- Secondary Analysis- 6MWT >= 200 
396 
Tip (kg)- % Predicted- Treatment Naïve Primary Analysis 
397 
Tip (kg)- % Predicted- Treatment Naïve Secondary Analysis 
398 
Tip (kg)- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
399 
6MWT- % Predicted- Summary 
400 
6MWT- % Predicted- Primary Analysis #1 
401 
6MWT- % Predicted- Primary Analysis #1- 6MWT >= 200 
402 
6MWT- % Predicted- Primary Analysis #2 
403 
6MWT- % Predicted- Primary Analysis #2- 6MWT >= 200 
404 
6MWT- % Predicted- Primary Analysis #3 
405 
6MWT- % Predicted- Primary Analysis #3- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 74 of 78 
Table 
ID(1) 
Table Description(2) 
406 
6MWT- % Predicted- Secondary Analysis 
407 
6MWT- % Predicted- Secondary Analysis- 6MWT >= 200 
408 
6MWT- % Predicted- Treatment Naïve Primary Analysis 
409 
6MWT- % Predicted- Treatment Naïve Secondary Analysis 
410 
6MWT- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
411 
Comfortable Gait Speed- % Predicted- Summary 
412 
Comfortable Gait Speed- % Predicted- Primary Analysis #1 
413 
Comfortable Gait Speed- % Predicted- Primary Analysis #1- 6MWT >= 200 
414 
Comfortable Gait Speed- % Predicted- Primary Analysis #2 
415 
Comfortable Gait Speed- % Predicted- Primary Analysis #2- 6MWT >= 200 
416 
Comfortable Gait Speed- % Predicted- Primary Analysis #3 
417 
Comfortable Gait Speed- % Predicted- Primary Analysis #3- 6MWT >= 200 
418 
Comfortable Gait Speed- % Predicted- Secondary Analysis 
419 
Comfortable Gait Speed- % Predicted- Secondary Analysis- 6MWT >= 200 
420 
Comfortable Gait Speed- % Predicted- Treatment Naïve Primary Analysis 
421 
Comfortable Gait Speed- % Predicted- Treatment Naïve Secondary Analysis 
422 
Comfortable Gait Speed- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
423 
Maximum Gait Speed- % Predicted- Summary 
424 
Maximum Gait Speed- % Predicted- Primary Analysis #1 
425 
Maximum Gait Speed- % Predicted- Primary Analysis #1- 6MWT >= 200 
426 
Maximum Gait Speed- % Predicted- Primary Analysis #2 
427 
Maximum Gait Speed- % Predicted- Primary Analysis #2- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 75 of 78 
Table 
ID(1) 
Table Description(2) 
428 
Maximum Gait Speed- % Predicted- Primary Analysis #3 
429 
Maximum Gait Speed- % Predicted- Primary Analysis #3- 6MWT >= 200 
430 
Maximum Gait Speed- % Predicted- Secondary Analysis 
431 
Maximum Gait Speed- % Predicted- Secondary Analysis- 6MWT >= 200 
432 
Maximum Gait Speed- % Predicted- Treatment Naïve Primary Analysis 
433 
Maximum Gait Speed- % Predicted- Treatment Naïve Secondary Analysis 
434 
Maximum Gait Speed- % Predicted- Treatment Naïve Secondary Analysis- 6MWT >= 200 
435 
FAS Total Score- Summary 
436 
FAS Total Score- Primary Analysis #1 
437 
FAS Total Score- Primary Analysis #1- 6MWT >= 200 
438 
FAS Total Score- Primary Analysis #2 
439 
FAS Total Score- Primary Analysis #2- 6MWT >= 200 
440 
FAS Total Score- Primary Analysis #3 
441 
FAS Total Score- Primary Analysis #3- 6MWT >= 200 
442 
FAS Total Score- Secondary Analysis 
443 
FAS Total Score- Secondary Analysis- 6MWT >= 200 
444 
FAS Total Score- Treatment Naïve Primary Analysis 
445 
FAS Total Score- Treatment Naïve Secondary Analysis 
446 
FAS Total Score- Treatment Naïve Secondary Analysis- 6MWT >= 200 
447 
FAS Mobility Score- Summary 
448 
FAS Mobility Score- Primary Analysis #1 
449 
FAS Mobility Score- Primary Analysis #1- 6MWT >= 200 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 76 of 78 
Table 
ID(1) 
Table Description(2) 
450 
FAS Mobility Score- Primary Analysis #2 
451 
FAS Mobility Score- Primary Analysis #2- 6MWT >= 200 
452 
FAS Mobility Score- Primary Analysis #3 
453 
FAS Mobility Score- Primary Analysis #3- 6MWT >= 200 
454 
FAS Mobility Score- Secondary Analysis 
455 
FAS Mobility Score- Secondary Analysis- 6MWT >= 200 
456 
FAS Mobility Score- Treatment Naïve Primary Analysis 
457 
FAS Mobility Score- Treatment Naïve Secondary Analysis 
458 
FAS Mobility Score- Treatment Naïve Secondary Analysis- 6MWT >= 200 
459 
FAS Upper Extremity Score- Summary 
460 
FAS Upper Extremity Score- Primary Analysis #1 
461 
FAS Upper Extremity Score- Primary Analysis #1- 6MWT >= 200 
462 
FAS Upper Extremity Score- Primary Analysis #2 
463 
FAS Upper Extremity Score- Primary Analysis #2- 6MWT >= 200 
464 
FAS Upper Extremity Score- Primary Analysis #3 
465 
FAS Upper Extremity Score- Primary Analysis #3- 6MWT >= 200 
466 
FAS Upper Extremity Score- Secondary Analysis 
467 
FAS Upper Extremity Score- Secondary Analysis- 6MWT >= 200 
468 
FAS Upper Extremity Score- Treatment Naïve Primary Analysis 
469 
FAS Upper Extremity Score- Treatment Naïve Secondary Analysis 
470 
FAS Upper Extremity Score- Treatment Naïve Secondary Analysis- 6MWT >= 200 
471 
FAS Self-care Score- Summary 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 77 of 78 
Table 
ID(1) 
Table Description(2) 
472 
FAS Self-care Score- Primary Analysis #1 
473 
FAS Self-care Score- Primary Analysis #1- 6MWT >= 200 
474 
FAS Self-care Score- Primary Analysis #2 
475 
FAS Self-care Score- Primary Analysis #2- 6MWT >= 200 
476 
FAS Self-care Score- Primary Analysis #3 
477 
FAS Self-care Score- Primary Analysis #3- 6MWT >= 200 
478 
FAS Self-care Score- Secondary Analysis 
479 
FAS Self-care Score- Secondary Analysis- 6MWT >= 200 
480 
FAS Self-care Score- Treatment Naïve Primary Analysis 
481 
FAS Self-care Score- Treatment Naïve Secondary Analysis 
482 
FAS Self-care Score- Treatment Naïve Secondary Analysis- 6MWT >= 200 
483 
Free Serum SA- Summary 
484 
Free Serum SA- Primary Analysis #1 
485 
Free Serum SA- Primary Analysis #1- 6MWT >= 200 
486 
Free Serum SA- Primary Analysis #2 
487 
Free Serum SA- Primary Analysis #2- 6MWT >= 200 
488 
Free Serum SA- Primary Analysis #3 
489 
Free Serum SA- Primary Analysis #3- 6MWT >= 200 
490 
Free Serum SA- Secondary Analysis 
491 
Free Serum SA- Secondary Analysis- 6MWT >= 200 
492 
Free Serum SA- Treatment Naïve Primary Analysis 
493 
Free Serum SA- Treatment Naïve Secondary Analysis 


Ultragenyx Pharmaceutical, Inc. 
 
 FINAL Version 1.1 
Study UX001-CL202 Statistical Analysis Plan 
2014-05-05 
IND#: 109,334 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
Page 78 of 78 
Table 
ID(1) 
Table Description(2) 
494 
Free Serum SA- Treatment Naïve Secondary Analysis- 6MWT >= 200 
495 
Serum CK- Summary 
496 
Serum CK- Primary Analysis #1 
497 
Serum CK- Primary Analysis #1- 6MWT >= 200 
498 
Serum CK- Primary Analysis #2 
499 
Serum CK- Primary Analysis #2- 6MWT >= 200 
500 
Serum CK- Primary Analysis #3 
501 
Serum CK- Primary Analysis #3- 6MWT >= 200 
502 
Serum CK- Secondary Analysis 
503 
Serum CK- Secondary Analysis- 6MWT >= 200 
504 
Serum CK- Treatment Naïve Primary Analysis 
505 
Serum CK- Treatment Naïve Secondary Analysis 
506 
Serum CK- Treatment Naïve Secondary Analysis- 6MWT >= 200 
507 
HHD Lower Extremity CS vs. 6MWT Analysis 
508 
HHD Lower Extremity CS vs. Gait Speed Analysis 
509 
FAS Total Score and FAS Upper Extremity Score vs. HHD Upper Extremity CS 
510 
FAS Total Score and FAS Mobility Score vs. HHD Lower Extremity CS 
511 
FAS Total Score and FAS Mobility Score vs. 6MWT Distance 
512 
FAS Total Score and FAS Mobility Score vs. Gait Speed Test 
513 
FAS Total Score and FAS Upper Extremity Score vs. Weighted Arm Lift Test 
(1) The final ICH compliant numbering schema will be completed with each delivery of planned analyses and/or final clinical study report. Numbering provided herein may be 
updated, without update or amendment to the SAP. 
(2) Supporting Figures will be developed for most tables. The title (and brief description of type of figure) are aligned for reference in development. Figures will assume the 
name numbering as the primary table.