Clinical trial NCT02599961
Conditions: Glucose Transporter Type 1 Deficiency Syndrome
Keywords: Glut 1 DS
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2015-09-10; Completion date: 2019-10-22
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to evaluate the long-term safety of UX007 in Glut1 DS participants.

Detailed description:
The study will enroll up to 40 pediatric, adolescent and adult Glut 1 DS participants who have completed the UX007G-CL201 (NCT019933186) study and, at the discretion of the Sponsor, additional participants from other clinical studies, investigator sponsored trials (ISTs), or expanded access/compassionate use treatment.

Arms: arm 1: UX007 dosing targeted and/or maintained at 35% of total daily caloric intake.
Interventions: intervention 1: UX007
Intervention descriptions: intervention 1: UX007 is a liquid intended for oral (PO) administration.

Protocol documents:
Prot_000.pdf: 
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Protocol Number:  UX007G-CL202  
Amendment 1: 02 June 2016 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL202 Amendment 1 
02 June 2016 
 
 
The original Protocol UX007G-CL202 has been modified by Amendment 1 to incorporate a 
number of changes based on additional information acquired since the beginning of the 
study, and from feedback provided by clinical investigators involved in the study.  The major 
changes impacting study design, conduct, and analyses are summarized below; additional 
minor changes have also been made for consistency, clarity, and updated information but are 
not included in this summary. 
1. The number of study sites was changed from “approximately 12” to “up to 16”. 
The number of subjects planned was approximated at 40 subjects from the 
UX007-CL201 study and additional subjects who participated in qualified ISTs. 
Rationale: The change clarifies the sample size and provides a more accurate 
estimate of the number of investigational sites.  
2. Edited Inclusion Criterion #2 to state that all subjects at least 1 year of age at time of 
informed consent are eligible for participation in this study.  
Rationale: This change was made for clarification. 
3. Inclusion Criterion #3 was modified to remove the 3 month window following 
completion of the feeder study.  
Rationale: The change allows more flexibility to the participant.  
4. 
Inclusion Criterion #6 (and corresponding information in Section 7.5.4.5) regarding 
pregnancy testing and contraception was split into 2 separate inclusion criteria as 
follows: 
• 
Females of childbearing potential must have a negative urine 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 not experienced 
menarche, are post-menopausal (defined as having no menses for at least 12 months 
without an alternative medical cause), or are permanently sterile due to total 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
• 
Participants of child-bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly-effective method of 


Protocol Number:  UX007G-CL202  
Amendment 1: 02 June 2016 
 
 
Proprietary and Confidential 
Page 3 
contraception as determined by the investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug. 
Rationale: The change provides clarification of study requirements. 
5. 
Exclusion Criterion #1 was removed thereby eliminating specification of serum 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels.  
Rationale: To date, elevated liver enzymes have not been observed in UX007G 
studies. Therefore, it is not considered a likely safety concern that rises to the need 
for an exclusion criterion. Laboratory samples for serum chemistry will be taken at 
every clinic visit to monitor for any significant laboratory changes in study subjects.    
6. Removed Exclusion Criterion # 2 thereby removing specific requirements regarding 
percent of daily fat intake.  
Rationale: Change was made to allow individual investigators to directly manage 
subject diet as appropriate. 
7. Exclusion Criterion #8 was modified to remove diabetes mellitus as an exclusionary 
condition. 
Rationale: The change provides additional flexibility for the Investigator. 
The presence of diabetes in the subject population treated with UX007 is not likely be 
a safety concern. 
8. The first secondary objective was changed to ‘Evaluate the long-term effect of UX007 
efficacy on seizures associated with Glut1 DS’. This change affects multiple sections 
of the protocol related to statistical evaluations and analyses.  
Rationale: This change was made for clarification and to be more in line with the 
objectives of the feeder study, UX007G-CL201.  
9. The Stopping Rules (Section 7.3.3.1) were modified to correct notification procedures 
should unexpected and study drug-related SAEs occur, or if the study                             
is restarted. 
Rationale: The change reflects current sponsor procedures and aligns with Regulatory 
requirements. 
10. Section 7.4.1 was modified to specify UX007 should be mixed with food; 
the requirement to never administer directly as the oil was removed. In addition, 
the language around dose level was modified to recognize and allow the subject to 
remain on current dose, which may be different (i.e. lower or higher) than 35% of 
total daily caloric intake. 


Protocol Number:  UX007G-CL202  
Amendment 1: 02 June 2016 
 
 
Proprietary and Confidential 
Page 4 
Rationale: The change provides more dosing flexibility and more realistic 
expectations for continued dosing long-term extension treatment.  
11. Section 7.4.4.1 was modified to state “The planned duration of treatment in this study 
is 3 years, or until one of the following occurs:  the subject withdraws consent or , the 
patient is discontinued from the study at the discretion of the Investigator or 
Ultragenyx; the study is terminated, or until UX007 becomes commercially available 
commercial availability of study drug in a subject’s region, whichever occurs first.”. 
Due to this change, specific references to a “3-year Treatment Extension” were 
changed to “Treatment Extension Period” throughout the protocol. 
Rationale:  This change was made per guidance from Regulatory Authorities and for 
clarification. 
12. Updated Section 7.4.6.1 to remove valproate, MCT oil, KetoCal or other KD 
supplements, or other prescribed diet plan as prohibited medications; pancreatic lipase 
inhibitors was added to the list of prohibited medications. Prohibited medications are 
now specified in Exclusion Criteria #4 and 5. Prescribed diet plans are allowed 
provided details are captured in the diet diary or concomitant medications as 
appropriate (Section 7.4.6.2) 
Rationale:  After a review of the literature on valproate, triheptanoin, and Glut1 DS, 
it did not appear that the addition of triheptanoin to valproate posed significant risk 
to those patients, due to the low concentrations of VPA in brain tissue; therefore, the 
Sponsor is allowing subjects stable on valproate into the study (Adkison et al. 
1995).The removal of dietary or dietary supplement restrictions provides additional 
flexibility for the investigator in managing the patient during this long-term extension 
study. Pancreatic lipase inhibitors were included in the list of prohibited medications 
because in vitro studies have shown that pancreatic lipases hydrolyze triheptanoin 
into free fatty acids and glycerol; therefore inhibitors of pancreatic lipases 
(e.g., orlistat) should be avoided while taking UX007. 
13. The frequency of overnight EEG assessments (Section 7.5.2.1.2 and Table 2.1) was 
increased. Interictal epileptiform discharges will not be examined as an efficacy variable. 
Rationale: Feeder study UX007G-CL201 was previously amended to include subjects 
who primarily experience absence seizures. Overnight EEG is an objective measure 
of seizures and diaries may not adequately capture the frequency of these events. 
Therefore, additional overnight EEG assessments will be conducted to capture these 
events and therefore increase the quality of data pertaining to maintenance of effect 
in these patients. However, the frequency of interictal epileptiform discharges is 
unlikely to yield informative data in this pre-treated study population and has been 
removed as an efficacy variable. 
14. Efficacy assessments including Cambridge Neuropsychological Test Automated 
Battery (CANTAB; Section 7.5.2.2.1), Six Minute Walk Test and associated 


Protocol Number:  UX007G-CL202  
Amendment 1: 02 June 2016 
 
 
Proprietary and Confidential 
Page 5 
paroxysmal exertional dyskinesia (6MWT/PED; Section 7.5.2.3), the Clinical Global 
Impression Scales (CGI; Section 7.5.2.4.1), and the Pediatric Evaluation of Disability 
Inventory – Computer Adaptive Test (PEDI-CAT; Section 7.5.2.4.3) were removed from 
the study. Study objectives and endpoints (Section 6) were updated to reflect this change. The 
Short Form Health Surveys (SF-10 and SF-12v2) will not be performed if no pre-treatment 
baseline data is available from feeder study.   
Rationale: Long-term efficacy data using the CANTAB, 6MWT, CGI, and PEDI-CAT 
assessments will be available from the feeder study, UX007-CL201; continuing to 
assess in this open-label, single-arm extension is unlikely to yield informative data. 
Assessing SF-10/SF-12v2 is unlikely to provide useful information if no pre-treatment 
baseline data are available from the feeder study. Removal of these assessments will 
reduce the burden to patients and investigational sites participating in the study. 
15. Beta-ketopentanoic acid (BKP) will no longer be assayed (Section 7.5.3 Drug 
Concentration Measurements). 
Rationale:  Assay methodology is not available to reliably evaluate this UX007 
metabolite.  
16. Physical examination of the genitourinary system is no longer specified 
(Section 7.5.4.3) 
Rationale: The genitourinary system is not directly impacted by study drug or 
indication. 
17. Section 7.5.4.9 was modified to remove the requirement for a 3-day diet diary prior to 
the Baseline Visit. Daily caloric intake and UX007 dose will be determined by 
interview with the dietitian at the Baseline Visit. 
Rationale: Participants may enter the study at the Baseline Visit (following 
completion of a feeder study); signing of informed consent and initiation of treatment 
may occur on the same day and completion of a 3-day diet diary would not be 
possible. 
18. The following changes were made to Section 7.6 (Statistical Methods): 
• Separate safety analysis and intent-to-treat populations were replaced with one 
analysis set to include all subjects who receive at least one dose of UX007 during 
the study. 
• The reduction in frequency of seizures was removed as an efficacy analysis and 
replaced with a list of efficacy measures to be assessed.    
Rationale:  This is a single arm study and the analyses will include all subjects 
enrolled who receive at least one dose of UX007. 


Protocol Number:  UX007G-CL202  
Amendment 1: 02 June 2016 
 
 
Proprietary and Confidential 
Page 6 
19. A coordinating investigator will be named for this multicenter study (Section 8.2 
Investigators and Study Administrative Structure).  
20. Section 8.4.3 (Record Retention) 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. 
21. Updated Section 8.5.4 (Adverse Event Reporting) 
Rationale: Updated to match the sponsor’s current safety reporting procedures. 
 


Protocol Number:  UX007G-CL202  
Amendment 2: 28 July 2016 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL202 Amendment 2 
28 July 2016 
 
 
Protocol UX007G-CL202 Amendment 1 has been modified by Amendment 2 to incorporate 
the following three changes. 
1. The list of examples of highly effective contraception methods was updated in 
Section 7.5.4.5. 
Rationale: This change was requested by Regulatory Authorities to better clarify 
examples of highly effective contraception methods.  
2. A Safety Follow-up Phone Call was added to the schedule of events and relevant sections 
of the protocol (e.g., Sections 7.4.4.1 and 7.5.1).  
Rationale: This change was requested by Regulatory Authorities to standardize how 
adverse event information is collected 30 days following the last dose of UX007. 
3. The synopsis (Study Duration) and Sections 7.1 and 7.5.1 were updated to clarify that the 
end of study is the last subject’s Safety Follow-up Phone Call. 
Rationale: This change was requested by Regulatory Authorities to clarify the end of 
study. 
     
 


Protocol Number:  UX007G-CL202 
Amendment 3: 20 September 2017 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL202 Amendment 3 
20 September 2017 
Protocol UX007G-CL202 Amendment 2 has been modified by Amendment 3 to incorporate 
the following changes. 
1. Phone calls were added 3 months between study site visits during Years 2 and 3 (as 
described in Table 2.1).
Rationale: Phone calls at  Visits 6, 8, 10, and 12 were added to provide additional safety 
reporting, including adverse events and concomitant medication updates, and to inquire 
about study drug consumption and remaining supply; in lieu of the phone call, subjects 
may visit the clinic at the study site’s discretion.
2. Optional study site visits were added 3 months between study site visits during Years 2 
and 3 (as described in Table 2.1).
Rationale: Optional study site visits were added for Visits 6, 8, 10, and 12 to allow 
subjects to attain study drug as needed at the request of the Investigator.
2. Additional language has been added throughout the protocol and within the Study 
Schema (Figure 2.1 and Figure 7.1.1) to specify that, at the discretion of the Sponsor, 
additional subjects who participated in other clinical studies, ISTs, or expanded
access/compassionate use treatment programs may be eligible for inclusion in UX007G-
CL202.
Rationale:  This addition is a clarification to include subjects already eligible for 
enrollment according to Inclusion Criterion #3 to ensure consistency throughout the 
study protocol.
4. The window of time to draw blood for UX007 metabolites has been expanded from 90 
min (+/- 5 min) to 90 min (+/- 10 min) following consumption of food and study drug, as 
specified within Footnote 6 in the Schedule of Events (Table 2.1).
Rationale: This change was made to reduce site burden and is not expected to affect the 
UX007 metabolite measurements. 


Protocol Number:  UX007G-CL202  
Amendment 3: 20 September 2017 
 
 
Proprietary and Confidential 
Page 3 
2 SYNOPSIS 
TITLE OF STUDY: 
An Open-label Extension Study to Assess the Long-term Safety and Efficacy of UX007 in Subjects with 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) 
PROTOCOL NUMBER: 
UX007G-CL202 
STUDY SITES: 
Up to 16 sites globally 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
Glut1 DS is a rare, severely debilitating disease characterized by seizures, developmental delay, and 
movement disorder.  Glut1 DS is caused by a mutation in the SLC2A1 gene encoding the Glut1 protein 
responsible for transporting glucose across the blood-brain barrier.  Because glucose is the primary 
source of energy for the brain, this disorder results in a chronic state of energy deficiency in the brain.  
Current therapy consists of ketogenic diet (KD) and antiepileptic drugs (AEDs) for the treatment of 
seizures.  Because of the difficulties in maintaining the KD, some patients are not able to fully comply 
with or tolerate the diet; these patients need an alternative therapy for Glut1 DS.  
UX007 (triheptanoin) is a triglyceride of medium, odd-carbon chain (C7) fatty acids.  The rationale for 
UX007 in Glut1 DS is that: (1) triheptanoin is metabolized to heptanoate and C4 and C5 ketone bodies, 
providing an alternative energy source to the brain, (2) triheptanoin provides anaplerotic substrates to 
resupply intermediates of the tricarboxylic acid (TCA) cycle, and (3) triheptanoin can support 
gluconeogenesis in the brain.  
A Phase 2 study (UX007G-CL201) is ongoing to assess the safety and efficacy of UX007 in 
reducing the frequency of seizures in Glut1 DS patients. Investigator-sponsored trials (ISTs) and 
other treatment programs are also evaluating UX007/triheptanoin as a treatment for Glut1 DS. 
This open-label long-term safety and efficacy study will provide an opportunity for Glut1 DS patients to 
be treated with UX007 for up to 3 years, or until one of the following occurs:  the subject withdraws 
consent, the subject is discontinued from the study at the discretion of the Investigator or Ultragenyx, the 
study is terminated, or until commercial availability of study drug in a subject’s region, whichever 
occurs first.  The study is designed to obtain long-term safety information and evaluate maintenance of 
efficacy in a pediatric and adult Glut1 DS population.   
STUDY DESIGN AND METHODOLOGY: 
UX007G-CL202 is an open-label, single-arm, multicenter extension study to assess the long-term safety 
and efficacy of UX007 in Glut1 DS.  The study will enroll approximately 40 pediatric, adolescent, 
and adult Glut1 DS subjects who have completed the UX007G-CL201 study and, at the discretion of the 
Sponsor, additional subjects who participated in other clinical studies, ISTs, or expanded 


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Protocol Number:  UX007G-CL202  
Amendment 3: 20 September 2017 
 
 
Proprietary and Confidential 
Page 5 
The secondary objectives of the study are to: 
 
Evaluate the long-term effect of UX007 efficacy on seizures associated with Glut1 DS 
 
Evaluate the long-term effect of UX007 on health-related quality of life related to Glut1 DS 
ENDPOINTS: 
The primary endpoint of the study is: 
 
Frequency of adverse events (AE) and serious adverse events (SAE) assessed as related to study 
drug over the Treatment Extension Period 
 
General secondary endpoints of the study are: 
 
Frequency of seizures over the Treatment Extension Period 
 
Measures of neurological function over the Treatment Extension Period 
 
Health-related quality of life over the Treatment Extension Period 
NUMBER OF SUBJECTS PLANNED: 
The study will enroll approximately 40 pediatric, adolescent, and adult subjects who have completed the 
UX007G-CL201 study and, at the discretion of the Sponsor, additional subjects who participated in 
other clinical studies, ISTs, or expanded access/compassionate use treatment programs.  
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Diagnosis of Glut1 DS as indicated by cerebrospinal fluid glucose concentration, erythrocyte 3-
O-methyl-D-glucose uptake assay, or molecular genetic testing obtained from medical records. 
2) Males and females, aged at least 1 year  at the time of informed consent 
3) Completion of UX007G-CL201 study (NCT01993186).  Glut1 DS patients who received 
UX007/triheptanoin treatment as part of other clinical studies, ISTs, or expanded 
access/compassionate use treatment programs may be eligible at the discretion of the sponsor. 
4) Provide written informed consent or verbal assent (if possible) with written informed consent by 
a legally authorized representative after the nature of the study has been explained, and prior to 
any research-related procedures 
5) Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, 
and comply with accurate completion of the seizure diary 
6) Females of childbearing potential must have a negative urine 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 not experienced menarche, are post-menopausal 
(defined as having no menses for at least 12 months without an alternative medical cause), or are 


Protocol Number:  UX007G-CL202  
Amendment 3: 20 September 2017 
 
 
Proprietary and Confidential 
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permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. 
7) Participants of child-bearing potential or fertile males with partners of child-bearing potential 
who are sexually active must consent to use a highly-effective method of contraception as 
determined by the investigator from the period following the signing of the informed consent 
through 30 days after last dose of study drug. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1) Any known hypersensitivity to triheptanoin that, in the judgment of the investigator, places the 
subject at increased risk for adverse effects 
2) History of, or current suicidal ideation, behavior and/or attempts  
3) Pregnant and/or breastfeeding an infant 
4) Unwilling or unable to discontinue use of a prohibited medication (i.e. barbiturates, pancreatic 
lipase inhibitors) or other substance that may confound study objectives.  Use of up to 
3 concomitant AEDs is allowed, provided dose has been stable at least 14 days prior to Baseline.  
5) Use of any investigational product, drug or supplement (other than UX007) within 30 days prior 
to Baseline, or at any time during the study 
6) Has a condition of such severity and acuity, in the opinion of the investigator, that it warrants 
immediate surgical intervention or other treatment 
7) Has a concurrent disease or condition, or laboratory abnormality that, in the view of the 
investigator, places the subject at high risk of poor treatment compliance or of not completing 
the study, or would interfere with study participation or introduce additional safety concerns 
(e.g. other concurrent neurological or psychiatric disorders)  
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: 
UX007 (triheptanoin) is a liquid, intended for oral (PO) administration.  UX007 is a colorless to yellow 
oil supplied in 1 L round, translucent high-density polyethylene (HDPE) or 1 L round amber-colored 
glass bottles.  
UX007 dosing will be targeted and/or maintained at 35% of total daily caloric intake.  If a subject has 
been receiving a different dose of UX007, the subject may be maintained on the UX007 dose that 
provided the maximum improvement in clinical status with acceptable tolerability, and continued on this 
dose for the duration of the study.  A subject may have been off UX007 treatment prior to enrollment; in 
these cases, the UX007 dose may be titrated at the discretion of the investigator. 
UX007 should be mixed with food (or formula, as appropriate) and administered PO or by gastronomy 
tube at least four times per day (breakfast, lunch, dinner, and before bed).  The dose may be divided into 
smaller more frequent doses with food as needed.   


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REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: 
The study is a single-arm, open-label study.  All subjects will be on active treatment; no reference 
therapy or placebo will be administered. 
DURATION OF TREATMENT: 
The planned duration of treatment in this study is 3 years, or until one of the following occurs:  the 
patient withdraws consent, the patient is discontinued from the study at the discretion of the Investigator 
or Ultragenyx, the study is terminated, or until commercial availability of study drug in a subject’s 
region, whichever occurs first. A Safety Follow-up Phone Call will be conducted 30-35 days after last 
dose of study drug. The last subject’s Safety Follow-up Phone Call is the End-of-study Time Point.  
CRITERIA FOR EVALUATION: 
Safety Assessments 
Adverse Events and Serious Adverse Events:  Incidence, frequency, severity, and relatedness of AEs and 
SAEs, including clinically significant changes in the following safety variables: 
 
Vital signs and weight 
 
Physical examination 
 
Clinical laboratory evaluations 
 
Pregnancy testing 
 
Suicidal ideation and behavior assessments 
 
Concomitant medications 
Efficacy Assessments* 
Seizures 
 
Seizure Diary:  Observable seizures recorded via patient-reported diary. Observable seizures 
include: Generalized Tonic-Clonic, Generalized Tonic, Generalized Clonic, Generalized Atonic, 
Partial/Focal with Secondary Generalization, Myoclonic, Myoclonic Atonic, Myoclonic Tonic, 
Complex Partial/Focal, and Simple Partial/Focal Motor.  Observable absence seizures will also be 
recorded, although the primary method of assessing them will be by EEG 
 
Electroencephalogram:  Seizures detected by EEG, including absence. 
Neurological Function and Development 
 
Columbia Neurological Score:  Neurological findings in 12 domains quantitated to produce a total 
score ranging from 0-76 
Health-related Quality of Life 
 
Short-Form Health Surveys (SF-10 for Children OR SF-12v2):  Quality of life as measured by 
subject or caregiverreported- physical and mental health status 


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* The Investigator may use clinical judgment in deciding whether to administer certain assessments to 
subjects based on age, development, and cognitive ability, as appropriate. The SF-10/SF-12v2 will not 
be performed if no pre-treatment baseline is available from feeder study (e.g. subjects entering from 
other clinical studies, ISTs, or expanded access/compassionate use treatment programs or subjects from 
UX007G-CL201 who were too young or compromised at pre-treatment Baseline). 
UX007 Metabolites: 
 
Plasma levels of UX007 metabolites 
STATISTICAL METHODS: 
General Principles: 
The statistical analyses will be reported using summary tables, figures, and data listings.  All analyses 
and tabulations will be performed using SAS®.  Continuous variables will be summarized with means, 
standard deviations, medians, minimums, and maximums.  Categorical variables will be summarized by 
counts and by percentages of subjects in corresponding categories.  For time-to-event data, the Kaplan-
Meier estimates will be computed and plotted.  Graphical data displays may also be used to summarize 
the data.  All raw data obtained from the CRFs as well as any derived data will be included in data 
listings. For certain data collected over time, the Generalized Estimating Equation (GEE) may be used as 
the marginal model approach.  
Tests of treatment effects will be conducted at a one-sided alpha level of 0.05 and/or one-sided 95% 
confidence interval where possible. Each secondary endpoint will be tested independently at one-sided 
alpha=0.05. No adjustments for multiple comparisons will be performed. The statistical method 
employed for the analysis of each assessment and detailed procedures for handling missing, unused, or 
spurious data, will be defined in the statistical analysis plan.  Analyses may be performed at any time 
during the study at the discretion of the Sponsor. Unblinding is not required during analysis since the 
study is open-label. 
Safety Analysis: 
The primary safety analysis will evaluate the incidence and frequency of AEs and SAEs, including 
clinically significant changes in safety parameters. The incidence and frequency of AEs will be 
summarized by System Organ Class and Preferred Term, relationship to study drug, and severity. 
No statistical significance will be assessed.  
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.  
Changes in findings from physical examinations will be tabulated and listed for each subject by 
examination category. If there are examination findings that change in more than one subject, these will 
be tabulated in a separate table and expressed as the number of subjects with the change out of the total. 


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Descriptive statistics of temperature, pulse, respiratory rate, and blood pressure (systolic and diastolic) 
values and changes from baseline will be summarized.  The percentage of subjects with values beyond 
clinically important limits will be summarized. 
Efficacy Analysis: 
The efficacy analyses are primarily focused on seizures and alternative domains of Glut1 DS disease to 
assess the breadth of treatment effect of UX007.  The analyses of secondary endpoints will evaluate 
maintenance of effect for each efficacy variable throughout the Treatment Extension Period.  


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Table 2.1:  Schedule of Events* 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
SAFETY 
FOLLOW 
UP 14 
VISIT TYPE Clinic Clinic Clinic Clinic Clinic 
PC 
Clinic 
PC 
Clinic 
PC 
Clinic 
PC 
Clinic 
PC 
MONTH 1 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36/ET 
 
Informed Consent 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seizure incidence 
(diary review) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Overnight EEG 4 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
Columbia 
Neurological Score 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
SF-10 or SF-12v2 
(age-appropriate 
instrument) 5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
UX007 
Metabolites6 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs & 
Weight 7 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical 
Examination 8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Clinical Laboratory 
Tests 9  
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy 
Test (if applicable) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Suicidal Ideation & 
Behavior 
Assessment 10 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 


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VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
SAFETY 
FOLLOW 
UP 14 
VISIT TYPE Clinic Clinic Clinic Clinic Clinic 
PC 
Clinic 
PC 
Clinic 
PC 
Clinic 
PC 
Clinic 
PC 
MONTH 1 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36/ET 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietitian 
Consultation & 
Diet Diary 11 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Dispense Study 
Drug 12 
X 
X 
X 
X 
X 
X12 
X 
X12 
X 
X12 
X 
X12 
 
 
Treatment 
Compliance & 
Accountability 13 
 
X 
X 
X 
X 
X13 
X 
X13 
X 
X13 
X 
X13 
X 
 
 
*Refer to the Study Reference Manual for a recommended schedule of the assessments during the 1-day and 2-day visits. The Investigator may use clinical 
judgment in deciding whether to administer certain assessments to subjects based on age, development, and cognitive ability, as appropriate. The SF-10/SF-12v2 
will not be performed if no pre-treatment baseline is available from feeder study (e.g. subjects entering from other clinical studies, ISTs, or expanded 
access/compassionate use treatment programs or subjects from UX007G-CL201 who were too young or compromised at pre-treatment Baseline).  
1 The Baseline Visit may occur in conjunction with the last scheduled visit from study UX007G-CL201 to avoid duplication of assessments. If the time elapsed 
between the last UX007G-CL201 study visit and the Baseline Visit for this study is > 1 month, the full panel of Baseline Visit assessments must be completed. 
Subjects will return to the clinic at 3-month intervals from Baseline during Treatment Extension Year 1 (± 1 week), and 6-month intervals from Baseline during 
Years 2 and 3 (± 2 weeks). Phone calls will take place 3-months between scheduled study site visits during Years 2 and 3 (Visits 6, 8, 10, and 12) to collect 
adverse events and concomitant medications updates and to inquire about study drug consumption and remaining supply; in lieu of the phone call, subjects may 
visit the clinic  at the study site’s discretion.  Additionally, optional study site visits may occur 3-months between scheduled study site visits during Years 2 and 3 
to allow subjects to attain study drug as needed at the request of the Investigator. 
2 Minors who reach legal age during the course of the study must provide written informed consent when eligible.  
3 Medical history includes subject demographics, triheptanoin treatment history, and Glut1 DS diagnosis, and will be collected only for subjects not previously 
enrolled in UX007G-CL201. 
4 A 2-day visit is required to complete the overnight EEG. 
5 If a subject is under 5 years of age at informed consent, the SF-10 will not be administered during the Extension study.  If a subject turns 18 years of age during 
the study, the SF-12v2 will be administered beginning at the next study visit. 


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6 Blood samples for UX007 metabolites will be drawn approximately 90 min (+/- 10 min) following consumption of food and study drug. 
7 Vital sign measurements consist of seated systolic/diastolic blood pressure (millimeters of mercury), heart rate (beats per minute), respiration rate (breaths per 
minute), and temperature in degrees Celsius (°C).  Vitals to be obtained at the beginning of each visit before any additional assessments are completed.  
8 Physical examinations include assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, respiratory, 
gastrointestinal, musculoskeletal, and neurologic systems. 
9 Clinical laboratory tests include standard serum chemistry, hematology, and urinalysis.  Fasting is not required. 
10 The Columbia Suicide Severity Rating Scale (C-SSRS) baseline questionnaire will be administered on the initial visit; the Since Last Visit questionnaire will 
be administered at all subsequent visits. 
11 At the Baseline visit, an interview with the study dietitian will establish daily caloric intake and UX007 dose.   Subjects and/or caregivers are required to 
maintain a record of the subject’s daily diet in a diary for the 3 days prior to each subsequent visit.  The diet diary will be reviewed by study personnel at each 
visit to the clinic.  The dietitian may telephone subjects and/or caregivers, as needed, to provide dietary advice and support. 
12 A subject may have been off UX007 treatment prior to enrollment; in these cases, UX007 may be titrated per discretion of the investigator.  Study drug may be 
dispensed at Visits 6, 8, 10, and 12 to subjects who make optional study site  visits to attain study drug as needed at the request of the Investigator.  
13 Refer to Pharmacy Manual for instructions on return of empty and opened study drug bottles.  Phone calls at Visits 6, 8, 10, and 12 will inquire about study 
drug consumption and remaining supply; in lieu of a phone call, subjects may also visit the study site at the study site’s discretion. 
14 Safety Follow-up Phone Call to be conducted 30-35 days after last dose of study drug. The last subject’s Safety Follow-up Phone Call is the End-of-study Time 
Point. The site personnel will initiate this safety follow-up telephone call to collect information on any ongoing or new AEs, serious adverse events (SAEs), and 
concomitant medications. Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, are resolved. 
 


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................13 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................17 
5 INTRODUCTION .............................................................................................................20 
5.1 Overview of Glucose Transporter Type 1 Deficiency Syndrome .............................20 
5.2 Brief Overview of UX007 Development ..................................................................21 
5.2.1 
Brief Description of the Investigational Product .........................................21 
5.2.1.1 
Mechanism of Action in Glut1 DS ..............................................22 
5.2.2 
Nonclinical Studies ......................................................................................22 
5.2.3 
Previous Clinical Studies .............................................................................23 
5.3 Summary of Overall Risks and Potential Benefits ....................................................24 
5.4 Study Rationale .........................................................................................................25 
6 STUDY OBJECTIVES ......................................................................................................26 
6.1 Study Endpoints ........................................................................................................26 
6.1.1 
Primary Endpoint ........................................................................................26 
6.1.2 
Secondary Endpoints ...................................................................................26 
7 INVESTIGATIONAL PLAN ............................................................................................27 
7.1 Overall Study Design and Plan .................................................................................27 
7.2 Discussion of Study Design, Including Choice of Control Group ............................28 
7.3 Selection of Study Population ...................................................................................28 
7.3.1 
Inclusion Criteria .........................................................................................29 
7.3.2 
Exclusion Criteria ........................................................................................30 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................31 
7.3.3.1 
Stopping Rules .............................................................................31 
7.4 Treatments .................................................................................................................32 
7.4.1 
Investigational Product ................................................................................32 


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7.4.2 
Reference Therapy ......................................................................................32 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................32 
7.4.4 
Selection of Doses and Study Duration .......................................................33 
7.4.4.1 
Study Duration .............................................................................33 
7.4.5 
Blinding .......................................................................................................33 
7.4.6 
Prior and Concomitant Therapy ..................................................................33 
7.4.6.1 
Prohibited Medications ................................................................33 
7.4.6.2 
Permitted Medications .................................................................34 
7.4.7 
Treatment Compliance ................................................................................34 
7.5 Study Procedures and Assessments ..........................................................................34 
7.5.1 
Visit Schedule ..............................................................................................34 
7.5.2 
Efficacy Measures .......................................................................................35 
7.5.2.1 
Seizure Monitoring ......................................................................35 
7.5.2.2 
Neurological Function .................................................................36 
7.5.2.3 
Health-related Quality of Life ......................................................37 
7.5.3 
Drug Concentration Measurements and Bioassays .....................................38 
7.5.4 
Safety Measures & General Assessments ...................................................38 
7.5.4.1 
Medical History and Triheptanoin Treatment History .................38 
7.5.4.2 
Vital Signs and Weight ................................................................38 
7.5.4.3 
Physical Examination...................................................................39 
7.5.4.4 
Clinical Laboratory Tests .............................................................39 
7.5.4.5 
Pregnancy Testing ........................................................................40 
7.5.4.6 
Suicidal Ideation and Behavior Assessments ..............................40 
7.5.4.7 
Concomitant Medications ............................................................41 
7.5.4.8 
Adverse Events ............................................................................41 
7.5.4.9 
Dietitian Consultation and Diet Assessment ................................41 
7.5.5 
Appropriateness of Measures ......................................................................41 
7.6 Statistical Methods and Determination of Sample Size ............................................42 


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7.6.1 
Subject Information .....................................................................................43 
7.6.2 
Analysis Population .....................................................................................43 
7.6.3 
Safety Analyses ...........................................................................................43 
7.6.4 
Efficacy Analysis ........................................................................................44 
7.6.5 
Pharmacokinetic and Bioassay Analyses ....................................................44 
7.6.6 
Subgroup Analysis ......................................................................................45 
7.6.7 
Interim Analysis ..........................................................................................45 
7.6.8 
Data Monitoring Committee .......................................................................45 
7.6.9 
Determination of Sample Size .....................................................................45 
8 STUDY CONDUCT ..........................................................................................................46 
8.1 Ethics .........................................................................................................................46 
8.1.1 
Institutional Review Board or Ethics Committee ........................................46 
8.1.2 
Ethical Conduct of Study ............................................................................46 
8.1.3 
Subject Information and Consent ................................................................46 
8.2 Investigators and Study Administrative Structure ....................................................47 
8.3 Investigational Product Accountability .....................................................................47 
8.4 Data Handling and Record Keeping .........................................................................48 
8.4.1 
Case Report Forms and Source Documents ................................................48 
8.4.2 
Data Quality Assurance ...............................................................................48 
8.4.3 
Record Retention .........................................................................................49 
8.5 Reporting and Follow-up of Adverse Events ............................................................49 
8.5.1 
Definition of Adverse Events ......................................................................49 
8.5.2 
Severity of Adverse Events .........................................................................50 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................51 
8.5.4 
Adverse Event Reporting ............................................................................51 
8.5.4.1 
General .........................................................................................51 
8.5.5 
Serious Adverse Events, Serious Adverse Drug Reactions, and 
Requirements for Immediate Reporting ......................................................52 


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8.5.5.1 
Pregnancy in Subject or Partner, and Requirements for 
Immediate Reporting ...................................................................52 
8.5.6 
Communication Plan ...................................................................................53 
8.5.6.1 
Serious Adverse Drug Reaction Reporting ..................................53 
8.5.6.2 
Urgent Safety Matters and Non-SUSAR Reporting ....................53 
8.5.6.3 
Pregnancy Reporting ....................................................................53 
8.5.7 
Safety Contact Information .........................................................................54 
8.6 Financing and Insurance ...........................................................................................54 
8.7 Publication Policy .....................................................................................................54 
9 REFERENCES ..................................................................................................................55 
10 SIGNATURE PAGE .........................................................................................................58 
 
LIST OF TABLES 
Table 2.1:  Schedule of Events* ...............................................................................................10 
Table 7.5.4.4.1:  Clinical Laboratory Assessments ..................................................................39 
 
LIST OF FIGURES 
Figure 2.1:  UX007G-CL202 Study Schema .............................................................................4 
Figure 5.2.1.1.1:  Proposed mechanism of UX007 action in Glut1 DS ...................................22 
Figure 7.1.1:  UX007G-CL202 Study Schema ........................................................................27 
 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
APBD 
adult polyglucosan body disease 
AST 
aspartate aminotransferase 
BHB 
beta-hydroxybutyrate 
BHP 
beta-hydroxypentanoic acid 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CNS 
Columbia Neurological Score 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
EC 
Ethics Committee 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAOD 
fatty acid oxidation disorders 
FDA 
Food and Drug Administration (United States) 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
Glut1 
glucose transporter type 1 
Glut1 DS 
glucose transporter type 1 deficiency syndrome 
GMP 
Good Manufacturing Practice 
GSD II 
glycogen storage disease type II 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
IRB 
IST 
Institutional Review Board 
Investigator-sponsored Trial 


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ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
KD 
ketogenic diet 
LC-FAOD 
long-chain fatty acid oxidation disorders 
L 
Litre 
MCS 
Mental health component score 
MCT 
medium chain triglyceride 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
no observed adverse effect level 
PC 
phone call 
PCS 
Physical health component score 
PHS-10 
physical summary score 
PK 
pharmacokinetic 
PO 
oral, by mouth, per os 
PSS-10 
psychosocial summary score 
PT 
Preferred Term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF-10 
Short Form 10 Health Survey for Children 
SF-12v2 
Medical Outcomes Study 12-item Short-Form Health Survey for Adults 
(version 2) 
SOC 
System Organ Class 
TCA 
tricarboxylic acid 
TK 
toxicokinetic 
US 
United States 
UX007 
Investigational Product/study drug, triheptanoin 
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 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) is a rare, severely 
debilitating disease characterized by seizures, developmental delay, and movement disorders 
(Pearson et al. 2013).  Current treatment consists of a ketogenic diet (KD) to provide an 
alternative energy source to glucose (Pong et al. 2012), (Pearson et al. 2013) and antiepileptic 
drugs (AEDs).  Because of the difficulties in maintaining a KD, some patients are not able to 
comply with or tolerate the diet.  Furthermore, the seizures due to Glut1 DS are often 
refractory to AEDs and are most prominent in the pediatric population.  These patients 
represent the subgroup of Glut1 DS patients who are most in need of an alternative therapy. 
UX007 (triheptanoin) is a triglyceride of medium, odd-carbon chain (C7) fatty acid.  
The rationale for UX007 in Glut1 DS is that triheptanoin metabolites may provide an 
alternative energy source and support gluconeogenesis for the brain, and/or provide 
anaplerotic substrates to resupply tricarboxylic acid (TCA) cycle intermediates (Deng et al. 
2009), (Kinman et al. 2006), (Marin-Valencia et al. 2013). 
A Phase 2 study (UX007G-CL201) is ongoing to assess the safety and efficacy of UX007 in 
reducing the frequency of seizures in Glut1 DS patients. Investigator-sponsored trials (ISTs) 
or treatment programs are also evaluating UX007/triheptanoin as a treatment for Glut1 DS. 
This open-label long-term safety and efficacy study will provide an opportunity for Glut1 DS 
patients to be treated with UX007 for up to 3 years, or until one of the following occurs:  the 
subject withdraws consent, the subject is discontinued from the study at the discretion of the 
Investigator or Ultragenyx, the study is terminated, or until commercial availability of study 
drug in a subject’s region, whichever occurs first. The study is designed to obtain long-term 
safety information and evaluate maintenance of efficacy in a pediatric and adult Glut1 DS 
population.  
5.1 
Overview of Glucose Transporter Type 1 Deficiency Syndrome 
Glut1 DS is a rare disease with an estimated birth incidence of 1:90,000 (Coman et al. 2006).  
This birth incidence translates to an estimated prevalence of ~ 8,500 in the US and Europe.  
Glut1 DS is caused by a mutation in the solute carrier family 2, member 1(SLC2A1) gene, 
which encodes Glut1.  This protein transports glucose from blood into the brain.  Because 
glucose is the primary source of energy for the brain, this disorder results in a chronic state of 
energy deficiency in the brain. Most commonly Glut1 DS is inherited in an autosomal 
dominant manner; approximately ~90 % of individuals with autosomal dominant Glut1 DS 
have a de novo heterozygous mutation in SLC2A1, and about 10% have a clinically-affected 
parent (Wang et al. 1993-2015). Autosomal recessive transmission has also been described in 
rare cases. 
Glut1 DS is a severely debilitating disease characterized by seizures, developmental delay, 
and movement disorder (Pearson et al. 2013).  Neurological symptoms in Glut1 DS fall into 
3 domains: (1) epilepsy, (2) cognitive/behavioral disturbances, and (3) movement disorders.  
The classic phenotype is a developmental encephalopathy encompassing all 3 domains.  


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Seizures are present in approximately 90% of Glut1 DS patients and usually present in early 
infancy.   
The laboratory hallmark of Glut1 DS is a low cerebrospinal fluid glucose concentration 
(<60 mg/dL or 3.3 mmol/L in all cases reported to date; <40 mg/dL or 2.2 mmol/L in the 
majority of cases). Decreased 3-O-methyl-D-glucose uptake in erythrocytes is observed and 
is abnormally low in almost all suspected cases of Glut1 DS (Wang et al. 1993-2015).  
Molecular genetic testing may also be used to detect pathogenic SLC2A1 variants, however 
some reports estimate approximately 20% to 30% do not carry mutations in SLC2A1 
(Klepper et al. 2007), (Klepper 2008), (Verrotti et al. 2012). 
There are currently no approved treatments specific to Glut1 DS.  Seizures are typically 
refractory to conventional AED treatment (Pong et al. 2012).   Reports suggest a KD is 
effective for the seizures of Glut1 DS by generating ketone bodies that provide an alternative 
energy source to glucose (Pong et al. 2012), (Pearson et al. 2013).  However, KD is difficult 
to tolerate and some patients are not compliant with or are otherwise not on the diet.  
There exists a significant unmet medical need in the subset of patients who are not on KD, 
and the proposed clinical development plan targets this specific subset of patients. 
5.2 
Brief Overview of UX007 Development 
A brief overview of existing information on UX007 (triheptanoin) is provided below; 
a comprehensive review of the data is contained in the Investigator’s Brochure (IB) provided 
by Ultragenyx Pharmaceutical Inc. (Ultragenyx), which should be reviewed prior to initiating 
the study. 
5.2.1 
Brief Description of the Investigational Product 
Triheptanoin is a triglyceride composed of three heptanoate (C7 fatty acid) esters. UX007 is 
manufactured by chemical synthesis from glycerol and heptanoic acid. The molecular 
formula and structure are as follows: 
Molecular Formula:  C24H44O6  
Structure: 
 
UX007 (triheptanoin) is a liquid, intended for oral (PO) administration.  One thousand grams 
(1025 ± 25 g) of neat triheptanoin drug substance is filled into 1 Litre (L), high density 


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polyethylene (HDPE) or round, amber-colored glass bottles.   UX007 is manufactured, 
packaged, and labeled according to Good Manufacturing Practice (GMP) regulations. 
5.2.1.1 
Mechanism of Action in Glut1 DS 
UX007 (triheptanoin) is metabolized to heptanoate, which in turn is further metabolized to 
4- and 5-carbon ketone bodies.  These metabolites bypass the Glut1 transporter to cross the 
blood-brain-barrier via the monocarboxylate transporter or potentially by mass action 
diffusion for heptanoate, and provide an alternative energy source to the brain 
(Figure 5.2.1.1.1). Once in the brain, the metabolites may be further metabolized by both glia 
and neurons to generate effective compounds to deliver energy.  These metabolites also have 
the ability to provide propionyl-CoA in order to resupply intermediates of the TCA cycle 
(i.e. anaplerosis) within the brain as well as support gluconeogenesis and glycogen 
production. 
Figure 5.2.1.1.1:  Proposed mechanism of UX007 action in Glut1 DS 
 
5.2.2 
 Nonclinical Studies 
Nonclinical studies evaluating triheptanoin and its metabolites in mice and rats have been 
published and further support the safety of UX007.  These studies provide data on the 
absorption, and metabolism of triheptanoin when administered intravenously and PO at 
doses up to 40% the recommended caloric intake.  Furthermore, triheptanoin has 
been found to be effective in 4 animal models of epilepsy, similar to that of other AEDs 
(Borges et al. 2012), (Willis et al. 2010), (Thomas et al. 2012), (Kim et al. 2013).  Studies of 
potential clinical significance and relevance to this protocol are summarized below; 
additional details are provided in the IB.  


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Triheptanoin is metabolized rapidly in the gut to form glycerol and heptanoate that is further 
metabolized in the liver to C4- and C5-ketone bodies (Kinman et al. 2006), (Deng et al. 
2009).  In the mouse model of Glut1 DS, triheptanoin administration led to the delivery of 
heptanoate to the brain which was metabolized into glucose and neurotransmitter 
intermediates, consistent with an important role of the odd-chain length C7 structure in 
restoring central nervous system metabolism (Marin-Valencia et al. 2013).  
The acute oral toxicity of triheptanoin was performed in rats at four dose levels ranging from 
0.5 ml/kg (n= 2) to 5 ml/kg (n=5M/5F). There were no deaths or signs of toxicity at any time 
throughout the duration of the study and up to 7 days post dose.  
A 9 month oral toxicity study in rats was performed with an experimental oil containing 
64% triheptanoin to determine the effects of a diet containing triheptanoin on animal 
growth, lipid digestibility, clinical chemistry, and toxicity in liver, kidney, and small intestine 
(Ataide et al. 2009). After 9 months of consumption of a standard diet containing doses up to 
1.14 g triheptanoin per kg of body weight per day, no toxic effects attributed to triheptanoin 
were found in rats.  There was also no significant difference in the clinical chemistries that 
would indicate hepatic damage or adverse effect on renal function compared to control 
animals fed a standard diet supplemented with soybean oil as the lipid source. 
A GLP 9 month chronic toxicity study in juvenile mini-pigs was performed with UX007. 
The study demonstrated that there is no evidence of accumulation of triheptanoin or 
metabolites in plasma after daily PO dosing as high as 50% of the animal’s daily caloric 
intake. UX007 was well-tolerated at up to 50% of the daily caloric intake and did not result 
in any evidence of systemic toxicity; therefore, the dose of 50% caloric replacement was 
considered the NOAEL for UX007 following 9-months of treatment. 
The standard battery of genotoxicity tests did not result in any evidence of genotoxic, 
clastogenic or mutagenic effects.  
5.2.3 
Previous Clinical Studies 
Approximately 200 subjects with various diseases have been treated with triheptanoin for 
periods of up to 15 years.  Of these subjects, approximately 50 were pediatric patients as 
young as neonates; a significant portion of pediatric patients had treatment duration of over 
5 years.  The clinical experience supports the safety of triheptanoin when administered at 
approximately 35% of daily caloric intake in pediatric patients as young as neonates. 
Triheptanoin has been studied for over a decade in a large cohort of patients with 
fatty-acid oxidation disorders (FAOD) as part of a compassionate use program (Roe et al. 
2002), (Roe et al. 2006), (Roe et al. 2008), (Barone et al. 2012).  Ultragenyx is currently 
developing UX007 as a substrate replacement therapy for long-chain FAOD (LC-FAOD). 
Patients with other disorders have also been treated with triheptanoin, including those with 
pyruvate carboxylase deficiency (Mochel et al. 2005), Huntington’s disease (Mochel et al. 
2010), adult polyglucosan body disease (APBD) (Roe et al. 2010), glycogen storage disease 


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type II (GSD-II; Pompe disease) (Roe et al. 2006) and congestive heart failure (IND 65827).  
Triheptanoin treatment has been generally safe and well tolerated in subjects with these 
disorders. 
Triheptanoin was studied in 14 Glut1 DS subjects (including 11 pediatric subjects) in a 
clinical trial sponsored by Dr. Juan Pascual at the University of Texas, Southwestern.  
The results of this open-label study suggest clinical activity with triheptanoin in reducing the 
frequency of absence seizures (Pascual et al. 2014).  No patient experienced serious or 
unexpected adverse events (AE).  One patient (7%) discontinued triheptanoin therapy after 
3 weeks owing to gastric discomfort.  One other patient (7%) experienced significant (10%) 
weight gain at 2 months that did not lead to discontinuation.  This patient did not follow 
recommended dietary and nutritional advice to decrease extra sources of fat and simple 
sugars.  Two patients (14%) experienced diarrhea and/or digestive discomfort within days of 
treatment initiation; symptoms resolved by reducing the triheptanoin dose by one-half and 
gradually increasing the amount to the target levels over several days. 
The Phase 2 randomized, double-blind, placebo-controlled study to assess the safety and 
efficacy of UX007 in pediatric, adolescent, and adult Glut1 DS patients (UX007G-CL201) is 
the primary feeder trial for subjects participating in this study, although subjects may also 
enroll from investigator-sponsored studies.  Ultragenyx also plans to conduct additional 
studies in patients with movement disorders associated with Glut1DS. The IB provides 
current information on the status of UX007 clinical development along with additional 
information on UX007 effects in humans and associated Reference Safety Information. 
5.3 
Summary of Overall Risks and Potential Benefits 
UX007 is intended as a substrate replacement therapy to restore the full process of energy 
metabolism in patients with Glut1 DS.  UX007 is being developed to address the needs of 
Glut1 DS patients who continue to have disease crises despite the best available treatment. 
For Glut1 DS patients, the current standard of care, KD and AEDs, is not sufficient to 
prevent all seizure events.  The KD is difficult to tolerate and some patients are not compliant 
with or are otherwise not on the diet; seizure are often refractory to AEDs.  There exists a 
significant unmet medical need in these patients. 
Triheptanoin has been used clinically for periods of up to 15 years in approximately 200 
subjects in human studies of a variety of different diseases, including Glut1 DS (Roe et al. 
2002), (Roe et al. 2006), (Mochel et al. 2010). Of these subjects, 11 were Glut1 DS pediatric 
subjects and approximately 50 were pediatric subjects with other diseases.  A significant 
portion of pediatric subjects received over 5 years of treatment duration with triheptanoin.  
These data support the safety of triheptanoin when administered at approximately 35% of 
daily caloric intake in pediatric patients as young as neonates. 
Nonclinical studies evaluating triheptanoin and its metabolites in mice and rats have been 
published and further support the safety of triheptanoin in the Glut1 DS population. 
Data from the animal pharmacokinetic (PK), TK, and toxicity studies indicate that 
triheptanoin is well absorbed after oral dosing and is well-tolerated without overt toxicities at 


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doses as high as 1.14 g/kg in mice and 50% daily caloric intake in juvenile minipigs for 
9 months, with no signs of hepatic or renal injury. 
Data from nonclinical and clinical studies to date suggest triheptanoin does not pose any 
serious safety risks that can be identified at this time.  Triheptanoin has been well tolerated in 
humans with no significant safety issues and toxicology or adverse pharmacology findings 
were not observed in triheptanoin-treated animals.  Studies in animals and humans suggest 
triheptanoin consumed orally has side effects that are similar to those of orally consumed 
medium chain triglycerides (MCT oil).  The most commonly reported adverse effects are 
gastrointestinal distress and excessive weight gain at high doses.  Both of these issues appear 
to resolve when triheptanoin is consumed in small doses mixed with foods throughout the 
day and when total caloric intake is appropriately managed.  Overall the risk-benefit ratio of 
UX007 is sufficient to support clinical development for the treatment of seizures associated 
with Glut1 DS. 
5.4 
Study Rationale 
Glut1 DS is a rare, severely debilitating disease characterized by seizures, developmental 
delay, and movement disorder.  Glut1 DS is caused by a mutation in SLC2A1 encoding the 
Glut1 protein responsible for transporting glucose across the blood brain barrier.  
Because glucose is the primary source of energy for the brain, this disorder results in a 
chronic state of energy deficiency in the brain.  Current therapy consists of KD, and AEDs 
for the treatment of seizures.  Because of the difficulties in maintaining the KD, some 
patients are not able to fully comply with or tolerate the diet; these patients need an 
alternative therapy for Glut1 DS.  
UX007 (triheptanoin) is a triglyceride of medium, odd-carbon chain (C7) fatty acids.  
The rationale for UX007 in Glut1 DS is that:  
1) triheptanoin is metabolized to heptanoate and C4 and C5 ketone bodies, providing an 
alternative energy source to the brain,  
2) triheptanoin provides anaplerotic substrates to resupply intermediates of the TCA 
cycle, and  
3) triheptanoin can support gluconeogenesis in the brain.  
A Phase 2 study (UX007G-CL201) is ongoing to assess the safety and efficacy of UX007 in 
reducing the frequency of seizures in Glut1 DS patients. ISTs and other treatment programs 
are also evaluating UX007/triheptanoin as a treatment for Glut1 DS. This open-label 
long-term safety and efficacy study will provide an opportunity for Glut1 DS patients to be 
treated with UX007 for up to 3 years, or until one of the following occurs:  the subject 
withdraws consent, the subject is discontinued from the study at the discretion of the 
Investigator or Ultragenyx, the study is terminated, or until commercial availability of study 
drug in a subject’s region, whichever occurs first, under a single standardized protocol for 
maintenance therapy and consistent safety monitoring.  The study is designed to obtain long-
term safety information and evaluate maintenance of efficacy in a pediatric and adult Glut1 
DS population. 


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6 STUDY OBJECTIVES 
The primary objective of the study is to:  
 Evaluate the long-term safety of UX007 in Glut1 DS subjects 
The secondary objectives of the study are to: 
 Evaluate the long-term effect of UX007 efficacy on seizures associated with 
Glut1 DS 
 Evaluate the long-term effect of UX007 on health-related quality of life related to 
Glut1 DS 
6.1 
Study Endpoints 
6.1.1 
Primary Endpoint 
The primary endpoint of the study is the frequency of AEs and SAEs assessed as related to 
study drug over the Treatment Extension Period.  
6.1.2 
Secondary Endpoints 
General secondary endpoints of the study are: 
 Frequency of seizures over the Treatment Extension Period 
 Measures of neurological function over the Treatment Extension Period 
 Health-related quality of life over the Treatment Extension Period 


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current established dose.  If a subject has been off UX007 treatment for > 1 month, the dose 
may be titrated at the discretion of the investigator. Enrolled subjects are able to maintain 
standard of care treatment with up to 3 AEDs throughout the duration of the study.   
7.2 
Discussion of Study Design, Including Choice of Control Group 
UX007G-CL202 is designed as an open-label, multicenter extension study.  The goal of the 
study is to evaluate the long-term safety of UX007 treatment in Glut1 DS patients while 
providing continuing treatment for clinical trial participants in an associated Phase 2 study 
and, at the discretion of the Sponsor, additional subjects who participated in other clinical 
studies, ISTs, or expanded access/compassionate use treatment programs.  The study will 
also explore maintenance of UX007 effects on clinical features associated with Glut1 DS.   
Sample size is limited to subjects who have completed the Phase 2 safety and efficacy study, 
UX007G-CL201, or, at the discretion of the Sponsor, additional subjects who participated in 
other clinical studies, ISTs, or expanded access/compassionate use treatment programs. The 
study is intended to provide the maximum amount of information regarding UX007 long-
term safety and efficacy in a diverse Glut1 DS population.  Since all subjects will continue to 
receive the same investigational product, randomization and blinding are unnecessary; study 
drug will be provided open-label.  
Historical data obtained from prior clinical study participation and/or medical records may be 
used as a comparator for the Treatment Extension Period, enabling those subjects to represent 
an internal control for assessment of safety and efficacy.  While the lack of a parallel control 
group may introduce difficulties in discerning natural disease progression from treatment 
effectiveness, a placebo-controlled study of this duration is difficult to conduct and possibly 
not ethical given the need for ongoing disease management. 
Given the chronic nature of Glut1 DS, subjects will be eligible to continue maintenance 
UX007 treatment for up to 3 years, or until one of the following occurs:  the subject 
withdraws consent, the subject is discontinued from the study at the discretion of the 
Investigator or Ultragenyx, the study is terminated, or until commercial availability of study 
drug in a subject’s region, whichever occurs first. The treatment duration is intended to 
provide additional long-term safety information and provide sufficient insight on sustained 
clinical effects in Glut1 DS patients under a single study protocol. 
7.3 
Selection of Study Population 
The study will be conducted in pediatric, adolescent, and adult Glut1 DS patients (aged at 
least 1 year at the time of informed consent) who have successfully completed the associated 
Phase 2 study (UX007G-CL201) or, at the discretion of the Sponsor, additional subjects who 
participated in other clinical studies, ISTs, or expanded access/compassionate use treatment 
programs.  Enrollment may include subjects from neighboring countries where clinical sites 
are located.  Appropriate local or country requirements will be followed.  All subjects in this 
study will have prior treatment exposure to UX007/triheptanoin. 


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Children with Glut1 DS have been included in the study population since they have the 
greatest medical need and an increased number of clinical events.  The manifestation of 
seizures in Glut1 DS occurs predominantly in the pediatric age range, especially under the 
age of 12 (Pong et al. 2012); adult patients may also continue to have a similar phenotype of 
breakthrough seizures into their thirties, significant movement disorders (estimated at 90%; 
De Vivo personal communication), and have a more difficult time maintaining the KD.  
The expanded age range of the population will strengthen the ability to evaluate a possible 
impact on seizures and movement disorders.  In addition, the seizures are typically refractory 
to AEDs (Pearson et al. 2013), (Pong et al. 2012) and thus represent a significant unmet 
medical need that justifies the study of UX007 for the treatment of Glut1 DS. 
Reports suggest that KD is effective for the treatment of the seizures of Glut1 DS, although 
controlled trials have not been performed (Pong et al. 2012), (Pearson et al. 2013).  
Nevertheless, KD is prescribed in most Glut1 DS patients.  There exists a subset of patients 
who are not on KD because it is difficult to tolerate and some patients are not compliant with 
or are otherwise not on the diet.  In addition, some subjects continue to experience 
breakthrough seizures while on KD.  Because the seizures of Glut1 DS are typically 
refractory to AEDs, the subset of patients who are not on KD represents those most in need 
of an alternative therapy. 
Additional exclusion criteria were incorporated to protect the study population from possible 
contraindicated treatments or unnecessary safety risks.  In vitro studies have shown that 
pancreatic lipases hydrolyze triheptanoin into free fatty acids and glycerol; therefore 
inhibitors of pancreatic lipases (e.g. orlistat) should be avoided while taking UX007.  
Many Glut1 DS patients are severely impacted by their disorder from early infancy.  
Triheptanoin has been administered previously to newborns, infants, children, and adults.  
The previous clinical experience and nonclinical data suggests a favorable risk/benefit profile 
for the target study population.  The sponsor has taken all reasonable measures to ensure the 
protection and safety of this population.  Appropriate pediatric expertise will be available at 
all trial sites with children enrolled, and efforts will be focused on minimizing risk, fear, pain 
and distress during conduct of the study. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1) Diagnosis of Glut1 DS by cerebrospinal fluid glucose concentration, erythrocyte 
3-O-methyl-D-glucose uptake assay, or SLC2A1 molecular genetic testing.  
Information will be obtained from medical records. 
2) Males and females, aged at least 1 year  at the time of informed consent  
3) Completion of UX007G-CL201 study (NCT01993186).  Glut1 DS patients who 
received UX007/triheptanoin treatment as part of other clinical studies, ISTs, or 


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expanded access/compassionate use treatment programs may be eligible at the 
discretion of the sponsor. 
4) Provide written informed consent or verbal assent (if possible) with written informed 
consent by a legally authorized representative after the nature of the study has been 
explained, and prior to any research-related procedures 
5) Must, in the opinion of the investigator, be willing and able to complete all aspects of 
the study, and comply with accurate completion of the seizures diary 
6) Females of childbearing potential must have a negative urine 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 not experienced 
menarche, are post-menopausal (defined as having no menses for at least 12 months 
without an alternative medical cause), or are permanently sterile due to total 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
7) Participants of child-bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly-effective method of 
contraception as determined by the investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug. 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1) Any known hypersensitivity to triheptanoin that, in the judgment of the investigator, 
places the subject at increased risk for adverse effects 
2) History of, or current suicidal ideation, behavior and/or attempts  
3) Pregnant and/or breastfeeding an infant 
4) Unwilling or unable to discontinue use of a prohibited medication (barbiturates, 
pancreatic lipase inhibitors) or other substance that may confound study objectives.  
Use of up to 3 concomitant AEDs is allowed, provided dose has been stable at least 
14 days prior to Baseline.  
5) Use of any investigational product, drug or supplement (other than UX007) within 
30 days prior to Baseline, or at any time during the study 
6) Has a condition of such severity and acuity, in the opinion of the investigator, that it 
warrants immediate surgical intervention or other treatment 
7) Has a concurrent disease or condition, or laboratory abnormality that, in the view of 
the investigator, places the subject at high risk of poor treatment compliance or of not 
completing the study, or would interfere with study participation or introduce 
additional safety concerns (e.g. other concurrent neurological or psychiatric 
disorders).  


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7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason.  The investigator and Ultragenyx also have the right to 
remove subjects from the study.  Ultragenyx must be notified of all subject withdrawals as 
soon as possible.  Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or Investigator due to poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
 Occurrence of an unacceptable AE 
 An illness that, in the judgment of the investigator or Ultragenyx, might place the subject 
at risk or invalidate the study  
 Pregnancy of subject 
 At the request of the subject, investigator, or Ultragenyx, for administrative or other 
reasons 
 Protocol deviation or unreliable behavior 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the 
Case Report Form (CRF).  Each clinically significant abnormal laboratory value or other 
clinically meaningful abnormality should be followed until the abnormality resolves or until 
a decision is made that it is not likely to resolve.  If such abnormalities do not return to 
normal within 30 days after the last dose given, their etiology should be identified and 
Ultragenyx should be notified.  All unscheduled tests must be reported to Ultragenyx 
immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within four weeks of discontinuation. 
7.3.3.1 
Stopping Rules 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs (Section 8.5.3) that represent a change in the nature or an increase in 
frequency of the serious event from their prior medical history or known Glut1 DS-related 
medical issues will be assessed as to whether the subject will continue on the study. 
The Institutional Review Board (IRB)/Ethics Committee (EC) will be informed should 
unexpected and possibly, probably, or definitely study drug-related SAEs occur. A full 
evaluation of the event will be performed in order to make a decision regarding what actions 
to take, including whether to recommend stopping the study. 


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Regulatory Authorities, as well as the IRBs/ECs, will be informed should unexpected and 
possibly, probably, or definitely study drug-related SAEs occur. A full evaluation of the 
event will be performed in order to make a decision regarding what actions to take, including 
whether to recommend stopping the study. Regulatory Authorities, as well as IRBs/ECs, 
will be informed if the study is paused or stopped. If the Sponsor deems it appropriate to 
restart the trial following an internal safety review, this will be done only following approval 
by Regulatory Authorities. 
7.4 
Treatments 
At the Baseline Visit and each subsequent visit through Month 30, each subject will be 
dispensed an adequate supply of study drug to comprise up to 35% total daily caloric intake.  
Due to the extended time between scheduled clinic visits, additional supplies of study drug 
may be shipped to directly the subject or a designated pharmacy for logistical purposes. 
7.4.1 
Investigational Product 
UX007 (triheptanoin) is a liquid, intended for PO administration.  UX007 is a colorless to 
yellow oil supplied in 1 L round, translucent high-density polyethylene (HDPE) or 1 L round 
amber-colored glass bottles.  UX007 is manufactured, packaged, and labeled according to 
GMP regulations. 
UX007 dosing will be targeted and/or maintained at 35% of total daily caloric intake.  If a 
subject has been receiving a different dose of UX007 at study entry, the subject may be 
maintained on the UX007 dose that provided the maximum improvement in clinical status 
with acceptable tolerability, and continued on this dose for the duration of the study.  
A subject may have been off UX007 treatment prior to enrollment; in these cases, the UX007 
dose may be titrated at the discretion of the investigator. 
UX007 should be mixed with food (or formula, as appropriate) and administered PO or by 
gastronomy tube at least four times per day (breakfast, lunch, dinner, and before bed).  
The dose may be divided into smaller more frequent doses with food as needed.    
7.4.2 
Reference Therapy 
The study is a single-arm, open-label study.  All subjects will be on active treatment; no 
reference therapy or placebo will be administered.   
7.4.3 
Method of Assigning Subjects to Treatment Groups 
Subjects continuing treatment following completion of the UX007-CL201 study will retain 
the same identification number. Eligible subjects entering from other studies will be enrolled 
in the study and sequentially assigned an identification number.  All subjects will receive 
active treatment (UX007); there is only one treatment group in the study.  


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7.4.4 
Selection of Doses and Study Duration 
The UX007 dose and regimen for this study was selected based on the extensive clinical 
information derived from over 15 years of clinical experience in a variety of diseases.  
Approximately 200 subjects have received triheptanoin treatment, 51 of which involved 
pediatric patients as young as neonates, with 23 of these 51 with over 5 years of treatment 
duration (Roe et al. 2002), (Roe et al. 2006), (Mochel et al. 2010). 
The data support the safety of triheptanoin when administered at approximately 35% of daily 
caloric intake in pediatric patients as young as neonates.  Previous clinical data also suggest 
an age-dependent dose that relates to the relatively higher energy requirements for young 
children versus older children versus adults. 
The target dose of 35% of calories by UX007 is consistent with prior clinical use in other 
diseases and is equivalent to approximately 2-4 g/kg in infants and young children, 
decreasing to 1-2 g/kg for older children and adolescents.  Triheptanoin treatment has been 
generally safe and well tolerated at the aforementioned dose levels.  Higher doses are 
generally poorly tolerated due to gastrointestinal disturbance, such as diarrhea; lower doses 
would likely provide suboptimal efficacy. 
7.4.4.1 
Study Duration 
The planned duration of treatment in this study is 3 years, or until one of the following 
occurs:  the subject withdraws consent, the subject is discontinued from the study at the 
discretion of the Investigator or Ultragenyx, the study is terminated, or until commercial 
availability of study drug in a subject’s region, whichever occurs first.  The length of the 
study is intended to define whether UX007 is safe for long-term use and provide sufficient 
insight on sustained clinical effects. A Safety Follow-up Phone Call will be conducted 30-35 
days after last dose of study drug. The last subject’s Safety Follow-up Phone Call is the End-
of-study Time Point.  
7.4.5 
Blinding 
The study drug will be administered open-label; no study participants will be blinded to study 
treatment. 
7.4.6 
Prior and Concomitant Therapy 
7.4.6.1 
Prohibited Medications 
Subjects may not be enrolled if they have used any investigational product (other than 
UX007) within the last 30 days prior to the Baseline Visit, or are unwilling to discontinue use 
of a substance that may confound study objectives.  The following medications are prohibited 
throughout the study: 
 Barbiturates 


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 Pancreatic lipase inhibitors (e.g. Orlistat) due to possible inhibition of metabolism of 
triheptanoin 
7.4.6.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol, subjects may receive 
concomitant medications as required.  Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 30 days prior to 
Baseline visit will be reviewed and recorded.  Prescribed diet plans (as managed by the 
investigator) are allowed provided details of diet are captured in the diet diary or concomitant 
medications as appropriate. Up to 3 AEDs are permitted, provided the dose has been stable 
for 14 days prior to study entry. 
7.4.7 
Treatment Compliance 
Subjects and/or caregivers will record consumption of study drug in a study diary.  The diary 
will be reviewed by a dietitian or site personnel upon each visit.  Subjects will be instructed 
to return all used (empty study drug containers) and open/partially used study drug.  Study 
personnel will maintain a record of all medication dispensed to each subject.  Refer to the 
Pharmacy Manual for additional information on study drug accountability. 
7.5 
Study Procedures and Assessments 
The parameters to be assessed, along with timing of assessments, are provided in the 
Schedule of Events (Table 2.1). Refer to the Study Reference Manual for additional details 
on specific assessments and the suggested order of administration.  Whenever possible, 
study site staff (including trained clinicians, physical therapists, and the Investigator or site 
designee) performing the assessments should be consistent from visit to visit throughout the 
study. 
The concept for evaluation is to study the long-term safety and continued effects of UX007 
treatment on clinical manifestations associated with Glut1 DS.  Safety and clinical efficacy 
assessments will be conducted throughout the Treatment Extension Period to enable primary 
and secondary endpoint analysis and achieve study objectives. Dosing compliance and will 
also be regularly monitored. 
7.5.1 
Visit Schedule 
The Baseline Visit may occur in conjunction with the last scheduled visit from study 
UX007G-CL201.  Assessments conducted at the last UX007G-CL201 visit will be used for 
Baseline data to avoid duplication.  If the time elapsed between the last UX007G-CL201 
study visit and the Baseline Visit for this study is > 1 month, the full panel of Baseline Visit 
assessments must be completed.  Informed consent must be obtained prior to any Baseline 
procedures specific to the UX007G-CL202 study.  Subjects will be provided UX007 
treatment continuation only after all inclusion/exclusion criteria have been confirmed.  


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The Baseline Visit will be 2 days in duration to complete all assessments and the overnight 
EEG. 
Subjects will return to the clinic at 3-month intervals from Baseline (± 1 week) during Year 
1, and at 6-month intervals from Baseline (± 2 weeks) during Years 2 and 3 of the Treatment 
Extension Period to assess long-term safety and efficacy.  Phone calls will take place 3-
months between scheduled study site visits during Years 2 and 3 to collect adverse events 
and concomitant medications updates and to inquire about study drug consumption and 
remaining supply; in lieu of the phone call, subjects may visit the clinic at the study site’s 
discretion.  Additionally, optional study site visits may occur 3-months between scheduled 
study site visits during Years 2 and 3 to allow subjects to attain study drug as needed at the 
request of the Investigator.  A Safety Follow-up Phone Call will be conducted 30-35 days 
after last dose of study drug. The last subject’s Safety Follow-up Phone Call is the End of 
Study Time Point. The site personnel will initiate this safety follow-up telephone call to 
collect information on any ongoing or new AEs, SAEs, and concomitant medications. 
Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, 
are resolved. Minors who reach legal age during the course of the study must provide written 
informed consent when eligible.  For subjects who discontinue prior to completing the study, 
every reasonable effort should be made to perform the Early Termination visit procedures 
within 4 weeks of discontinuation. 
7.5.2 
Efficacy Measures 
The concept for evaluation is to study maintained effects of UX007 treatment on seizures, 
neurological examination, and movement disorders in Glut1 DS subjects through clinical 
assessments conducted throughout the Treatment Extension Period.  Patient-reported 
outcomes to evaluate health-related quality of life will also be administered. The Investigator 
may use clinical judgment in deciding whether to administer certain assessments to subjects 
based on age, development, and cognitive ability, as appropriate. The SF-10/SF-12v2 will not 
be performed if no pre-treatment baseline is available from feeder study (e.g. subjects 
entering from other clinical studies, ISTs, or expanded access/compassionate use treatment 
programs or subjects from UX007G-CL201 who were too young or compromised at pre-
treatment Baseline). 
The primary objective of the study is to assess long-term safety; all efficacy endpoints are 
therefore considered secondary (Section 6.1). The efficacy measures and assessments are 
described below; planned analysis of efficacy endpoints is described in Section 7.6.4.  
Refer to the Study Reference Manual for additional details on efficacy measures. 
7.5.2.1 
Seizure Monitoring 
7.5.2.1.1 
Seizure Diary 
Seizures are a hallmark of Glut1 DS in approximately 90% of affected individuals (Wang et 
al. 1993-2015).  The frequency of seizures varies among individuals; some experience daily 
events while others may have seizures separated by days, weeks, or even months.  


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The number of observable seizures will be recorded by the subject or caregiver via diary 
throughout the study.  Seizure types will be defined and standardized according to the ILAE 
Commission on Classification and Terminology (Berg et al. 2010).  Indicated seizure types 
are consistent with those observed in a large Glut1 DS cohort study designed to define 
epilepsy phenotypes in this population (Pong et al. 2012). 
Observable seizures are defined as: 
 Generalized Tonic-Clonic, Generalized Tonic, Generalized Clonic, Generalized Atonic 
 Partial/Focal with Secondary Generalization 
 Myoclonic, Myoclonic (Astatic) Atonic, Myoclonic Tonic 
 Complex Partial/Focal 
 Simple Partial/Focal Motor 
 Absence (although the primary method of assessing will be by EEG) 
7.5.2.1.2 
Electroencephalography 
Case-report studies in limited groups of Glut1 DS patients suggest a normal interictal 
background is the most common finding on both routine and prolonged EEG recordings.  
Both absence and myoclonic seizures have been observed in pediatric Glut1 DS patients 
during overnight continuous monitoring (Leary et al. 2003).  Several studies have examined 
electrophysiologic characteristics in Glut1 DS patients on KDs (Kessler et al. 2011). 
Abnormalities on EEG (including absence seizures) will be recorded with an overnight 
EEG conducted as indicated in Table 2.1. Indicated visits require a 2-day period to complete 
the overnight monitoring.  The frequency of seizures, including absence is the key measure. 
7.5.2.2 
Neurological Function 
The classic phenotype of Glut1 DS is also characterized by delayed neurologic development, 
acquired microcephaly, and complex movement disorders (Pascual et al. 2004).  
The majority of Glut1 DS patients experience some degree of developmental delay and 
cognitive impairment.  The broad spectrum of neuropsychological features in Glut1 DS 
includes effects on general intellectual function (ranging from mild learning disability to 
severe intellectual impairment), language development, adaptive behavior, behavior and 
sustained attention.  Clinical efficacy measures in this study also include measures of 
neurological function.   
7.5.2.2.1 
Columbia Neurological Score 
The CNS is a quantitative tool developed to summarize neurological exam findings 
(Kaufmann et al. 2004).  The tool focuses on physical findings, capturing the following 
domains: 1) height, weight, and head circumference; 2) general medical examination; 
3) general neurologic examination; 4) cranial nerves; 5) stance and gait; 6) involuntary 


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movements; 7) sensation; 8) cerebellar function; 9) muscle bulk, tone, and strength; 
10) myotatic reflexes; 11) Babinski signs; and 12) other findings.  The CNS total score 
ranges from 0 to 76; higher scores are associated with higher neurological function.  
The CNS will be administered at the Baseline Visit and at Months 6, 12, 24, and 36 (or Early 
Termination). 
7.5.2.3 
Health-related Quality of Life 
Individuals with Glut1 DS are affected by a broad spectrum of clinical symptoms, including 
seizures, cognitive and speech impairment and movement disorders which may impact 
physical and mental health status.  The following efficacy measures will evaluate patient-
reported quality of life.  
7.5.2.3.1 
Short Form Health Surveys 
Short-Form (SF) health surveys capture practical, reliable, and valid information about 
functional health and well-being from the patient's perspective.  Depending on the age of the 
subject, the SF-10 Health Survey for Children (SF-10) or Medical Outcomes Study 12-Item 
Short Form version 2 (SF-12v2) will be administered during at the Baseline Visit and at 
6-month intervals thereafter (or Early Termination). SF-10/SF-12v2 will not be performed if 
no pre-treatment baseline is available from feeder study (e.g. other clinical studies, ISTs, or 
expanded access/compassionate use treatment programs or subjects from UX007G-CL201 
who were too young or compromised at pre-treatment Baseline). 
The SF-10 is a 10-item caregiver-completed questionnaire for pediatric subjects designed to 
assess physical and psychosocial health-related quality of life in healthy and ill individuals 
(Saris-Baglama et al. 2006).  The 10 items were adapted from the Child Health Questionnaire 
and utilize a 4-week recall period.  Responses are used to generate 2 component summary 
scores: physical summary score (PHS-10) and psychosocial summary score 
(PSS-10).  Higher global scores are associated with better quality of life.  The SF-10 will be 
administered to caregivers of subjects aged 5 to 17 years at the time of informed consent for 
this study.  If a subject is under 5 years of age at informed consent, the SF-10 will not be 
administered during the Extension study. The responder completing the first administration 
should complete subsequent administrations to minimize variability.   
The SF-12v2 is a 12-item interview and self-administered questionnaire designed to assess 
generic health-related quality of life in healthy and ill adult populations (Ware et al. 1996).  
The 12 items in the SF-12v2 are a subset of the items in the SF-36v2 and measure physical 
functioning, role limitations due to physical health problems, bodily pain, general health, 
vitality (energy/fatigue), social functioning, role limitations due to emotional problems, and 
mental health.  Responses are used to generate 2 component summary scores: physical health 
(PCS) and mental health (MCS). Higher global scores are associated with better quality of 
life. The standard version of the instrument with a 4-week recall period will be used in this 
study.  The SF-12v2 will be administered to subjects 18 years of age and older at the time of 
informed consent for this study. If a subject turns 18 years of age during the study, 
the SF-12v2 will be administered beginning at the next study visit. 


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7.5.3 
Drug Concentration Measurements and Bioassays 
To assess the UX007 metabolites, blood samples will be collected approximately 90 minutes 
following consumption of food and study drug at the Baseline Visit and at 6-month intervals 
throughout the Treatment Extension Period (or Early Termination).  For each sample 
collection, the time elapsed since last study drug administration will be recorded on the CRF.  
The following UX007 metabolites will be assessed: 
 C4 ketone:  beta-hydroxybutyrate (BHB) 
 C5 ketones:  beta-hydroxypentanoate (BHP)  
 Heptanoate 
7.5.4 
Safety Measures & General Assessments 
General assessments include medical history and demographics.  Safety will be evaluated by 
the incidence, frequency, severity, and relatedness of AEs and SAEs, including clinically 
significant changes from baseline to scheduled time points in vital signs, weight, physical 
examination, and clinical laboratory evaluations.  Pregnancy testing (or pregnancy of 
partner), suicidal ideation and behavior assessments, and concomitant medications will also 
be monitored.  Refer to the Study Reference Manual for additional details. 
7.5.4.1 
Medical History and Triheptanoin Treatment History 
Medical history will be obtained at the Baseline Visit for all subjects not previously enrolled 
in UX007G-CL201. General medical information includes subject demographics (date of 
birth, ethnicity, and sex) and a history of major medical illnesses, diagnoses, and surgeries.  
The review will also include an assessment of phenotypic characteristics associated with 
Glut1 DS, including seizures, cognitive impairment, movement disorders, and microcephaly.  
The specific history of Glut1 DS will be recorded, along with date of onset, clinical 
presentation, and date and method of confirmed diagnosis.  Any available family history of 
Glut1 DS will be noted including diagnosis, disease course, treatment and outcome. 
Glut1 DS maintenance treatment history, including UX007 (triheptanoin) treatment history, 
and relevant concomitant medications will be recorded (start date, stop date, dose, dose 
regimen).  Treatments include prescribed diets, other standard of care treatments, and all 
other relevant concomitant medications (e.g. seizure medications, L-carnitine, vitamin 
supplements, etc.).  Medications include prescription, over-the-counter, herbal and nutritional 
supplements.  Any relevant concomitant therapy, including physical/occupational therapy 
will be recorded. 
7.5.4.2 
Vital Signs and Weight 
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 


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performed at every clinic visit before any additional assessments are completed.  At each 
visit, weight (in kilograms) will be obtained using a scale.  Clinically significant changes will 
be recorded as AEs. 
7.5.4.3 
Physical Examination 
Complete physical examinations will be performed at the Baseline Visit and at 6-month 
intervals for the duration of the study (or Early Termination Visit).  Physical examinations 
will include assessments of general appearance; head, eyes, ears, nose, and throat; the 
cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, musculoskeletal, and 
neurologic systems.  Clinically significant changes will be recorded as AEs. 
7.5.4.4 
Clinical Laboratory Tests 
The clinical laboratory evaluations to be performed in this study include routine serum 
chemistry, hematology, and urinalysis; specific analytes are listed in Table 7.5.4.4.1.  
Clinical laboratory testing will be performed at each scheduled study clinic visit (or Early 
Termination visit).  Blood and urine samples will be collected; fasting is not required.  
Refer to the Study Reference Manual for additional details. 
Table 7.5.4.4.1:  Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Hematocrit 
Appearance 
Alkaline phosphatase 
Hemoglobin 
Color 
Aspartate aminotransferase (AST) 
Platelet count 
pH 
Bilirubin (total) 
Red blood cell (RBC) count 
Specific gravity 
Blood urea nitrogen (BUN) 
White blood cell (WBC) count 
Ketones 
Calcium 
 
Protein  
Chloride 
 
Glucose  
Serum creatinine 
 
 
Gamma-glutamyl transpeptidase 
(GGT) 
 
Pregnancy test  
(if applicable) 
Serum glucose 
 
 
Potassium 
 
 
Protein (albumin and total) 
 
 
Sodium 
 
 
 
Subjects who experience a SAE possibly, probably, or definitely related to study drug or 
other AE of concern may, at the discretion of the investigator (and/or medical monitor), have 
additional blood or urine samples taken for safety laboratory tests. 


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7.5.4.5 
Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests at each scheduled 
study visit (or Early Termination).  Females considered not of childbearing potential include 
those who have not experienced menarche, are post-menopausal (defined as having no 
menses for at least 12 months without an alternative medical cause); or are permanently 
sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Female subjects with a positive pregnancy test at the Baseline visit will not be enrolled in the 
study. Pregnancy in subject or partner must be reported (Section 8.5.5.1); pregnant subjects 
will be discontinued from the study. Additional pregnancy tests may be performed at any 
time in which pregnancy status is in question.  A serum pregnancy test will be performed in 
the event of a positive or equivocal urine pregnancy test result, or can be performed if 
pregnancy test by urine is not feasible. 
Experience with UX007 (triheptanoin) in pregnant women is limited.  The study drug may 
involve risks to a pregnant female or unborn baby which are currently unknown.  
Sexually active fertile males or females of childbearing potential must use highly effective 
contraception as determined by the investigator during heterosexual intercourse throughout 
the study period and for 30 days after stopping the study drug.  Examples of some highly 
effective methods (CTFG 2014) include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
 Progestogen-only hormonal contraception associated with inhibition of ovulation 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system ( IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Sexual abstinence (i.e., refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments, when this is in line with the preferred and 
usual lifestyle of the subject) 
7.5.4.6 
Suicidal Ideation and Behavior Assessments 
Assessment of suicidal ideation and behavior is a regular part of development programs 
involving AEDs and other neurologic drugs with central nervous system activity (FDA Draft 
Guidance 2012).  The Columbia Suicide Severity Rating Scale (C-SSRS) is a standardized 
suicidal rating instrument used to assess the suicidal ideation and behavior in an at-risk 
population (Posner et al. 2011).  To prospectively assess suicidal ideation and behavior, 
the C-SSRS will be administered by a clinician.  Depending on the cognitive state of the 
subject, some questions within the C-SSRS may be deemed by the investigator to be 
inappropriate to ask the subject and can be omitted.  Suicidal ideation and behavior will be 


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assessed in subjects ≥ 10 years of age at each visit.  The Baseline questionnaire will be 
administered on the initial visit; the Since Last Visit questionnaire will be administered at all 
subsequent visits.  The responses to the questionnaire will be reviewed by site personnel 
during the study visit; if emergent suicidal ideation or behavior is indicated, the investigator 
should promptly evaluate the subject to ensure proper management and protection of subject 
safety. Determination of whether the subject should continue on study will be made by the 
investigator based on the severity of symptoms and follow-up needed, and the Sponsor will 
be informed.  
7.5.4.7 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit or phone call, beginning at the Baseline Visit.  Medications (investigational, 
prescription, over-the-counter, and herbal) and nutritional supplements taken during the 30 
days prior to Baseline will be reviewed and recorded. At each subsequent visit or phone call, 
change in medications since the previous visit will be recorded.  A discussion of concomitant 
medications is provided in Section 7.4.6. 
7.5.4.8 
Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent through 
30 days following the last administration of study drug.  The determination, evaluation, 
reporting, and follow-up of AEs will be performed as outlined in Section 8.5.  At each visit 
or phone call, subjects will be asked about any new or ongoing AEs since the previous visit.  
Assessments of AEs will occur at each study visit. 
Clinically significant changes in physical examination findings, vital signs, weight, clinical 
laboratory parameters, and suicidal ideation and behavior will be recorded as AEs or SAEs, if 
appropriate. 
7.5.4.9 
Dietitian Consultation and Diet Assessment 
At the Baseline visit, an interview with the study dietitian will establish daily caloric intake 
and UX007 dose.  Subjects and/or caregivers are required to maintain a record of the 
subject’s daily diet in a diary for the 3 days prior to each subsequent visit.  The diet diary will 
be reviewed by study personnel at each visit to the clinic.  The dietitian may telephone 
subjects and/or caregivers, as needed, to provide dietary advice and support. Refer to the 
Study Reference Manual for details on the dietary assessment. 
7.5.5 
Appropriateness of Measures 
The efficacy parameters to be evaluated in this study encompass the characteristic phenotype 
observed in Glut1 DS affected individuals, including seizures, delayed neurologic 
development, and complex movement disorders.  The clinical assessments in the study 
employ standard measures used in other diseases and conditions that impact the central 
nervous and skeletal muscle systems.   


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Seizure frequency is the most commonly used endpoint in AED trials for refractory epilepsy 
and would be able to similarly determine the clinically relevant effects of UX007 on the 
seizure due to Glut1 DS.  Diaries will be used by subjects and/or caregivers to capture 
seizure events, thereby minimizing recall bias at site visits.  EEG is a routine, non-invasive 
procedure inflicting minimal pain/distress for the subject, while providing relevant indicators 
of absence seizure events.  The incorporation of overnight EEGs may introduce a level of 
inconvenience for the subject, however a higher proportion of abnormalities in pediatric 
Glut1 DS patients were observed in 24-h EEG data compared with routine EEGs (Leary et al. 
2003). The CNS was included as a measure of neurological involvement. 
Since the study will be conducted in a pediatric, adolescent, and adult population, 
ageappropriate- efficacy measures and patient-reported outcomes were included to assess 
health-related quality of life (SF-10/SF-12v2). 
UX007 metabolites will be assessed using blood samples.  The panel has been included to 
provide additional metabolite data on peak levels at steady-state.  Where possible, timing of 
assessments has been coordinated with standard safety laboratory tests to minimize risk and 
discomfort and avoid unnecessary sampling. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs and weight, 
serum chemistry, concomitant medications, and other routine clinical and laboratory 
procedures.  Suicidal ideation and behavior will be assessed as an additional safety measure 
given the central nervous system involvement with Glut1 DS and the likelihood for most if 
not all subjects to be prescribed at least 1 AED as concomitant treatment. 
7.6 
Statistical Methods and Determination of Sample Size 
The completeness of the data affects the integrity and accuracy of the final study analysis.  
Therefore, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data.  The procedures for handling missing, unused, or spurious data, 
along with the detailed method for analyses will be presented in the Statistical Analysis Plan 
(SAP); in general, missing data will be treated as missing unless stated otherwise.  
The information below is intended as a guide to planned analyses. 
The statistical analyses will be reported using summary tables, figures, and data listings.  
Statistical tests will be one-sided at the alpha =0.05 significance level.  All analyses and 
tabulations will be performed using SAS®.  Continuous variables will be summarized with 
means, standard deviations, medians, minimums, and maximums.  Categorical variables will 
be summarized by counts and by percentages of subjects in corresponding categories.  
For time-to-event data, the Kaplan-Meier estimates will be computed and plotted. Graphical 
data displays may also be used to summarize the data. All raw data obtained from the CRFs 
as well as any derived data will be included in data listings. For certain data collected over 
time, the Generalized Estimating Equation (GEE) may be used as the marginal model 
approach.  


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Tests of treatment effects will be conducted at a one-sided alpha level of 0.05 and/or 
one-sided 95% confidence interval where possible. Each secondary endpoint will be tested 
independently at one-sided alpha=0.05. No adjustments for multiple comparisons will be 
performed. 
Specific details of primary and secondary endpoints as defined in Section 6.1, and associated 
analyses will be provided in the SAP. 
7.6.1 
Subject Information 
Summaries and listings will be provided for all subjects who received at least 1 dose of study 
drug and provided at least 1 safety or efficacy evaluation.  Subject disposition summaries 
will include the number of enrolled subjects, the number of subjects receiving study 
medication, the number of subjects completing the study, and the reasons for discontinuation.  
Demographic variables include age, sex, and race. 
7.6.2 
Analysis Population 
The analysis set will include all subjects who receive at least one dose of UX007 during the 
study. 
7.6.3 
Safety Analyses 
The primary safety analysis will evaluate the incidence and frequency of AEs and SAEs, 
including clinically significant changes in safety parameters throughout the Treatment 
Extension Period. The incidence and frequency of AEs will be summarized by System Organ 
Class and Preferred Term, relationship to study drug, and severity. No formal hypothesis 
testing will be performed. 
Safety will be evaluated by the incidence, frequency and severity of AEs and SAEs, 
including clinically significant changes from baseline to scheduled time points in: 
 Vital signs and weight 
 Physical examination 
 Clinical laboratory evaluations 
 Pregnancy testing 
 Suicidal ideation and behavior assessments 
 Concomitant medications 
The analyses of safety will be performed on the safety analysis population. 
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.  All reported AEs with onset 


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during treatment (i.e. treatment-emergent AEs) will be included in the analysis. For each AE, 
the percentage of subjects who experienced at least 1 occurrence of the given event will be 
summarized by treatment group.  The numbers (frequency) and incidence rates of AEs and 
SAEs will be summarized during exposure to UX007 throughout the study.  Special attention 
will be given to those subjects who died, discontinued treatment due to an AE, 
or experienced a SAE (e.g. summaries, listings, and narrative preparation, as appropriate). 
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.  
Changes in findings from physical examinations will be tabulated and listed for each subject 
by examination category. If there are examination findings that change in more than one 
subject, these will be tabulated in a separate table and expressed as the number of subjects 
with the change out of the total. 
Descriptive statistics of temperature, pulse, respiratory rate, and blood pressure (systolic and 
diastolic) values and changes from baseline will be summarized.  The percentage of subjects 
with values beyond clinically important limits will be summarized. 
The SAP will provide additional details on the planned safety analyses. 
7.6.4 
Efficacy Analysis 
The efficacy analyses are focused on alternative domains of Glut1 DS disease to assess the 
long-term effect of UX007 throughout the Treatment Extension Period. 
The following efficacy measures will be assessed: 
 Seizures: Observable generalized and partial-onset seizures measured by diary, and 
absence seizures measured by overnight EEG.  Seizure types include: Generalized Tonic-
Clonic, Generalized Tonic, Generalized Clonic, Generalized Atonic, Partial/Focal with 
Secondary Generalization, Myoclonic, Myoclonic Atonic, Myoclonic Tonic, Complex 
Partial/Focal, Simple Partial/Focal Motor, and Absence seizures 
 Neurological function using the CNS 
 Subject or caregiver-reported quality of life using SF-10 for children or SF-12v2 for 
adults 
The specific tests and analyses will be defined in the SAP. 
7.6.5 
Pharmacokinetic and Bioassay Analyses 
Descriptive statistics, including mean, standard deviation, coefficient of variation, 
geometric mean, median, minimum, and maximum will be calculated for each plasma 
UX007 metabolite (BHB, BHP, and heptanoate) at each sampling time point to evaluate peak 


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levels.  Data will be listed for all subjects with available plasma concentrations.  All 
concentrations below the lowest quantifiable concentration of the assay or missing data will 
be labeled as such in the concentration data listings.  Concentrations below the lowest 
quantifiable concentration of the assay will be treated as zero in the summary statistics.  
All subjects and samples excluded from the analysis will be clearly documented in the study 
report.  Results for each plasma UX007 metabolite will be provided.  Additional details of 
the UX007 metabolite analyses will be provided in the SAP. 
7.6.6 
Subgroup Analysis 
Details on any planned subgroup analysis will be provided in the SAP. 
7.6.7 
Interim Analysis 
No formal interim analysis is planned for this study.  Analyses may be performed at any time 
during the study at the discretion of the Sponsor.  There is no unblinding during these 
analyses since it is an open-label study.  
7.6.8 
Data Monitoring Committee 
A data monitoring committee will not be constituted for this open-label treatment extension 
study. 
7.6.9 
Determination of Sample Size 
Sample size is limited to subjects who have completed the Phase 2 safety and efficacy study, 
UX007G-CL201, or, at the discretion of the Sponsor, additional subjects who participated in 
other clinical studies, ISTs, or expanded access/compassionate use treatment programs.  
The current study design is open-label with all subjects receiving the same treatment; 
therefore the study is not powered to assess treatment comparisons.  Instead, the sample size 
is intended to provide the maximum amount of information regarding UX007 long-term 
safety, along with indicators of sustained efficacy and durability of response in Glut1 DS 
patients. 


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


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from it at any time.  Subjects under the age of 18 years (or 16 years, depending on the region) 
will provide written assent (if possible), and his/her legally authorized representative 
(parent or legal guardian) will provide written informed consent for such subjects.  Minors 
who reach legal age during the course of the study must provide written informed consent 
when eligible.   
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements.  Subjects will be given a copy 
of the signed ICF and will be provided any new information during the course of the study 
that might affect their continued participation in the study.  The investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction.  If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
The date of written informed consent will be documented in each potential subject’s CRF.  
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure  
Each investigator must provide Ultragenyx and/or its designee a completed and signed 
Form FDA 1572 and a Financial Disclosure Form.  All sub-investigators must be listed on 
Form FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators 
listed on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines.  Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site, 
to perform source document verification.  The monitor will verify the investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
A Coordinating Investigator will be identified for multicenter trials. The Coordinating 
Investigator will be selected on the basis of active participation in the trial, thorough 
knowledge of the therapeutic area being studied, and the ability to interpret data. 
The Coordinating Investigator will read and sign the Clinical Study Report.  
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 


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


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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 
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 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 Adverse Event (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. 
Suspected Adverse Reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  For the purposes of expedited safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
Life-threatening adverse event or life-threatening suspected adverse reaction is an adverse 
event or suspected adverse reaction that, in the view of either the investigator or sponsor, 
places the patient or subject at immediate risk of death.  It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 


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Serious adverse event (SAE) or serious suspected adverse reaction is an adverse event or 
suspected adverse reaction that at any dose, in the view of either the investigator or sponsor, 
results in any of the following outcomes: 
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
 A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
Important medical events that may not result in death, be immediately life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE version 4.0.  
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 are of a minor 
irritant type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
 Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
 Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
 Life-threatening (Grade 4): Events that place the participant at immediate risk of death 
or are disabling. 
 Death (Grade 5): Events that result in death. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 


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provided.  The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This is not the same 
as "serious" which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject's life or functioning.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
 Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure. 
 Unlikely Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure.  
Categories of attributions for “Related” events: 
 Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
 Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
 Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Adverse Event Reporting  
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the CRF. The Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and ensuring documentation of the event is adequate. Details of the AE must 
include severity, relationship to study drug, duration, and outcome.  
All AEs will be collected from the time the subject signs informed consent through 30 days 
following the last dose of study drug. In addition, the Investigator should report any AE that 
occurs after this time period that is believed to have a reasonable possibility of being 
associated with study drug.  


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AEs ongoing at 30 days following the last dose of study drug should have a comment in the 
source document by the Investigator whether the event has recovered, recovered with 
sequelae, or stabilized.  
8.5.5 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Ultragenyx or its designee must be notified of any SAE that occurs at any time during the 
reporting period within 24 hours of the Investigator, designee, or site personnel’s knowledge 
of the event.  SAEs will be reported by completing and submitting SAE report forms to 
Ultragenyx or its designee.  
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected.  
All deaths, regardless of causality, occurring from the signing of the informed consent until 
30 days following the last dose of study drug are to be reported as SAEs to Ultragenyx or its 
designee within 24 hours of knowledge.   
8.5.5.1 
Pregnancy in Subject or Partner, and Requirements for Immediate Reporting 
Ultragenyx or its designee must be notified of the occurrence of any pregnancy in a subject 
or subject’s partner that occurs during the reporting period within 24 hours of the 
Investigator, designee, or site personnel’s knowledge of the event. Pregnancies will be 
reported by completing and submitting Pregnancy Notification forms to Ultragenyx or 
designee. 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. 
Ultragenyx or its designee must be notified of the outcome of the pregnancy within 24 hours 
of the Investigator, designee, or site personnel’s knowledge of the outcome. Pregnancy 
outcomes will be reported by completing and submitting Pregnancy Outcome forms to 
Ultragenyx or designee.  


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8.5.6 
Communication Plan 
8.5.6.1 
Serious 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.  
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.  
8.5.6.2 
Urgent Safety Matters and Non-SUSAR Reporting 
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
ECs, and Investigators of any events (e.g. change to the safety profile of UX007, 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/ REB/ECs of urgent safety matters, in accordance with 
IRB/REB/EC requirements and local laws and regulations. A copy of this notification must 
be provided to Ultragenyx or its designee. 
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and ECs, as per local laws and regulations.  
8.5.6.3 
Pregnancy Reporting 
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. Any pregnancy-associated SAEs must be reported as per the SUSAR reporting 
process indicated in Section 8.5.6.1. 


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Barone, A, DeWard, S, Payne, N, Goldstein, A, and Vockley, J. 2012. "Triheptanoin therapy 
for inherited disorders of fatty acid oxidation.  Poster presentation. ." Society for Inherited 
Metabolic Disorders Annual Meeting, Charlotte, NC, Mar 31 – Apr 3, 2012. 
Berg, AT, Berkovic, SF, Brodie, MJ, Buchhalter, J, Cross, JH, van Emde, BW, Engel, J, 
French, J, Glauser, TA, Mathern, GW, Moshe, SL, Nordli, D, Plouin, P, and Scheffer, IE. 
2010. "Revised terminology and concepts for organization of seizures and epilepsies: report 
of the ILAE Commission on Classification and Terminology, 2005-2009." Epilepsia 51 
(4):676-685. 
Borges, K, and Sonnewald, U. 2012. "Triheptanoin--a medium chain triglyceride with odd 
chain fatty acids: a new anaplerotic anticonvulsant treatment?" Epilepsy Res. 100 (3):239-
244. 
Coman, DJ, Sinclair, KG, Burke, CJ, Appleton, DB, Pelekanos, JT, O'Neil, CM, Wallace, 
GB, Bowling, FG, Wang, D, De Vivo, DC, and McGill, JJ. 2006. "Seizures, ataxia, 
developmental delay and the general paediatrician: glucose transporter 1 deficiency 
syndrome." J.Paediatr.Child Health 42 (5):263-267. 
Deng, S, Zhang, GF, Kasumov, T, Roe, CR, and Brunengraber, H. 2009. "Interrelations 
between C4 ketogenesis, C5 ketogenesis, and anaplerosis in the perfused rat liver." 
J.Biol.Chem. 284 (41):27799-27807. 
FDA. Draft Guidance 2012. Guidance for Industry: Suicidal Ideation and Behavior:  
Prospective Assessment of Occurrence in Clinical Trials (Draft), Available at: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf.  Accessed 07 Jul 2013. 
IND 65827. "One Time Emergency Use of Anaplerotic Dietary Therapy (Triheptanoin) for 
Congestive Heart Failure & Cardiomyopathy under Charles Roe MD, Baylor Research 
Institute." 
Kaufmann, P, Shungu, DC, Sano, MC, Jhung, S, Engelstad, K, Mitsis, E, Mao, X, Shanske, 
S, Hirano, M, Dimauro, S, and De Vivo, DC. 2004. "Cerebral lactic acidosis correlates with 
neurological impairment in MELAS." Neurology 62 (8):1297-1302. 
Kessler, SK, Gallagher, PR, Shellhaas, RA, Clancy, RR, and Bergqvist, AG. 2011. "Early 
EEG improvement after ketogenic diet initiation." Epilepsy Res 94 (1-2):94-101. 


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Kim, TH, Borges, K, Petrou, S, and Reid, CA. 2013. "Triheptanoin reduces seizure 
susceptibility in a syndrome-specific mouse model of generalized epilepsy." Epilepsy Res. 
103 (1):101-105. 
Kinman, RP, Kasumov, T, Jobbins, KA, Thomas, KR, Adams, JE, Brunengraber, LN, Kutz, 
G, Brewer, WU, Roe, CR, and Brunengraber, H. 2006. "Parenteral and enteral metabolism of 
anaplerotic triheptanoin in normal rats." Am.J.Physiol Endocrinol.Metab 291 (4):E860-E866. 
Klepper, J. 2008. "Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic 
diet." Epilepsia 49 Suppl 8:46-49. 
Klepper, J, and Leiendecker, B. 2007. "GLUT1 deficiency syndrome--2007 update." Dev 
Med Child Neurol 49 (9):707-16. 
Leary, LD, Wang, D, Nordli, DR, Jr., Engelstad, K, and De Vivo, DC. 2003. "Seizure 
characterization and electroencephalographic features in Glut-1 deficiency syndrome." 
Epilepsia 44 (5):701-707. 
Marin-Valencia, I, Good, LB, Ma, Q, Malloy, CR, and Pascual, JM. 2013. "Heptanoate as a 
neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-
deficient (G1D) brain." J Cereb.Blood Flow Metab 33 (2):175-182. 
Mochel, F, DeLonlay, P, Touati, G, Brunengraber, H, Kinman, RP, Rabier, D, Roe, CR, and 
Saudubray, JM. 2005. "Pyruvate carboxylase deficiency: clinical and biochemical response 
to anaplerotic diet therapy." Mol.Genet.Metab 84 (4):305-312. 
Mochel, F, Duteil, S, Marelli, C, Jauffret, C, Barles, A, Holm, J, Sweetman, L, Benoist, JF, 
Rabier, D, Carlier, PG, and Durr, A. 2010. "Dietary anaplerotic therapy improves peripheral 
tissue energy metabolism in patients with Huntington's disease." Eur.J.Hum.Genet. 18 
(9):1057-1060. 
Pascual, JM, Liu, P, Mao, D, Kelly, DI, Hernandez, A, Sheng, M, Good, LB, Ma, Q, Marin-
Valencia, I, Zhang, X, Park, JY, Hynan, LS, Stavinoha, P, Roe, CR, and Lu, H. 2014. 
"Triheptanoin for Glucose Transporter Type I Deficiency (G1D): Modulation of Human 
Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement." JAMA 
Neurol. 
Pascual, JM, Wang, D, Lecumberri, B, Yang, H, Mao, X, Yang, R, and De Vivo, DC. 2004. 
"GLUT1 deficiency and other glucose transporter diseases." Eur J Endocrinol 150 (5):627-
33. 
Pearson, TS, Akman, C, Hinton, VJ, Engelstad, K, and De Vivo, DC. 2013. "Phenotypic 
spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS)." 
Curr.Neurol.Neurosci.Rep. 13 (4):342. 


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Pong, AW, Geary, BR, Engelstad, KM, Natarajan, A, Yang, H, and De Vivo, DC. 2012. 
"Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes." 
Epilepsia 53 (9):1503-1510. 
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, 
Melvin, GA, Greenhill, L, Shen, S, and Mann, JJ. 2011. "The Columbia-Suicide Severity 
Rating Scale: initial validity and internal consistency findings from three multisite studies 
with adolescents and adults." Am J Psychiatry 168 (12):1266-77. 
Roe, CR, Bottiglieri, T, Wallace, M, Arning, E, and Martin, A. 2010. "Adult Polyglucosan 
Body Disease (APBD): Anaplerotic diet therapy (Triheptanoin) and demonstration of 
defective methylation pathways." Mol.Genet.Metab 101 (2-3):246-252. 
Roe, CR, and Mochel, F. 2006. "Anaplerotic diet therapy in inherited metabolic disease: 
therapeutic potential." J.Inherit.Metab Dis. 29 (2-3):332-340. 
Roe, CR, Sweetman, L, Roe, DS, David, F, and Brunengraber, H. 2002. "Treatment of 
cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an 
anaplerotic odd-chain triglyceride." J.Clin.Invest 110 (2):259-269. 
Roe, CR, Yang, BZ, Brunengraber, H, Roe, DS, Wallace, M, and Garritson, BK. 2008. 
"Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy." Neurology 
71 (4):260-264. 
Saris-Baglama, RN, DeRosa, MA, Raczek, AE, Bjorner, JB, and Ware, JE. 2006. 
"Development, validation, and norming of the SF-10 for Children Health Survey." Quality of 
Life Research 15 (S1):A-145. 
Thomas, NK, Willis, S, Sweetman, L, and Borges, K. 2012. "Triheptanoin in acute mouse 
seizure models." Epilepsy Res. 99 (3):312-317. 
Verrotti, A, D'Egidio, C, Agostinelli, S, and Gobbi, G. 2012. "Glut1 deficiency: when to 
suspect and how to diagnose?" Eur J Paediatr Neurol 16 (1):3-9. 
Wang, D, Pascual, JM, and De Vivo, D. 1993-2015. "Glucose Transporter Type 1 Deficiency 
Syndrome." In GeneReviews(R), edited by R. A. Pagon, M. P. Adam, H. H. Ardinger, T. D. 
Bird, C. R. Dolan, C. T. Fong, R. J. H. Smith and K. Stephens. Seattle (WA): University of 
Washington, Seattle. 
Ware, J, Jr., Kosinski, M, and Keller, SD. 1996. "A 12-Item Short-Form Health Survey: 
construction of scales and preliminary tests of reliability and validity." Med Care 34 (3):220-
33. 
Willis, S, Stoll, J, Sweetman, L, and Borges, K. 2010. "Anticonvulsant effects of a 
triheptanoin diet in two mouse chronic seizure models." Neurobiol.Dis. 40 (3):565-572. 
 


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10 SIGNATURE PAGE 
Protocol Title:  An Open-label Extension Study to Assess the Long-term Safety and 
Efficacy of UX007 in Subjects with Glucose Transporter Type 1 Deficiency Syndrome 
Protocol Number:  UX007G-CL202 Amendment 3 
I have read the amended Protocol UX007G-CL202.  I agree to conduct the study as detailed 
in this protocol and in compliance with the Declaration of Helsinki, Good Clinical Practices 
(GCP), and all applicable regulatory requirements and guidelines. 
 
 
 
Investigator Signature 
Date 
Printed 
Name: 
 
 
 
 
Accepted for the Sponsor: 
As the Sponsor representative, I confirm that Ultragenyx will comply with all Sponsor 
obligations as detailed in all applicable regulations and guidelines.  I will ensure the 
investigator is informed of all relevant information that becomes available during the conduct 
of this study. 
 
 
 
Melanie Brandabur, MD 
Medical Director  
Ultragenyx Pharmaceutical Inc. 
 
Date 
 

SAP_001.pdf: 
Study Number: UX007G-CL202   
Statistical Analysis Plan  
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STATISTICAL ANALYSIS PLAN 
 
 
 
Title 
An Open-label Extension Study to Assess the Long-term 
Safety and Efficacy of UX007 in Subjects with Glucose 
Transporter Type 1 Deficiency Syndrome 
Protocol: 
UX007G-CL202 
Investigational Product: UX007 (Triheptanoin) 
Phase: 
2 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Author: 
 
Manager Biostatistics 
Date: 
25 April 2018 
Version Number: 
1.0 
 
 
 
PPD


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TABLE OF CONTENTS 
1  INTRODUCTION ...............................................................................................................7 
2  STUDY OBJECTIVE(S) .....................................................................................................8 
2.1  Primary Objective .......................................................................................................8 
2.2  Secondary Objectives ..................................................................................................8 
3  STUDY DESIGN.................................................................................................................9 
3.1  Study Population .........................................................................................................9 
3.2  Dosage and Administration .......................................................................................10 
3.3  Blinding and Randomization Methods .....................................................................10 
3.4  Stratification Factors .................................................................................................10 
3.5  Sample Size Considerations ......................................................................................10 
3.6  Interim Analysis ........................................................................................................10 
3.7  Data Monitoring Committee .....................................................................................10 
4  STUDY ENDPOINTS AND COVARIATES ...................................................................11 
4.1  Safety Endpoints .......................................................................................................11 
4.2  Efficacy Endpoints ....................................................................................................11 
4.3  Potential Covariate(s) ................................................................................................11 
5  DEFINITIONS ...................................................................................................................12 
5.1  Classification of Subjects ..........................................................................................12 
5.2  Study Day 1 ...............................................................................................................12 
5.3  Baseline .....................................................................................................................12 
5.4  Duration of Exposure ................................................................................................12 
5.5  Age ............................................................................................................................12 
5.6  Classification of Observable Seizures and Absence Seizures ..................................12 
5.7  Classification of Subjects at Baseline by Seizure Type for Rollover Subjects .........14 
5.8  Derived Seizure Efficacy Variables ..........................................................................15 
5.8.1 
Observable/Absence Seizure Frequency by Diary ......................................15 


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5.8.2 
Absence/Non-absence Seizure Frequency by EEG .....................................15 
5.9  Columbia Neurological Score (CNS) total score ......................................................15 
5.10  SF-10 Health Survey .................................................................................................15 
5.11  SF-12 Health Survey version 2 .................................................................................16 
6  ANALYSIS POPULATIONS ...........................................................................................17 
7  DATA SCREENING AND ACCEPTANCE ....................................................................18 
7.1  General Principles .....................................................................................................18 
7.2  Handling of Missing and Incomplete Data ...............................................................18 
7.2.1 
Missing Date of the Last Dose of Investigational Product ..........................18 
7.2.2 
Missing Medical History Related Dates (eg, diagnosis date) or Birth 
Dates ............................................................................................................18 
7.2.3 
Missing Date Imputation for Adverse Events and Concomitant 
Medications .................................................................................................19 
7.2.4 
Missing Causal Relationship to Investigational Product for Adverse 
Events ..........................................................................................................19 
7.2.5 
Visit Time Windows ...................................................................................20 
7.3  Testing/Validation Plan .............................................................................................21 
7.4  Software ....................................................................................................................21 
8  STATISTICAL METHODS OF ANALYSES ..................................................................22 
8.1  General Principles .....................................................................................................22 
8.2  Subject Accountability ..............................................................................................22 
8.3  Protocol Deviations ...................................................................................................22 
8.4  Demographic and Baseline Characteristics ...............................................................22 
8.5  Disease Characteristics and Medical History ............................................................22 
8.6  Prior and Concomitant Medication ...........................................................................23 
8.7  Investigational Product Administration ....................................................................23 
8.7.1 
Extent of Exposure ......................................................................................23 
8.7.2 
Measurement of Treatment Compliance .....................................................23 


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8.7.3 
Diet Diary Review .......................................................................................23 
8.8  Efficacy Analysis ......................................................................................................24 
8.9  Safety Analysis .........................................................................................................25 
8.9.1 
Adverse Events ............................................................................................25 
8.9.2 
Laboratory Parameters ................................................................................25 
8.9.3 
Vital Signs ...................................................................................................26 
8.9.4 
Physical Examination ..................................................................................26 
8.9.5 
Suicidal Ideation and Behavior ...................................................................26 
8.9.6 
PK Analyses ................................................................................................26 
9  REFERENCES ..................................................................................................................27 
10  APPENDICES ...................................................................................................................28 
10.1  Appendix A. Efficacy Endpoint Summary Table .....................................................28 
10.2  Appendix B. Schedule of Events ..............................................................................29 
10.3  Appendix C. Gastrointestinal Standardized MedDRA Query ..................................31 
 
List of Tables 
Table 1: Seizure Classification by Diary .................................................................................13 
Table 2: Seizure Classification by EEG ...................................................................................13 
Table 3:  Visit Time Windows for Scheduled Efficacy and Safety Assessments ....................20 
Table 4:  Visit Time Windows for Seizure Diary ....................................................................21 
 
List of Figures 
Figure 1: UX007G-CL202 Study Schema ..................................................................................9 
 


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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Curve 
CNS 
Columbia Neurological Scores 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
GEE 
generalized estimating equations 
GGT 
Gamma-glutamyl transpeptidase 
KD 
Ketogenic Diet 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
PCS 
Physical Component Summary 
PHS 
Psychosocial Summary Score 
PK 
Pharmacokinetics 
PSS 
Physical Summary Score 
PT 
Preferred Term 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-10 
Short Form-10 
SF-12 
Short Form-12 
SI 
Le Système International d’Unités (International System of Units) 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 


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ULN 
Upper Limit of Normal 
UX007 
Triheptanoin 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the UX007G-CL202 original protocol and all 
amendments through Protocol Amendment 3 dated 20 Sep 2017. This is the original version 
of SAP for this study. Changes from these guidelines must be substantiated by sound 
statistical reasoning and documented in the clinical study report (CSR). 


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2 STUDY OBJECTIVE(S) 
2.1 
Primary Objective 
 Evaluate the long-term safety of UX007 in Glut1 DS subjects 
2.2 
Secondary Objectives 
 Evaluate the long-term effect of UX007 efficacy on seizures associated with 
Glut1 DS 
 Evaluate the long-term effect of UX007 on health-related quality of life related to 
Glut1 DS 


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3 STUDY DESIGN 
UX007G-CL202 is an open-label, single-arm, multicenter extension study to assess the 
long-term safety and efficacy of UX007 in Glut1 DS. The study will enroll up to 40 pediatric, 
adolescent, and adult Glut1 DS subjects who have completed the UX007G-CL201 study and, 
at the discretion of the Sponsor, additional subjects who have participated in other clinical 
studies, Investigator-sponsored Trials (ISTs), or expanded access/compassionate use treatment 
programs. Figure 1 provides a schematic of the study design. 
Figure 1: 
UX007G-CL202 Study Schema 
 
For continuing UX007G-CL201 subjects, the Week 52 visit of that study may be conducted 
in conjunction with the Baseline visit for this study to avoid duplication of assessments. 
Following the Baseline visit, subjects will return to the study site at 3-month intervals from 
Baseline during Year 1 of the Treatment Extension, and 6-month intervals from Baseline 
during Years 2 and 3. Phone calls will take place 3-months between scheduled study site 
visits during Years 2 and 3 to collect adverse events and concomitant medications updates 
and to inquire about study drug consumption and remaining supply; in lieu of the phone call, 
subjects may also visit the clinic at the study site’s discretion. Additionally, optional study 
site visits may occur 3-months between scheduled study site visits during Years 2 and 3 to 
allow subjects to attain study drug as needed at the request of the Investigator. A Safety 
Follow-up Phone Call will be conducted 30-35 days after last dose of study drug. The last 
subject’s Safety Follow-up Phone Call is the End-of-study Time Point. Subjects will record 
seizure occurrence in a diary throughout the study; diet diaries will also be completed by the 
subject for the 3 days preceding each scheduled visit after Baseline. Overnight 
electroencephalograms (EEG) will be conducted in all subjects to monitor absence seizures. 
Safety assessments and a clinical neurological evaluation will further enable the 
characterization of long-term safety and maintenance of effect. Metabolites of UX007 in the 
blood will also be assayed.  
3.1 
Study Population 
The study will be conducted in pediatric, adolescent, and adult Glut1 DS patients (aged at 
least 1 year at the time of informed consent) who have successfully completed the associated 
Phase 2 study (UX007G-CL201) or, at the discretion of the Sponsor, additional subjects who 
Baseline
Treatment Extension
Year 1
(UX007 35% of total daily caloric intake)
Treatment Extension
Years 2‐3
(UX007 35% of total daily caloric intake)*
Study Visits Every 3 Months
Study Visits Every 6 Months
Day 0 
(UX007G‐CL201 Week 52)
Approximately 40 pediatric, adolescent, or adult subjects with Glut1 DS and additional IST subjects 
UX007G‐CL201
UX007 
Investigator‐
Sponsored Trials
* A safety follow‐up call will be completed 30‐35 days after the last dose of study drug


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participated in other clinical studies, ISTs, or expanded access/compassionate use treatment 
programs. Enrollment may include subjects from neighboring countries where clinical sites 
are located. Appropriate local or country requirements will be followed. All subjects in this 
study will have prior treatment exposure to UX007/triheptanoin. Refer to the protocol for 
detailed inclusion and exclusion criteria.   
3.2 
Dosage and Administration 
UX007 dosing will be targeted at 35% of total daily caloric intake throughout the study. 
Subjects receiving a different dose of UX007 at study entry may continue treatment at the 
current established dose. If a subject has been off UX007 treatment for > 1 month, the dose 
may be titrated at the discretion of the investigator. Enrolled subjects are able to maintain 
standard of care treatment with up to 3 anti-epileptic drugs (AEDs) throughout the duration 
of the study.  
3.3 
Blinding and Randomization Methods 
Not applicable. 
3.4 
Stratification Factors 
Not applicable. 
3.5 
Sample Size Considerations 
This study will enroll up to 40 pediatric, adolescent, and adult Glut1 DS subjects who have 
completed the UX007G-CL201 study and, at the discretion of the Sponsor, additional 
subjects from participated in other clinical studies, ISTs, or expanded access/compassionate 
use treatment programs. The sample size is intended to provide the maximum amount of 
information regarding UX007 long-term safety, along with indicators of sustained efficacy 
and durability of response in Glut1 DS patients.  
3.6 
Interim Analysis 
No interim analysis is planned for this study. Additional administrative analysis might be 
done at sponsor’s discretion to support regulatory submission or product planning. 
3.7 
Data Monitoring Committee 
Not applicable. 


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4 STUDY ENDPOINTS AND COVARIATES  
All data are collected according to the schedule of assessments (Appendix B). 
4.1 
Safety Endpoints 
 Subject incidenceand severity of Adverse events (AEs) and serious adverse events 
(SAEs) 
 Subject incidence of  treatment related AEs, AEs leading to discontinuation, fatal 
AEs, and Gastrointestinal AEs using the standardized MedDRA query (SMQ) as 
listed in Appendix C. 
 Prior and concomitant medication 
 Observed value of vital signs and weight during the study  
 Observed value of clinical laboratory test results and percentage of subjects who 
experience abnormal clinical laboratory results (i.e. outside of reference ranges) 
and/or clinically significant abnormalities 
 The number and percentage of subjects with suicidal ideation and behavior 
assessment as measured by the Columbia Suicide Severity Rating Scale (C-SSRS)  
 Physical examination 
 Pregnancy testing if applicable 
 
4.2 
Efficacy Endpoints 
 Reduction from baseline in frequency of seizures (normalized to a 4-week rate) 
during the study: Observable seizures from the diary will be used for Observable 
Seizures Subjects. For Absence Seizures Only Subject (See Section 5.7), the absence 
EEG data measured at the scheduled visit will be used. 
 Observed value and reduction from baseline in frequency of observable seizure and 
absence seizure (normalized to a 4-week rate) by seizure diary 
 Observed value and reduction from baseline in frequency of absence seizure and non-
absence seizure (normalized to a 24-hour rate) by EEG 
 Observed value and change from baseline in CNS total score 
 Observed value and change from baseline in SF-10 summary scores 
 Observed value and change from baseline in SF-12 domain/summary score 
 Plasma levels of UX007 metabolites 
4.3 
Potential Covariate(s) 
Not applicable. 


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5 DEFINITIONS 
5.1 
Classification of Subjects 
The following grouping of subjects will be applied in analysis: 
 Rollover subjects: include UX007G-CL201 study rollover subjects. 
 Non-Rollover subjects: include all other subjects including IST and expanded 
access/compassionate use subjects. 
5.2 
Study Day 1 
For all subjects, study day 1 is defined as the day of the first UX007 dose during study 
UX007G-CL202.  
5.3 
Baseline 
For Rollover subjects: 
The baseline defined in UX007G-CL201 study will be used for UX007G-CL202 study. 
For Non-Rollover subjects: 
In general, assessment performed on or prior to Month 0 visit (See Section 7.2.5, Error! 
Reference source not found.) in UX007G-CL202 study will be considered as study baseline 
for Non-Rollover subjects. The initial baseline (assessment prior to initial dose of UX007) is 
not available for Non-Rollover subjects. 
5.4 
Duration of Exposure  
Duration of exposure to UX007, in days is defined as: 
The last dose date of UX007 in UX007G-CL202 study – Study Day 1 + 1 day 
5.5 
Age 
Unless specified, age will be derived based on the informed consent date as Age = (Inform 
Consent Date in UX007G-CL202 study – Birth Date +1)/365.25. Age will be rounded down 
and keep 1 decimal place.  When date of birth is missing, then age recorded on case report 
form (CRF) at time of informed consent will be used. 
5.6 
Classification of Observable Seizures and Absence Seizures 
Table 1 shows the seizure classifications that are distinguished in the seizure diary, and 
which are counted towards study inclusion criteria and when deriving the observable seizures 
endpoints. 


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Table 1: Seizure Classification by Diary 
Seizure 
Code 
(Diary) 
Seizure Classification  
Counted 
Towards 
Inclusion 
Criteria 
Counted as 
Observable 
Seizure 
 
Counted as 
Absence 
Seizure 
A 
Generalized Tonic-Clonic  
X 
X 
 
B 
Generalized Tonic 
X 
X 
 
C 
Generalized Clonic 
X 
X 
 
D 
Generalized Atonic  
X 
X 
 
E 
Partial/Focal with Secondary Generalization 
X 
X 
 
F 
Myoclonic 
X 
X 
 
G 
Myoclonic (Astatic) Atonic 
X 
X 
 
H 
Myoclonic Tonic 
X 
X 
 
I 
Complex Partial/Focal 
X 
X 
 
J 
Simple Partial/Focal Motor 
X 
X 
 
K 
Simple Partial/Focal Sensory 
 
X 
 
L 
Simple Partial/Focal Psychological 
 
X 
 
M 
Typical Absence 
X [*] 
 
X 
N 
Atypical Absence 
X [*] 
 
X 
O 
Absence with Special Features (Myoclonic absence) 
X [*] 
 
X 
P 
Absence with Special Features (Eyelid myoclonia) 
X [*] 
 
X 
Q 
Unclassified (Inc. epileptic spasms) 
 
 
 
UNK 
Unknown 
 
 
 
[*] Note that for the 3 subjects in UX007G-CL201 study 
 seizure codes MNOP were not 
counted towards study inclusion criteria because they were randomized prior to the implementation of Protocol 
Amendment 3. 
See Table 2 below for the list of absence seizure types that are counted. 
Table 2: Seizure Classification by EEG 
Label 
Definition 
Absence 
Seizure 
Non-absence 
Seizure 
GenTC-BMS 
Generalized Tonic-Clonic 
 
X 
GenT-BMS 
Generalized Tonic 
 
X 
GenC-BMS 
Generalized Clonic 
 
X 
Partial-BMS 
Partial 
 
X 
AbsenceAwake-BMS 
Absence Awake (≥10sec) 
X 
 
AbsenceSleep-BMS 
Absence Sleep  (≥10sec) 
X 
 
IndetAbsenceAwake-BMS 
Indeterminate Absence Awake (3-10sec)  
X 
 
IndetAbsenceSleep-BMS 
Indeterminate Absence Sleep (3-10sec) 
X 
 
Myoclonus-BMS 
Myoclonus 
 
X 
PPD


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5.7 
Classification of Subjects at Baseline by Seizure Type for Rollover Subjects  
For UX007G-CL201 rollover subjects, the classification of subjects defined at randomization 
during UX007G-CL201 study will be used.  
 Observable Seizures Subject: a subject who meets any of the following: 
 Observable seizure frequency (types A, B, C, D, E, F, G, H, I, J, K and L; see 
Section 5.6:  Table 2) greater than or equal to 4 during the baseline period. 
 Observable seizure frequency less than 4 at randomization and absence seizure 
frequency less than 4 during the baseline period 
 Absence Seizures Subject: a subject who meets any of the following: 
 has seizure types M, N, O or P (see Section 5.6:  Table 2) recorded on the seizure 
diary during the baseline period 
 has absence seizures documented on the screening EEG 
 Absence seizure frequency (see Section 5.6, Table 2 and Section 5.8.2) greater than 0 
during the baseline period 
All subjects will either be an Observable Seizures Subject, an Absence Seizures Subject, or 
both. Since there is potential overlap, the following definitions are used to classify enrolled 
subjects into three mutually exclusive groups: 
 Observable Seizures Only Subject: a subject who is an Observable Seizures Subject but 
not an Absence Seizure Subject 
 Absence Seizures Only Subject: a subject who is an Absence Seizures Subject but not an 
Observable Seizure Subject 
 Both Seizures Subject: a subject who is both an Observable Seizures Subject and an 
Absence Seizure Subject 
Classification by seizure type at baseline is not defined for Non-Rollover subjects since all 
subjects in UX007G-202 study had prior treatment exposure to UX007 and there is no 
seizure diary measurement data prior to the initial UX007 treatment for Non-Rollover 
subjects. 


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5.8 
Derived Seizure Efficacy Variables 
5.8.1 
Observable/Absence Seizure Frequency by Diary 
Observable/Absence seizure frequency from the diary (normalized to a 4-week rate), is 
defined as: 
Observable/Absence Seizure Frequency ൌTotal number of seizures
Number of days observed ൈ28 
See Section 5.6, Table 2 for the list of observable/absence seizure types from diary that are 
counted.  For analyses, observable/absence seizure frequency from the diary will be defined 
for every 3 month during Year 1 and every 6 month during Year 2 and 3. Refer to 
Section 7.2.5, Table 3 for visit window mapping for seizure frequency by diary. 
5.8.2 
Absence/Non-absence Seizure Frequency by EEG 
The absence/non-absence seizure frequency from EEG (normalized to a 24-hour rate) is 
defined as: 
Absence/non-absence Seizure Frequency ൌTotal number of seizures
Number of hours observed ൈ24 
See Section 5.6, Table 2 for the list of absence/non-absence seizure types that are counted.  
Refer to Section 7.2.5, Table 3 for visit window mapping for seizure frequency by EEG. 
5.9 
Columbia Neurological Score (CNS) total score 
The CNS is the sum of scores for the following domains: Weight (max=1), Height (max=1), 
Head Circumference (max=1), General Medical Exam (max=13), Funduscopic Exam 
(max=4), Cranial Nerves (max=12), Stance & Gait (max=7), Involuntary Movements 
(max=7), Sensation (max=3), Cerebellar Function (max=8), Muscle Bulk, Tone & Strength 
(max=6), Myotatic Reflexes (max=10), Toe Sign (max=2), Other Findings (max=1).  
The CNS is only scored when all domains are measured and ranges from 0 (abnormal exam) 
to 76 (normal exam).  Higher scores are associated with higher neurological function. 
5.10 SF-10 Health Survey 
The SF-10 will be administered to caregivers of subjects aged 5 through 17 years. Responses 
are used to generate 2 component summary scores: Physical Summary Score (PSS) and the 
Psychosocial Summary Score (PHS).  
The T-score Based scoring (described in Section 5.11) is used to score the SF-10 
Health Survey for Children summary scales. The scale scores have been centered so  


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that a score of 50 corresponds to the average score in a comprehensive 2006 sample 
(a combination of general population and supplemental disability and chronic condition 
samples).  
5.11 SF-12 Health Survey version 2 
The SF-12 Health Survey version 2 is assessed for adults 18 years of age and older. Eight 
domain scores (Physical Functioning, Role Limitations due to Physical Health, Bodily Pain, 
General Health Perceptions, Vitality, Social Functioning, Role Limitations due to Emotions 
Problems, and Mental Health) are calculated from raw scores. And additionally, the domain 
scores are used to generate 2 component summary scores: physical health (PCS) and mental 
health (MCS). 
Raw scores range from 0 to 100 with higher scores indicating better health. Domain scores 
are calculated from raw scores such that domain scores have a mean of 50 and SD of 10. 
The PCS and MCS summary component scores also have mean of 50 and SD of 10 to allow 
comparisons with domain scores. 
Scoring the SF-12 version 2 is accomplished using T-score Based scoring software from 
Quality Metric Inc. (Lincoln, RI). T-score Based scoring is standardized across the SF family 
of adult tools using the means and standard deviations from the 2009 U.S. general 
population. The T-score Based scores in the U.S. general population have a mean of 50 and a 
standard deviation of 10. The Medical Outcomes Study (MOS) tools utilize 2009 t-scores.  
T-score based scoring method scores the data in relation to U.S. general population t-scores. 
Therefore, all scores obtained that are below 50 can be interpreted as below the U.S. general 
population t-score and scores above 50 can be interpreted as above the U.S. general 
population t-score. 


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6 ANALYSIS POPULATIONS 
Full Analysis Set (FAS): consists of all enrolled subjects who received at least one dose of 
investigational product during the study. 
Full Analysis Set – SF-10 (FAS – SF-10): consists of the subset of subjects in the full 
analysis set who had a non-missing baseline. 
Full Analysis Set – SF-12v2 (FAS – SF-12v2):  consists of the subset of subjects in the full 
analysis set who had a non-missing baseline. 


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7 DATA SCREENING AND ACCEPTANCE 
7.1 
General Principles 
Data will be reviewed periodically and any questionable data will be reported to the clinical 
data manager promptly for query and resolution. 
7.2 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified through the data quality review plan for this study.  Missing and incomplete data 
will be identified for investigation, and possible resolution, by Data Management prior to the 
study database lock or snapshot. 
Unless specified otherwise, only the observed data (not imputed data) will be presented in 
listings. 
For efficacy analyses related to seizure diary or EEG, the following imputation rules will be 
applied for subjects with incomplete diary/EEG data, 
 For subjects who have incomplete diary data, observable/absence seizure frequency will 
be calculated by averaging over the days with complete diary data during the 
corresponding visit period. 
 For subjects who have incomplete EEG, absence/non-absence seizure frequency will be 
calculated by averaging over the time that is complete during the corresponding visit 
time, even if the EEG is not done overnight.  
7.2.1 
Missing Date of the Last Dose of Investigational Product  
When the date of the last dose of investigational product is missing for a subject, all efforts 
should be made to obtain the date from the Investigator. If after all efforts are made it is still 
missing, the last visit date will be used as the last dose date. 
7.2.2 
Missing Medical History Related Dates (eg, diagnosis date) or Birth Dates 
 If only day is missing, impute 1. 
 If month is missing, impute January 1st. 
 If year is missing, then no imputation will be done; the date will be missing.  
If the imputed date is earlier than the birth date, then the birth date will be used. 


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7.2.3 
Missing Date Imputation for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.   
Missing Start Dates 
 If the day is unknown, then: 
o If the month and year match the first dose of investigational product start date 
month and year in this study, then impute the day of the first dose date. 
o Otherwise, assign the first day of the month. 
 If the month is unknown, then: 
o If the year matches the year of the first dose of investigational product date in 
this study, then impute the month and day of the first dose date in this study. 
o Otherwise, assign ‘January’  
 If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
If the imputed date is earlier than birth date, then birth date will be used. If the imputed start 
date is later than the end date, then the start date will be set as the same date as the end date. 
Missing Stop Dates and not ongoing 
 If the day is unknown, then assign the last day of the month. 
 If the month is unknown, then assign ‘December.’ 
 If the year is unknown, then the date will not be imputed and will be assigned a 
missing value, and the event will be considered ongoing. If the AE has been recorded 
as resolved/recovered, all efforts should be made to obtain the date from the 
Investigator. 
If the resulting end date is after the date of study completion / discontinuation/ data 
cutoff, set the imputed end date as close to the date of study completion / discontinuation/ 
data cutoff as possible without overwritten existing information 
If the year is missing for the start date, and stop date (observed or imputed) is on or after the 
first dose or event is ongoing. The start date will be imputed as the first dose date. 
7.2.4 
Missing Causal Relationship to Investigational Product for Adverse Events 
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of investigational product, a causality of “definitely related” 
will be assigned. The imputed values for causal relationship to investigational product will be 
used for the incidence summary; the values will be shown as missing in the data listings. 


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7.2.5 
Visit Time Windows 
For all scheduled efficacy and safety assessments except seizure diary, the visit window 
assigned and the corresponding target treatment days during which an actual visit may occur 
is specified in Table 3.  
Termination visit for subjects who didn’t complete the study, and unscheduled visits will be 
mapped to the closest post baseline scheduled visits if the scheduled visits are missing. If there 
are more than one unscheduled/end of study visits mapped to the same window, the one closer to 
the target day will be used. If more than one visit has the equal distance to the target day then the 
later one will be used, if more than one visits on the same day, use the time or the sequence 
number to select the later record. For listings and shift tables, all data points will be included. 
For assessments where both the planned study visit and an unscheduled visit or early 
termination visit corresponding to that study visit are both available, the planned study visit 
will be used for the analysis. 
In general, all summary tables by visit include all scheduled assessments per schedule of 
assessments. For seizure diary data to measure, it will be mapped to time period between the 
visit time points as specified in Table 4 and will be used to define observable seizure 
frequency (refer to Section 5.8.1). If a subject misses a visit, then the expected visit date will 
be used in place of the actual visit date to define observable seizure frequency. Expected visit 
date is the date of the previous visit + the expected number of days between the previous visit 
and the missing visit. If the previous visit is also missing, then the expected date of the 
previous visit would be used instead. 
Table 3: 
Visit Time Windows for Scheduled Efficacy and Safety Assessments 
Period 
Visit 
Scheduled Visit Day 
Window 
Treatment Year 1 
Month 0 
Day 1 
Days ≤ 1 
 
Month 3 
Day 92 
Days [2, 138] 
 
Month 6 
Day 184 
Days [139, 230] 
 
Month 9 
Day 276 
Days [231, 322] 
 
Month 12 
Day 368 
Days [323, 414] 
Treatment Year 2 - 3 
Month 18 
Day 552 
Days [507, 598] 
 
Month 24 
Day 736 
Days [691, 782] 
 
Month 30 
Day 920 
Days [875, 966] 
 
Month 36 
Day 1104 
Days [1059, 1150] 
       *Number of days in 3-month visit period = (365.25/12) * 3 ≈ 92 days 
 


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Table 4: 
Visit Time Windows for Seizure Diary 
Period 
Visit Period 
Scheduled Visit Day 
Window* 
Treatment 
Year 1 
Month 0 – 3 
Day 1 – Day 92 
Days ≤ 1 – Study Day of Month 3 visit 
 
Month 4 – 6 
Day 93 – Day 184 
Study day of Month 3 visit + 1 – Study day of 
Month 6 visit 
 
Month 7 – 9 
Day 185 – Day 276 
Study day of Month 6 visit + 1 – Study day of 
Month 9 visit 
 
Month 10 – 12 
Day 277 – Day 368 
Study day of Month 9 visit + 1 – Study day of 
Month 12 visit 
Treatment 
Year 2 - 3 
Month 13 –  18 
Day 369 – Day 552 
Study day of Month 12 visit + 1 – Study day of 
Month 18 visit 
 
Month 19 – 24 
Day 553 – Day 736 
Study day of Month 18 visit + 1 – Study day of 
Month 24 visit 
 
Month 25 – 30 
Day 737 – Day 920 
Study day of Month 24 visit + 1 – Study day of 
Month 30 visit 
 
Month 31 – 36 
Day 921 – Day 1104 
Study day of Month 30 visit + 1 – Study day of 
Month 36 visit 
*refer to Table 3 for visit window of each visit time point. 
Study Day is calculated as (visit date – date of the first dose in UX007G-CL202 study + 1), if visit date is on or 
after the date of the first dose in UX007G-CL202 study; and as (visit date – date of the first dose), if visit date is 
before the date of the first dose in UX007G-CL202 study. 
7.3 
Testing/Validation Plan 
Data will be reviewed by cross functional team periodically and issues will be addressed by 
clinical data management.  
7.4 
Software 
SAS® software version 9.4 or higher will be used to perform statistical analyses unless 
otherwise specified. 


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8 STATISTICAL METHODS OF ANALYSES 
8.1 
General Principles 
All statistical tests will be two-sided and tested at statistical significant level of 0.05. 
The statistical analyses will be reported using summary tables, figures, and data listings. 
Continuous variables will be summarized by number of subjects and mean, standard 
deviation (SD), median, minimum, and maximum values. Categorical variables will be 
summarized by number and percentage of subjects. All raw data obtained from the CRFs will 
be included in data listings. In general, analysis will be performed for Rollover subjects and 
Non-Rollover subjects, separately.  
8.2 
Subject Accountability 
The number and percentage of subjects in the Full Analysis Set, Full Analysis Set – SF-10 
and Full Analysis Set – SF-12v2 will be summarized by subject group and subject seizure 
type.  Subjects excluded from the analysis sets will be listed. The number and percentage of 
subjects who complete the study, and who prematurely discontinue will be presented. 
The reasons for premature discontinuation from treatment as recorded on CRFs will be 
summarized as well.   
8.3 
Protocol Deviations 
Protocol deviations will be summarized for the Full Analysis Set. Both major and minor 
protocol deviations will be listed. 
8.4 
Demographic and Baseline Characteristics 
For all subjects, age at informed consent in UX007G-CL202 study will be presented. 
Other demographic parameters (e.g., gender, race, ethnicity and age at Glut1 DS diagnosis) 
and other baseline characteristics measured at baseline of the feeder study will be used for 
Rollover subjects. For Non-Rollover subjects, demographic and other baseline characteristics 
measured at the baseline of UX007G-CL202 study will be used. 
8.5 
Disease Characteristics and Medical History 
Summary statistics will be presented for the Full Analysis Set, for the following parameters: 
 Duration of Glut1 DS symptom 
 Glut1 DS mutation description 
 Glut1 DS symptoms history including whether ongoing 
 Ketogenic Diet (KD) history and reason for KD discontinuation 
 Seizure history by type 
 Average number of observable seizures per month over the last 6 months 


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For Rollover subjects, medical history recorded at the baseline of the UX007G-CL201 study 
and the current study will be used. For Non-Rollover subjects, medical history recorded at in 
the current study will be used. 
8.6 
Prior and Concomitant Medication 
For Rollover subjects, prior medication will be defined as any medication taken before the 
first dose in the UX007G-CL201 study. For Non-Rollover subjects, prior medication will be 
defined as any medication taken prior to the first dose of UX007 in the current study. 
Concomitant medication is defined as any medication taken during the study between the day 
of the first dose of the investigational product and the day of the last dose of the 
investigational product in UX007G-CL202 study. A medication started before the date of the 
first dose of investigational product and also taken after the date of first dose of 
investigational product will be counted both as a prior and concomitant medication.  
Both prior and concomitant medications will be coded by drug name and therapeutic class 
using World Health Organization (WHO) Drug Dictionary. The number and proportion of 
subjects receiving each reported prior and concomitant medication will be summarized by 
Anatomical Therapeutic Chemical (ATC) code and preferred term for the Full Analysis Set. 
Multiple uses by a subject of the same drug will be counted only once in the summary tables. 
8.7 
Investigational Product Administration 
8.7.1 
Extent of Exposure 
Exposure duration to UX007 will be summarized for the Full Analysis Set.  
8.7.2 
Measurement of Treatment Compliance 
Number of days during a visit period is calculated as (end of visit period date – start of visit 
period date + 1). Percent of days missed for a period is 100×(number of days during the visit 
period with dose non-compliance)/(number of days during the period). Descriptive statistics 
for dosing compliance will be summarized. Number and percent of days with missing dose 
will also be summarized. 
8.7.3 
Diet Diary Review 
The following measures will be summarized by visit based on the 3-day Diet Diary Review: 
 Average Study Drug Calories, as calculated as the average of the 3 entries for study 
drug 
 Average Total Daily Calories 


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8.9 
Safety Analysis 
All safety analysis will be performed using the Full Analysis Set. No statistical comparisons 
will be performed. 
8.9.1 
Adverse Events 
The latest Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
AEs to a system organ class (SOC) and preferred term.  
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurred on or after the first dose in this study, and was not present prior to the 
first dose in this study, or it was present at the first dose in this study but increased in severity 
during the study.  
Subject incidence of TEAEs will be tabulated by SOC and preferred term. Serious TEAEs, 
treatment-related TEAEs, grade 3/4 TEAEs, fatal TEAEs, TEAEs leading to study 
discontinuation, and TEAEs leading to treatment discontinuation will be summarized. 
Gastrointestinal TEAE will also be summarized. 
Detailed listings for all AEs, SAEs, treatment related TEAEs, treatment related SAEs, AEs 
leading to the discontinuation, and death will also be generated. The severity will be based on 
Common Terminology Criteria for Adverse Events (CTCAE). If an AE cannot be graded 
based on CTCAE, the investigator will assign a severity based on 1 = mild, 2 = moderate, 
3 = severe, 4 = life threatening, and 5 = Death related to AE. 
8.9.2 
Laboratory Parameters 
Clinical laboratory values (in SI units) at each assessment time point will be summarized for 
laboratory parameters in hematology, chemistry and urinalysis. 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 by laboratory measurement. 
The clinical laboratory parameters include the following: 
 Chemistry: Alanine aminotransferase (ALT), Alkaline phosphatase, Aspartate 
aminotransferase (AST), Bilirubin (total), Blood urea nitrogen (BUN), Calcium, 
Chloride, Serum creatinine, Gamma-glutamyl transpeptidase (GGT), Serum glucose, 
Potassium, Protein (albumin and total), Sodium, Creatine Kinase 
 Hematology: Hematocrit, Hemoglobin, Platelet count, Red blood cell (RBC) count, 
White blood cell (WBC) count 
 Urinalysis: Appearance, Color, pH, Specific gravity, Ketones, Protein, Glucose, 
Pregnancy test (if applicable) 


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Hy’s Law criteria will be applied against test results. Subjects with serum total bilirubin >2 x 
ULN and ALT or AST >3 x ULN will be considered positive for Hy’s law status. Results 
will be presented in shift tables. For Hy’s Law, shift tables will be produced:  
 Hy’s Law negative at baseline, remaining Hy’s Law negative throughout the study  
 Hy’s Law negative at baseline, becoming Hy’s Law positive at any point during the 
study  
 Hy’s Law positive at baseline and Hy’s Law negative throughout the study  
 Hy’s Law positive at baseline and Hy’s Law positive at any point during the study  
A data listing of all subjects who are Hy’s Law positive will be produced. 
8.9.3 
Vital Signs 
The following vital signs and weight will be summarized by time point. 
 Temperature (°C) 
 Respiration Rate (breaths/min) 
 Heart Rate (beats/min) 
 Systolic Blood Pressure (mmHg) 
 Diastolic Blood Pressure (mmHg) 
 Weight (kg) 
8.9.4 
Physical Examination 
Physical examinations will include assessments of general appearance; head, eyes, ears, nose, 
and throat; the cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, 
genitourinary, musculoskeletal, and neurologic systems. Physical examination abnormality 
findings will be listed over time by subject.  
8.9.5 
Suicidal Ideation and Behavior  
The number and percentage of subjects with suicidal ideation or suicidal behavior will be 
presented at study baseline and post-baseline by category. If more than one suicidal ideation 
or suicidal behavior was reported for the same period/visit, the one with greatest severity will 
be used for the same visit in the summary. 
8.9.6 
PK Analyses 
Plasma levels of UX007 metabolites will be summarized using descriptive statistics. 


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Page 27 
9 REFERENCES 
Not applicable. 
 


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Statistical Analysis Plan  
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Page 28 
10 APPENDICES 
10.1 Appendix A. Efficacy Endpoint Summary Table 
Endpoint 
Statistical 
Method 
Analysis 
Population 
Reduction from baseline in frequency of 
seizures up to first year 
GEE 
FAS 
(Rollover subjects) 
Frequency of seizures 
Descriptive statistics 
FAS 
(Rollover subjects) 
Frequency of seizures  
Descriptive statistics 
FAS 
(Non-Rollover subjects) 
Frequency of observable/absence seizures 
by seizure diary 
Descriptive statistics 
FAS 
Frequency of absence/non-absence 
seizures by EEG 
Descriptive statistics 
FAS 
CNS total score 
Descriptive statistics 
FAS 
SF-10 summary scores 
Descriptive statistics 
FAS – SF10 
SF-12 domain/summary score 
Descriptive statistics 
FAS – SF12v2 


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Statistical Analysis Plan  
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10.2 Appendix B. Schedule of Events 
VISIT NUMBER 
1 
2 
3  
4 
5 
TC 
6 
TC 
7 
TC 
8 
TC 
9 
SAFETY 
FOLLOW 
UP PC14 
MONTH 1 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36/ET 
 
Informed Consent 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seizure incidence (diary 
review) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Overnight EEG 4 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
Columbia Neurological Score 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
SF-10 or SF-12v2 (age-
appropriate instrument) 5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
UX007 Metabolites 6 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital Signs & Weight 7 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical Examination 8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Clinical Laboratory Tests 9  
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy Test (if 
applicable) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Suicidal Ideation & Behavior 
Assessment 10 
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 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietitian Consultation & Diet 
Diary 11 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Dispense Study Drug 12 
X 
X 
X 
X 
X 
X12 
X 
X12 
X 
X12 
X 
X12 
 
 
Treatment Compliance & 
Accountability 13 
 
X 
X 
X 
X 
X13 
X 
X13 
X 
X13 
X 
X13 
X 
 
*Refer to the Study Reference Manual for a recommended schedule of the assessments during the 1-day and 2-day visits. The Investigator may use clinical 
judgment in deciding whether to administer certain assessments to subjects based on age, development, and cognitive ability, as appropriate. The SF-10/SF-12v2 


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will not be performed if no pre-treatment baseline is available from feeder study (e.g. subjects entering from ISTs or subjects from UX007G-CL201 or other 
Ultragenyx-sponsored clinical studies who were too young or compromised at pre-treatment Baseline).  
1 The Baseline Visit may occur in conjunction with the last scheduled visit from study UX007G-CL201 to avoid duplication of assessments. If the time elapsed 
between the last UX007G-CL201 study visit and the Baseline Visit for this study is > 1 month, the full panel of Baseline Visit assessments must be completed. 
Subjects will return to the clinic at 3-month intervals during Treatment Extension Year 1 (± 1 week), and 6-month intervals during Years 2 and 3 (± 2 weeks).  
Reporting of adverse events and concomitant medications at Months 15, 21, 27, and 33 will be completed via telephone call (TC) or optional study site visit; 
visits to the study site at these time points are not required and are optional at the subject’s discretion.   
2 Minors who reach legal age during the course of the study must provide written informed consent when eligible.  
3 Medical history includes subject demographics, triheptanoin treatment history, and Glut1 DS diagnosis, and will be collected only for subjects not previously 
enrolled in UX007G-CL201. 
4 A 2-day visit is required to complete the overnight EEG. 
5 If a subject is under 5 years of age at informed consent, the SF-10 will not be administered during the Extension study.  If a subject turns 18 years of age during 
the study, the SF-12v2 will be administered beginning at the next study visit. 
6 Blood samples for UX007 metabolites will be drawn approximately 90 min following consumption of food and study drug. 
7 Vital sign measurements consist of seated systolic/diastolic blood pressure (millimeters of mercury), heart rate (beats per minute), respiration rate (breaths per 
minute), and temperature in degrees Celsius (°C).  Vitals to be obtained at the beginning of each visit before any additional assessments are completed.  
8 Physical examinations include assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, respiratory, 
gastrointestinal, musculoskeletal, and neurologic systems. 
9 Clinical laboratory tests include standard serum chemistry, hematology, and urinalysis.  Fasting is not required. 
10 The Columbia Suicide Severity Rating Scale (C-SSRS) baseline questionnaire will be administered on the initial visit; the Since Last Visit questionnaire will 
be administered at all subsequent visits. 
11 At the Baseline visit, an interview with the study dietitian will establish daily caloric intake and UX007 dose.   Subjects and/or caregivers are required to 
maintain a record of the subject’s daily diet in a diary for the 3 days prior to each subsequent visit.  The diet diary will be reviewed by study personnel at each 
visit to the clinic.  The dietitian may telephone subjects and/or caregivers, as needed, to provide dietary advice and support. 
12 A subject may have been off UX007 treatment prior to enrollment; in these cases, UX007 may be titrated per discretion of the investigator.  Study drug 
dispensation is not required at the Months 15, 21, 27, or 33 but may be dispensed to subjects who opt to return to the study sites for these visits.  
13 Refer to Pharmacy Manual for instructions on return of empty and opened study drug bottles.  Treatment compliance and accountability will only be evaluated 
at Months 15, 21, 27, and 33 for those subjects who opt to return to the study sites for these visits.   
14 Safety Follow-up Phone Call to be conducted 30-35 days after last dose of study drug. The last subject’s Safety Follow-up Phone Call is the End-of-study Time 
Point. The site personnel will initiate this safety follow-up telephone call to collect information on any ongoing or new AEs, serious adverse events (SAEs), and 
concomitant medications. Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, are resolved.


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