Clinical trial NCT01993186
Conditions: Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Keywords: Glucose Transporter Type 1 Deficiency Syndrome Glut1
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2014-02-28; Completion date: 2017-09-20
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of the study are to evaluate the efficacy of UX007 compared to placebo as measured by the reduction from randomization to Week 8 in frequency of seizures and to evaluate the safety of UX007 via adverse event (AE) rates, laboratory values, and electrocardiogram (ECG).

Detailed description:

Arms: arm 1: Participants randomized to receive UX007 enter a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

Following completion of the Week 8 study visit, participants continue treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52). arm 2: Participants randomized to receive placebo enter a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

Following completion of the Week 8 study visit, placebo participants continue treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Interventions: intervention 1: UX007 intervention 2: Placebo
Intervention descriptions: intervention 1: oral liquid intervention 2: oral liquid

Protocol documents:
Prot_000.pdf: 
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PPD


Protocol Number:  UX007G-CL201  
Amendment 1 – 04 OCT 2013  
 
 
 
Proprietary and Confidential 
Page 2 of 83 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL201 Amendment 1 
04 October 2013  
 
 
The Original Protocol version of Protocol UX007G-CL201 (dated 07 August 2013) has been 
modified by Amendment 1 to incorporate a number of changes based on additional 
information acquired since the beginning of the study, feedback from clinical investigators 
involved in the study, and review by the United States Food and Drug Administration (US 
FDA).  The major changes to the protocol are summarized below; additional minor changes 
have also been made for consistency and clarity but are not included in this summary. 
1. Sponsor’s Responsible Medical Officer and associated contact information have been 
updated to:  Emil Kakkis, MD PhD, Chief Executive Officer, Ultragenyx.   
2. Study Sites.  The number of study sites has increased from 8 to 10 sites globally.  
3. Number of Subjects Planned.  If the interim analysis criteria have been met, the 
additional enrollment has been changed to 30-90 subjects, for a total of 
80-140 subjects. 
4. Study Procedures and Assessments.  The following modifications have been made to 
the Schedule of Events (Table 2.1) and Study Procedures and Assessments 
(Section 7.5): 
• The visit to the site previously indicated at Week 2 will now be conducted by 
telephone.  The Week 4 visit (originally a telephone visit) will now be conducted 
at the clinic and include clinical assessments of secondary efficacy variables (i.e. 
CANTAB, 6MWT, and GMFM-88). 
• In lieu of the Borg Scale referenced in the ATS guideline, the Borg Rating of 
Perceived Exertion (RPE) will be used to assess PED occurring during the test. 
• The 24-hour EEG has been changed to an overnight EEG.   
• At Week 26, a Population PK assessment has been added which requires a total of 
3 blood samples (pre-dose for all subjects and 2 additional specimens 30-180 
minutes post-dose).   
• Table 2.1 has been modified to list efficacy assessments in order of administration 
and reflect the range allowed to collect the sample for the Erythrocyte Glucose 
Uptake Assay (i.e. once during Week 26, 39, or 52 Visits). 


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• The requirement to complete a 3-day diet diary following dose adjustment was 
removed. 
Rationale:  During the 8-week placebo-controlled Treatment Period, visits to the 
clinic will now be conducted at 4-week intervals.  A telephone assessment of seizure 
incidence and safety/tolerability will take place at the end of the 2-week dose titration 
period.  At Week 4, all subjects will be stable at the maximum dose of study drug, 
providing for additional assessment of safety and efficacy during the placebo-
controlled phase of the study. 
Changes in the conduct of the 6MWT and associated PED assessment provide 
clarification of proper study procedures. 
The duration of EEG monitoring has been shortened to minimize discomfort and 
inconvenience to the subject.  A minimum of 12 hours EEG monitoring is believed to 
provide sufficient data to assess the frequency of EEG seizures and interictal 
epileptiform discharges.  
The changes to PK and Bioassays are consistent with the study objectives and provide 
for a population PK assessment (as requested by the FDA) in addition to peak PK and 
metabolites.  Modifying the range of visits for the Erythrocyte Glucose Uptake Assay 
provides greater flexibility and opportunity to obtain the sample in conjunction with 
other blood draws, thereby minimizing additional procedures for the subject. 
A 3-day diet diary is used solely for the purposes of establishing caloric intake, and 
not necessary following dose adjustment during the Titration Period. 
5. Primary Efficacy Hypothesis.  The primary efficacy hypothesis as stated in Section 
5.5 has been modified as follows: 
“The primary efficacy hypothesis for the study is that UX007 is superior to more 
effective than placebo for the treatment reduction of seizures in patients with Glut1 
DS…” 
Rationale:  The revised language provides a more accurate description of the 
statistical methodology planned for the study. 
6. Study Objectives, Efficacy Measures and Endpoints.  There is no change to the 
primary efficacy measure; the primary objective language has been modified as 
follows: 
“Evaluate the efficacy of UX007 compared to placebo between Weeks 2 and 8 of 
treatment as measured by the median percent reduction from baseline in frequency of 
generalized or partial-onset seizures” 


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Secondary and exploratory objectives and associated efficacy measures/endpoints of 
the study have been modified as outlined below: 
Modifications to Study Objectives, Efficacy Assessments and Endpoints 
Objective/Efficacy Measure 
Related To: 
Original Protocol 
Designation 
Amended Protocol 
Designation 
Description of Change 
Seizure response 
rate/frequency & EEG 
abnormalities 
Secondary 
Secondary 
Seizure response rate is now 
defined as the percentage of 
subjects with ≥50% 
reduction from baseline in 
generalized or partial-onset 
seizures. 
Frequency of EEG 
abnormalities is now a 
separate objective. 
6MWT 
Secondary 
Secondary 
Modified objective to 
specify distance walked and 
combine with PED 
GMFM-88 
Secondary 
Secondary 
No change 
CNS 
Secondary 
Exploratory 
Moved 
CANTAB 
Secondary 
Secondary 
Generalized objective to 
“cognitive function” 
CGI-S/CGI-I 
Secondary 
Exploratory 
Moved 
Time to event assessment of 
seizures 
Exploratory 
Secondary analysis of 
primary endpoint 
To be defined in the SAP 
Within cohort analysis  
Exploratory 
N/A 
Deleted 
PED 
Exploratory 
Secondary 
Moved and combined with 
6MWT as above 
Gait analysis 
Exploratory 
Exploratory 
Modified to include base of 
support 
Removed requirement for 
GAITRite walkway 
Beery-VMI, RCPM 
Exploratory 
Optional Exploratory 
Site-specific assessments 
only 
PPVT, SF-10, PEDI-CAT, PK 
Exploratory 
Exploratory 
No change 
EEG: degree of background 
slowing 
Exploratory 
N/A 
Deleted 
Long-term safety, persistence 
of effect, suicidal 
ideation/behavior 
Exploratory 
Removed from 
objectives 
Not a specific study 
objective; conducted as 
safety analyses 


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Rationale:  Upon further consideration of pre-specified endpoints and the potential 
implications for statistical analysis and interpretation of the data, the primary 
objective language has been modified, and a number of secondary endpoints have 
now been designated as exploratory endpoints. The secondary endpoints are focused 
on independent domains of disease: 1) motor dysfunction, 2) cognitive dysfunction, 
and 3) absence and unrecognized seizure activity by EEG count.  We will also assess 
the fraction of patients achieving a clinically large response of 50% reduction in 
seizures.  The secondary objectives and associated efficacy endpoints will now focus 
on the following: 
• Seizure response rate, defined as the percentage of subjects with at least 50% 
reduction from baseline in generalized or partial-onset seizures 
• Change from baseline in frequency of seizure activity as measured by 
electroencephalography (EEG) abnormalities 
• Change from baseline in cognitive function using the Cambridge 
Neuropsychological Test Automated Battery (CANTAB)  
• Change from baseline in distance walked as measured by 6MWT 
• Time to onset of paroxysmal exertional dyskinesia (PED) as measured during 
6MWT. 
• Change from baseline in gross motor function using the Gross Motor Function 
Measure-88 (GMFM-88)  
 
7. Inclusion Criteria.  The inclusion criteria have been modified as follows: 
1) “Confirmed diagnosis of Glut1 DS Diagnosis of Glut1 DS confirmed by SLC2A1 
mutation” 
7)  “Not on, or not fully compliant with a prescribed diet plan (e.g. ketogenic diet) 
comprised of at least 50% total daily caloric intake from fat during previous 60 
days (confirmed by 3-day diet diary at Screening), or at any time during the 
course of the trial” 
Rationale.  The change to inclusion criterion #1 specifies all subjects must have the 
diagnosis of Glut1 DS confirmed by genetic analysis of SLC2A1 mutations, thereby 
providing added assurance that the study population is consistent with the proposed 
indication.  The mutation analysis must be completed prior to study entry; Ultragenyx 
will not collect additional blood samples for SLC2A1 mutation analysis as previously 
indicated in Section 7.5.4.1 Medical History.  The change to inclusion criterion #7 
provides a degree of guidance to the investigator in assessing a potential subject’s 
level of compliance with a prescribed diet plan. 


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8. Treatment Administration.   
A recommended dose titration schedule has been inserted (Table 7.4.1).  In addition, 
dose administration guidelines have been modified as follows: 
“Treatment will be mixed with food and administered PO with food or by 
gastronomy tube at least four times per day (breakfast, lunch, dinner, and before 
bed).  The dose should be divided into smaller more frequent doses with food as 
needed.  The dose should always be mixed with small amounts of food or drink as 
indicated in the administration guideline, and never administered as the oil 
directly.” 
Rationale:  The original protocol specified initiation of dosing using a 2-week fixed 
titration schedule until the subject has reached a target of 35% of total daily calories 
by the end of the period.  The table provides recommended guidelines for the 
titration, while providing for some degree of discretion by the investigator for 
individual subject needs.  
By removing the provision to administer study drug by mixing with drink, and 
assuring the oil is never directly administered will provide more consistent dosing 
across the study population and reduce the potential risk of GI-associated adverse 
reactions. 
9. Drug Concentration Measurements.  As described in Section 7.5.3, a population PK 
assessment will replace the planned PK sampling for peak UX007 and metabolites at 
Week 26.  Samples will be obtained pre- and post-dose as specified in the Schedule of 
Events.  The assessment will take place irrespective of the study adaptation decision. 
Rationale: The additional population PK assessment will further characterize the PK 
properties of UX007 at steady-state, including trough levels, following 6 months of 
continuous treatment. 
10. Pregnancy Testing.  A provision to perform a serum pregnancy test if pregnancy test 
by urine is not feasible has been added to the protocol (Section 7.5.4.6). 
Rationale: The addition of the serum pregnancy test option provides flexibility for the 
site and the subject, as both methods will provide an accurate assessment of 
pregnancy status. 
11. Suicidal Ideation and Behavior Assessments.  The Ask Suicide Screening Questions 
(ASQ) has been replaced by the Columbia Classification Algorithm of Suicide 
Assessment (C-CASA) to assess suicidal ideation and behavior in this study.  
The timing and age range for the assessment remain as specified in the original 
protocol. 


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Rationale:  The Columbia algorithm has been used to classify suicidal adverse events 
in an antidepressant safety analysis by the US FDA.  The US FDA has recommended 
the use of the C-CASA as a standardized suicidal rating system for anticonvulsant 
trials and other centrally acting agents and nonpsychotropic drugs. 
12. Statistical Methods.  Populations for data analyses have been defined (Section 7.6.2).  
The description of the primary efficacy endpoint analysis has been generalized to 
state an appropriate rank-based analysis will be applied, instead of pre-specifying the 
2-sided Wilcoxon Rank Sum test (Section 7.6.3).  The secondary efficacy analyses 
will compare the secondary efficacy variables scores after treatment to before 
treatment between the treated and placebo groups (Section 7.6.4).  An alpha-
spending function will be used to adjust the type-I error significance level for the 
interim and final analysis (Section 7.6.6).  The sample size assumptions for the 
maximum of 140 subjects have been provided in Section 7.6.8.  
Rationale: While full-details of planned statistical analyses will be presented in a 
formal Statistical Analysis Plan, the revised information provides transparency as 
pre-specified changes from the original protocol. 


Protocol Number:  UX007G-CL201  
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL201 Amendment 2 
20 May 2014 
 
 
The amended version of Protocol UX007G-CL201 (Amendment 1, dated 04 October 2013) 
has been modified by Amendment 2 to incorporate a number of changes based on additional 
information acquired since the beginning of the study, feedback from clinical investigators 
involved in the study, and review by Health Authorities.  The major changes to the protocol 
are summarized below; additional minor changes have also been made for consistency and 
clarity but are not included in this summary. 
1. Sponsor’s Responsible Medical Officer and associated Medical Monitor contact 
information (Section 8.5.6) have been updated to: 
Javier San Martin, MD, Vice President, Clinical Development, Ultragenyx. 
2. Number of Subjects Planned.  Section 7.8.6 has been revised to reflect statistical 
assumptions for the interim analysis used to determine enrollment and sample size 
re-estimation.  An interim analysis will now be conducted after approximately 
16 subjects have completed the double-blind Treatment Period.  If the interim 
analysis criteria have been met, the total number of subjects has been changed from 
80 - 140 to now be 40-100 subjects.  If the interim analysis criteria are not met, 
the study will continue as a Phase 2 study until ~40 subjects have been enrolled.  
The previous protocol stated subjects may be replaced after receiving study drug and 
prior to Week 8.  This has been amended such that subjects who withdraw or are 
removed from the study prior to randomization may be replaced on a case-by-case 
basis, at the discretion of Ultragenyx (Section 7.3.3). 
Rationale:  As described in Section 7.6.10, for the study to be adequately powered as 
a pivotal study, a sample of approximately 40 completed subjects was estimated to be 
adequate to detect a 50% between-group difference in seizure rate per 4 weeks with 
power of 80% and population standard deviation of 55% using Wilcoxon’s rank sum 
test.  
3. Primary Efficacy Hypothesis.  Section 5.5 has been modified as follows to clarify 
specific seizure types to be investigated as part of the primary efficacy hypothesis. 


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UX007 is more effective than placebo for the reduction of seizures in patients with 
Glut1 DS, as measured by the reduction from baseline in frequency of generalized or 
partial- onset seizures, including: 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 seizures, between Weeks 2 and 8 of 
treatment.   
4. Study Objectives.  The following objectives have been modified or added to Section 6 
to align study objectives with modifications to study design and endpoints: 
Modified Primary Objectives: 
• Evaluate the efficacy of UX007 compared to placebo, between Weeks 2 and 
8 of treatment, as measured by the reduction from the Baseline Period in 
frequency of generalized or partial-onset seizures 
Modified Secondary, Exploratory, and Optional Exploratory Objectives: 
The periods during which the efficacy of UX007 compared to placebo will be 
evaluated have been modified from “change from baseline” to specify either 
change from Randomization or the Baseline Period  
Additional Secondary Objectives: 
• Evaluate long term efficacy as measured by changes from baseline in 
frequency of generalized or partial-onset seizures over time through week 52 
• Evaluate the optimal dose to control seizures and impact on other clinical 
manifestations during the Dose Exploration Period  
Additional Exploratory Objective: 
• Evaluate the efficacy of UX007 compared to placebo, between Weeks 2 and 8 
of treatment, as measured by the reduction from the Baseline Period 
frequency of absence seizures 
5. Overall Study Design and Plan.  Section 7.1 has been modified to include a Dose 
Exploration Period which will be conducted in a subset of approximately 40 subjects.  
The remaining subjects enrolled will continue with the optimal dose achieved during 
the previous 26 weeks. The study schematic (Figure 7.1.1) has been modified to 
reflect the design change.  Specific rationale for the selection of 20 and 40% dose 
levels is provided in Section 7.4.4.1.  The Dose Exploration Period is described as 
follows: 


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Following the Week 26 visit, approximately the first 40 subjects will participate in a 
10-week Dose Exploration Period to assess the impact of UX007 dose level on 
seizure control, other clinical manifestations such as movement disorders and 
cognitive deficits, and tolerability. For subjects participating in the Dose Exploration 
Period, the dose will be titrated over 1 week down to 20% of total daily caloric 
intake.  After 4 weeks at the 20% dose level, the subject will be evaluated for safety 
and efficacy measures of seizure control, motor and cognitive function. 
If there are breakthrough seizures during the down titration period, as defined by an 
increase in frequency of 1 seizure in a 4 week period [except absence], relative to the 
previous 4 week period on a stable UX007 dose, or in the opinion of the investigator 
there has been a worsening of symptoms prior to completion of the 4 week period, 
the subject may begin the up-titration phase early. 
After 4 weeks at the 20% dose level, the UX007 dose will then be titrated up over 
1 week to 40% of total daily caloric intake and maintained at that level for 4 weeks. 
If a subject cannot tolerate titrating up to the 40% dose level, the dose should be 
titrated to the maximum tolerated dose as determined by the Investigator.  After 4 
weeks at the 40% (or maximum tolerated) dose level, the subject will be evaluated for 
safety, and efficacy measures of seizure control, motor and cognitive function. 
At the end of the Dose Exploration Period, the subject will continue in the open-label 
Extension period, and maintained on the UX007 dose (as determined by the 
Investigator) that provided the maximum improvement in clinical status with 
acceptable tolerability, and continued on this dose for the duration of the study. 
If marked improvements in clinical status were not observed at a higher dose level 
and/or tolerability was unacceptable, the subject will return to the UX007 dose level 
where maximal benefit was achieved as defined by seizure control and improvements 
in motor and/or cognitive symptoms.  As determined by the Investigator, this may be 
the pre-titration UX007 dose from Week 26 or the 20% dose given during the down 
titration phase. 
Rationale (also provided in Section 7.2):  A dose exploration evaluation in 
approximately 40 subjects has been added to the protocol to determine whether the 
proposed dose is the optimal and necessary dose for UX007 to control seizures and 
impact other clinical manifestations. The demonstration of a withdrawal effect 
(with an exit clause that would allow the subject to more quickly move to the up 
titration phase if there is a marked change in clinical status during the down titration 
phase), and a return to control afterward would demonstrate both that a higher dose 
was necessary and that UX007 had a sustained effect. 
6. Inclusion Criteria:  Section 7.3.1 has been modified as follows: 
2)  Males and females, aged 3 - 17  1 – 35 years (inclusive) at the time of informed 
consent 


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3) Average of at least 5 4 observable seizures (generalized [except absence] or 
partial-onset [simple partial motor, complex partial, or secondarily generalized] 
seizures) per month in 4 weeks over the last 6 months 24 weeks, by subject or 
caregiver report 
4) At least 4 observable seizures (generalized [except absence] or partial-onset 
[simple partial motor, complex partial, or secondarily generalized] seizures) per 
month in 4 weeks during the Baseline Period, with no 3-week seizure-free period 
during the Baseline Period 
7) Not on, or not fully compliant with a prescribed diet plan (e.g. ketogenic diet) 
comprised of at least 60% 50% total daily caloric intake from fat during previous 
60 14 days (confirmed by 3-day diet diary at Screening), or at any time during the 
course of the trial) 
12) Females who have reached menarche of childbearing potential must have a 
negative pregnancy test at Screening, be willing to use acceptable method of 
contraception and have additional pregnancy tests during the study. Females 
considered not of childbearing potential include those who have not reached 
menarche, had total hysterectomy, have been in menopause for at least two 
years, or have had tubal ligation at least one year prior to Screening. 
Rationale:  The United States Food and Drug Administration (FDA) has 
recommended expanding recruitment to include patients younger than 3 years.  
Clinical experience with triheptanoin and nonclinical data with UX007 support 
dosing of children as young as 6 months of age.  A GLP 3-month interim toxicology 
study in juvenile Yucatan Mini-Pigs which ran concurrently as part of the 9 month 
chronic toxicity study to allow dosing in younger age groups, has been completed; 
interim results have been inserted in Section 5.2.2. 
The patient population was further expanded to also include adult subjects up to 
35 years of age.  The trial investigators have noted there are adult Glut1 DS patients 
who continue to have a similar phenotype of breakthrough seizures into their thirties, 
significant movement disorders (estimated at 90% by De Vivo), and have a more 
difficult time maintaining the ketogenic diet. The expanded age range of the 
population will strengthen the ability to evaluate a possible impact on seizures and 
movement disorders. 
Modifications to inclusion criteria #3 and 4 provide alignment with study endpoints 
used to capture seizure frequency. 


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Based on feedback from investigators and experts in the field, inclusion criterion 
#7 was modified to increase the percent of calories from fat to 60% in a prescribed 
diet.  The change aligns with standard practices.  In addition, these investigators and 
experts in the field noted the potential for carryover effects from ketogenic or other 
high-fat prescribed diets are minimal, and a 7-14 day washout period would be more 
than adequate for patients who wish to discontinue or are non-compliant with current 
diet plans.  Therefore, the duration required to demonstrate non-compliance (or no 
treatment) with a prescribed diet plan has been reduced to 14 days to minimize the 
time a potential subject would be without adequate dietary control of their condition, 
and thereby minimize burden and possible risk to the individual.  In addition, 
guidance was added to Section 7.5.4.11 that subjects should be below 25% dietary fat 
(not including the oil) on the day of randomization and throughout the trial.  
The rationale is that if patients are on a diet with >25% dietary fat, then they could 
possibly become ketotic with the addition of placebo oil at 35% of caloric intake. 
Modifications to inclusion criterion #12 provide alignment with the expanded age 
range for eligible patients. 
7. Investigational Product.  To ensure adequate blinding of the investigational product 
during the double-blind Treatment Period, 1000 mL UX007 and placebo will be 
provided in 1 L round amber-colored glass bottles. During the open-label Extension 
Period of the study, UX007 will be dispensed in 1 L round, translucent high-density 
polyethylene (HDPE) bottles (Section 7.4.1).  A provision to allow mixing of 
UX007 (or placebo) with formula has been included given the revised age range of 
the study population. 
8. Prohibited Medications.  Barbituates and prescribed high-fat diets (e.g. ketogenic 
diet) have been added to the list of medications prohibited throughout the study 
(Section 7.4.6.1). 
Rationale: Barbituates may inhibit the Glut1 transporter, thereby confounding 
efficacy and interpretation of study results.  As required for study inclusion, 
the subject must not be on, or compliant with a prescribed high-fat diet plan, 
and should not participate in such a plan throughout the course of the study. 
9. Study Procedures and Assessments. The following modifications have been made to 
the Schedule of Events (Table 2.1) and Study Procedures and Assessments 
(Section 7.5): 
• Subjects participating in the Dose Exploration Period will return for 2 additional 
visits to assess efficacy, pharmacokinetic/metabolites, and safety following 
1 week titration and 4-weeks treatment at each dose level (i.e. Weeks 31 and 36, 
within a 3 day visit window). 
• The visit previously scheduled at Week 39 has been changed to Week 44. 
• Peabody Picture Vocabulary Test will be administered at select sites only. 


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Rationale:  Several components of efficacy and safety will be measured before and 
after each titration during the Dose Exploration Period to assess change in efficacy, 
safety and tolerability.  These will include change in seizure frequency, cognition 
(i.e. CANTAB, PPVT), motor function (i.e. 6MWT, GMFM-88), EEG abnormalities 
(Week 31 only), levels of triheptanoin metabolites, AE rate, and changes in 
assessments of how the subject is doing (i.e. PEDI-CAT, CGI).  Given the 
2 additional visit requirements at Weeks 31 and 36, the Week 39 visit was moved out 
to Week 44.    
10. Efficacy Measures.  The following changes have been made to Section 7.5: 
• The description of the primary efficacy measure (Section 7.5.2.1) has been 
modified to clarify seizure types defined and recorded in the study diary.   
• The Borg Rating of Perceived Exertion (RPE) has been removed as an assessment 
during the 6-minute walk test (6MWT).   
• The severity of paroxysmal exertional dyskinesia (PED) will be assessed by the 
physical therapist, not the subject as previously indicated. 
• The frequency of absence (and other) seizures as captured in the study diary has 
been defined as an exploratory measure (Section 7.5.2.2).  
• The Short-Form 12 (SF-12) Health Survey for adults will be administered to adult 
subjects as an exploratory measure.  
Rationale:  The listing of specific seizure types provides alignment with the study 
diary.  Following review of the study protocol, the US FDA requested the daily diary 
be used in addition to electroencephalography to document absence and myoclonic 
seizures.   
The Borg RPE scale was removed as it is not possible to capture perceived exertion in 
the middle of the 6MWT.  In addition the scale is difficult for children to comprehend 
and many subjects have cognitive impairment. The physical therapist is trained to 
assess the severity of PED events, as such PED severity will not be assessed by the 
subject. 
Since the age range of the population has expanded to include young children and 
adults, age-appropriate modifications have been made to the secondary and 
exploratory efficacy measures.  The SF-12 was included to assess functional health 
and well-being in adult subjects (as a parallel assessment to the SF-10 in children). 
11. Drug Concentration Measurements.  Based on feedback received from the FDA, 
Section 7.5.3 has been modified to specify the trough (pre-dose) population 
PK sample will be obtained within 15 minutes of dosing.  Additional PK samples 
will also be obtained should potentially related serious adverse events occur, if 
feasible. 


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12. Pregnancy Testing.  The language in Section 7.5.4.6 has been modified to specify 
unknown risks and detail acceptable methods of contraception, including abstinence, 
for females and males of childbearing potential. 
13. Suicidal Ideation & Behavior Assessments.  Section 7.5.4.7 has been corrected to 
describe the Columbia-Suicide Severity Rating Scale (C-SSRS) as the instrument 
used to prospectively assess suicidal ideation and behavior. 
14. Statistical Analysis & Determination of Sample Size.  Section 7.6 has been updated to 
mention the handling of missing, unused, or spurious data, and include the 
aforementioned clarifications, additional endpoints, interim analyses, and 
determination of sample size. The analysis populations have been further defined. 
The FDA also requested a secondary analysis for the potential of tachyphylaxis 
(i.e., long term efficacy). 
 
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL201 Amendment 3 
09 Dec 2014 
 
 
The amended version of Protocol UX007G-CL201 (Amendment 2, dated 20 May 2014) has 
been modified by Amendment 3 to incorporate a number of changes based on additional 
information acquired since the beginning of the study, from feedback provided by clinical 
investigators involved in the study, and review by Health Authorities.  The major changes to 
the protocol are summarized below; additional minor changes have also been made for 
consistency and clarity but are not included in this summary. 
1. Sponsor’s Responsible Medical Officer and associated Medical Monitor contact 
information (Section 8.5.6) have been updated to: 
Sunil Agarwal, MD, Chief Medical Officer. 
2. The adaptive study design component of the protocol was eliminated. This change 
was carried throughout the protocol and the title of the study was updated to reflect 
this change.   
Rationale:  An interim analysis to adapt this study design is no longer planned. The 
plan is to look at the totality of the data from this Phase 2 study to determine what 
additional studies will be needed to better characterize the safety and efficacy of 
UX007 in patients with Glut1 DS. 
3. 
Inclusion criteria 3 and 4 were updated to include subjects with treatment-resistant 
absence seizures. This change was also updated in multiple sections of the protocol; 
the term absence seizure includes both typical and/or atypical absence seizures.  
Rationale: The inclusion criteria are being updated to also include subjects that have 
only absence seizures (based on medical history and Screening EEG). This change is 
secondary to recently published data by Pascual et al., which demonstrated clinical 
activity of triheptanoin in patients with Glut1 DS with absence seizures. In this study 
patients receiving triheptanoin demonstrated a reduction in their rate of absence 
seizures and improvements in their neuropsychological performance (Pascual et al. 
2014). 
 


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4. Inclusion criterion #3 was updated to allow for fewer observable seizures in 4 weeks 
over the last 24 weeks; originally set at 4, this amendment reduces the observable 
seizures to 2. 
Rationale: This will allow potentially for the inclusion of more subjects into the study 
without compromising the ability to detect a signal with UX007, assuming UX007 
meaningfully reduces seizure activity.  
5. Inclusion criterion #9 was removed; subjects no longer are required to be naïve to 
UX007. 
Rationale: Taking into account the short-lived pharmacokinetic and 
pharmacodynamics profile of UX007, there should be no residual effect of UX007 if 
subjects have not been exposed in the past 30 days prior to screening. Additionally, 
taking into account the Screening period, the time off of drug would be even longer 
than 30 days.   
6. Inclusion criterion #6 was updated to clarify that “up to” 3 concomitant AEDs are 
allowed for inclusion into the study. 
  
Rationale: This change was made for clarification. 
7. 
The primary and secondary objectives of the study were updated (refer to the 
synopsis and Section 6). Similarly, the criteria for evaluation (synopsis and Section 
7.5) and the primary and secondary endpoints (Section 7.6) were updated to reflect 
the changes to the objectives to include a more robust evaluation of triheptanoin in 
patients with absence seizures.   
Rationale: This change was made for clarification since we are now including 
patients who can qualify based on absence seizures only. This change was made 
secondary to the recent publication by Pascual et al. as referenced earlier.   
8. 
The randomization was changed from 1:1 to 3:1 (UX007: placebo).  
Rationale: This change was based on discussions with caregivers of patients with 
Glut1 DS. The caregivers have stated that in a disease for which seizures are a 
primary manifestation, a 50% chance of receiving placebo has not been acceptable to 
the majority of potential patients and their families. Also, appreciating that this is a 
Phase 2 study and the fact that this change to the randomization schema will also 
enable the collection of additional safety data on subjects who receive UX007 during 
the study, the sponsor believes this change is clinically appropriate.  
 
 


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9. 
An EEG assessment was added at the Screening Visit.  
Rationale: The decision to add an EEG assessment at the Screening Visit is to 
confirm the diagnosis of absence seizures for patients who potentially qualify for the 
study based on a history of absence seizures. EEG is well recognized as the most 
reliable method to capture absence seizures, whereas for other seizure types a patient 
history is considered clinically acceptable.  
10. Study drug accountability in Section 8.3 was clarified to indicate that study drug will 
be properly packaged for transport by the subject or for shipment by the clinical site. 
Rationale: This text was clarified to ensure a clear process for chain of custody of 
study drug. 
11. Selection of Study Population in Section 7.3 was updated to clarify that enrollment 
may include subjects from neighboring countries within the European Union, Canada, 
and South America. 
Rationale: There are limited investigative sites participating in this study and 
because Glut1 DS is a rare disease, there may be subjects from neighboring countries 
who may be considered for study participation. 
12. Exclusion criterion #5 was changed to read “pregnant and/or breastfeeding an infant 
at Screening” from “breastfeeding an infant at Screening.” 
Rationale: This change was made for clarification that both pregnant and 
breastfeeding subjects will be excluded from participation in the study.    
13. Section 7.3.3 (Removal of Subjects from Therapy or Assessment) was updated to 
clarify the conditions under which subjects either will be removed or may be removed 
from study participation. 
Rationale: It was important to clarify that subjects will be removed when an 
unacceptable AE occurs or if an illness occurs that (in the judgment of the investigator 
or Ultragenyx) might invalidate the study or place the subject at risk. Alternatively, 
subjects may be removed if requested (by subject, investigator, or Ultragenyx) for 
administrative/other reasons or if the subject has a protocol deviation or exhibits 
unreliable behavior. 
 


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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL201 Amendment 4 
30 Nov 2015 
 
The amended version of Protocol UX007G-CL201 (Amendment 3, dated 09 December 2014) 
has been modified by Amendment 4 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 and other experts in the field.  The major changes 
to the protocol are summarized below; additional minor changes have also been made for 
consistency and clarity but are not included in this summary. 
1. Sponsor’s Responsible Medical Officer and associated Medical Monitor contact 
information (Section 8.5.5) have been updated to Melanie Brandabur, MD, Medical 
Director. In addition, the safety contact information in Section 8.5.5 has been 
updated. 
2. Edited Inclusion Criterion #2 to state that all subjects at least 1 year of age are eligible 
for participation in this study. There is no longer an age limit of 35 years in the study. 
This change affected the synopsis and Section 7.3.1 of the protocol.  
Rationale: This change was made to allow inclusion of subjects regardless of age. 
3. Edited Inclusion Criterion #7 by removing specific instructions regarding percent of 
daily fat intake.  
Rationale: This change was made for clarity. 
4. Updated Exclusion Criterion #1 to allow for subjects to have serum alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceeding 3X 
(previously 2X) the upper limit of normal at Screening.  
Rationale: This change was made to be more consistent with agency guidelines for 
industry regarding drug-induced liver injury. USDHHS FDA, CDER, CBER, 2009.  
5. Updated Section 7.4.6.1 of the protocol to remove valproate as a prohibited 
medication and include pancreatic lipase inhibitors in the list of excluded 
medications. A list of these medications was added to Exclusion Criterion 6. 
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). 


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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. 
6. Updated Section 8.5.1 (Definition of Adverse Events) with the following text: “Note 
that hospitalizations planned prior to study enrollment (e.g., for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs.” 
Rationale: Updated for clarification of the SAE definition. 
7. Updated Section 8.5.4 (Adverse Event Reporting to Ultragenyx) 
Rationale: Updated to match the current Ultragenyx template. 
8. Primary objective changed to ‘Evaluate the efficacy of UX007 compared to placebo 
as measured by the reduction from randomization to week 8 in frequency of seizures’. 
This change affects multiple sections of the protocol related to statistical evaluations 
and analyses.   
Rationale: To correctly reflect that the primary endpoint is to measure change in 
seizure frequency for all seizure types, including absence seizures, as was the intent 
with the previous amendment. 
9. The text “at select sites” is now used consistently for the Pediatric Evaluation of 
Disability Inventory – Computer Adaptive Test (PEDI-CAT) and Gross Motor Function 
Measure-88 (GMFM-88) assessments in the schedule of events and body of protocol.   
Rationale: This change was made for clarification. 
10. The EEG at Screening for patients with absence seizures only is required for 
~3 hours, not overnight.   
Rationale: This change was made for patient convenience.  
11. The Erythrocyte Glucose Uptake Assay has been removed from the protocol. This 
change affects the schedule of events (Table 2.1) and Section 7.5.3.   
Rationale: This change was made to reduce patient burden. 
12. Plasma level sample collection range for the population PK study at Week 26 was 
changed from 30 – 180 minutes to 60 and 180 minutes.   
Rationale: In consultation with a PK expert/advisor, sampling timepoints have been 
defined as 60 and 180 minutes post-dose.  


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2 SYNOPSIS 
TITLE OF STUDY: 
A randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy 
of UX007 in subjects with glucose transporter type 1 deficiency syndrome 
PROTOCOL NUMBER: 
UX007G-CL201 
STUDY SITES: 
Approximately 15 sites globally 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
Glucose Transporter Type 1 Deficiency Syndrome (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 treatment 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 represent the subgroup of Glut1 DS patients who are most in need of an alternative therapy to 
the KD.  Given the significant unmet medical need in Glut1 DS patients not on KD, UX007 will be 
studied in this subgroup.  
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.  
The seizures due to Glut1 DS are most prominent in the pediatric population and are typically 
refractory to AEDs.  For these reasons, the proposed Phase 2 study is designed to assess the safety and 
efficacy of UX007 in reducing the frequency of seizures in the pediatric population (and older patients 
who are still having seizures) that are not able to comply with or tolerate the KD. The study will also 
evaluate the pharmacokinetics (PK) of energy-containing metabolites and correlate these to the 
potential treatment effects.   
OBJECTIVES: 
The primary objectives of the study are to:  
• 
Evaluate the efficacy of UX007 compared to placebo as measured by the reduction from 


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randomization to week 8 in frequency of seizures. Observable generalized and partial-onset 
seizures measured for 6 weeks by diary and absence seizures measured overnight by 
electroencephalography (EEG). 
• 
Evaluate the safety of UX007 via adverse event (AE) rates, laboratory values, and 
electrocardiogram (ECG) 
The secondary objectives of the study are to: 
• 
Evaluate the efficacy of UX007 compared to placebo, as measured by: 
- Seizure response rate, defined as the percentage of subjects with at least 50% reduction 
from randomization to week 8 in frequency of seizures  
- Change from randomization to Week 8 in cognitive function using the Cambridge 
Neuropsychological Test Automated Battery (CANTAB) 
- Change from randomization to Week 8 in distance walked as measured by 6MWT 
- Time to onset of paroxysmal exertional dyskinesia (PED) as measured during 6MWT 
from randomization to Week 8 
- Change from randomization to Week 8 in gross motor function using the Gross Motor 
Function Measure-88 (GMFM-88) 
• Evaluate long-term efficacy as measured by changes from randomization in frequency of 
seizures over time through Week 52  
• 
Evaluate the optimal dose to control seizures and impact on other clinical manifestations during 
the Dose Exploration Period  
Exploratory objectives are to:  
• 
Evaluate the effects of UX007, from randomization through Weeks 8 and 52 on: 
- Neurological function using the Columbia Neurological Score (CNS) 
- Physician global impression of change in clinical status using the Clinical Global 
Impression - Severity scale (CGI-S) and Clinical Global Impression - Improvement scale 
(CGI-I) 
- Receptive vocabulary using the Peabody Picture Vocabulary Test (PPVT) 
- Subject or caregiver-reported quality of life using Short Form-10™ (SF-10) Health Survey 
for Children or SF-12 for adults 
- Functional disability by caregiver report using the Pediatric Evaluation of Disability 


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Inventory – Computer Adaptive Test (PEDI-CAT) 
- Gait, using gait analysis by computerized mat 
- PK properties of UX007 and its metabolites 
Exploratory objectives are to evaluate the effects of UX007, from randomization through Weeks 8 
and 52 on (to be administered at select sites): 
• 
Visual motor integration using the Beery-Buktenica Developmental Test of Visual Motor 
Integration (Beery-VMI) 
• 
Spatial understanding and abstract reasoning using the Raven’s Coloured Progressive Matrices 
(RCPM) 
PRIMARY EFFICACY HYPOTHESIS: 
UX007 is more effective than placebo for the reduction of seizures in patients with Glut1 DS, 
as measured by the reduction from randomization in frequency of generalized or partial-onset seizures, 
including: Generalized Tonic-Clonic, Generalized Tonic, Generalized Clonic, Generalized Atonic, 
Partial/Focal with Secondary Generalization, Myoclonic, Myoclonic Atonic, Myoclonic Tonic, 
Complex Partial/Focal, Absence, and Simple Partial/Focal Motor seizures. 
STUDY DESIGN AND METHODOLOGY: 
UX007G-CL201 is a randomized, double-blind, placebo-controlled, parallel-group study to assess the 
safety and efficacy of UX007 in Glut1 DS.  The study will enroll approximately 40 pediatric, 
adolescent, and adult subjects who are currently not on, or not compliant with a KD or other high fat 
diet.  Enrolled subjects are otherwise able to maintain standard of care treatment with up to 3 AEDs 
throughout the duration of the study.  
Beginning with the Screening visit, subjects will record seizure frequency during the 6-week Baseline 
Period.  If the subject does not meet the seizure count criteria, the subject will be considered a screen 
failure and will not be randomized.  At the end of the Baseline Period, eligible subjects will be 
randomized in a 3:1 ratio to either UX007 or placebo.  Dosing will be initiated using a 2-week titration 
schedule until the subject has reached 35% of total daily calories from study drug (~1-4 g/kg/day 
depending on age).  If a subject has not reached the target of 35% of total daily calories by the end of 
the 2-week titration period, dose titration should continue until the maximum tolerated dose is 
reached.  
After the initial 8-week double-blind Treatment Period, the open-label Extension Period will begin, 
wherein all subjects will be treated with UX007 through Week 52 of the study.  A population-PK 
analysis at Week 26 will provide data on metabolite levels with all subjects on UX007.  Following the 
Week 26 visit, all 40 subjects will participate in a 10-week Dose Exploration Period to assess the 
impact of UX007 dose level on seizure control, other clinical manifestations such as movement 
disorders and cognitive deficits, and tolerability.  At the end of the Dose Exploration Period, the 


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subject will continue in the open-label Extension period, maintained on the UX007 dose (as 
determined by the Investigator) that provided the maximum improvement in clinical status with 
acceptable tolerability, and continued on this dose for the duration of the study.  Long term safety and 
maintenance of effect of UX007 will be assessed during the Extension Period.   
Figure 2.1 provides a schematic of the study design.  Subjects who complete treatment through 
Week 52 may have the option to continue UX007 treatment, if warranted, in a separate open-label 
extension study.   
Figure 2.1:  UX007G-CL201 Study Schema 
 
NUMBER OF SUBJECTS PLANNED: 
The study will enroll approximately 40 pediatric, adolescent, and adult subjects who are currently not 
on, or not compliant with a KD or other high fat diet.  Subjects who withdraw or are removed from the 
study prior to randomization may be replaced on a case-by-case basis, at the discretion of Ultragenyx. 
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 confirmed by SLC2A1 mutation  
2) 
Males and females at least 1 year of age at the time of informed consent 
3) 
Average of at least 2 observable seizures (generalized or partial-onset [simple partial motor, 
complex partial, absence, or secondarily generalized seizures) in 4 weeks over the last 
24 weeks, by subject or caregiver report 
4) 
At least 2 observable seizures (generalized or partial-onset [simple partial motor, complex 
partial, or secondarily generalized seizures) in 4 weeks during the Baseline Period, with no 
3-week seizure-free period during the Baseline Period OR absence seizures documented on 
Screening
Baseline on SOC*
(6 wks)
3:1 Randomization
Double-Blind, Placebo-Controlled 
Treatment Period (8 wks)
2 wks
Titration
Placebo (safflower oil) + SOC*
Open-Label 
Extension Period
(18 wks)
UX007 + SOC*
*SOC: Standard of Care 
(up to 3 stable AEDs)
UX007 (triheptanoin) + SOC*
Target Dose 20%
Caloric Intake
(4 wks)
Target Dose 40%
Caloric Intake
(4 wks)
Target Dose 35%
Caloric Intake
Individualized
Target Dose (16 wks)
Dose Exploration (~40 subjects)
1 wk Titration


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Screening EEG  
5) 
Continuing to have seizures despite a prior or current use of at least 1 AED 
6) 
Allowed to be on up to 3 concomitant AEDs that must have been stable in dose at least 
2 weeks prior to the beginning of screening and anticipated to remain stable in dose through 
the end of the 8-week, placebo-controlled Treatment Period 
7) 
Not on, or not fully compliant with a prescribed diet plan (e.g. KD)   
8) 
Plasma level of beta-hydroxybutyrate (BHB) ≤ 1 mmol/L (non-fasting) at Screening 
9) 
Provide written or verbal assent (if possible) and written informed consent by a legally 
authorized representative after the nature of the study has been explained, and prior to any 
research-related procedures 
10) 
Must, in the opinion of the investigator, be willing and able to complete all aspects of the 
study, comply with accurate completion of the seizures diary, and likely to complete the 
8-week, placebo-controlled, Treatment Period 
11) 
Females of childbearing potential must have a negative pregnancy test at Screening, 
be willing to use an acceptable method of contraception, and have additional pregnancy tests 
during the study. Females considered not of childbearing potential include those who have 
not reached menarche, had total hysterectomy, have been in menopause for at least two 
years, or have had tubal ligation at least one year prior to Screening. 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 
exceeding 3X the upper limit of normal at Screening 
2) Any known hypersensitivity to triheptanoin or safflower oil that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects 
3) Prior use of triheptanoin within 30 days prior to Screening 
4) History of, or current suicidal ideation, behavior and/or attempts  
5) Pregnant and/or breastfeeding an infant at Screening  
6) Participants unwilling or unable to discontinue use of a prohibited medication 
(Section 7.4.6.1 [MCT oil, barbiturates, pancreatic lipase inhibitors, KetoCal or other KD 
supplements, and/or KD]) or other substance that may confound study objectives  
7) Use of any investigational product (drug or supplement, including medium chain 


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triglyceride [MCT] oil) within 30 days prior to Screening, or at any time during the study 
8) Has a condition of such severity and acuity, in the opinion of the investigator, that it 
warrants immediate surgical intervention or other treatment 
9) 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 introduces additional 
safety concerns (e.g., diabetes mellitus, other concurrent neurological or psychiatric 
disorders)  
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: 
UX007 (triheptanoin) is a colorless to yellow oil.  During the 8 week double blind period of the study 
1000 mL UX007 will be provided in 1 L round amber colored glass bottles. During the open label 
Extension Period of the study, UX007 will be dispensed in 1 L round, translucent high-density 
polyethylene (HDPE).  
UX007 is titrated over 2 weeks to a dose of 35% of total daily caloric intake.  During the Dose 
Exploration Period, the dose will be titrated down over 1 week to 20% of total daily caloric intake.  
If there are breakthrough seizures during the down titration period, as defined by an increase in 
frequency of 1 seizure in a 4 week period, relative to the previous 4 week period on a stable UX007 
dose, or in the opinion of the investigator there has been a worsening of symptoms prior to completion 
of the 4 week period, the subject may begin the up-titration phase early.  The UX007 dose will then be 
titrated up over 1 week to 40% of total daily caloric intake and maintained at that level for 4 weeks. If 
a subject cannot tolerate titrating up to the 40% dose level, the dose should be titrated to the maximum 
tolerated dose as determined by the Investigator. 
At the end of the Dose Exploration Period, the subject will 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. If marked improvements in clinical status were not observed at 
a higher dose level and/or tolerability was unacceptable, the subject will return to the UX007 dose 
where maximal benefit was achieved as defined by seizures control and improvements in motor and/or 
cognitive symptoms. 
UX007 is a liquid, intended for oral (PO) administration.  UX007 will 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.  The dose should always be mixed with small amounts of food as indicated in the 
administration guidelines and never administered as the oil directly. 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: 
Placebo will consist of safflower oil matching the appearance of UX007.  Dose level and mode of 
administration will be identical to that of UX007 during the double-blind Treatment Period. 


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DURATION OF TREATMENT: 
The planned duration of treatment in this study is 52 weeks, consisting of an 8-week placebo-
controlled, double-blind Treatment Period, followed by a 44-week open-label Extension Period.  
Within the open-label Extension Period, up to 40 subjects will participate in a 10-week Dose 
Exploration Period, beginning after the Week 26 visit.  All subjects who have completed the 8-week 
Treatment Period will be eligible for the Extension Period, during which all subjects will receive 
UX007; no placebo will be administered during the Extension Period.   
CRITERIA FOR EVALUATION: 
Efficacy: 
Primary Efficacy Variable:    
• 
Seizure frequency reduction: Percent reduction from randomization to week 8 in frequency of 
seizures.  Observable generalized and partial-onset seizures measured for 6 weeks by diary 
and absence seizures measured overnight by electroencephalography (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, and Simple Partial/Focal Motor and Absence. 
Secondary Efficacy Variables*: 
• 
Seizure response rate: Percentage of subjects with at least 50% reduction from randomization to 
week 8 in frequency of seizures 
• 
Observable seizures via diary: Observable seizure frequency reduction and observable seizure 
response rate as measured by diary 
• 
Absence seizures via EEG: Absence seizure frequency reduction and absence seizure response 
rate as measured by EEG   
• 
Cambridge Neuropsychological Test Automated Battery:  Neuropsychological function measured 
using a standardized, computerized battery of tests designed to assess visual memory, working 
memory, new learning and reaction time 
• 
Six Minute Walk Test:  Walking ability measured by the total distance walked (meters) in a 
6-minute period.  The percent of predicted normal distance walked will be determined. 
• 
Paroxysmal Exertional Dyskinesia: Time to onset of PED as observed during the 6MWT  
• 
Gross Motor Function Measure-88:  Gross motor function evaluated using a standardized 
observational measure of abilities in the following 5 domains: lying/rolling, sitting, 
crawling/kneeling, standing, and walking/running/jumping (at select sites) 


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Exploratory Efficacy Variables*: 
• 
Columbia Neurological Score:  Neurological findings in 12 domains quantitated to produce a total 
score ranging from 0-76 
• 
Clinical Global Impression - Severity scale and Clinical Global Impression - Improvement scale:  
The global impression of disease severity at baseline (CGI-S) and the degree of change in clinical 
status (CGI-I) as assessed by a physician 
• 
Peabody Picture Vocabulary Test:  Receptive vocabulary measured using picture tests 
administered by a clinician (at select sites) 
• 
Short-Form Health Surveys (SF-10 for Children OR SF-12):  Quality of life as measured by 
subject or caregiver-reported physical and mental health status 
• 
Pediatric Evaluation of Disability Inventory – Computer Adaptive Test:  Functional disability as 
measured by caregiver-reported ability to perform activities of daily living in the following 
functional domains: Daily Activities, Mobility, Social/Cognitive and Responsibility (at select 
sites) 
• 
Gait analysis:  Stride length, cadence, velocity, base of support and percentage of cycle time spent 
in double support performed and evaluated by a physical therapist during the 6MWT (at select 
sites) 
• 
Beery-Buktenica Developmental Test of Visual Motor Integration:  Visual-motor integration 
measured using a design copy test administered by a clinician (at select sites) 
• 
Raven’s Coloured Progressive Matrices:  Spatial understanding and abstract reasoning using 
picture tests administered by a clinician (at select sites) 
* The Investigator may use clinical judgment in deciding whether to administer certain assessments to 
subjects based on age, development, and cognitive ability, as appropriate. 
Pharmacokinetics of UX007 and Metabolites: 
• 
Plasma peak levels of UX007 and metabolites at specific times during the Treatment and 
Extension Periods 
• 
Population PK study at Week 26: Plasma levels at trough (pre-dose [within 15 minutes]) and at 60 
and 180 minutes after administration of UX007 
Safety Assessments: 
Safety will be evaluated by the incidence, frequency and severity of AEs and serious adverse events 
(SAEs), including clinically significant changes from baseline to scheduled time points in: 
• 
Vital signs and weight 
• 
Physical examination and ECG findings 
• 
Clinical laboratory evaluations 


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• 
Pregnancy testing/pregnancy of partner 
• 
Suicidal ideation and behavior assessments 
• 
Concomitant medications 
Data Monitoring Committee  
An independent DMC with appropriate expertise in the conduct of clinical trials in children will act in 
an advisory capacity to monitor subject safety on a routine basis throughout the trial. 
STATISTICAL METHODS: 
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan (SAP). 
Sample size estimate: 
For the study to be adequately powered, a sample of approximately 40 completed subjects was 
estimated to be adequate to detect a 50% between-group difference in seizure rate per 4 weeks with 
power of approximately 80% and population standard deviation of 55% using two-sample t test at 
one-sided alpha level of 0.05.    
Primary Efficacy Analysis: 
The primary efficacy evaluation is the percent reduction from randomization to week 8 in frequency, 
normalized to a 4 week rate, of seizures  The primary efficacy comparison will be made using an 
appropriate analysis as defined in the SAP.  
Secondary Efficacy Analyses 
The secondary efficacy analyses will compare the secondary efficacy variables scores after treatment 
to before treatment between the treated and placebo groups.  The specific tests and analyses will be 
defined in the SAP. 
Included in these analyses will be a predefined per protocol analysis of those subjects that achieve at 
least 30% of calorie intake or higher as the tolerated dose level, in addition to receiving at least 80% of 
expected doses, to assess whether a subpopulation of the highest dose subjects have a larger difference 
in efficacy. 
Adverse Events Analysis: 
The original terms used in the CRFs by investigators to identify AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during treatment 
(i.e., treatment-emergent AE) 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 using 
the safety population.  Special attention will be given to those subjects who died, discontinued 
treatment due to an AE, or experienced a SAE. 


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Table 2.1:  Schedule of Events 
VISIT NUMBER* 
1 
2 
3 (Phone) 
4 
5 
6 
7 
DE
1# 
DE
2# 
8 
9 
VISIT NAME 
Screening 
Randomization 
End of 
Titration 
Treatment Period 
Extension Period 
WEEK 1 
-6 
0 
2 
4 
8 
14 
26 
31 
36 
44 
52/
ET 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 2 
X 
 
 
 
 
 
 
 
 
 
 
EFFICACY MEASURES 
Seizure incidence (diary review) 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Computerized Neuropsychological Test - 
Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 4 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Peabody Picture Vocabulary Test (PPVT) 4 
X 
 
 
 
X 
 
X 
X 
X 
 
X 
Short Form-10 (SF-10) or SF-12 Health Survey 
(age-appropriate instrument) 
 
X 
 
 
X 
 
X 
 
 
 
X 
Pediatric Evaluation of Disability Inventory 
Computer Adaptive Test (PEDI-CAT)4 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
6-minute Walk Test (6MWT)5 
PED Observation  
Gait Analysis [select sites] 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Gross Motor Function Measure-88 
(GMFM-88)4, 5 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Columbia Neurological Score (CNS) 
 
X 
 
 
X 
 
X 
 
 
 
X 
Clinical Global Impression: 
Improvement (CGI-I) & Severity (CGI-S)6 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
Overnight Electroencephalogram (EEG)7 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Beery-Buktenica Developmental Test of Visual 
Motor Integration (Beery-VMI) 4 
X 
 
 
 
X 
 
X 
 
 
 
X 


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VISIT NUMBER* 
1 
2 
3 (Phone) 
4 
5 
6 
7 
DE
1# 
DE
2# 
8 
9 
VISIT NAME 
Screening 
Randomization 
End of 
Titration 
Treatment Period 
Extension Period 
WEEK 1 
-6 
0 
2 
4 
8 
14 
26 
31 
36 
44 
52/
ET 
Raven’s Coloured Progressive Matrices 
(RCPM)4 
X 
 
 
 
X 
 
X 
 
 
 
X 
PHARMACOKINETICS/BIOASSAYS 
Peak Plasma UX007 and Metabolites8 
X7 
X 
 
 
X 
 
 
X 
X 
 
X 
Population PK assessment8 
 
 
 
 
 
 
X 
 
 
 
 
SAFETY ASSESSMENTS 
Vital Signs & Weight9 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG)10 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination11 
X 
 
 
 
X 
 
X 
 
 
 
X 
Clinical Laboratory Tests12  
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
Urine Pregnancy Test (if applicable) 
X 
X 
 
 
X 
 
X 
 
 
 
X 
Suicidal Ideation & Behavior Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Interim Monitoring Calls13 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
TREATMENT & DIETARY ASSESSMENTS 
Dispense Study Drug14 
 
X 
 
X 
X 
X 
X14 
 
 
X 
 
Treatment Compliance & Accountability15 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietitian Consultation & Diet Diary16 
X 
X 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*The Study Reference Manual will outline and describe a recommended schedule of the assessments during the 1-day and 2-day visits. 
# DE = Dose Exploration Period.  Visits DE-1 (Week 31) and DE-2 (Week 36) (± 3 days) apply only to subjects who participate in the Dose Exploration Period. 
1 Assessments at Week 2 will be completed via telephone call; no visit to the study site will be required.  Subjects will return to the clinic at Week 4 and at the 
end of the double-blind Treatment Period for Week 8 (± 3 days).  Visits during the Extension period will occur at 6-13 week intervals (± 2 weeks). 
2 Medical history includes subject demographics and Glut1 DS diagnosis confirmed by SLC2A1 mutation analysis. 


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3 The seizure diary should be completed each study day, even on study days without seizures. Site personnel should help ensure that participants 
(parents/caregivers) are not leaving any blank pages in the seizure diaries.  
4 All neuropsychological tests and assessments should be performed after the consumption of food and, as indicated, study drug.  PPVT, Beery-VMI, RCPM, 
PEDI-CAT, and GMFM-88 will be administered at select sites only. 
 5 The 6MWT will include assessments of PED; a subset of sites may also perform gait analysis using a computerized portable walkway.  Portions of the 6MWT, 
gait analysis and the GMFM-88 tests may be videotaped to monitor administration technique and assess qualitative changes in function.  Subject identity will be 
protected by blurring out the facial area in the video.  
6 CGI-S will be assessed at Baseline (Week 0); CGI-I will be assessed at Weeks 8, 26, 31, 36 and 52 (or Early Termination). 
7 Confirmatory EEG at Screening for patients with absence seizures only is required for ~3 hours.  For Week 0 EEG, begin EEG PRIOR TO Randomization date 
(requires 2-day visit); Week 8, 26, and 31 visits require a 2-day overnight visit to complete EEG. Monitoring periods of less than 12 hours in duration for Week 
8, 26, and 31 visits will be considered a protocol violation. 
8 At the Screening and Randomization Visits, a non-fasting blood sample will be drawn to assess non-fasting BHB. At subsequent post-randomization visits, 
blood samples for UX007 and metabolites will be drawn approximately 90 min following consumption of food and study drug.  At Week 26, 3 blood samples 
will be drawn: pre-dose (within 15 min), and 2 additional timepoints at 60 and 180 min following consumption of food and study drug.   
9 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.  
10 Perform ECG prior to, or at least 15 min after administration of any motor function tests (if indicated at visit) so that the ECG is performed at resting heart rate. 
11 Physical examinations to include assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, 
respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. 
12 Clinical laboratory tests include standard serum chemistry, hematology, and urinalysis.  Fasting is not required. 
13 The study coordinator will telephone the subject/caregiver between each Extension Period visit to assess AE, discuss any problems or difficulties with 
treatment, assess protocol compliance, and inquire about study drug consumption and remaining supply.  Additional telephone contacts may be made as needed.  
A follow-up call is recommended within 4 weeks following early termination or study completion. 
14 Following Randomization, study drug will be titrated over a 2-week period to achieve up to 35% of total daily calories from study drug. Subjects in the Dose 
Exploration Period will titrate study drug as outlined in the Administration Guideline in the Study Reference Manual. The manual randomization process will be 
followed at Randomization and Week 4 visits only. 
15 Instruct subjects to return all empty and opened study drug bottles to the next visit. 
 
16 Subjects and/or caregivers are required to maintain record of daily diet in the study diary for at least 3 days prior to each visit (except Screening).  The diet 
diary will be reviewed with the dietitian or study staff upon each visit. The dietitian may telephone subjects and/or caregivers, as needed, to provide dietary 
advice and support. The 3-day diet history is recorded during the Screening (Baseline) Period and will be used to qualify subjects for the study. A 3-day diet 
diary is not required at the time of the Screening Visit, only a dietitian consultation. The 3-day diet history recorded prior to randomization will be reviewed by 
the site dietitian to establish daily caloric intake 


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................4 
Figure 2.1:  UX007G-CL201 Study Schema .......................................................................7 
Table 2.1:  Schedule of Events ..........................................................................................13 
3 TABLE OF CONTENTS ...................................................................................................16 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................21 
5 INTRODUCTION .............................................................................................................24 
5.1 Overview of Glucose Transporter Type 1 Deficiency Syndrome .............................24 
5.2 Brief Overview of UX007 Development ..................................................................25 
5.2.1 
Brief Description of the Investigational Product .........................................25 
5.2.1.1 
Mechanism of Action in Glut1 DS ..............................................26 
5.2.2 
Nonclinical Studies ......................................................................................26 
5.2.3 
Previous Clinical Studies .............................................................................27 
5.3 Summary of Overall Risks and Potential Benefits ....................................................28 
5.4 Study Rationale .........................................................................................................29 
5.5 Primary Efficacy Hypothesis ....................................................................................30 
6 STUDY OBJECTIVES ......................................................................................................31 
7 INVESTIGATIONAL PLAN ............................................................................................33 
7.1 Overall Study Design and Plan .................................................................................33 
7.2 Discussion of Study Design, Including Choice of Control Group ............................34 
7.3 Selection of Study Population ...................................................................................35 
7.3.1 
Inclusion Criteria .........................................................................................37 
7.3.2 
Exclusion Criteria ........................................................................................38 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................38 
7.3.3.1 
Stopping Rules .............................................................................39 


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7.4 Treatments .................................................................................................................40 
7.4.1 
Investigational Product ................................................................................41 
7.4.2 
Reference Therapy ......................................................................................41 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................41 
7.4.4 
Selection of Doses and Study Duration .......................................................42 
Table 7.4.4.1:  Demographics and Treatment Duration in Clinical 
Trials ............................................................................................42 
7.4.4.1 
Dose Exploration Period ..............................................................43 
7.4.4.2 
Study Duration .............................................................................43 
7.4.5 
Blinding .......................................................................................................44 
7.4.6 
Prior and Concomitant Therapy ..................................................................45 
7.4.6.1 
Prohibited Medications ................................................................45 
7.4.6.2 
Permitted Medications .................................................................45 
7.4.7 
Treatment Compliance ................................................................................45 
7.5 Study Procedures and Assessments ..........................................................................46 
7.5.1 
Schedule of Events ......................................................................................46 
7.5.2 
Efficacy Measures .......................................................................................46 
7.5.2.1 
Primary Efficacy Variable ...........................................................47 
7.5.2.2 
Secondary Efficacy Variables ......................................................48 
7.5.2.3 
Exploratory Efficacy Measures....................................................50 
7.5.3 
Drug Concentration Measurements and Bioassays .....................................53 
7.5.4 
Safety Measures & General Assessments ...................................................53 
7.5.4.1 
Medical History ...........................................................................53 
7.5.4.2 
Vital Signs and Weight ................................................................54 
7.5.4.3 
Electrocardiogram ........................................................................54 
7.5.4.4 
Physical Examination...................................................................54 
7.5.4.5 
Clinical Laboratory Tests .............................................................54 


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7.5.4.6 
Pregnancy Testing ........................................................................55 
7.5.4.7 
Suicidal Ideation and Behavior Assessments ..............................56 
7.5.4.8 
Concomitant Medications ............................................................56 
7.5.4.9 
Adverse Events ............................................................................57 
7.5.4.10 
Interim Monitoring Calls .............................................................57 
7.5.4.11 
Dietitian Consultation and Diet Assessment ................................57 
7.5.5 
Appropriateness of Measures ......................................................................57 
7.6 Statistical Methods and Determination of Sample Size ............................................58 
7.6.1 
Subject Information .....................................................................................59 
7.6.2 
Analysis Populations ...................................................................................59 
7.6.3 
Primary Efficacy Analysis ...........................................................................59 
7.6.4 
Secondary Efficacy Analyses ......................................................................60 
7.6.5 
Exploratory Efficacy Analyses ....................................................................60 
7.6.6 
Pharmacokinetic Analyses ..........................................................................61 
7.6.7 
Safety Analyses ...........................................................................................61 
7.6.8 
Data Monitoring Committee .......................................................................62 
7.6.9 
Determination of Sample Size .....................................................................63 
8 STUDY CONDUCT ..........................................................................................................64 
8.1 Ethics .........................................................................................................................64 
8.1.1 
Institutional Review Board or Ethics Committee ........................................64 
8.1.2 
Ethical Conduct of Study ............................................................................64 
8.1.3 
Subject Information and Consent ................................................................64 
8.2 Investigators and Study Administrative Structure ....................................................65 
8.3 Investigational Product Accountability .....................................................................65 
8.4 Data Handling and Record Keeping .........................................................................66 
8.4.1 
Case Report Forms and Source Documents ................................................66 
8.4.2 
Data Quality Assurance ...............................................................................66 


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8.4.3 
Record Retention .........................................................................................67 
8.5 Reporting and Follow-up of Adverse Events ............................................................67 
8.5.1 
Definition of Adverse Events ......................................................................67 
8.5.2 
Severity of Adverse Events .........................................................................68 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................69 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................70 
8.5.4.1 
General .........................................................................................70 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................71 
8.5.4.3 
Urgent Safety Reporting ..............................................................71 
8.5.4.4 
Adverse Drug Reaction Reporting ...............................................72 
8.5.4.5 
Pregnancy in Subject or Partner ...................................................72 
8.5.5 
Safety Contact Information .........................................................................73 
8.6 Financing and Insurance ...........................................................................................73 
8.7 Publication Policy .....................................................................................................73 
9 REFERENCES ..................................................................................................................74 
10 SIGNATURE PAGE .........................................................................................................79 
 
 
LIST OF TABLES 
Table 2.1:  Schedule of Events ................................................................................................13 
Table 7.4.1: 
Dose Titration Recommendation .........................................................40 
Table 7.4.4.1:  Demographics and Treatment Duration in Clinical Trials ..............................42 
Table 7.5.4.5.1:  Clinical Laboratory Assessments .................................................................55 
 
 
 


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LIST OF FIGURES 
Figure 2.1:  UX007G-CL201 Study Schema .............................................................................7 
Figure 5.2.1.1.1: 
Proposed mechanism of UX007 action in Glut1 DS ...........................26 
Figure 7.1.1: 
UX007G-CL201 Study Schema ..........................................................34 
 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
APBD 
adult polyglucosan body disease 
AST 
aspartate aminotransferase 
Beery-VMI 
Beery-Buktenica Developmental Test of Visual Motor Integration 
BHB 
beta-hydroxybutyrate 
BHP 
beta-hydroxypentanoic acid 
BKP 
beta-ketopentanoic acid 
BUN 
blood urea nitrogen 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
CNS 
Columbia Neurological Score 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
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 
GMFM-88 
Gross Motor Function Measure-88 
Glut1 
glucose transporter type 1 
Glut1 DS 
glucose transporter type 1 deficiency syndrome 


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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 
ISG 
Institutional Review Board 
Independent Statistical Group 
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 
MOT 
Motor Screening Test 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
no observed adverse effect level 
PAL 
Paired Associates Learning Test 
PCS 
Physical health component score 
PED 
paroxysmal exertional dyskinesia 
PEDI-CAT 
Pediatric Evaluation of Disability Inventory- Computer Adaptive Test 
PHS-10 
physical summary score 
PK 
pharmacokinetic 
PO 
oral, by mouth, per os 
PPVT 
Peabody Picture Vocabulary Test 
PSS-10 
psychosocial summary score 
PT 
Preferred Term 
RBC 
red blood cell 
RCPM 
Raven’s Coloured Progressive Matrices 
RPE 
Rating of Perceived Exertion 
RTI 
Reaction Time 
SAE 
serious adverse event 


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SAP 
Statistical Analysis Plan 
SF-10 
Short Form 10 Health Survey for Children 
SF-12 
Medical Outcomes Study 12-item Short-Form Health Survey for Adults 
SOC 
System Organ Class 
SSP 
Spatial Span 
SWM 
Spatial Working Memory 
TCA 
tricarboxylic acid 
US 
United States 
UX007 
Investigational Product/study drug, triheptanoin 
WBC 
white blood cell 
 
Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use [ICH] Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice). 
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 


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5 INTRODUCTION 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) is a rare, severely 
debilitating disease characterized by seizures, developmental delay, and movement disorder 
(Pearson et al. 2013).  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 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.  These patients represent the subgroup of Glut1 DS patients 
who are most in need of an alternative therapy to ketogenic diet. 
UX007 (triheptanoin) is a triglyceride of medium, odd-carbon chain (C7) fatty acid.  
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  
(Deng et al. 2009), (Kinman et al. 2006), (Marin-Valencia et al. 2013). 
The seizures due to Glut1 DS are typically refractory to antiepileptic drugs (AEDs) and are 
most prominent in the pediatric population.  In addition, a subset of Glut1 DS patients is 
either not on, or unable to comply with or tolerate the KD. For these reasons, the proposed 
Phase 2 study is designed to assess the safety and efficacy of UX007 in reducing the 
frequency of seizures in this pediatric, adolescent, and adult population. 
5.1 
Overview of Glucose Transporter Type 1 Deficiency Syndrome 
Glut1 DS is a rare, severely debilitating disease characterized by seizures, developmental 
delay, and movement disorder (Pearson et al. 2013).  It is caused by a mutation in solute 
carrier family 2, member 1 gene (SLC2A1), 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. 
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.  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). The majority of reported patients (~90 %) have a de novo heterozygous 
mutation in SLC2A1. About 10 % of affected individuals have an affected parent (autosomal 


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dominant inheritance pattern). Autosomal recessive transmission has also been described in 
rare cases. 
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.  
There are currently no approved treatments specific to Glut1 DS.  Seizures are 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 
polyethylene (HDPE) or round, amber-colored glass bottles.   UX007 is manufactured, 
packaged, and labeled according to Good Manufacturing Practice (GMP) regulations. 


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5.2.1.1 
Mechanism of Action in Glut1 DS 
UX007 is highly purified triheptanoin, a triglyceride of 3 fatty acids with 7 carbons each.  
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 
Studies of potential clinical significance and relevance to this protocol are summarized 
below.  
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). 


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Nonclinical studies in rats have demonstrated that triheptanoin is hydrolyzed to heptanoate 
and glycerol, which are efficiently absorbed by the liver (Kinman et al. 2006).  Studies have 
demonstrated that triheptanoin is metabolized rapidly in the gut to form a series of energy 
containing metabolites, including heptanoate, 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 CNS 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 (IND-59303)  
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.  Liver, kidney and small intestine were collected for histological analysis. 
Significantly, from the limited histopathology data available, there were no target organs of 
toxicity identified in this study.  Microscopic examination of the liver demonstrated that all 
diet groups showed macrovesicular hepatic steatosis, but this finding was not considered a 
hepatotoxic effect since the control group also contained the lesion.  This is likely to be due 
to the high fat in the diet. The severity of hepatic steatosis was determined to be less in the 
rats fed 30% and 50% experimental oil compared to the control group fed the soybean 
oil-based diet.  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.  No major systemic 
toxicities were observed in either general toxicity study. 
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 


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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).  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 
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 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). 
Ultragenyx is currently developing UX007 as a substrate replacement therapy for long-chain 
FAOD (LC-FAOD).  A prospective open-label Phase 2 study to assess safety and clinical 
effects of UX007 in subjects with LC-FAOD (UX007-CL201) is currently underway. 
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 was developed to address the needs of 
Glut1 DS patients who continue to have disease crises despite the best available treatment. 
The current standard of care, KD and AEDs, for these patients 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.  There exists a significant unmet medical need in the subset of 
pediatric patients who are not on, or not compliant with a KD; the proposed Phase 2 study 
targets this specific subset of patients. 
Triheptanoin has been used clinically for over 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, approximately 50 were pediatric 
subjects with some as young as neonates; a significant portion of pediatric subjects received 
over 5 years of treatment duration with triheptanoin (Table 7.4.4.1).  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. 


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Data from the animal pharmacokinetic (PK) and toxicity studies indicates that triheptanoin is 
well absorbed after oral dosing and is well-tolerated without overt toxicities at doses as high 
as 1.14 g/kg in mice 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 subjects consume triheptanoin 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 (Pearson et al. 2013).  It is caused by a mutation in SLC2A1, 
which encodes for 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.  Current treatment consists of KD and 
AEDs. KD generates 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. 
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.  
These metabolites provide an alternative energy source to the brain. 
2. Triheptanoin has the ability to provide succinyl-CoA via propionyl-CoA to resupply 
intermediates of the TCA cycle (i.e., anaplerosis). 
3. Triheptanoin can support gluconeogenesis in the brain. 
Because of the difficulties in maintaining a KD, some patients are not able to fully comply 
with or tolerate the diet.  These patients represent the subgroup of Glut1 DS patients who are 
most in need of an alternative therapy to KD.  Given the significant unmet medical need in 
Glut1 DS patients not on KD, UX007 will be studied in this subgroup.  The seizures due to 


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Glut1 DS are most prominent in the pediatric population and are typically refractory to AEDs 
(Pearson et al. 2013).  For these reasons, the proposed Phase 2 study is designed to assess the 
safety and efficacy of UX007 in reducing the frequency of seizures in the pediatric, 
adolescent, and adult population.  The study will also evaluate the PK of energy-containing 
metabolites and correlate the achieved concentrations of different metabolites to the potential 
treatment effects. 
5.5 
Primary Efficacy Hypothesis 
UX007 is more effective than placebo for the reduction of seizures in patients with Glut1 DS, 
as measured by the reduction from randomization in frequency of seizures, including: 
Generalized Tonic-Clonic, Generalized Tonic, Generalized Clonic, Generalized Atonic, 
Partial/Focal with Secondary Generalization, Myoclonic, Myoclonic Atonic, Myoclonic 
Tonic, Complex Partial/Focal, Absence, and Simple Partial/Focal Motor seizures.   


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6 STUDY OBJECTIVES 
The primary objectives of the study are to: 
• Evaluate the efficacy of UX007 compared to placebo as measured by the reduction from 
randomization to week 8 in frequency of seizures. Observable generalized and partial-
onset seizures measured for 6 weeks by diary and absence seizures measured overnight 
by electroencephalography (EEG).  
• Evaluate the safety of UX007 via adverse event (AE) rates, laboratory values, 
and electrocardiogram (ECG) 
The secondary objectives of the study are to: 
• Evaluate the efficacy of UX007 compared to placebo, as measured by: 
- Seizure response rate, defined as the percentage of subjects with at least 
50% reduction from randomization to week 8 in frequency of seizures  
- Change from randomization to Week 8 in cognitive function using the Cambridge 
Neuropsychological Test Automated Battery (CANTAB) 
- Change from randomization to Week 8 in distance walked as measured by 6MWT 
- Time to onset of paroxysmal exertional dyskinesia (PED) as measured during 
6MWT from randomization to Week 8 
- Change from randomization to Week 8 in gross motor function using the Gross 
Motor Function Measure-88 (GMFM-88)  
• Evaluate long-term efficacy as measured by changes from randomization in frequency of 
seizures over time through week 52  
• Evaluate the optimal dose to control seizures and impact on other clinical manifestations 
during the Dose Exploration Period  
Exploratory objectives are to:  
• Evaluate the effects of UX007, from randomization through Weeks 8 and 52 on: 
- Neurological function using the Columbia Neurological Score (CNS) 
- Physician global impression of change in clinical status using the Clinical Global 
Impression - Severity scale (CGI-S) and Clinical Global Impression - 
Improvement scale (CGI-I) 


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- Receptive vocabulary using the Peabody Picture Vocabulary Test (PPVT)  
- Subject or caregiver-reported quality of life using Short Form-10™ (SF-10) Health 
Survey for Children or SF-12 for adults 
- Functional disability by caregiver report using the Pediatric Evaluation of 
Disability Inventory – Computer Adaptive Test (PEDI-CAT)  
- Gait, using gait analysis by computerized mat 
- PK properties of UX007 and its metabolites  
Exploratory objectives are to evaluate the effects of UX007, from randomization through 
Weeks 8 and 52 on (to be administered at select sites): 
• Visual motor integration using the Beery-Buktenica Developmental Test of Visual Motor 
Integration (Beery-VMI)  
• Spatial understanding and abstract reasoning using the Raven’s Coloured Progressive 
Matrices (RCPM) 
 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX007G-CL201 is a randomized, double-blind, placebo-controlled, parallel-group study to 
assess the safety and efficacy of UX007 in Glut1 DS.  The study will enroll approximately 
40 pediatric, adolescent, and adult subjects who are currently not on, or not fully compliant 
with a ketogenic or other prescribed high-fat diet.  Enrolled subjects are otherwise able to 
maintain standard of care treatment with up to 3 AEDs throughout the duration of the study. 
Beginning with the Screening visit, subjects will record seizure frequency during the 6-week 
Baseline Period.  At the end of the Baseline Period, eligible subjects will be randomized in a 
3:1 ratio to either UX007 or placebo.  Dosing will be initiated using a 2-week titration 
schedule until the subject has reached 35% of total daily calories from study drug 
(~1-4 g/kg/day depending on age) (Section 7.4).  If a subject has not reached the target of 
35% of total daily calories by the end of the 2-week titration period, dose titration should 
continue until the maximum tolerated dose is reached. 
After an 8-week double-blind Treatment Period, the open-label Extension Period will begin, 
wherein all subjects will be treated with UX007 through Week 52 of the study.  
A population-PK analysis at Week 26 will provide data on metabolite levels with all subjects 
on UX007. 
Following the Week 26 visit, all 40 subjects will participate in a 10-week Dose Exploration 
Period to assess the impact of UX007 dose level on seizure control, other clinical 
manifestations such as movement disorders and cognitive deficits, and tolerability. For 
subjects participating in the Dose Exploration Period, the dose will be titrated over 1 week 
down to 20% of total daily caloric intake.  After 4 weeks at the 20% dose level, the subject 
will be evaluated for safety and efficacy measures of seizure control, motor and cognitive 
function. 
If there are breakthrough seizures during the down titration period, as defined by an increase 
in frequency of 1 seizure in a 4 week period, relative to the previous 4-week period on a 
stable UX007 dose, or in the opinion of the investigator there has been a worsening of 
symptoms prior to completion of the 4-week period, the subject may begin the up-titration 
phase early. 
After 4 weeks at the 20% dose level, the UX007 dose will then be titrated up over 1 week to 
40% of total daily caloric intake and maintained at that level for 4 weeks. If a subject cannot 
tolerate titrating up to the 40% dose level, the dose should be titrated to the maximum 
tolerated dose as determined by the Investigator.  After 4 weeks at the 40% (or maximum 
tolerated) dose level, the subject will be evaluated for safety, and efficacy measures of 
seizure control, motor and cognitive function.   


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At the end of the Dose Exploration Period, the subject will continue in the open-label 
Extension period, and maintained on the UX007 dose (as determined by the Investigator) that 
provided the maximum improvement in clinical status with acceptable tolerability, and 
continued on this dose for the duration of the study.  If marked improvements in clinical 
status were not observed at a higher dose level and/or tolerability was unacceptable, the 
subject will return to the UX007 dose level where maximal benefit was achieved as defined 
by seizure control and improvements in motor and/or cognitive symptoms.  As determined by 
the Investigator, this may be the pre-titration UX007 dose from Week 26 or the 20% dose 
given during the down titration phase. 
Forty subjects will participate in the Dose Exploration Period; the remaining subjects 
enrolled will continue with the optimal dose achieved during the previous 26 weeks. Long 
term safety and maintenance of effect of UX007 will be assessed during the Extension 
Period.  Subjects who complete treatment through Week 52 may have the option to continue 
UX007 treatment, if warranted, in a separate open-label extension study.  Figure 7.1.1 
provides a schematic of the study design. 
Figure 7.1.1: UX007G-CL201 Study Schema 
 
7.2 
Discussion of Study Design, Including Choice of Control Group 
The study is a randomized, double-blind, placebo-controlled, parallel-group study to assess 
the safety and efficacy of UX007 in Glut1 DS.  Beginning with the Screening visit, subjects 
will record their seizure frequency during the 6-week Baseline Period.  At the end of the 
Baseline Period, eligible subjects will be randomized to either UX007 or placebo (3:1 ratio) 
and begin a 2-week titration schedule to increase dosing until they have reached 35% of total 
daily calories (~1-4 g/kg/day depending on age).  The dose will then be maintained for an 
additional 6 weeks (total 8-week Treatment Period). 
Screening
Baseline on SOC*
(6 wks)
3:1 Randomization
Double-Blind, Placebo-Controlled 
Treatment Period (8 wks)
2 wks
Titration
Placebo (safflower oil) + SOC*
Open-Label 
Extension Period
(18 wks)
UX007 + SOC*
*SOC: Standard of Care 
(up to 3 stable AEDs)
UX007 (triheptanoin) + SOC*
Target Dose 20%
Caloric Intake
(4 wks)
Target Dose 40%
Caloric Intake
(4 wks)
Target Dose 35%
Caloric Intake
Individualized
Target Dose (16 wks)
Dose Exploration (~40 subjects)
1 wk Titration


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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. 
The goal of the study is to assess whether UX007 is more effective than placebo for the 
reduction of seizures in patients with Glut1 DS.  Therefore, specific criteria were included to 
define a study population experiencing a quantifiable number of events despite current 
treatment.  The inclusion criteria are structured to enroll subjects currently experiencing 
observable seizures despite a prior or current use of at least 1 AED, with an average 
frequency of at least 2 seizures in 4 weeks over the last 24 weeks.  To confirm seizure 
activity and establish an accurate baseline frequency for treatment comparison, only subjects 
with at least 2 observable seizures per 4 weeks during the Baseline Period will be 
randomized. 
Glut1 DS patients currently on or fully compliant with a KD or other prescribed high-fat diet 
of at least 60% calories from fat will be excluded from the study population.  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 to KD.  
Thus, a significant unmet medical need exists in this subgroup that justifies the study of 
UX007 in subjects not on KD. 
Additional exclusion criteria were incorporated to protect the study population from possible 
contraindicated treatments or unnecessary safety risks.  Although triheptanoin is not known 
to adversely affect the liver, many of the commonly prescribed AEDs are.  In order to 
minimize confounding factors on interpreting the safety of UX007, subjects with greater than 
3 times the upper limit of normal of either alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) will be excluded from the study. 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 


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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 confirmed by SLC2A1 mutation 
2)    Males and females at least 1 year of age at the time of informed consent 
3) 
Average of at least 2 observable seizures (generalized  or partial-onset [simple 
partial motor, complex partial, absence, or secondarily generalized] seizures) in 
4 weeks over the last 24 weeks, by subject or caregiver report 
4) 
At least 2 observable seizures (generalized  or partial-onset [simple partial motor, 
complex partial, or secondarily generalized] seizures) in 4 weeks during the 
baseline period, with no 3-week seizure-free period during the Baseline Period OR 
absence seizures documented on Screening EEG 
5) 
Continuing to have seizures despite a prior or current use of at least 1 AED 
6) 
Allowed to be on up to 3 concomitant AEDs that must have been stable in dose at 
least 2 weeks prior to the beginning of screening and anticipated to remain stable in 
dose through the end of the 8-week, placebo-controlled Treatment Period 
7) 
Not on, or not fully compliant with a prescribed diet plan (e.g. KD)  
8) 
Plasma level of beta-hydroxybutyrate (BHB) ≤ 1 mmol/L (non-fasting) at Screening 
9) 
Provide written or verbal assent (if possible) and written informed consent by a 
legally authorized representative after the nature of the study has been explained, 
and prior to any research-related procedures 
10) Must, in the opinion of the investigator, be willing and able to complete all aspects 
of the study, comply with accurate completion of the seizures diary, and likely to 
complete the 8-week, placebo-controlled, Treatment Period 
11) Females of childbearing potential must have a negative pregnancy test at Screening, 
be willing to use an acceptable method of contraception, and have additional 


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pregnancy tests during the study.  Females considered not of childbearing potential 
include those who have not reached menarche, had total hysterectomy, have been in 
menopause for at least two years, or have had tubal ligation at least one year prior 
to Screening. 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1) Serum ALT or AST levels exceeding 3X the upper limit of normal at Screening 
2) Any known hypersensitivity to triheptanoin or safflower oil that, in the judgment of 
the investigator, places the subject at increased risk for adverse effects 
3) Prior use of triheptanoin with 30 days prior to Screening 
4) History of, or current suicidal ideation, behavior and/or attempts 
5) Pregnant and/or breastfeeding an infant at Screening  
6) Participants unwilling or unable to discontinue use of a prohibited medication 
(Section 7.4.6.1 [MCT oil, barbiturates, pancreatic lipase inhibitors, KetoCal or other 
KD supplements, and/or KD]) or other substance that may confound study objectives  
7) Use of any investigational product (drug or supplement, including MCT oil) within 
30 days prior to Screening, or at any time during the study 
8) Has a condition of such severity and acuity, in the opinion of the investigator, that it 
warrants immediate surgical intervention or other treatment 
9) 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 introduces 
additional safety concerns (e.g., diabetes mellitus, other concurrent neurological or 
psychiatric disorders)  
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 


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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 will 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 invalidate the 
study or place the subject at risk 
Subjects may be removed from the study for the following reasons: 
• 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. 
Subjects who withdraw or are removed from the study prior to randomization may be 
replaced on a case-by-case basis, at the discretion of Ultragenyx. 
7.3.3.1 
Stopping Rules 
A DMC will be constituted for Study UX007G-CL201 and will act in an advisory capacity to 
monitor the safety of UX007 on a routine basis throughout the trial (Section 7.6.8).  
The DMC may provide advice to Ultragenyx in any determination of whether study 
enrollment should be paused or if the study should be halted. 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs (Section 8.5.2) that represent a change in the nature or an increase in 
frequency of the serious event from their prior medical history will be assessed as to whether 
the subject will continue on 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 
Subjects will be randomized to receive either investigational product (UX007) or reference 
therapy (matched placebo) and begin a 2-week dose titration period to achieve study drug 
treatment comprising up to 35% of total daily calories or to the maximum tolerated dose 
level (Table 7.4.1). If a subject has not reached the target of 35% of total daily calories by the 
end of the 2-week titration period, dose titration should continue until the maximum tolerated 
dose is reached. 
Table 7.4.1: Dose Titration Recommendation 
The table is an example for how to titrate subject to 35% of caloric intake or the maximum 
tolerated dose if it is < 35% within two weeks.  Discretion and flexibility may be used by the 
Investigator for each subject. 
Days of Dosing 
Caloric Intake 
If Tolerability Issues Arise: 
Days 1-2 
~10% 
N/A 
Days 3-5 
~15% 
N/A 
Days 6-8 
~20% 
N/A 
Days 9-11 
~25% 
Down-titrate to 20% for 3 more days, 
then continue to titrate up if possible 
Days 12-14 
~30% 
Down-titrate to 25% for 3 more days, 
then continue to titrate up if possible 
Day 15 - study duration 
~35%* 
Down-titrate to 30% for 3 more days, , 
then continue to titrate up if possible 
*Some subjects may not be able to tolerate up to 35% of daily caloric intake, despite down titration and re-
titrating up.  For those subjects, their individual maximum tolerated dose, as determined by the Investigator, 
will be administered for the duration of the study. 
Treatment will always be mixed with food (or formula, if appropriate) and administered 
PO or by gastronomy tube at least four times per day (breakfast, lunch, dinner, and before 
bed).  The dose should be divided into smaller more frequent doses with food as needed.  


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The dose should always be mixed with small amounts of food as indicated in the 
administration guideline and never administered as the oil directly. 
Subjects will maintain treatment at the 35% total daily calorie dose level for a 6-week 
Treatment Period (Weeks 2-8).  Following completion of the Week 8 study visit, all subjects 
will continue treatment with open-label UX007 at the 35% dose level for an additional 
44 weeks (Weeks 8-52). 
For subjects participating in the Dose Exploration Period, the dose will be titrated down over 
1 week to 20% of total daily caloric intake.  Provided there is no significant loss of efficacy 
during the down-titration phase, the subject will remain at the 20% dose level for 4 weeks.  
The dose will then be titrated up over 1 week to 40% of total daily caloric intake.  Following 
4 weeks at the 40% dose level, the subject will be maintained on the minimum dose of drug 
that provided the maximum achievable efficacy and tolerability, and continued on this dose 
for the duration of the study.  Refer to the Dose Administration Guidelines in the Study 
Reference Manual for additional information on dosing and dose titration. 
7.4.1 
Investigational Product 
UX007 (triheptanoin) is a colorless to yellow oil.  UX007 is a liquid, intended for oral (PO) 
administration.   One thousand grams (1025 ± 25 g) of neat triheptanoin drug substance is 
filled into 1 L bottles.  During the 8 week double blind period of the study 1000 mL UX007 
will be provided in 1 L round amber colored glass bottles.  During the open label Extension 
Period of the study, UX007 will be dispensed in 1 L round, translucent HDPE bottles. 
UX007 is manufactured, packaged, and labeled according to GMP regulations. 
7.4.2 
Reference Therapy 
Placebo will consist of safflower oil and will match the appearance of UX007.  Dose level, 
titration, and mode of administration will be identical to that of UX007 during the 
double-blind Treatment Period.   
7.4.3 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be enrolled in the study and sequentially assigned an identification 
number.  Subjects will be assigned to investigational product or placebo treatment groups 
based on a manual randomization process developed by the Sponsor. Patients with a broad 
spectrum of seizure types and frequency will be eligible for enrollment in the study.  The 
frequency of seizures varies among individuals affected with Glut1 DS; some experience 
daily events, while others experience occasional seizures separated by days, weeks, or 
months (Pascual et al. 2004).  Seizure frequency does not correlate with phenotypic severity 
(Wang et al. 2012).  Randomization will seek to stratify subjects based on seizure frequency 
reported during the 6-week baseline period.  At the end of the Baseline Period, eligible 
subjects will be randomized in a 3:1 ratio to either UX007 or placebo.  


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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 13 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 (Table 7.4.4.1), (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. 
Table 7.4.4.1:  Demographics and Treatment Duration in Clinical Trials  
Age at Start of 
Treatment 
Duration of Treatment 
0-6 
months 
6 months - 
1 year 
1-2 years 
2-5 years 
>5 years 
Total 
N (%) 
0-1 month (Neonates) 
  
1 
  
  
2 
3 (3.7%) 
1 month-2 years (Children) 
  
3 
1 
3 
3 
10 (12.2%) 
2-12 years (Children) 
5 
2 
4 
4 
18 
33 (40.2%) 
12-16 years (Adolescents) 
  
1 
2 
2 
  
5 (6.1%) 
>16 years (Other) 
11 
5 
11 
2 
2 
31 (37.8%) 
Total 
N (%) 
16 
(19.5%) 
12 
(14.6%) 
18 
(22.0%) 
11 
(13.4%) 
25 
(30.5%) 
82 (100%) 
Source:  Summary of Clinical Trials of Triheptanoin Therapy for Metabolic Disorders Done at the Institute of 
Metabolic Disease from Dec. 28, 1999 to Aug. 7, 2009 at Baylor Research Institute, and Personal 
Communication, Dr. Vockley, U. Pittsburgh 2013. 
N (%) is defined as the total from each column or row divided by the total number of study subjects (82). 
The target dose of 35% of calories by UX007 will be administered PO with food (or formula, 
as appropriate) divided into at least 4 doses per day, as tolerated (breakfast, lunch, dinner, 
and before bed).  The dose may be divided into smaller more frequent doses with food as 
needed.  The daily dose 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 poorly tolerated due to 
gastrointestinal disturbance, such as diarrhea; lower doses would likely provide suboptimal 


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efficacy.  The planned Dose Exploration Period is intended to evaluate the effect of 
UX007 dose level on safety and efficacy. 
7.4.4.1 
Dose Exploration Period 
Based on the historical use of triheptanoin, it is expected that sufficient energy substrate 
replacement will be obtained with dosing of 35% of calories (roughly equivalent to 
2-4 grams per kg for small children and 1-2 grams per kg for teenagers and adults).  
The Dose Exploration Period will also explore doses above and below the anticipated clinical 
dose of 35% in a subset of approximately 40 subjects and assess for maintenance of effect.  
In addition to seizures, efficacy in other parameters should be considered before making the 
assessment of dose adequacy in Glut1 DS, and may necessitate individualized dosing.  
Therefore it is important to integrate the response in seizures frequency, developmental 
testing and motor dysfunction to establish the impact of dose level and to test a series of 
doses in the same individuals to allow for proper individualization of dose.  This is also best 
done after a period of stable treatment to assure that a steady state has been reached in energy 
metabolism.  This proposed design has been successfully used in a prior development 
program for sapropterin dihydrochloride for the treatment of phenylketonuria (Lee et al. 
2008). 
The Dose Exploration Period will look at forced dose titration establishment of efficacy as an 
approach to verify the benefit of the proposed dose range across all domains of disease. 
At the same time it should verify that there is maintenance of treatment effect after all 
patients have been on active treatment for at least 18 weeks, by titrating patients downward 
to observe for recurrence of symptoms. 
The lower dose of 20% was chosen for the down titration phase based on anecdotal reports of 
a significant loss of efficacy when triheptanoin is dosed below 25%. The upper dose of 
40% was chosen based on anecdotal reports that tolerability becomes an issue above 25% in 
some patients and above 35% in most patients.  If there are breakthrough seizures during the 
down titration period, as defined by an increase in frequency of 1 seizure in a 4 week period, 
relative to the previous 4 week period on a stable UX007 dose, or in the opinion of the 
investigator there has been a worsening of symptoms prior to completion of the 4 week 
period, the subject may begin the up-titration phase early.  The demonstration of a 
withdrawal effect and a return to control afterward would demonstrate both that a higher dose 
was necessary and that UX007 had a sustained effect. 
7.4.4.2 
Study Duration 
Subject participation will be up to 58 weeks in duration, including screening, the Baseline 
Period, titration/Treatment Period, and Extension Period.  Following completion of the 
double-blind Treatment Period (8 weeks), subjects may continue open-label UX007 
treatment for an additional 44 weeks within the Extension Period, if indicated by the 
investigator.  The total treatment duration of up to one year enables a long-term assessment 


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of the safety and efficacy of UX007 in subjects with Glut1 DS.  Beyond this period, 
subjects may be eligible for an extension study, if warranted, through a separate protocol. 
7.4.5 
Blinding 
The titration and Treatment Period (Weeks 0-8) will be conducted as a randomized, 
double-blind, placebo-controlled study.  Double-blind conditions will be established so that 
neither the sponsor, subject or site personnel involved in study conduct will know the identity 
of a subject’s treatment.  Following completion of the double-blind period, all eligible 
subjects will receive open-label UX007 for a 44-week Extension Period (Weeks 8-52) to 
assess long-term safety and duration of effect. 
Study parameters to achieve and maintain the double-blind status of the study include: 
• Sequential assignment of subject numbers 
• A randomization schedule developed by an independent third-party vendor so that 
Ultragenyx and site personnel receive no knowledge of treatment assignment during the 
study 
• Management of subject treatment assignment via manual randomization 
• Labeling of study drug with the study number and a unique kit number 
• Packaging and delivery of study drug supplies to sites in a manner that maintains blinding 
of site personnel 
• Matched appearance of investigational product and placebo 
The investigator and site personnel will remain blinded to the randomization code during the 
study.  Treatment assignment for an individual subject should be unblinded by the 
Investigator only in an emergency, and only if when knowledge of the treatment assignment 
is urgently needed for the clinical management or welfare of the subject.  Treatment should 
be provided in accordance with the medical condition and with regard to the information 
provided in the IB.  The Investigator should contact the medical monitor or project manager 
before unblinding, when possible, but priority should be given to treatment of the subject. 
The Investigator must record the date and reason for revealing the blinded treatment 
assignment for that subject on the CRF.  Treatment assignment may be unblinded by the 
sponsor to satisfy expedited reporting requirements of regulatory authorities.  If a subject’s 
treatment assignment is unblinded prior to completion of the study, the subject will be 
discontinued from the double-blind portion of the study (but may still be eligible to complete 
the open-label Extension Period). 


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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 within the last 
30 days prior to screening, or are unwilling to discontinue use of a substance that may 
confound study objectives.  The following medications are prohibited throughout the study: 
• MCT oil 
• KetoCal or other KD supplements 
• Barbiturates 
• Pancreatic lipase inhibitors (e.g., Orlistat) due to possible inhibition of metabolism of 
triheptanoin 
• A prescribed diet plan (e.g. KD) comprised of at least 60%  total daily caloric intake from 
fat 
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 
Screening visit will be reviewed and recorded.  Some medications, such as AEDs, must not 
be changed or discontinued, and must be kept at the same dose for the Baseline and 
double-blind Treatment Periods. 
7.4.7 
Treatment Compliance 
At the Randomization visit and each subsequent visit through Week 36, each subject will be 
dispensed an adequate supply of study drug to comprise 35% total daily caloric intake 
(or appropriate dose level if participating in the Dose Exploration Period).  Subjects and/or 
caregivers will record consumption of study drug in a study diary.  The diary will also be 
used to maintain a daily diet record for the 3 days prior to each visit.  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 to the site at the 
next visit for administration during the day(s) of the visit.  Site personnel will maintain a 
record of all medication dispensed to each subject.  The remaining volume of unused 
medication returned to the site upon early termination or study completion will be estimated 
for study drug accountability. 


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7.5 
Study Procedures and Assessments 
7.5.1 
Schedule of Events 
Following the signing of informed consent at the Screening visit, each subject will 
complete a 6-week Baseline Period to establish a clinical baseline and confirm eligibility.  
The Randomization visit (Week 0 ± 3 days) will be 2 days in duration to complete all 
assessments and the overnight EEG (prior to randomization).  Subjects will be randomized to 
treatment after inclusion/exclusion criteria have been confirmed.  Assessments at Week 2 
will be completed during a telephone call, including the dietitian consultation; no visit to the 
study site will be required.  Subjects will return to the clinic at Week 4 (± 3 days) and at the 
end of the double-blind Treatment Period for a 2-day study visit (Week 8 ± 3 days).  
If deemed feasible by the investigator, subjects will continue on open-label UX007 treatment 
and return for study visits at 6-13 week intervals (± 2 weeks) to assess long-term safety and 
efficacy during the Extension Period.  Subjects participating in the Dose Exploration Period 
will return for additional visits following 1 week titration and 4-weeks treatment at each dose 
level (i.e. Weeks 31 and 36 ± 3 days).  The study coordinator will telephone the 
subject/caregiver as needed throughout the study for additional monitoring.  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. 
The parameters to be assessed in Study UX007G-CL201, along with timing of assessments, 
are provided in the Schedule of Events (Table 2.1). Where caregiver assessments are 
required, the same individual should complete the assessment for consistency of reporting, 
when possible.  Refer to the Study Reference Manual for additional details on specific 
assessments. 
7.5.2 
Efficacy Measures 
The concept for evaluation is to study the effects of UX007 treatment on seizures, movement 
disorders, and neurological development in Glut1 DS subjects through clinical assessments 
within the double-blind Treatment Period and the open-label Extension Period. 
The primary efficacy endpoint is the reduction from Randomization in seizure frequency.  
This endpoint is the most commonly used primary 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. Secondary efficacy endpoints related to the effects of UX007 on 
seizures will help further understand the effects of UX007 on seizure activity from different 
methodologies.  The long term effects will be examined using the same endpoints. 
The effect of UX007 treatment on Glut1 DS will be assessed by evaluating additional critical 
variables of disease impacting motor and neurological function, along with relevant 
biomarkers and metabolites.  Secondary and exploratory efficacy endpoints related to the 


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effects of UX007 on parameters other than seizures will help to define whether UX007 has 
effects on the developmental delay and motor abnormalities due to Glut1 DS. 
The effects on Glut1 DS clinical features will be studied over the Treatment and Extension 
Periods of the study (52 weeks total).  While changes in seizure frequency can occur within 
6 weeks, a longer treatment period is needed to observe maintenance of effect and long-term 
safety. 
7.5.2.1 
Primary Efficacy Variable 
Seizure Frequency Reduction: Percent reduction from randomization to week 8 in 
frequency of seizures.  Observable generalized and partial-onset seizures measured for 
6 weeks by diary and absence seizures measured overnight by electroencephalography 
(EEG). 
Seizures are a hallmark of Glut1 DS in approximately 90% of affected individuals  (Wang et 
al. 2012).  The frequency of seizures varies among individuals; some experience daily events 
while others may have seizures separated by days, weeks, or even months.  The number of 
observable seizures will be recorded by the subject or caregiver via diary throughout the 
study. 
The frequency of different seizure types will be recorded.  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 for the primary efficacy measure 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 
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).  


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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 at the Week 0, 8, 26, and 31 visits. Confirmatory EEG at Screening for 
patients with absence seizures only is required for ~3 hours.  For Week 0 EEG, begin EEG 
PRIOR TO Randomization date.  Monitoring periods of less than 12 hours in duration for 
Week 0, 8, 26, and 31 visits will be considered a protocol violation. Key measures will 
include: (1) frequency of EEG seizures, including absence; and (2) frequency of interictal 
epileptiform discharges. 
7.5.2.2 
Secondary Efficacy Variables 
The secondary clinical efficacy variables in this study will evaluate additional measures of 
seizure frequency and response, movement disorders, and neurological function using the 
evaluations detailed below. Portions of physical therapy assessments may be videotaped to 
monitor assessment administration and assess for qualitative changes in function (e.g. gait).  
Subject identity will be protected by blurring the facial area in the video(s).  The Investigator 
may use clinical judgment in deciding whether to administer certain assessments to subjects 
based on age, development, and cognitive ability, as appropriate. 
Refer to the Study Reference Manual for additional details on secondary clinical efficacy 
measures. 
Seizure Response Rate:  The seizure response rate is defined as the percentage of subjects 
with at least a 50% reduction from randomization to week 8 in seizures 
Observable seizures via diary: Observable seizure frequency reduction and observable 
seizure response rate as measured by diary 
Absence seizures via EEG: Absence seizure frequency reduction and absence seizure 
response rate as measured by EEG  
Cambridge Neuropsychological Test Automated Battery:  Cognitive impairment is 
common in Glut1 DS patients and can range from learning disabilities to severe intellectual 
disability  (Wang et al. 2012).  Neuropsychological function will be measured using 
CANTAB tests, which have been applied to many age groups, including evaluation in 
children as young as 4 years of age (Luciana et al. 2002).  A standardized, computerized 
battery of the following 5 nonverbal tests: 1) Motor Screening Test (MOT), 2) Paired 
Associates Learning Test (PAL), 3) Reaction Time (RTI), 4) Spatial Span (SSP) and 5) 
Spatial Working Memory (SWM) will be administered.  Completion time is approximately 
20 minutes. The MOT will be used as a screening tool to identify visual, motor and 
comprehension difficulties that could impact the reliability of the test.  The remaining 4 tests 
will not be administered to subjects who are not able to complete the MOT.  The PAL is a 


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visual memory test that assesses episodic memory and new learning and is most sensitive to 
changes in medial temporal lobe function.  The RTI is an attention test that measures 
movement and speed of response to a visual target.  The SSP is a test of executive function, 
working memory and planning test that evaluates working memory capacity and is most 
sensitive to changes in frontal lobe function.  The SWM is also a test of working memory 
that evaluates the ability to retain visual information and manipulate it in working memory 
using heuristic strategy. The CANTAB tests will be administered by a trained clinician in a 
standardized order to minimize variability.  CANTAB tests will be administered to 
age-appropriate subjects during the Screening visit (Week -6), Randomization visit (Week 0), 
and Weeks 4, 8, 26 and 52 (or Early Termination).  CANTAB test will also be performed on 
subjects participating in the Dose Exploration Period at Weeks 31 and 36.CANTAB tests 
should be performed within 90 minutes of food consumption and, as indicated, study drug 
administration. 
Six Minute Walk Test:  Glut1 DS patients often develop complex movement disorders and 
gait disturbances characterized by ataxia, dystonia, and chorea (Pons et al. 2010).  As some 
subjects may be too young, cognitively impaired, or physically impaired to reliably perform 
the test, a practice administration will be performed at the Screening visit to determine 
feasibility.  The 6MWT will not be performed at subsequent study visits if the subject is 
unable to reliably or safely perform the test at Screening. The 6MWT will be administered to 
appropriate subjects during the Randomization visit (Week 0), and Weeks 4, 8, 26 and 52 
(or Early Termination).  The 6MWT will also be conducted at Weeks 31 and 36 for subjects 
participating in the Dose Exploration Period. 
The 6MWT will be administered by a physical therapist in accordance with American 
Thoracic Society (ATS) guidelines (ATS 2002).  Subjects will be observed by trained study 
staff throughout the duration of the 6MWT, and the test will be terminated if there are any 
concerns as to whether the subjects can reliably and safely complete the test.  Pre-existing 
gait or balance disturbances, or PED induced by the testing may have the potential to 
compromise safety. 
Subjects will be instructed to walk the length of a pre-measured 20-30 meter course in a 
hallway for 6 consecutive minutes.  Instructions and encouragement will be given according 
to the script provided in the ATS guidelines. The total distance walked (meters) in a six 
minute period will be recorded.  The percent of predicted normal distance walked will also be 
determined based on published normative data.  PED occurring during the 6MWT will be 
assessed as an exploratory variable; a subset of sites may also perform gait analysis 
(Section 7.5.2.3). 
Time of Onset of Paroxysmal Exertional Dyskinesia:  PED is characterized by transient 
abnormal, involuntary movements primarily affecting the legs and feet, and typically 
precipitated by prolonged exertion.  PED and co-occurring epilepsy have been associated 
with Glut1 deficiency (Suls et al. 2008).  The presence, time of onset (i.e. time elapsed from 


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start of 6MWT), and severity of PED events during the 6MWT will be recorded on the CRF.  
Severity will be assessed as mild, moderate, or severe. 
Gross Motor Function Measure:  The GMFM-88 was initially designed and validated to 
evaluate change in gross motor function in children with disabilities (Russell et al. 1989).  
The original validation sample included children 5 months to 16 years of age.  Gross motor 
function in Glut1 DS subjects will be evaluated using this standardized observational 
measure of abilities that includes the following 5 domains: lying/rolling, sitting, 
crawling/kneeling, standing, and walking/running/jumping.  Completion time is typically 
30-45 minutes. The assessment will be administered at select sites by a trained physical 
therapist at the Randomization visit and Weeks 4, 8, 26, and 52 (or Early Termination) visits. 
GMFM-88 will also be conducted at Weeks 31 and 36 for subjects participating in the 
Dose Exploration Period. 
7.5.2.3 
Exploratory Efficacy Measures 
The Investigator may use clinical judgment in deciding whether to administer certain 
assessments to subjects based on age, development, and cognitive ability, as appropriate. 
Columbia Neurological Score:  The classic phenotype of Glut1 DS is also characterized by 
delayed neurologic development, acquired microcephaly, and complex movement disorders 
(Pascual et al. 2004).  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 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 Randomization visit and at Weeks 8, 26, 
and 52 (or Early Termination). 
Clinical Global Impression-Severity scale and Clinical Global Impression-Improvement 
scale:  The CGI-S and CGI-I scales evaluate global impression of disease severity (CGI-S) 
at baseline and the degree of change in clinical status (CGI-I) at subsequent study visits as 
assessed by a physician.  Both assessments utilize 7-point scales to rate the degree of severity 
and improvement, respectively (Guy 1976).  The CGI-S will be administered during the 
Randomization visit (Week 0).  The CGI-I will be administered at Weeks 8, 26 and 
52 (or Early Termination).  The CGI-I will also be assessed at Weeks 31 and 36 for subjects 
participating in the Dose Exploration Period 
Neuropsychological Assessments:   
The majority of Glut1 DS patients experience some degree of developmental delay and 
cognitive impairment.  The broad spectrum of neuropsychological features in Glut1 DS 


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includes effects on general intellectual function (ranging from mild learning disability to 
severe intellectual impairment), language development, adaptive behavior, behavior and 
sustained attention.  Therefore, a panel of neuropsychological assessments will be 
administered (some at select sites only) to provide additional characterization of the cognitive 
and behavioral features in the Glut1 DS population.  All neuropsychological tests and 
assessments should be performed within 90 minutes of food consumption and, as indicated, 
study drug administration. 
Peabody Picture Vocabulary Test: Individuals with Glut1 DS commonly have receptive 
language deficits that affect their vocabulary and ability to communicate.  The PPVT is a test 
of receptive vocabulary achievement and verbal ability that is normed for children as young 
as 2 years of age (Dunn et al. 2007).  Administration time is typically 20-30 minutes.  The 
PPVT will be administered at select sites to subjects 2 years of age and older by a trained 
clinician during the Screening visit (Week -6), and Weeks 8, 26 and 52 (or Early 
Termination).  The PPVT will also be conducted at Weeks 31 and 36 for subjects 
participating in the Dose Exploration Period. 
Beery-Buktenica Developmental Test of Visual Motor Integration: Individuals with 
Glut1 DS have verbal and motor deficits that limit the ability to complete tasks that require 
visual and motor coordination.  The Beery-VMI measures the extent to which individuals can 
integrate their visual and motor abilities (Beery et al. 2004).  The test is normed for children 
2-18 years of age.  Administration time is typically 10-15 minutes.  The Beery-VMI will be 
administered to subjects at select sites by a trained clinician during the Screening visit 
(Week -6), and Weeks 8, 26 and 52 (or Early Termination). 
Raven’s Coloured Progressive Matrices: Spatial reasoning deficits are a key feature of the 
cognitive deficits observed in individuals with Glut1 DS.  The RCPM is a test of spatial 
understanding and abstract reasoning developed for individuals 5 years of age and older  
(Raven et al. 1998).  Administration time is typically 15-30 minutes.  At select sites, the 
RCPM will be administered to all subjects, at the clinical judgment of the test administrator, 
during the Screening visit (Week -6), and Weeks 8, 26 and 52 (or Early Termination). 
Short Form Health Surveys: 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. 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 or 
SF-12 will be administered during the Randomization visit (Week 0), and Weeks 8, 
26 and 52 (or Early Termination). 
The SF-10 Health Survey for Children 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 


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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.  Every attempt will be made to ensure that the responder completing the 
first administration completes subsequent administrations to minimize variability.  
Completion time is approximately 10 minutes. 
The Medical Outcomes Study 12-Item Short Form (SF-12) 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-12 are a subset of the 
items in the SF-36 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-12 will be 
administered to subjects 18 years of age and older at the time of informed consent. 
Pediatric Evaluation of Disability Inventory-Computer Adaptive Test: The constellation 
of clinical signs and symptoms of Glut1 DS can impact a patient’s ability to independently 
perform activities of daily living.  The PEDI-CAT is a measure of functional capabilities and 
performance designed for use in children and youth from birth to 20 years of age with a 
variety of physical conditions (Haley et al. 2011).  The PEDI-CAT measures abilities in the 
three functional domains of Daily Activities, Mobility and Social/Cognitive.  The PEDI-CAT 
also includes a Responsibility domain to measure the extent to which a child takes 
responsibility for the managing multi-step activities of daily living. The PEDI-CAT will be 
completed for all subjects, as deemed appropriate. Caregivers will be asked to complete the 
questionnaire for subjects less than 14 years of age at the time of informed consent.  
Subjects who are 14 years of age or older at the time of informed consent may be asked to 
complete the questionnaire by self-report.  The PEDI-CAT will be administered at select sites 
during the Randomization visit (Week 0), and Weeks 8, 26 and 52 (or Early Termination).  
The PEDI-CAT will also be assessed at Weeks 31 and 36 for subjects participating in the 
Dose Exploration Period. 
Gait Analysis:  Most Glut1 DS patients present with a spectrum of movement disorders.  
A study characterizing the spectrum of movement disorders in Glut1 DS observed gait 
disturbances in 89% of Glut1 DS subjects (Pons et al. 2010).  A computerized walkway mat 
is an electronic walkway providing objective spatial and temporal measurements of gait, 
with demonstrated test-retest reliability (van Uden et al. 2004).  Gait parameters include 
stride length, velocity, cadence, base of support, and percentage of cycle time spent in double 
support.  The computerized mat will be placed between meters 11 and 15 on the 20-30 meter 
walking course used for the 6MWT.  At select sites, the computerized mat may be used to 
assess gait during the 6MWT as the subject walks across the mat.  Gait assessments will be 
performed and evaluated by a physical therapist at select sites during the Screening visit, 


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Randomization visit (Week 0), and Weeks 4, 8, 26 and 52 (or Early Termination).  Gait will 
also be assessed at Weeks 31 and 36 for subjects participating in the Dose Exploration 
Period. 
7.5.3 
Drug Concentration Measurements and Bioassays 
To assess the peak PK of UX007 and UX007 metabolites, blood samples will be collected 
approximately 90 minutes following consumption of food and study drug at Weeks 8 and 
52 (or Early Termination), and at Weeks 31 and 36 for subjects participating in the 
Dose Exploration Period.  For each sample collection, the time elapsed since last study drug 
administration will be recorded on the CRF.  The following analytes will be assessed: 
• Plasma peak levels of UX007 
• Plasma levels of UX007 metabolites:  C4 ketone (BHB), C5 ketones 
(beta-hydroxypentanoate [BHP] and beta-ketopentanoate [BKP]), and heptanoate 
At the Screening and Randomization (Week 0) study visits, the blood samples will be 
collected in the non-fasting state in order to assess a non-fasting BHB. 
All subjects are on study drug at Week 26, at which time a population PK study will be 
conducted.  Samples for trough (pre-dose [within 15 minutes]) UX007 and metabolites 
(same as above) will be obtained from all subjects, and 2 additional time points will be drawn 
for each subject at 60 and 180 minutes following consumption of food and study drug.   
If feasible, additional PK samples will be collected whenever a potentially related 
SAE occurs. 
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 serious adverse events (SAEs), 
including clinically significant changes from baseline to scheduled time points in vital signs, 
weight, physical examination and ECG findings, clinical laboratory evaluations, pregnancy 
testing (or pregnancy of partner), suicidal ideation and behavior assessments, and 
concomitant medications.  Refer to the Study Reference Manual for additional details. 
7.5.4.1 
Medical History 
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 laboratory diagnosis.  Diagnosis must be confirmed by SLC2A1 


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mutation analysis.  Any available family history of Glut1 DS will be noted including 
diagnosis, disease course, treatment and outcome. 
Glut1 DS maintenance 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 
performed at every clinic visit before any additional assessments are completed.  At each 
visit, weight (in kilograms) will be obtained using a scale. 
7.5.4.3 
Electrocardiogram 
At the Screening visit and Weeks 8 and 52 (or Early Termination), a standard 12-lead 
ECG will be performed prior to or at least 15 minutes after administration of any motor 
function tests (where indicated) so that the ECG is performed at a resting heart rate.  
The Screening ECG should be within normal limits or have abnormalities that clearly reflect 
a stable condition that would not pose a risk to an individual participating in this trial.  
Abnormal findings and clinically significant changes from baseline will be recorded as AE. 
7.5.4.4 
Physical Examination 
Complete physical examinations will be performed at Screening and the Week 8, 26 and 
52 study visits (or Early Termination Visit).  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.  Clinically significant changes from Baseline will be recorded as AEs. 
7.5.4.5 
Clinical Laboratory Tests 
The clinical laboratory evaluations to be performed in this study are listed in Table 7.5.4.5.1.  
Clinical laboratory testing will be performed at the Screening, Randomization (Week 0), 
and Week 8, 26, 31, 36, and 52 study visits (or Early Termination visit).  Blood and urine 
samples will be collected; fasting is not required.  At the Screening and Randomization 
(Week 0) study visits, the blood samples should be collected in the non-fasting state in order 
to collect a non-fasting BHB.  Refer to the Study Reference Manual for additional details. 


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Table 7.5.4.5.1:  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) 
Beta-hydroxybutyrate (BHB)  (at 
Screening) 
Pregnancy test  
(if applicable) 
Serum glucose 
 
 
Potassium 
 
 
Protein (albumin and total) 
 
 
Sodium 
 
 
Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the investigator (and/or medical monitor), have additional 
blood samples taken for safety laboratory tests. 
7.5.4.6 
Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests at the 
Screening and Randomization visits and at Weeks 8, 26, and 52 (or Early Termination).  
Females considered not of childbearing potential include those who have not reached 
menarche, had total hysterectomy, or have been in menopause for at least one year prior to 
Screening. 
Female subjects with a positive pregnancy test at the Screening visit will not be enrolled in 
the study; female subjects who become pregnant during the study will be removed 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 males or females of childbearing potential must use two forms of highly 
effective methods of contraception during heterosexual intercourse throughout the study 
period and for 30 days after stopping the study drug. Examples of highly effective methods 
include: 
• Established use of hormonal contraceptives, such as the birth control pill, injection or 
implant 
• Barrier method, such as a condom with spermicide, or cervical cap 


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• Intrauterine device (IUD) or intrauterine system (IUS), a small device with hormones that 
goes inside the uterus 
• Male sterilization, also called vasectomy  
• True abstinence which means not having sex because subject chooses not to (when this is 
in line with the preferred and usual lifestyle of the subject) 
7.5.4.6.1 
Pregnancy in Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee.  The investigator must make every effort to follow the 
pregnancy of either subject or partner through resolution of the pregnancy (delivery or 
termination) and report the resolution to Ultragenyx or its designee. In the event of a 
pregnancy in the partner of a subject, the investigator should make every effort to obtain the 
female partner’s consent for release of protected health information.  Refer to the Study 
Reference Manual for details on the reporting procedures to follow in the event of pregnancy. 
7.5.4.7 
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 
pediatric 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 
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. 
7.5.4.8 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit, beginning at the Screening visit.  Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 30 days prior to 
Screening will be reviewed and recorded. At each subsequent visit, change in medications 
since the previous visit will be recorded.  A discussion of concomitant medications is 
provided in Section 7.4.6. 


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7.5.4.9 
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 
subjects will be asked about any new or ongoing AEs since the previous visit.  Assessments 
of AEs will occur at each study visit. 
Clinically significant changes from Baseline in physical examination findings, vital signs, 
clinical laboratory parameters, suicidal ideation and behavior, and ECGs will be recorded as 
AEs or SAEs, if appropriate.  If feasible, additional PK samples will be collected whenever a 
potentially related SAE occurs. 
7.5.4.10 Interim Monitoring Calls 
For additional safety monitoring, the study coordinator will telephone the subject/caregiver 
between each Extension Period study visit through Week 52.  Additional telephone contacts 
may be made during the Baseline and Treatment Periods as needed.  A follow-up call is 
recommended within 4 weeks following early termination or study completion.  The calls 
will be used to assess AE, discuss any problems or difficulties with treatment, and assess 
protocol compliance.  Study staff will ask about potential adverse effects of study drug 
including presence of gastrointestinal upset, steatorrhea or frequent loose stools, and weight 
gain.  Staff will inquire about study drug consumption and remaining supply. 
7.5.4.11 Dietitian Consultation and Diet Assessment 
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 visit.  The initial 3-day diet history obtained during 
screening will be used to confirm the subject is not currently on a KD or other high-fat diet, 
and thereby satisfies requisite inclusion/exclusion criteria.  The 3-day diet history recorded 
prior to randomization will be reviewed by the site dietitian to establish daily caloric intake 
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. 
A dietitian consultation will also take place during the Week 2 telephone assessment.  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.  EEG and ECG are routine, non-invasive procedures 
inflicting minimal pain/distress for the subject, while providing relevant indicators of seizure 


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events and cardiac safety, respectively.  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). 
Performance measures such as the 6MWT and GMFM-88 have been successfully used in 
clinical development programs.  The 6MWT and GMFM-88 were incorporated into the study 
design as a performance measure of muscle function to evaluate movement disorders 
characteristic in Glut1 DS patients.  The CNS and CANTAB were included as measures of 
neurological involvement and cognitive function. 
Diaries will be used by subjects and/or caregivers to capture seizure events on a daily basis, 
thereby minimizing recall bias at site visits.  Where possible, additional validated, 
age-appropriate patient-reported outcomes were included to assess health-related quality of 
life and activities of daily living (SF-10/SF-12 and PEDI-CAT). 
Additional measurements of UX007 and known triheptanoin metabolites will be assessed 
using blood samples.  The panel has been included in this Phase 2 study to provide 
information on relevant PK parameters following a single-dose and 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, ECGs, 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. 
Since the study will be conducted in a pediatric, adolescent, and adult population, 
age-appropriate efficacy measures and additional safety measures including interim 
telephone calls and a DMC have been incorporated into the study design. 
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.  The information below is intended as a guide to 
planned analyses.  Planned analyses will occur at the end of the double-blind Treatment 
Period, and at the end of the study (Extension Period). 


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The statistical analyses will be reported using summary tables, figures, and data listings.  
Statistical tests will be at one-sided alpha level of 0.05.  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.  All raw data obtained 
from the CRFs as well as any derived data will be included in data listings. 
Each secondary endpoint will be tested independently.  No adjustments for multiple 
comparisons on secondary and exploratory analyses will be performed.  The statistical 
method employed for the analysis of each assessment will be defined in more detail 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 randomized subjects, the number of subjects receiving study 
medication, the number of subjects completing the study, and the reasons for discontinuation.  
Demographic variables include age, sex, and race. 
7.6.2 
Analysis Populations 
The efficacy analysis set will include all randomized subjects who received at least one dose 
of investigational product. Subjects will be analyzed as randomized. 
The safety analysis set will include all subjects who receive at least one dose of 
investigational product, and subjects will be included in the treatment corresponding to the 
study treatment actually received for the safety analysis. 
7.6.3 
Primary Efficacy Analysis 
The primary efficacy analysis will be based on the efficacy analysis set.  The UX007 
treatment group will be compared with placebo.  The primary efficacy evaluation is the 
percent reduction from randomization to week 8 in frequency, normalized to a 4 week rate, 
of seizures  Observable generalized and partial-onset seizures measured for 6 weeks by diary 
and absence seizures measured overnight by electroencephalography (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.  
Summaries using descriptive statistics: n, mean, SE, median, minimum and maximum will be 
provided.  The primary efficacy comparison will be made using an appropriate analysis as 
defined in the SAP. 


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7.6.4 
Secondary Efficacy Analyses 
The secondary efficacy analyses are primarily focused on alternative domains of Glut1 DS 
disease to assess the breadth of treatment effect of UX007.  The secondary analyses will 
compare the secondary efficacy variables scores after treatment to before treatment between 
the treated and placebo groups.  The specific tests and analyses will be defined in the SAP. 
Included in these analyses will be a predefined  per protocol analysis of those subjects that 
achieve at least 30% of calorie intake or higher as the tolerated dose level and have received 
at least 80% of the expected doses,  to assess whether a subpopulation of the highest dose 
subjects have a larger difference in efficacy. 
In general, each of the efficacy variables assessed at Week 52 (or Week 26 for EEG only) 
will be compared to the value obtained during the Baseline Period or Randomization 
(i.e., Screening visit if not performed at the Baseline visit) utilizing the same statistical test as 
conducted at the Week 8 analysis, but adjusted for the difference that the analyses for the 
Week 52 data will only utilize a within-cohort comparison and not a between-cohort 
comparison. 
Secondary endpoints evaluating the efficacy of UX007 compared to placebo will include: 
• Seizure response rate, defined as the percentage of subjects with at least 50% reduction 
from randomization to week 8 in frequency of seizures  
• Observable seizure frequency reduction and observable seizure response rate as measured 
by diary 
• Absence seizure frequency reduction and absence seizure response rate as measured by 
EEG 
• Change from randomization to Week 8  in cognitive function using the CANTAB 
• Change from randomization to Week 8  in distance walked as measured by 6MWT 
• Time to onset of PED as measured during 6MWT from randomization to Week 8 
• Change from randomization to Week 8  in gross motor function using the GMFM-88 
• Long term efficacy as measured by changes from randomization in frequency of 
generalized or partial-onset seizures over time through week 52 
• Optimal dose to control seizures and impact on other clinical manifestations during the 
Dose Exploration Period 
7.6.5 
Exploratory Efficacy Analyses 
Exploratory endpoints, evaluating the efficacy of UX007 compared to placebo, will include: 


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• The effects of UX007, from randomization through Weeks 8 and 52 on: 
o Neurological function using the CNS 
o Physician global impression of change in clinical status using the CGI-S and CGI-I 
o Receptive vocabulary using the PPVT  
o Subject or caregiver-reported quality of life using SF-10 Health Survey for 
Children or SF-12 for adults 
o Functional disability by caregiver report using the PEDI-CAT  
o Gait, using gait analysis by computerized mat 
o PK properties of UX007 and its metabolites  
Optional exploratory endpoints evaluating the efficacy of UX007, from randomization 
through Weeks 8 and 52, will include: 
• Visual motor integration using the Beery-VMI 
• Spatial understanding and abstract reasoning using the RCPM 
7.6.6 
Pharmacokinetic Analyses 
Descriptive statistics, including mean, standard deviation, coefficient of variation, 
geometric mean, median, minimum, and maximum will be calculated for the plasma 
UX007 concentrations and its metabolites (including plasma BHB, BHP, BKP, and 
heptanoate) at each sampling time point for peak 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.  Individual plasma UX007 
concentrations and its metabolites (including plasma BHB, BHP, BKP, and heptanoate) will 
be provided.  Additional details of the peak PK and population PK analyses will be provided 
in the SAP. 
7.6.7 
Safety Analyses 
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 


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• Physical examination and ECG findings 
• Clinical laboratory evaluations 
• Pregnancy testing/pregnancy of partner 
• Suicidal ideation and behavior assessments 
• Concomitant medications 
The analyses of safety will include all subjects in the safety analysis set.  Safety data will be 
periodically reviewed by the DMC. 
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 
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 
including the continuation period.  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 may be provided, as appropriate). 
Clinical laboratory data will be summarized by the type of laboratory test.  Reference ranges 
and markedly abnormal results (specified in the SAP) will be used in the summary of 
laboratory data.  Descriptive statistics will be calculated for each laboratory analyte at 
baseline and at each scheduled time point.  Changes from baseline results will be presented in 
pre- versus post-treatment cross tabulations (with classes for below, within, and above 
normal ranges).  A listing of subjects with any markedly abnormal laboratory results will be 
provided.  The frequency and percentage of subjects who experience abnormal clinical 
laboratory results (i.e., outside of reference ranges) and/or clinically significant abnormalities 
will be presented for each clinical laboratory measurement. 
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. 
7.6.8 
Data Monitoring Committee  
A DMC with appropriate expertise in the conduct of clinical trials in children will act in an 
advisory capacity to monitor subject safety on a routine basis throughout the trial.  


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The DMC will also monitor individual subject tolerability and implement individual subject 
stopping criteria based on the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), Version 4.0. The DMC will be consulted for the 
management of individual subjects who experience unacceptable tolerability issues (such as 
significant gastrointestinal distress). 
The DMC may: 
• Review the study protocol and informed consent documents, and plans for data 
monitoring 
• Evaluate the progress of the trial, study data quality, timeliness, subject recruitment, 
accrual and retention, subjects’ risk versus potential benefit,  and other factors that could 
affect the study outcome 
• Consider relevant information that may have an impact on the safety of the participants or 
the ethics of the study 
• Make other recommendations to Ultragenyx concerning continuation, termination or 
other modifications of the study based on their observations of the study 
7.6.9 
Determination of Sample Size 
The proposed Phase 2 study will have a sample size that would likely detect a 50% reduction 
from randomization in seizure frequency compared to placebo.  Such a treatment effect 
would be greater than or equal to that demonstrated by many of the approved AEDs for 
refractory epilepsy, such as lamotrigine, oxcarbazepine and levetiracetam (Glauser et al. 
2000), (Glauser et al. 2006), (Trevathan et al. 2006).  A theoretical treatment effect of this 
magnitude, in light of the benign safety profile of UX007 shown to date, is considered to be 
clinically meaningful by physician experts.  From the perspective of accurately determining 
seizure frequency, the proposed durations are deemed sufficient and are accounted for in the 
standard deviation (55%) used in the power calculation. 
For the study to be adequately powered, a sample of approximately 40 completed subjects 
was estimated to be adequate to detect a 50% between-group difference in seizure rate per 
4 weeks with power of approximately 80% and population standard deviation of 55% using 
two-sample t test at one-sided alpha level of 0.05. 


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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 


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


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will be properly packaged for transport by the subject or for shipment by the clinical site.  
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 two years after the last approval of a marketing 
application in the US or an ICH region and until:  1) there are no pending or contemplated 
marketing applications in the US or an ICH region, or 2) at least two years have elapsed since 
the formal discontinuation of clinical development of the investigational product under study.  
The investigator/institution should retain subject identifiers for at least 15 years after the 
completion or discontinuation of the study.  Subject files and other source data must be kept 
for the maximum period of time permitted by the hospital, institution or private practice, 
but not less than 15 years.  These documents should be retained for a longer period, however, 
if required by the applicable regulatory requirements or by an Ultragenyx agreement.  
Ultragenyx must be notified and will assist with retention should the investigator/institution 
be unable to continue maintenance of subject files for the full 15 years.  All study records 
must be stored in a secure and safe facility. 
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) products. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 


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Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
Life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the investigator or Ultragenyx, places the patient 
or subject at immediate risk of death.  It does not include an AE or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at 
any dose, in the view of either the investigator or Ultragenyx, results in any of the following 
outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs.  
Important medical events that may not result in death, be immediately life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE.  
The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions. 
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and of a minor 
irritant type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 


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• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death or 
are disabling. 
• Death (Grade 5): Events that result in death. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided.  The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This is not the same 
as "serious" which is based on subject/event outcome or action criteria usually associated 
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 “Not Related” events: 
• Definitely Not Related:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. That is, another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is inconsistent 
with the onset of the event and the exposure to study drug and/or a causal relationship is 
considered biologically implausible. 
• Probably Not Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure. That is, an alternative explanation is more likely, e.g., 
concomitant drug(s), concomitant disease(s), known consequences of the disease under 
investigation or the relationship in time suggest that a causal relationship is unlikely. 
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. That is the AE follows a reasonable temporal sequence 
from administration of the study drug and that follows a known or expected response 


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pattern to the suspected study drug, but that could readily have been produced by a 
number of other factors. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure. That is, the AE has a temporal relationship to the 
administration of the investigational agent(s) or research intervention, follows a known or 
suspected pattern of response, and is strongly associated with study drug exposure. An 
alternative explanation is less likely, e.g., concomitant drugs(s), concomitant 
medication(s). 
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. That is, the AE is listed as a possible adverse reaction 
and cannot be reasonably explained by an alternative explanation, e.g., concomitant 
drug(s), concomitant disease(s), known consequences of the disease under investigation 
or the relationship in time is very suggestive (e.g., it is confirmed by dechallenge and 
rechallenge). 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Definitely Not or Probably 
Not Related will be considered Unrelated. 
8.5.4 
Adverse Event Reporting to Ultragenyx 
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the AE eCRF via the EDC system. The Principal Investigator is responsible for evaluating all 
AEs, obtaining supporting documents, and ensuring documentation of the event is adequate. 
Details of the AE must include severity, relationship to study drug, duration, and outcome.  
All AEs will be collected from the time the subject signs 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.  
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. 


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8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Any SAE that occurs at any time during the study, including a clinically significantly 
abnormal laboratory test result that is considered serious, must be reported within 24 hours of 
knowledge of the event to Ultragenyx or its designee. These requirements apply equally to all 
subjects, regardless of the study phase or the at-risk subject's treatment assignment or dosage. 
The reporting requirement for SAEs is from the time of signing of the ICF through 30 days 
following the last study drug administration.  
SAEs will be reported by completing and submitting SAE report forms to Ultragenyx or its 
designee. Initial SAE reports must be followed by detailed descriptions. These should include 
copies of hospital case records and other documents when requested. Follow-up SAE 
information must be submitted in a timely manner as additional information becomes 
available. All SAEs regardless of relationship to study drug must be followed to resolution or 
stabilization if improvement is not expected. 
A death occurring during the study, during the per-protocol follow-up period, or within 
30 days after stopping treatment with the study drug must be reported to Ultragenyx or its 
designee within 24 hours of knowledge of the death whether or not it is considered 
treatment-related.  
The investigator also must notify the IRB/EC of the occurrence of the SAE, in writing, as 
soon as is practicable and in accordance with IRB/EC requirements and local law. A copy of 
this notification must be provided to Ultragenyx or its designee. 
8.5.4.3 
Urgent Safety Reporting 
The regulations governing clinical studies state that the sponsor and investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
Ethics Committee (EC) is notified at the same time.”  The reporting period for urgent safety 
issues is the period from the signing of the ICF through 30 days following the last dose of 
study drug. Investigators are required to report any urgent safety measures to Ultragenyx 
within 24 hours. 


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8.5.4.4 
Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Ethics Committees, and Investigators as per local laws and 
regulations. Fatal and life-threatening SUSARs will be submitted no later than 7-calendar 
days of first knowledge of the event and follow-up information submitted within an 
additional eight (8) days. All other SUSARs will be submitted within 15-calendar days of 
first knowledge of the event.  
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
Ethics Committees, and Investigators of any events (e.g. change to the safety profile of 
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/Research Ethics Boards (REB)/ECs of SAEs and urgent 
safety matters, in accordance with IRB/REB/EC requirements and local laws and regulations. 
A copy of this notification must be provided to Ultragenyx or its designee.  
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and Ethics Committees, as per local laws and regulations. 
8.5.4.5 
Pregnancy in Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee. The reporting period for pregnancies is the period from 
the signing of the ICF through 30 days following the last dose of study drug. 
Reported pregnancy of a subject or a subject’s partner, while participating in the study, will 
be monitored for the full duration and/or followed until the outcome of the pregnancy is 
known. In the event of a pregnancy in the partner of a subject, the Investigator should make 
every effort to obtain the female partner’s consent for release of protected health information. 
Refer to the Study Reference Manual for details on the reporting procedures to follow in the 
event of pregnancy. Pregnancy-associated SAEs will be processed and submitted, as 
necessary, as per the SUSAR reporting process (Section 8.5.4.4).   
 


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Protocol Number:  UX007G-CL201 
Amendment 4 – 30 Nov 2015  
 
 
Proprietary and Confidential 
Page 74 
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Dunn, L, and Dunn, D. 2007. PPVT-4 Manual. Bloomington, MN: NCS Pearson, Inc. 


Protocol Number:  UX007G-CL201 
Amendment 4 – 30 Nov 2015  
 
 
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Page 75 
FDA. Draft Guidance 2012. Guidance for Industry: Suicidal Ideation and Behavior:  
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Jacobs, T, Mesenbrink, P, Kramer, L, and D'Souza, J. 2000. "Adjunctive therapy with 
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Haley, SM, Coster, WJ, Dumas, HM, Fragala-Pinkham, MA, Kramer, J, Ni, P, Tian, F, Kao, 
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Congestive Heart Failure & Cardiomyopathy under Charles Roe MD, Baylor 
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valproate on cerebral energy metabolism in mice." Epilepsy Res. 47 (3):247-256. 
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Kessler, SK, Gallagher, PR, Shellhaas, RA, Clancy, RR, and Bergqvist, AG. 2011. "Early 
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Kim, TH, Borges, K, Petrou, S, and Reid, CA. 2013. "Triheptanoin reduces seizure 
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Res. 103 (1):101-105. 


Protocol Number:  UX007G-CL201 
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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. 
Leary, LD, Wang, D, Nordli, DR, Jr., Engelstad, K, and De Vivo, DC. 2003. "Seizure 
characterization and electroencephalographic features in Glut-1 deficiency 
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Lee, P, Treacy, EP, Crombez, E, Wasserstein, M, Waber, L, Wolff, J, Wendel, U, 
Dorenbaum, A, Bebchuk, J, Christ-Schmidt, H, Seashore, M, Giovannini, M, Burton, 
BK, Morris, AA, and Sapropterin Research, G. 2008. "Safety and efficacy of 22 
weeks of treatment with sapropterin dihydrochloride in patients with 
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Luciana, M, and Nelson, CA. 2002. "Assessment of neuropsychological function through use 
of the Cambridge Neuropsychological Testing Automated Battery: performance in 4- 
to 12-year-old children." Dev.Neuropsychol. 22 (3):595-624. 
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." 
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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. 
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Human Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food 
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(5):627-33. 


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Pearson, TS, Akman, C, Hinton, VJ, Engelstad, K, and De Vivo, DC. 2013. "Phenotypic 
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outcomes." Epilepsia 53 (9):1503-1510. 
Pons, R, Collins, A, Rotstein, M, Engelstad, K, and De Vivo, DC. 2010. "The spectrum of 
movement disorders in Glut-1 deficiency." Mov Disord 25 (3):275-281. 
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 
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Page 78 
Suls, A, Dedeken, P, Goffin, K, Van Esch, H, Dupont, P, Cassiman, D, Kempfle, J, Wuttke, 
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Wang, D, Pascual, JM, and De Vivo, D. 2012. "Glucose Transporter Type 1 Deficiency 
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572. 
 
 


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Study Number: UX007G-CL201 
Statistical Analysis Plan 
11 January 2017, Version 2.0 
 
 
Proprietary and Confidential 
Page 2 
STATISTICAL ANALYSIS PLAN 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL201 Version 2.0 
11 January 2017 
 
The amended version of the Statistical Analysis Plan for UX007G-CL201 (Version 1.0, dated 
17 October 2016) has been modified by Version 2.0 to clarify the primary endpoint and 
analysis.  The major changes to the protocol are summarized below; additional minor 
changes have also been made for consistency and clarity but are not included in this 
summary. 
1. Added language to the primary efficacy endpoint (Section 4.1) stating that the 
endpoint derivation depends on the subject seizure type at randomization. 
Rationale: This change was made for clarity. 
2. Revised Section 5.6 on classification of subjects at randomization by seizure type to 
clarify purpose of classification and that all subjects are either an observable seizures 
subject, an absence seizures subject, or both. 
Rationale: This change was made for clarity. 
3. Added Unknown (UNK) type to diary seizures classification (Section 5.7.5). 
4. Added language to the primary efficacy analysis (Section 8.6.3) stating that sensitivity 
analyses assessing the impact of missing data will be performed. 
Rationale: This change was made for clarity. 
5. Added Appendix D with SAS code for the primary statistical analysis. 
 
 


 
Study Number: UX007G-CL201 
Statistical Analysis Plan 
11 January 2017, Version 2.0 
 
 
Proprietary and Confidential 
Page 3 
TABLE OF CONTENTS 
TITLE PAGE………………………………………………………………………………….1 
SUMMARY OF CHANGES AND RATIONALE…………………………………………   2 
LIST OF ABBREVIATIONS........................................................................................................ 8 
1 INTRODUCTION.................................................................................................................. 10 
2 STUDY OBJECTIVES.......................................................................................................... 11 
2.1 Primary Objectives........................................................................................................ 11 
2.2 Secondary Objectives ................................................................................................... 11 
2.3 Exploratory Objectives ................................................................................................. 11 
3 STUDY DESIGN ................................................................................................................... 13 
3.1 Study Population ........................................................................................................... 13 
3.2 Dosage and Administration .......................................................................................... 13 
3.3 Blinding and Randomization Methods ........................................................................ 14 
3.4 Stratification Factors ..................................................................................................... 14 
3.5 Sample Size Considerations ......................................................................................... 14 
3.6 Primary Analyses .......................................................................................................... 15 
3.7 Data Monitoring Committee ........................................................................................ 15 
4 STUDY ENDPOINTS, COVARIATES AND SUBGROUPS ........................................... 16 
4.1 Primary Efficacy Endpoint ........................................................................................... 17 
4.2 Secondary Efficacy Endpoints ..................................................................................... 17 
4.3 Exploratory Efficacy Endpoints ................................................................................... 18 
4.4 Safety Endpoints ........................................................................................................... 20 
4.5 Covariates ...................................................................................................................... 20 
4.6 Subgroups ...................................................................................................................... 21 
5 DEFINITIONS ....................................................................................................................... 21 
5.1 Baseline ......................................................................................................................... 21 
5.2 Duration of Investigational Product Exposure ............................................................ 21 


 
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5.3 Study Day ...................................................................................................................... 21 
5.4 Dosing Compliance....................................................................................................... 21 
5.5 Change from Baseline and Percent Change from Baseline ........................................ 22 
5.6 Classification of Subjects at Randomization by Seizure Type .................................. 22 
5.7 Derived Seizure Efficacy Variables ............................................................................. 23 
5.7.1 
Observable Seizure Frequency ...................................................................... 23 
5.7.2 
Absence Seizure Frequency ........................................................................... 23 
5.7.3 
Percent Reduction from Baseline in Seizure Frequency .............................. 23 
5.7.4 
Seizure Response ............................................................................................ 24 
5.7.5 
Classification of Seizures from Diary ........................................................... 24 
5.7.6 
Classification of Seizures from EEG ............................................................. 25 
5.8 Other Derived Efficacy Variables ................................................................................ 25 
5.8.1 
Cambridge Neuropsychological Test Automated Battery 
(CANTAB) ..................................................................................................... 25 
5.8.2 
Percent predicted 6MWT distance................................................................. 26 
5.8.3 
Gross Motor Function Measure-88 (GMFM-88) ......................................... 27 
5.8.4 
Columbia Neurological Score (CNS) total score.......................................... 27 
5.8.5 
Peabody Picture Vocabulary Test (PPVT) standardized score .................... 27 
5.8.6 
SF-10 Health Survey ...................................................................................... 28 
5.8.7 
SF-12 Health Survey version 2 ...................................................................... 28 
5.8.8 
Pediatric Evaluation of Disability Inventory Computer Adaptive 
Test (PEDI-CAT) ........................................................................................... 29 
5.8.9 
Gait, using gait analysis by computerized mat during the 6MWT .............. 29 
5.8.10 Beery-Buktenica Developmental Test of Visual Motor Integration 
(Beery-VMI) ................................................................................................... 29 
5.8.11 Raven’s Coloured Progressive Matrices (RCPM) ........................................ 29 
6 ANALYSIS POPULATIONS ............................................................................................... 30 
6.1 Screened Population ..................................................................................................... 30 


 
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6.2 Randomized Population ................................................................................................ 30 
6.3 Efficacy Analysis Set .................................................................................................... 30 
6.3.1 
Efficacy Analysis Set – Observable Seizures ............................................... 30 
6.3.2 
Efficacy Analysis Set – Absence Seizures .................................................... 30 
6.3.3 
Efficacy Analysis Set – Observable Seizures Only ...................................... 30 
6.3.4 
Efficacy Analysis Set – Absence Seizures Only .......................................... 30 
6.3.5 
Efficacy Analysis Set – CANTAB ................................................................ 30 
6.3.6 
Efficacy Analysis Set – 6MWT ..................................................................... 31 
6.3.7 
Efficacy Analysis Set – GMFM-88 ............................................................... 31 
6.3.8 
Efficacy Analysis Set – CNS ......................................................................... 31 
6.3.9 
Efficacy Analysis Set – CGI-I ....................................................................... 31 
6.3.10 Efficacy Analysis Set – SF-10 ....................................................................... 31 
6.3.11 Efficacy Analysis Set – SF-12 ....................................................................... 31 
6.4 Per Protocol Analysis Set ............................................................................................. 31 
6.4.1 
Per Protocol Analysis Set – Observable Seizures......................................... 32 
6.4.2 
Per Protocol Analysis Set – Absence Seizures ............................................. 32 
6.4.3 
Per Protocol Analysis Set – CANTAB.......................................................... 32 
6.5 Safety Analysis Set ....................................................................................................... 32 
6.6 Extension Analysis Set ................................................................................................. 32 
6.7 Pharmacokinetics Analysis Set .................................................................................... 33 
7 DATA HANDLING AND ACCEPTANCE ........................................................................ 34 
7.1 Handling of Missing and Incomplete Data.................................................................. 34 
7.2 Missing Date Imputation Rules .................................................................................... 35 
7.3 Unscheduled or Early Termination Visits ................................................................... 35 
7.4 Analysis Software ......................................................................................................... 36 
7.5 Coding of Events and Medications .............................................................................. 36 
8 STATISTICAL METHODS OF ANALYSIS ..................................................................... 37 


 
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8.1 General Principles ......................................................................................................... 37 
8.2 Subject Accountability.................................................................................................. 37 
8.2.1 
Protocol Deviations ........................................................................................ 38 
8.3 Demographics................................................................................................................ 38 
8.4 Disease Characteristics and Medical History .............................................................. 38 
8.5 IP Administration .......................................................................................................... 39 
8.5.1 
Study Drug Exposure ..................................................................................... 39 
8.5.2 
Dose Titration ................................................................................................. 39 
8.5.3 
Diet Diary Review .......................................................................................... 39 
8.5.4 
Dosing Compliance ........................................................................................ 40 
8.6 Efficacy Analyses ......................................................................................................... 40 
8.6.1 
Comparisons Between UX007 and Placebo Groups .................................... 41 
8.6.2 
Estimation by Treatment Group and Overall ................................................ 42 
8.6.3 
Primary Efficacy Endpoint ............................................................................. 42 
8.6.4 
Secondary Endpoints ...................................................................................... 44 
8.6.5 
Exploratory Efficacy Endpoints..................................................................... 46 
8.6.6 
Subset Analyses of Primary and Select Secondary Endpoints .................... 46 
8.7 Safety Analyses ............................................................................................................. 46 
8.7.1 
Adverse Events ............................................................................................... 46 
8.7.2 
Vital Signs and Weight................................................................................... 48 
8.7.3 
Physical Examination ..................................................................................... 48 
8.7.4 
Electrocardiogram........................................................................................... 49 
8.7.5 
Select Clinical Laboratory Parameters .......................................................... 49 
8.7.6 
Suicidal Ideation and Behavior ...................................................................... 51 
8.7.7 
Prior and Concomitant Medications .............................................................. 52 
8.7.8 
Pharmacokinetics of UX007 .......................................................................... 52 
9 PLANNED DATA PRESENTATIONS ............................................................................... 53 


 
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10 REFERENCES ....................................................................................................................... 61 
11 APPENDICES ........................................................................................................................ 63 
LIST OF FIGURES 
Figure 1: UX007G-CL201 Study Schema .................................................................................. 13 
LIST OF TABLES 
Table 1: Study Outcomes ............................................................................................................. 16 
Table 2: Seizure Classification by Diary .................................................................................... 24 
Table 3: Seizure Classification by EEG ...................................................................................... 25 
Table 4: CANTAB Scores........................................................................................................... 26 
Table 5: Efficacy Analyses by Study Period and Endpoint Level............................................ 40 
Table 6: Planned Data Presentations ........................................................................................... 53 
Table 7: Gastrointestinal SMQs .................................................................................................. 77 
LIST OF APPENDICES 
Appendix A: Efficacy Endpoint Summary Table ...................................................................... 64 
Appendix B: Schedule of Events ................................................................................................. 74 
Appendix C: Gastrointestinal Standardized MedDRA Query ................................................... 77 
Appendix D: SAS Code for Primary Statistical Analysis .......................................................... 78 
 
 
 


 
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LIST OF ABBREVIATIONS 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
Beery-VMI 
Beery-Buktenica Developmental Test of Visual Motor Integration 
BHB 
beta-hydroxybutyrate 
BHP 
beta-hydroxypentanoic acid 
BUN 
blood urea nitrogen 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
CNS 
Columbia Neurological Score 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EEG 
electroencephalogram 
FDA 
Food and Drug Administration (United States) 
GEE 
Generalized Estimating Equation (statistical model) 
GGT 
gamma glutamyl transpeptidase 
GI 
Gastrointestinal 
Glut1 
glucose transporter type 1 
Glut1 DS 
glucose transporter type 1 deficiency syndrome 
GMFM-88 
Gross Motor Function Measure-88 
KD 
ketogenic diet 
L 
Litre 
LSM 
Least Square Mean 
MCS 
Mental Component Summary Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PAL 
Paired Associates Learning Test 
PCS 
Physical Component Summary Scale 
PED 
paroxysmal exertional dyskinesia 
PEDI-CAT 
Pediatric Evaluation of Disability Inventory Computer Adaptive Test 


 
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PHS-10 
physical summary score 
PK 
Pharmacokinetics 
PPVT 
Peabody Picture Vocabulary Test 
PSS-10 
psychosocial summary score 
PT 
Preferred Term 
RBC 
red blood cell 
RCPM 
Raven’s Coloured Progressive Matrices 
RTI 
Reaction Time 
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 – version 2 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SSP 
Spatial Span 
SWM 
Spatial Working Memory 
TEAE 
Treatment-Emergent Adverse Event 
UX007 
Investigational Product/study drug, triheptanoin 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 


 
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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-CL201 original protocol and all 
amendments through Amendment 4 dated 30 November 2015. The data collected in this 
study will evaluate the safety and efficacy of UX007 in subjects with glucose transporter type 
1 deficiency syndrome. The primary efficacy endpoint is the reduction from baseline to week 
8 in frequency of seizures. 


 
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2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of the study are to: 
• Evaluate the efficacy of UX007 compared to placebo as measured by the reduction from 
baseline to week 8 in frequency of seizures: observable generalized and partial-onset 
seizures measured by diary for 6 weeks prior to randomization and after 2-week titration 
until Week 8, and absence seizures measured by overnight electroencephalography 
(EEG) at baseline and Week 8 
• Evaluate the safety of UX007 via adverse event (AE) rates, laboratory values, 
and electrocardiogram (ECG) 
2.2 
Secondary Objectives 
The secondary objectives of the study are to: 
• Evaluate the efficacy of UX007 compared to placebo, as measured by: 
 Seizure response at Week 8, defined as at least 50% reduction from baseline to week 
8 in frequency of seizures  
 Change from baseline to Week 8 in cognitive function using the Cambridge 
Neuropsychological Test Automated Battery (CANTAB) 
 Change from baseline to Week 8 in distance walked as measured by 6MWT 
 Time to onset of paroxysmal exertional dyskinesia (PED) as measured during 6MWT 
from baseline to Week 8 
 Change from baseline to Week 8 in gross motor function using the Gross Motor 
Function Measure-88 (GMFM-88) (assessed at select sites) 
• Evaluate long-term efficacy as measured by changes from baseline in frequency of 
seizures over time  
• Evaluate the optimal dose to control seizures and impact on other clinical manifestations 
during the Dose Exploration Period  
2.3 
Exploratory Objectives 
Exploratory objectives are to:  
• Evaluate the effects of UX007, from baseline through Weeks 8 and 52 on: 
 Neurological function using the Columbia Neurological Score (CNS) 


 
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 Physician global impression of change in clinical status using the Clinical Global 
Impression - Severity scale (CGI-S) and Clinical Global Impression - Improvement 
scale (CGI-I) 
 Receptive vocabulary using the Peabody Picture Vocabulary Test (PPVT) (assessed 
at select sites) 
 Subject or caregiver-reported quality of life using Short Form-10™ (SF-10) Health 
Survey for Children or SF-12 for adults 
 PK properties of UX007 and its metabolites 
• Evaluate the effects of UX007, from baseline through Weeks 8 and 52 on (assessed at 
select sites): 
 Functional disability by caregiver report using the Pediatric Evaluation of Disability 
Inventory – Computer Adaptive Test (PEDI-CAT) 
 Gait, using gait analysis by computerized mat 
 Visual motor integration using the Beery-Buktenica Developmental Test of Visual 
Motor Integration (Beery-VMI)  
 Spatial understanding and abstract reasoning using the Raven’s Coloured Progressive 
Matrices (RCPM) 
 
 


 
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3 STUDY DESIGN 
UX007G-CL201 is a randomized, double-blind, placebo-controlled, parallel-group study to 
assess the safety and efficacy of UX007 in Glut1 DS. Figure 1 provides a schematic of the 
study design. As background for the statistical methods presented in the SAP, this section 
provides an overview of the study design. This overview is a summary only. The protocol is 
the definitive reference for all matters discussed in what follows.     
Figure 1: UX007G-CL201 Study Schema 
 
3.1 
Study Population 
The study will enroll approximately 40 pediatric, adolescent, and adult subjects who are 
currently not on, or not fully compliant with a ketogenic or other prescribed high-fat diet.  
Enrolled subjects are otherwise able to maintain standard of care treatment with up to 
3 antiepileptic drugs (AEDs) throughout the duration of the study. 
3.2 
Dosage and Administration 
Dosing will be initiated using a 2-week titration schedule until the subject has reached 
the target of 35% of total daily calories from study drug (~1-4 g/kg/day depending on age).  
If a subject has not reached the target of 35% of total daily calories by the end of the 2-week 
titration period, dose titration should continue until the maximum tolerated dose is reached.  
After an 8-week double-blind Treatment Period, the open-label Extension Period will begin, 
wherein all subjects will be treated with UX007 through Week 52 of the study.  
Following the Week 26 visit, all 40 subjects will participate in a 10-week Dose Exploration 
Period. The dose will be titrated over 1 week down to 20% of total daily caloric intake.  
If there are breakthrough seizures during the down titration period, or in the opinion of the 
investigator there has been a worsening of symptoms prior to completion of the 4-week 
period, the subject may begin the up-titration phase early. After 4 weeks at the 20% dose 
level, the UX007 dose will then be titrated up over 1 week to 40% of total daily caloric 
Screening
Baseline on SOC*
(6 wks)
3:1 Randomization
Double-Blind, Placebo-Controlled 
Treatment Period (8 wks)
2 wks
Titration
Placebo (safflower oil) + SOC*
Open-Label 
Extension Period
(18 wks)
UX007 + SOC*
*SOC: Standard of Care 
(up to 3 stable AEDs)
UX007 (triheptanoin) + SOC*
Target Dose 20%
Caloric Intake
(4 wks)
Target Dose 40%
Caloric Intake
(4 wks)
Target Dose 35%
Caloric Intake
Individualized
Target Dose (16 wks)
Dose Exploration (~40 subjects)
1 wk Titration


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For the study to be adequately powered, a sample of approximately 40 completed subjects 
was estimated to be adequate to detect a 50% between-group difference in seizure frequency 
per 4 weeks with power of approximately 80% and population standard deviation of 55% 
using two-sample t test at one-sided alpha level of 0.05. 
3.6 
Primary Analyses 
Evaluations will occur at the following key time points:   
• Primary Analysis: The primary, week 8, analysis will occur when all subjects have 
completed the 8 week double-blind placebo-controlled treatment period, or withdrawn 
from the study prior to the week 8 visit. 
• Final Analysis: The final analysis will occur when all subjects have completed the 
open-label extension period, or withdrawn from the study. 
3.7 
Data Monitoring Committee 
A DMC with appropriate expertise in the conduct of clinical trials in children will act in an 
advisory capacity to monitor subject safety on a routine basis throughout the trial.  
The DMC will also monitor individual subject tolerability and implement individual subject 
stopping criteria based on the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), Version 4.0. The DMC will be consulted for the 
management of individual subjects who experience unacceptable tolerability issues (such as 
significant gastrointestinal distress). The DMC may: 
• Review the study protocol and informed consent documents, and plans for data 
monitoring 
• Evaluate the progress of the trial, study data quality, timeliness, subject recruitment, 
accrual and retention, subjects’ risk versus potential benefit, and other factors that could 
affect the study outcome 
• Consider relevant information that may have an impact on the safety of the participants or 
the ethics of the study 
• Make other recommendations to Ultragenyx concerning continuation, termination or 
other modifications of the study based on their observations of the study. 
The detailed roles and responsibilities of the DMC are specified in the DMC Charter. 
 


 
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4 STUDY ENDPOINTS, COVARIATES AND SUBGROUPS 
The clinical efficacy tests / instruments evaluated in this study are summarized in Table 1. 
See the study protocol for the detailed description of each test. 
Table 1: Study Outcomes 
Seizure Frequency and Response 
• 
Observable seizures measured by seizure diary [**] 
• 
Absence seizures measured by overnight electroencephalogram (EEG) [**] 
 
Movement 
• 
Movement ability measured by 6-minute Walk Test (6MWT) [*] 
• 
Paroxysmal exertional dyskinesia (PED) events measured by 6MWT [*] 
• 
Gross motor function measured by Gross Motor Function Measure-88 (GMFM 88) [*][#] 
• 
Gait analysis measured during 6MWT [#] 
 
Neurological Function 
• 
Neuropsychological function measured by Computerized Neuropsychological Test - Cambridge 
Neuropsychological Test Automated Battery (CANTAB) [*] 
• 
Physical neurological findings measured by Columbia Neurological Score (CNS) 
• 
Global impression of disease improvement measured by Clinical Global Impression –Improvement (CGI-I) 
• 
Receptive vocabulary achievement and verbal ability measured by Peabody Picture Vocabulary Test (PPVT) 
[#] 
• 
Visual and motor coordination measured by Beery-Buktenica Developmental Test of Visual Motor Integration 
(Beery-VMI) [#] 
• 
Spatial understanding and abstract reasoning measured by Raven’s Coloured Progressive Matrices (RCPM) [#] 
 
Quality of Life 
• 
Physical and psychosocial health-related quality of life measured by Short Form-10 (SF-10) Health Survey in 
subjects under 18 years of age 
• 
Physical and psychosocial health-related quality of life measured by Short Form-12 (SF-12) Health Survey in 
subjects 18 years of age and over 
• 
Functional capabilities and performance measured by Pediatric Evaluation of Disability Inventory Computer 
Adaptive Test (PEDI-CAT)[#] 
 
[**] Primary efficacy measures 
[*] Secondary efficacy measures 
[#] Measured at select sites only 
 
Each of the primary and secondary endpoints will be compared between the UX007 and 
placebo groups during the double-blind, placebo-controlled treatment period. 


 
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4.1 
Primary Efficacy Endpoint 
The primary endpoint to evaluate the efficacy of UX007 in Glut1 DS is as follows: 
• Reduction from baseline to week 8 in frequency of seizures (normalized to a 4-week 
rate): observable seizures measured for 6 weeks after 2-week titration by diary and 
absence seizures measured overnight by electroencephalography (EEG).  The primary 
efficacy endpoint will be derived for each subject based on subject seizure type at 
randomization: observable seizures from the diary will be used for Observable Seizures 
Subjects and absence seizures from EEG will be used for Absence Seizures Only 
Subjects (see Section 5.6). 
4.2 
Secondary Efficacy Endpoints 
The following are considered secondary endpoints to evaluate the efficacy of UX007 in 
Glut1 DS: 
• Reduction from baseline to week 8 in frequency of observable seizures (normalized to a 
4-week rate) measured for 6 weeks after 2-week titration by diary 
• Reduction from baseline to week 8 in frequency of absence seizures (normalized to a 
4-week rate) measured overnight by EEG 
• Seizure response at Week 8, defined as at least 50% reduction from baseline to week 8 in 
frequency of seizures 
• Observable seizure response at Week 8, defined as at least 50% reduction from baseline 
to week 8 in frequency of observable seizures measured by diary 
• Absence seizure response at Week 8, defined as at least 50% reduction from baseline to 
week 8 in frequency of absence seizures measured overnight by EEG 
• Cognitive function using the Cambridge Neuropsychological Test Automated Battery 
(CANTAB): change from baseline to Week 8 in the following scores: 
 Reaction Time (RTI): 
− Simple Choice Median Reaction Time (RTIMDSRT) 
− Five Choice Median Reaction Time (RTIMDFRT) 
− Simple Choice Standard Deviation (RTISRTSD) 
 Spatial Span (SSP): 
− Span Length (SSPSLF) 
 Paired Associates Learning (PAL): 
− Total Errors (Adjusted) (PALTEA) 
− First Trial Memory Score (PALFTMS) 


 
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 Spatial Working Memory (SWM): 
− Between Errors (SWMBE48) 
− Strategy (SWMS68) 
• Change from baseline to Week 8 in distance traveled (in meters) as measured by 6MWT 
• Change from baseline to Week 8 in distance traveled (in percent predicted) as measured 
by 6MWT 
• Time (in minutes) to onset of paroxysmal exertional dyskinesia (PED) as measured 
during 6MWT through Week 8 
• Gross motor function using the Gross Motor Function Measure-88 (GMFM-88): change 
from baseline to Week 8 in Total Score. 
• Reduction from baseline over time in frequency of seizures (normalized to a 4-week 
rate): observable seizures measured daily by diary and absence seizures measured 
overnight by electroencephalography (EEG) 
• Reduction from baseline over time in frequency of observable seizures (normalized to a 
4-week rate) measured daily by diary 
• Reduction from baseline over time in frequency of absence seizures (normalized to a 
4-week rate) measured overnight by EEG 
4.3 
Exploratory Efficacy Endpoints 
The following are considered exploratory endpoints and provide supplemental information to 
evaluate the efficacy of UX007 in Glut1 DS: 
• Cognitive function using the Cambridge Neuropsychological Test Automated Battery 
(CANTAB), change from baseline over time in the following scores: RTIMDSRT, 
RTIMDFRT, RTISRTSD, SSPSLF, PALTEA, PALFTMS, SWMBE48, SWMS68 
• Change from baseline over time in distance traveled (in meters) as measured by 6MWT 
• Change from baseline over time in distance traveled (in percent predicted) as measured 
by 6MWT 
• Time (in minutes) to onset of paroxysmal exertional dyskinesia (PED) as measured 
during 6MWT over time 
• Gross motor function using the Gross Motor Function Measure-88 (GMFM-88): change 
from baseline over time in the following scores: Lying and Rolling; Sitting; Crawling and 
Kneeling; Standing; Walking, Running and Jumping; Total Score 
• Change from baseline in Neurological function using the Columbia Neurological Score 
(CNS) total score 
• Physician global impression of change in clinical status (Guy 1976) 


 
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 Clinical Global Impression - Improvement scale (CGI-I) 
• Change from baseline in Receptive vocabulary using the Peabody Picture Vocabulary 
Test (PPVT) standardized score 
• Subject or caregiver-reported quality of life using Short Form-10™ (SF-10) Health 
Survey for children (subjects 5 through 17 years of age): change from baseline in two 
component summary T-scores: 
 Physical Summary Score (PHS-10) 
 Psychosocial Summary Score (PSS-10) 
• Subject or caregiver-reported quality of life using Short Form-12v2 (SF-12v2) Health 
Survey for adults (subjects 18 years of age and older): change from baseline in 8 domain 
norm based scores and two component T-scores: 
 Physical Functioning (PF) 
 Role Limitations due to Physical Health (RP) 
 Bodily Pain (BP) 
 General Health Perceptions (GH) 
 Vitality (VT) 
 Social Functioning (SF) 
 Role Limitations due to Emotions Problems (RE) 
 Mental Health (MH) 
 Physical Component Summary Scale (PCS-12) 
 Mental Component Summary Scale (MCS-12) 
• Functional disability by caregiver report using the Pediatric Evaluation of Disability 
Inventory – Computer Adaptive Test (PEDI-CAT) for all subjects under the age of 18 (or 
for subjects 18- 20 years as clinically indicated) at the time of informed consent: change 
from baseline in domain scale scores and T-scores 
 Daily Activities 
 Mobility 
 Social/Cognitive 
 Responsibility 
• Gait, using gait analysis by computerized mat during 6MWT: change from baseline in the 
following measures: 
 Stride Length 
 Base of Support 


 
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 Double Support 
 Velocity 
 Cadence 
• Visual motor integration using the Beery-Buktenica Developmental Test of Visual Motor 
Integration (Beery-VMI) for subjects between 2 and 18 years of age: change from 
baseline. 
• Spatial understanding and abstract reasoning using the Raven’s Coloured Progressive 
Matrices (RCPM): change from baseline in total score 
4.4 
Safety Endpoints 
The following endpoints will be used to evaluate the safety of UX007: 
• Treatment emergent adverse events (TEAEs) including treatment emergent serious 
adverse events (TESAEs), fatal AEs, TEAEs leading to discontinuation, treatment related 
TEAEs and treatment related TESAEs 
• Gastrointestinal (GI) TEAEs categorized using the standardized MedDRA query (SMQ) 
as listed in Appendix C 
• Clinically significant changes from baseline in the following: 
 Vital signs and weight 
 Physical examination and ECG findings 
 Clinical laboratory evaluations 
 Pregnancy testing/pregnancy of partner 
 Suicidal ideation and behavior assessments 
 Concomitant medications 
• Drug concentration measurements and bioassays 
 Plasma peak levels of UX007 
 Plasma levels of UX007 metabolites:  C4 ketone (BHB), C5 ketones 
(beta-hydroxypentanoate [BHP]), and heptanoate 
 Non-fasting BHB 
 Trough UX007 and metabolites 
4.5 
Covariates 
Covariates that may be incorporated into models include an appropriate associated baseline 
value and an indicator for whether a subject is an Absence Seizures Only Subject. 
Transformations will be considered for model covariates that are overly skewed. 


 
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4.6 
Subgroups 
Subgroup analyses will be done based on the derived seizure variables at baseline 
(see Section 5.6). 
5 DEFINITIONS 
5.1 
Baseline 
Baseline observable seizure frequency (see Section 5.7.1) from the seizure diary will be 
derived by measuring over approximately 6 weeks between the screening visit and the day 
prior to the randomization visit. 
For all other measures, baseline value will be the last non-missing assessment prior to or on 
the date of the first dose of investigational product. 
The baseline value will be used for all analyses of changes from the randomization visit and 
the phrases “change from baseline” and “change from randomization” will be used 
interchangeably. 
5.2 
Duration of Investigational Product Exposure 
For each subject, the duration of investigational product exposure is defined for a given study 
period as the date of last dose of study drug during the study period – date of first dose of 
study drug during the study period + 1. 
For each subject, the duration of UX007 exposure is defined for a given study period as the 
date of last dose of UX007 during the study period – date of first dose of UX007 during the 
study period + 1. 
5.3 
Study Day 
Study day is calculated as (visit date – date of the first dose of investigational product + 1) if 
the date is on or after the first dose of investigational product; or (visit date – date of the first 
dose of investigational product) if the date is prior the first dose of investigational product. 
5.4 
Dosing Compliance 
Number of days during a period is calculated as (end of period date – first dose date + 1) for 
the titration and treatment periods, and (end of period date – week 8 visit date + 1) for the 
extension period. Percent of days missed for a period is 100×(number of days during the 
period with dose non-compliance)/(number of days during the period). 


 
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5.5 
Change from Baseline and Percent Change from Baseline 
Generally, for measurements at any timepoint T after baseline, change from baseline is 
defined as 
Change from Baseline at T = Measurement at T −Measurement at Baseline 
Percent change from baseline at T is defined as 
Percent Change from Baseline at T
= 100 × Measurement at T −Measurement at Baseline
Measurement at Baseline
 
5.6 
Classification of Subjects at Randomization by Seizure Type 
Classification of subjects is used to derive the primary efficacy endpoint and to define which 
subjects are included in secondary endpoint analyses of specific seizure types.  At the 
Randomization Visit, subjects can be classified according to the types of seizures that are 
recorded on the diary as follows:  
• 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 5.7.5) greater than or equal to 4 at Randomization 
• Observable Seizure Frequency less than 4 at Randomization and Absence Seizure 
Frequency less than 4 at Randomization 
• Absence Seizures Subject: a subject who meets any of the following: 
• has seizure types M, N, O or P (see Section 5.7.5) recorded on the seizure diary 
during the Baseline Period 
• has absence seizures documented on the Screening EEG 
• Absence Seizure Frequency (see Section 5.7.2) greater than 0 at Randomization 
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 
randomized 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 


 
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5.7 
Derived Seizure Efficacy Variables 
5.7.1 
Observable Seizure Frequency 
Observable seizure frequency, the observable non-absence seizure frequency from the diary 
(normalized to a 4-week rate), is defined as 
Observable Seizure Frequency = Total number of seizures
Number of days observed × 28 
See Section 5.7.5 for the list of observable seizure types that are counted.  For analyses, 
observable seizure frequency will be defined at each of the following timepoints as follows: 
• Baseline: approximately 6 weeks between the day of the screening visit and the day prior 
to the randomization visit 
• End of Titration: approximately 2 weeks between the day of the randomization visit and 
the day prior to the end of titration visit 
• Week 8: approximately 6 weeks between the day of the end of titration visit and the day 
prior to the week 8 visit 
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 weeks 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. 
5.7.2 
Absence Seizure Frequency 
The absence seizure frequency from EEG (normalized to a 24-hour rate) is defined as 
Absence Seizure Frequency = Total number of absence seizures
Number of hours observed
× 24 
See Section 5.7.6 for the list of absence seizure types that are counted. Absence seizure 
frequency at baseline is measured at the randomization visit. Absence seizure frequency at 
8 weeks is measured at the week 8 visit (Visit 5). 
5.7.3 
Percent Reduction from Baseline in Seizure Frequency 
For observable or absence seizures, the percent reduction from baseline in seizure frequency 
during a period T is defined as 
Percent Reduction from Baseline = 100 × Frequency at Baseline −Frequency at T
Frequency at Baseline
 


 
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The maximum percent reduction is 100% and occurs when the frequency is reduced to zero.  
If the frequency increases then the percent reduction is a negative number. 
5.7.4 
Seizure Response 
Seizure response is defined as a percent reduction from baseline in seizure frequency greater 
than or equal to 50%. 
Observable seizure response, at least 50% reduction from baseline in frequency of observable 
seizures measured by diary, is defined as percent reduction in observable seizure frequency 
greater than or equal to 50%. 
Absence seizure response, at least 50% reduction from baseline in frequency of absence 
seizures measured overnight by EEG, is defined as percent reduction in absence seizure 
frequency greater than or equal to 50%. 
5.7.5 
Classification of Seizures from Diary 
Table 2 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. 
Table 2: Seizure Classification by Diary 
Seizure 
Code 
(Diary) 
Seizure Classification  
Counted 
Towards 
Inclusion 
Criteria 
Counted as 
Observable 
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 [*] 
 
N 
Atypical Absence 
X [*] 
 
O 
Absence with Special Features (Myoclonic absence) 
X [*] 
 
P 
Absence with Special Features (Eyelid myoclonia) 
X [*] 
 


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Table 4: 
CANTAB Scores 
Cognitive Domain  
Specification  
Sense  
Form  
Range  
Attention  
RTI Simple choice reaction time standard 
deviation (RTISRTSD)  
Lower is 
better  
Continuous  
0-5000  
Reaction Time  
RTI median simple choice reaction time 
(RTIMDSRT)  
Lower is 
better  
Continuous  
100-5100 
(ms)  
Reaction Time  
RTI median 5-choice reaction time 
(RTIMDFRT)  
Lower is 
better  
Continuous  
100-5100 
(ms)  
Episodic memory/ 
new learning  
PAL total errors adjusted (PALTEA)  
Lower is 
better  
Discrete 
ordinal  
0-137  
Episodic memory  
PAL first trial memory score (PALFTMS)  Higher is 
better  
Discrete 
ordinal  
0-27  
Sequential memory  
SSP Span Length (SSPSLF)  
Higher is 
better  
Discrete 
ordinal  
2-9  
Working Memory  
SWM between errors (SWMBE48)  
Lower is 
better  
Discrete 
ordinal  
0-360  
Executive function/ 
strategy  
SWM strategy (SWMS68)  
Lower is 
better  
Discrete 
ordinal  
4-28  
 
5.8.2 
Percent predicted 6MWT distance 
The percent predicted 6MWT formula which is applicable at enrollment will be used for that 
subject throughout the study. 
To calculate the percent predicted 6MWT value, the following formulas will be applied for 
subjects aged < 20 years old (Geiger et al. 2007). 
For males: 
𝑋𝑖=
𝑋0𝑖
196.72 + (39.81 ∗𝐴𝐴𝐴) −(1.36 ∗𝐴𝐴𝐴2) + (132.28 ∗𝐻𝐻𝐻𝐻ℎ𝑡) ∗100 
and for females: 
𝑋𝑖=
𝑋0𝑖
188.61 + (51.50 ∗𝐴𝐴𝐴) −(1.86 ∗𝐴𝐴𝐴2) + (86.10 ∗𝐻𝐻𝐻𝐻ℎ𝑡) ∗100 
where Xi is the percent predicted 6MWT result at time i for subject X, and X0i is the 6MWT 
result (in meters) at time i for subject X. Height and age at the study visit will be used for the 
calculation for the duration of the study. If height is missing at the study visit then the nearest 
available measurement will be used. If there are no height measurements then percent 
predicted will not be calculated. 


 
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To calculate the percent predicted 6MWT value, the following formula will be applied for 
subjects aged  ≥ 20 years old (Gibbons et al. 2001).  
𝑋𝑖=
𝑋0𝑖
868.8 −(2.99 × 𝐴𝐴𝐴) −(74.7 × 𝐺𝐺𝐺𝐺𝐺𝐺) ∗100 
where Xi is the percent predicted 6MWT result at time i for subject X, X0i is the 6MWT result 
(in meters) at time i for subject X, and Gender is equal to 0 if the subject is male or 1 if the 
subject is female. Height at baseline will be used for calculation for the duration of the study, 
and age at the study visit will be used for the calculation for the duration of the study.  
If height is missing then the nearest available measurement will be used. 
5.8.3 
Gross Motor Function Measure-88 (GMFM-88) 
The GMFM-88 scores include the following: 
• Lying & Rolling Score, Range 0–100%, Higher is better 
• Sitting Score, Range 0–100%, Higher is better 
• Crawling & Kneeling Score, Range 0–100%, Higher is better 
• Standing Score, Range 0–100%, Higher is better 
• Walking, Running & Jumping Score, Range 0–100%, Higher is better 
• Total Score = (Sum of 5 Above Scores) / 5, Range 0–100%, Higher is better 
5.8.4 
Columbia Neurological Score (CNS) total score 
The CNS is a quantitative tool developed to summarize neurological exam findings 
(Kaufmann et al. 2004). The Columbia Neurologic Score (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. 
5.8.5 
Peabody Picture Vocabulary Test (PPVT) standardized score 
The PPVT is a test of receptive vocabulary achievement and verbal ability that is normed for 
children as young as 2 years of age (Dunn et al. 2007). The PPVT results in the following 
scores: 
• Raw Score [PPVTRAW], Range 0–228, higher is better 


 
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• Standard Score [PPVSTSCR], Range 20–160, higher is better 
• 95% Confidence Interval-Upper [PPVCONUP], Range 20–166, higher is better 
• 95% Confidence Interval-Lower [PPVCONLO], Range 14–154, higher is better 
• Percentile Rank [PPVTPERC], Range <0.1 – >99.9, higher is better 
• Age Equivalent [PPVTAGEQ], Range <2:0 – >24:11, higher is better 
• Growth Scale Value (GSV) [PPVTGSV], Range 12–271, higher is better 
5.8.6 
SF-10 Health Survey 
The SF-10 Health Survey is assessed for children 5 to 17 years of age. Two summary 
measures (the Physical Summary Score and the Psychosocial Summary Score) are calculated 
from raw scores to have a mean of 50 and SD of 10. 
The T-score Based scoring (described in Section 5.8.7) is also used to score the SF-10 
Health Survey for Children summary scales. The scale scores have been centered so 
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). Although scale scores are standardized to a mean of 50 and a standard deviation of 
10 in the combined U.S. general population and clinical samples, age-specific t-scoreative 
data should always be used for comparison purposes when results for individual children are 
being considered or when aggregate data are limited to a specific age range for which 
t scoreative data are available. 
5.8.7 
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. Additionally two 
summary component scores are calculated from domain scores (Physical Component 
Summary Scale [PCS] and the Mental Component Summary Scale [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 
QualityMetric 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.  


 
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The main advantage of T-score Based scoring of the adult SF tools is easier interpretation. 
By using the T-score Based scoring method, your data are scored 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. Because the standard deviation for each scale is 10, it is 
easier to see exactly how far above or below the mean a score is in standard deviation units 
(10 points = 1 standard deviation unit). 
5.8.8 
Pediatric Evaluation of Disability Inventory Computer Adaptive Test 
(PEDI-CAT) 
The Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) is a 
measure of functional capabilities and performance designed for use in children and youth 
from birth through 20 years of age with a variety of physical conditions (Haley et al. 2011).   
PEDI-CAT includes 4 domains (daily activities, mobility, social/cognitive and 
responsibility). Only 3 domain scores (daily activities, mobility, social/cognitive) will be 
included in the analysis for the subjects under 3 years of old. Each of the 4 PEDI CAT 
domains will be presented as Score, SE, T-Score and Percentile. Higher is better for Score, 
T-Score and Percentile. The assessment will be administered at select sites. 
5.8.9 
Gait, using gait analysis by computerized mat during the 6MWT 
At select sites, the computerized mat may be used to assess gait during the 6MWT as the 
subject walks across the mat. The following gait assessments will be assessed at select sites: 
• Stride Length (cm) 
• Base of Support (cm) 
• Double Support (% of gait cycle) 
• Velocity (cm/sec) 
• Cadence (steps/minute) 
5.8.10 Beery-Buktenica Developmental Test of Visual Motor Integration (Beery-VMI) 
The Beery-VMI measures the extent to which individuals can integrate their visual and 
motor abilities (Beery et al. 2004). The test is normed for children 2-18 years of age. 
The Beery-VMI will be administered to subjects at select sites to obtain the following scores: 
Raw Score (Range 0–30, higher is better), Standard Score, Scaled Score, and Percentile. 
5.8.11 Raven’s Coloured Progressive Matrices (RCPM) 
The RCPM is a test of spatial understanding and abstract reasoning developed for individuals 
5 years of age and older (Raven et al. 1998). At select sites, the RCPM will be administered 
to all subjects, at the clinical judgment of the test administrator, to obtain Total Score 
(Range 0–60, higher is better) and Percentile. 


 
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6 ANALYSIS POPULATIONS 
The following analysis sets are defined for this study. 
6.1 
Screened Population 
The Screened Population will consist of all subjects who underwent a Screening Visit. 
6.2 
Randomized Population 
The Randomized Population will consist of all subjects in the Screened Population who were 
randomized to a treatment group in the study. 
6.3 
Efficacy Analysis Set 
The Efficacy Analysis Set includes all randomized subjects who received at least one dose of 
investigational product. For efficacy analyses, subjects are analyzed according to study 
treatment as randomized. 
6.3.1 
Efficacy Analysis Set – Observable Seizures 
The Efficacy Analysis Set – Observable Seizures is the subset of subjects in the Efficacy 
Analysis Set who are Observable Seizures Subjects (see Section 5.6). 
6.3.2 
Efficacy Analysis Set – Absence Seizures 
The Efficacy Analysis Set – Absence Seizures is the subset of subjects in the Efficacy 
Analysis Set who are Absence Seizures Subjects (see Section 5.6). 
6.3.3 
Efficacy Analysis Set – Observable Seizures Only 
The Efficacy Analysis Set – Observable Seizures Only is the subset of subjects in the 
Efficacy Analysis Set who are Observable Seizures Only Subjects (see Section 5.6). 
6.3.4 
Efficacy Analysis Set – Absence Seizures Only 
The Efficacy Analysis Set – Absence Seizures Only is the subset of subjects in the Efficacy 
Analysis Set who are Absence Seizures Only Subjects (includes some subjects with fewer 
than 4 observable seizures per 4 weeks, see Section 5.6). 
6.3.5 
Efficacy Analysis Set – CANTAB 
The efficacy analysis set – CANTAB is the subset of subjects in the efficacy analysis set who 
had a baseline and at least one post baseline (Week 4 or Week 8) CANTAB assessment 
performed. 


 
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6.3.6 
Efficacy Analysis Set – 6MWT 
The efficacy analysis set – 6MWT is the subset of subjects in the efficacy analysis set who 
had a baseline and at least one post baseline (Week 4 or Week 8) 6MWT assessment 
performed. 
6.3.7 
Efficacy Analysis Set – GMFM-88 
The efficacy analysis set – GMFM-88 is the subset of subjects in the efficacy analysis set 
who had a baseline and at least one post baseline (Week 4 or Week 8) GMFM-88 assessment 
performed. 
6.3.8 
Efficacy Analysis Set – CNS 
The efficacy analysis set – CNS is the subset of subjects in the efficacy analysis set who had 
a baseline and Week 8 CNS assessment performed. 
6.3.9 
Efficacy Analysis Set – CGI-I 
The efficacy analysis set – CGI-I is the subset of subjects in the efficacy analysis set who had 
CGI-I assessment performed at Week 8. 
6.3.10 Efficacy Analysis Set – SF-10 
The efficacy analysis set – SF-10 is the subset of subjects in the efficacy analysis set who had 
a baseline and Week 8 SF-10 assessment performed. 
6.3.11 Efficacy Analysis Set – SF-12 
The efficacy analysis set – SF-12 is the subset of subjects in the efficacy analysis set who had 
a baseline and Week 8 SF-12 assessment performed. 
6.4 
Per Protocol Analysis Set 
The Per Protocol Analysis Set is the subset of subjects in the Efficacy Analysis Set who also 
meet the following criteria: 
• met all inclusion and exclusion criteria at the time of randomization 
• have ≥80% dosing compliance from baseline to week 8 
• have sufficiently complete seizure data 
 Observable Seizures Subjects: completed at least 28 days of the seizure diary during 
the 6-week baseline period and again during weeks 3-8 of the double-blind placebo-
controlled treatment period 


 
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 Absence Seizures Only Subjects: at least 8 hours evaluable EEG at randomization and 
again at week 8 
6.4.1 
Per Protocol Analysis Set – Observable Seizures 
The Per Protocol Analysis Set – Observable Seizures is the subset of subjects in the Efficacy 
Analysis Set – Observable Seizures who met the following criteria: 
• met all inclusion and exclusion criteria at the time of randomization 
• have ≥80% dosing compliance from baseline to week 8 
• have sufficiently complete seizure data: completed at least 28 days of the seizure diary 
during the 6-week baseline period and again during weeks 3-8 of the double-blind 
placebo-controlled treatment period 
6.4.2 
Per Protocol Analysis Set – Absence Seizures 
The Per Protocol Analysis Set – Absence Seizures is the subset of subjects in the Efficacy 
Analysis Set – Absence Seizures who met the following criteria: 
• met all inclusion and exclusion criteria at the time of randomization 
• have ≥80% dosing compliance from baseline to week 8 
• have sufficiently complete seizure data: at least 8 hours evaluable EEG at randomization 
and again at week 8 
6.4.3 
Per Protocol Analysis Set – CANTAB 
The Efficacy Analysis Set – CANTAB is the subset of subjects in the Efficacy Analysis Set – 
CANTAB who met all inclusion and exclusion criteria at the time of randomization and have 
≥80% dosing compliance from baseline to week 8. 
6.5 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who receive at least one dose of 
investigational product. For safety analyses during the double-blind period, subjects are 
summarized according to first study treatment actually received: either UX007 or placebo. 
Separate listings will capture actual dosing throughout. 
6.6 
Extension Analysis Set 
The Extension Analysis Set is the subset of subjects in the Safety Analysis Set who 
continued after the 8 week double-blind placebo-controlled treatment period into the open-
label extension period. 


 
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6.7 
Pharmacokinetics Analysis Set 
The Pharmacokinetics Analysis Set (PK Analysis Set) includes all subjects with available PK 
data. 


 
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7 DATA HANDLING AND ACCEPTANCE  
7.1 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified through a review of tables and listings for this study. Missing and incomplete data 
will be identified for investigation and possible resolution by Data Management prior to the 
study database lock.    
Unless otherwise specified, for missing assessments for an individual subject, these data 
would remain as missing. When a change from baseline is assessed, only subjects with a 
baseline and at least one post baseline measurement will be included in the analysis. 
For primary and secondary analyses related to reduction in seizures from baseline to Week 8, 
imputation will be used to enable inclusion in analyses of all subjects in the Efficacy 
Analysis Set, the Efficacy Analysis Set – Observable Seizures and the Efficacy Analysis Set 
– Absence Seizures. 
• For observable seizures subjects who have incomplete diary data during the Baseline 
Period but at least one day complete, observable seizure frequency will be calculated by 
averaging over the days with complete diary data. The same rule will be used for the 
Double-Blind Placebo-Controlled Treatment Period. Note that this also applies to 
subjects who terminate early. 
• For absence seizures subjects who have incomplete EEG at either Randomization or 
Week 8, absence seizure frequency will be calculated by averaging over the time that is 
complete, even if the EEG is not done overnight. 
• For subjects who have completely missing data for either Randomization or Week 8, 
a reduction from baseline in the natural logarithm of seizure frequency (+ 1) value of zero 
will be imputed for the response variable in any analyses of reduction from baseline, and 
non-response will be imputed for the response variable in any analyses of seizure 
response. For subjects who have completely missing data for Randomization, the Week 8 
value will be imputed if available for the baseline covariate; if both Randomization and 
Week 8 are missing then the average baseline value of the subjects with complete data in 
the same treatment group will be imputed for the baseline covariate. In additional 
analyses related to reduction in seizures, two alternate methods will be implemented: 
• the average reduction from baseline in the logarithm of seizure frequency (+ 1) of the 
subjects with complete data in the same treatment group will be imputed for the 
response variable in any analyses of reduction from baseline; and response will be 
imputed as yes if the imputed reduction from baseline is greater than or equal to the 
natural logarithm of 2 and no otherwise in any analyses of seizure response 
• no imputation, or complete case analysis – these data would remain as missing. 


 
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Imputation will not be used for analyses involving the open label period. 
7.2 
Missing Date Imputation Rules 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications. 
1. Start Dates 
a. If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
b. If the month is unknown, then: 
i. If the year matches the first dose date year, then impute the month and 
day of the first dose date. 
ii. Otherwise, assign “January.” 
c. If the day is unknown, then: 
i. 
If the month and year match the first dose date month and year, then 
impute the day of the first dose date. 
ii. 
Otherwise, assign the first day of the month. 
2. Stop Dates 
a. If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
b. If the month is unknown, then assign “December.” 
c. If the day is unknown, then assign the last day of the month. 
7.3 
Unscheduled or Early Termination Visits 
In general, data collected by study visit will be summarized using the visit number specified 
in the database. Outcomes scheduled at a planned study visit but collected during an 
unscheduled visit or early termination visit will be mapped into the closest study visit based 
on the study day of the unscheduled visit or early termination visit, and the schedule of 
events in the protocol. 
For outcomes where both the planned study visit and an unscheduled visit or early 
termination visit corresponding to that study visit are available, the planned study visit 
measurement will be used for the analysis. 
All safety data including the planned study visits and unscheduled/early termination visits 
will be included in the shift tables. 


 
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All data will be included in the data listings and outcomes measured during unscheduled 
visits and early termination visits will be marked as acquired during an unscheduled visit. 
Observable seizure frequency will be mapped to visits as described in Section 5.7.1.   
7.4 
Analysis Software 
Data manipulation, tabulation of summary statistics, graphical representations and estimation 
of model parameters will be performed primarily using SAS (release 9.4 or higher) for 
Windows. If the use of other software is warranted, the final clinical study report will detail 
what software was used and for what purposes. Scoring software from Cambridge Cognition 
(Cambridge, UK) will be used to score the CANTAB instrument described in Section 5.8.1.  
T-score Based scoring software from QualityMetric Inc. (Lincoln, RI) will be used to score 
the SF-12 and SF-10 Health Survey instruments described in Sections 5.8.6 and 5.8.7 
respectively. 
7.5 
Coding of Events and Medications 
Adverse events will be coded to standardize presentation of AEs and TEAEs. AEs will be 
mapped to the Medical Dictionary for Regulatory Activities (MedDRA) system for reporting 
system organ classes and preferred terms. 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD).  


 
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8 STATISTICAL METHODS OF ANALYSIS 
8.1 
General Principles  
During the Double-Blind Placebo-Controlled Treatment Period, efficacy analyses will be 
based on the Efficacy Analysis Set or the Per Protocol Analysis Set. During the open label 
period, efficacy analyses will be based on the Extension Set. Safety analyses will be based 
on the Safety Analysis Set. Unless stated otherwise, statistical tests will be 1-sided 
hypothesis tests performed at the 5% level of significance and confidence intervals will be 
2-sided 90% confidence intervals. 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. 
Analyses and summaries by study period will be done for the following time periods: 
• Double-blind placebo-controlled treatment period: after the date of the randomization 
visit until the date of the week 8 visit 
• Open-label extension period: after the date of the week 8 visit until the date of the 
week 52 visit 
• Dose exploration period: after the date of the week 26 visit until the date of the 
week 36 visit 
Overall analyses and summaries will include all subjects and ignore treatment assignment. 
For logarithmic transformations of seizure frequency, the natural logarithm will be used and 
a value of 1 will be added prior to performing the transformation. 
For analyses and summaries of subjects while taking UX007, the time while taking placebo 
will be excluded and the original baseline will be used for all subjects regardless of which 
treatment was taken during the double-blind placebo-controlled treatment period. 
Graphical displays of select study endpoints will be completed and include both observed 
study data and modeled analyses. Arithmetic means, least square means (LSM), and 
appropriate measure of dispersion (e.g., standard deviation, standard error) or confidence 
intervals may be displayed in figures. 
8.2 
Subject Accountability 
The number and percentage of subjects in each of the analysis populations (Screened, 
Randomized, Efficacy, Per Protocol, Safety, Extension, PK) will be summarized by treatment 
group and overall. 
Screen-failure subjects (i.e., subjects screened but not randomized) and the associated 
reasons for failure to randomize will be tabulated overall for the Screened Population. 
The number and percentage of subjects in the Randomized Population who complete the 


 
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double-blind placebo-controlled treatment period, who complete the open-label extension 
period and who prematurely discontinue will be presented for each treatment group and 
overall. The reasons for early discontinuation will be summarized. 
8.2.1 
Protocol Deviations 
Protocol deviations will be summarized for the Efficacy Analysis Set and listed by type. 
8.3 
Demographics 
A table will be presented for the Efficacy Analysis Set by treatment group and overall for the 
following variables: 
• Ethnicity 
• Race 
• Age at informed consent and age group using the following categories: 
 Under 2 
 2 to less than 12 
 12 to less than 18 
 18 to less than 65 
 65 and above 
A table will be presented by treatment group and overall, by Age at informed consent 
(Pediatrics under 18 vs. Adults 18 and above), for the following variables: 
• Ethnicity 
• Race 
• Sex 
8.4 
Disease Characteristics and Medical History 
Summary statistics will be presented for the Efficacy Analysis Set by treatment group and 
overall, by age at informed consent (under 18 vs. 18 and above), for the following variables: 
• Time at randomization since Glut1 DS diagnosis by mutation analysis 
• Glut1 DS mutation description 
• Glut1 DS symptoms history including whether ongoing: seizures, walking abnormality, 
coordination or motor abnormalities besides walking, paroxysmal exertional dyskinesia, 
movement disorder besides PED, cognitive abnormality, behavioral abnormality, 
developmental delay 


 
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• Ketogenic diet history (yes/no) 
• Seizure history by type: 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, Simple Partial/Focal Sensory, Simple Partial/Focal Psychological, 
Typical Absence, Atypical Absence, Absence with Special Features (Myoclonic 
absence), Absence with Special Features (Eyelid myoclonia), Unclassified (Inc. epileptic 
spasms) 
• Average number of observable seizures (generalized [except absence] or partial-onset 
seizures) per month over the last 6 months 
Listings will be provided for the following: 
• Medical history: major illnesses, diagnoses, and surgeries 
8.5 
IP Administration 
8.5.1 
Study Drug Exposure 
Duration of IP exposure and duration of UX007 exposure will be summarized by study 
period, and by treatment group, for subjects while taking UX007, and overall. A listing will 
also be provided. 
8.5.2 
Dose Titration 
Summary statistics for dose titration will be presented by treatment group, and overall, for 
the Efficacy Analysis Set. The following parameters will be summarized: 
• Missed Dose (Yes/No) 
• Reason Dose Missed 
• Total Daily Dose Taken (ml) 
• Tolerability Issues (Yes/No) 
• Target Dose (ml) 
A listing will also be provided. 
8.5.3 
Diet Diary Review 
The following measures will be summarized by visit based on the 3 day Diet Diary Review 
for the 3 days prior to each visit: 
• Average Study Drug Calories, the average of the 3 entries for Study Drug 


 
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• Average Total Daily Calories 
• Maximum Tolerated Dose Achieved (%) 
• Maximum Tolerated Dose Achieved ≥20% (yes/no) 
• Prescribed Dose through next visit (ml) 
A listing will also be provided. 
8.5.4 
Dosing Compliance 
Number and percent of days missed will be summarized for the titration period, the double-
blind placebo-controlled treatment period and the open-label extension period. 
8.6 
Efficacy Analyses 
The statistical approach for each efficacy analysis is summarized in Table 5 and will depend 
on the level of endpoint (primary, secondary, exploratory) and the study periods involved 
(double-blind placebo-controlled treatment, open-label extension). The statistical approach 
for Week 8 analyses of primary and secondary endpoints will be comparisons between 
UX007 and placebo. A more thorough table showing Test/Instrument, Eligible Study 
Population, Endpoint, Subjects Applicable, Endpoint Level, Timepoints for Assessments, and 
Statistical Approach by Study Period Analysis is provided in Appendix A. The statistical 
approach is defined for the following study period analyses: 
• Week 8 Analyses: incorporate data up to the end of the double-blind placebo-controlled 
treatment period 
• Week 52 Analyses: incorporate data from the entire study 
Each statistical approach is described in the following sections. 
Table 5: 
Efficacy Analyses by Study Period and Endpoint Level 
Endpoint Level 
Statistical Approach: 
Week 8 Analyses 
Statistical Approach: 
Week 52 Analyses 
Primary and Secondary 
Endpoints 
Comparison Between UX007 and 
Placebo Groups 
Estimation by Treatment Group and 
Overall 
Exploratory Endpoints 
Summary Statistics by Treatment 
Group 
Summary Statistics by Treatment 
Group and Overall 
Exploratory Endpoints at 
Select Sites 
Data Listing 
Data Listing 
 


 
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8.6.1 
Comparisons Between UX007 and Placebo Groups 
Comparisons of primary and secondary endpoints will be performed to test for a difference in 
the endpoint between UX007 and placebo groups during the double-blind placebo-controlled 
treatment period. Model based estimates will be presented, with 90% confidence intervals, 
for each endpoint by treatment group and also for the treatment effect (difference between 
treatment groups for continuous endpoints and difference between treatment groups for 
binary endpoints). 
Endpoints measured during the double-blind placebo-controlled treatment period only at 
Week 8 and those measured at both Week 4 and Week 8 will be analyzed differently as 
described below. Endpoints measured only at Week 8 include those derived from the seizure 
diary and EEG. Endpoints measured at both Week 4 and Week 8 included those derived from 
CANTAB, 6MWT and GMFM-88. 
Continuous Endpoints: 
• Continuous endpoints measured only at Week 8 will be analyzed using linear regression 
(ANCOVA), with change from baseline to Week 8 as the response variable, treatment 
group (UX007 vs. placebo) as the primary variable of interest and an appropriate baseline 
value as an additional covariate. 
• Continuous endpoints measured at both Week 4 and Week 8 will be analyzed using 
generalized estimating equations (GEE), with change from baseline at each timepoint as 
the response variable; treatment group (UX007 vs. placebo), a factor for visit, visit by 
treatment interaction and an appropriate baseline value as covariates; identity link 
function and exchangeable within subject working correlation matrix. The comparison of 
interest will be based on the LS means difference at Week 8. 
Binary Endpoints: 
• Categorical (binary) endpoints measured only at Week 8 will be analyzed using logistic 
regression, with a yes/no indicator as the response variable, treatment group (UX007 vs. 
placebo) as the primary variable of interest and an appropriate baseline value as an 
additional covariate. 
• Categorical (binary) endpoints measured at both Week 4 and Week 8 will be analyzed 
using generalized estimating equations (GEE), with a yes/no indicator at each timepoint 
as the response variable; treatment group (UX007 vs. placebo), a factor for visit, visit by 
treatment interaction and an appropriate baseline value as covariates; logit link function 
and exchangeable within subject working correlation matrix. The comparison of interest 
will be based on the LS means difference at Week 8. 
If the number of observations is insufficient for analyses, between group comparisons may 
not be done and within group tests for no change from baseline may be provided instead. 


 
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8.6.2 
Estimation by Treatment Group and Overall 
Estimation by randomized treatment group, for subjects while taking UX007 and overall will 
be done over time will be analyzed using a generalized estimation equations (GEE) model as 
follows: 
• Continuous endpoints will be analyzed using a GEE linear model, with change from 
baseline at each timepoint as the response variable; treatment group (UX007 vs. placebo), 
a factor for visit, visit by treatment interaction and an appropriate baseline value as 
covariates; identity link function and exchangeable within subject working correlation 
matrix. 
• Categorical (binary) endpoints will be analyzed using a GEE logistic model, with a 
yes/no indicator at each timepoint as the response variable; treatment group (UX007 vs. 
placebo), a factor for visit, visit by treatment interaction and an appropriate baseline 
value as covariates, logit link function and exchangeable within subject working 
correlation matrix. 
All available measurements during the appropriate study period will be included in the 
model. 
If the number of observations is insufficient for analyses, summary statistics will be 
provided. 
8.6.3 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the reduction from baseline to week 8 in frequency of 
seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 
2-week titration by diary and absence seizures measured overnight by 
electroencephalography (EEG). Observable seizure frequency at baseline will be calculated 
based on approximately 6 weeks between the screening and randomization visits and 
observable seizure frequency at week 8 will be calculated based on approximately 6 weeks 
between the end of titration and the week 8 visit (see Section 5.7.1). Absence seizure 
frequency will be based on overnight EEG at the randomization and week 8 visits. 
The primary efficacy endpoint will be derived for each subject based on subject seizure type 
at randomization: observable seizures from the diary will be used for Observable Seizures 
Subjects and absence seizures from EEG will be used for Absence Seizures Only Subjects 
(see Section 5.6). 
The primary efficacy endpoint will be analyzed, based on the Efficacy Analysis Set, using a 
linear regression (ANCOVA) model as described for continuous endpoints in Section 8.6.1. 
Logarithmic transformations will be used for modeling.  The response variable in the model 
will be the reduction in the natural logarithm of the seizure frequency (+ 1) from baseline to 
Week 8 and the baseline covariate will be the natural logarithm of the baseline seizure 
frequency (+ 1): observable seizures from the diary will be used for Observable Seizures 
Subjects and absence seizures from EEG will be used for Absence Seizures Only Subjects. 


 
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An additional covariate will be included that indicates whether the subject is an Observable 
Seizures Subject or an Absence Seizures Only Subject. Estimates and 90% confidence 
intervals of percent reduction in seizure frequency will be derived from the model for each 
treatment group and for the difference between groups. 
Missing data will be imputed as specified in Section 7.1.  Sensitivity analysis assessing the 
impact of missing data will be performed using the methods described in Section 7.1. 
Percent reduction from baseline in frequency of seizures over the entire study period will be 
summarized by visit (see Section 5.7.1), and by treatment group, for subjects while taking 
UX007, and overall. 
The following additional analyses will be performed: 
• An analysis will be performed incorporating multiplicity adjustment for analyses of 
absence and observable seizures using a fallback method (Wiens et al. 2005).  The 
absence seizures and observable seizures analyses may include overlapping subjects.  For 
each of these subgroups, a within UX007 group test will be performed first and the 
between group test will only be performed if the p-value for the within group test is less 
than the appropriate level according to the procedure.  The one-sided type I error 
(α=0.05) will be split into 3 components: α1(Overall) = 0.04, α2(Absence) = 0.005, 
α3(Observable) = 0.005.  The following null hypotheses will be tested: 
• H01(Overall, Between Group): Reduction from baseline to week 8 in frequency of 
seizures with UX007 is not greater than with placebo 
• H02W(Absence, Within Group): Reduction from baseline to week 8 in frequency of 
absence seizures with UX007 is not greater than zero 
• H02B(Absence, Between Group): Reduction from baseline to week 8 in frequency of 
absence seizures with UX007 is not greater than with placebo 
• H03W(Observable, Within Group): Reduction from baseline to week 8 in frequency of 
observable seizures with UX007 is not greater than zero 
• H03B(Observable, Between Group): Reduction from baseline to week 8 in frequency 
of observable seizures with UX007 is not greater than with placebo 
The corresponding nominal p-values are defined as p1(Overall), p2W(Absence), 
p2B(Absence), p3W(Observable), p3B(Observable).  The testing procedure will be 
performed as follows: 
1. If p1 ≤ α1 = 0.04, then reject H01 and set α2
*= α1+0.005; otherwise, accept H01 and set 
α2
*=0.005. 
2. If p2W ≤ α2
*, then reject H02W; otherwise, accept H02W, accept H02B and set α3
*=0.005. 
3. If p2W ≤ α2
* and p2B ≤ α2
*, then reject H02B and set α3
*= α2+0.005; otherwise, accept 
H02B and set α3
*= 0.005. 


 
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4. If p3W ≤ α3
*, then reject H03W; otherwise, accept H03W and accept H03B. 
5. If p3W ≤ α3
* and p3B ≤ α3
*, then reject H03B; otherwise, accept H02B. 
• An analysis will be performed with seizure frequency at baseline and Week 8 derived for 
each subject based on subject seizure type at randomization: observable seizures from the 
diary will be used for Observable Seizures Only Subjects and absence seizures from EEG 
will be used for Absence Seizures Subjects (see Section 5.6). 
• An analysis will be performed using observable seizure frequency at week 8, including 
titration period, calculated based on seizure diary data collected for approximately 
8 weeks from baseline to week 8. 
• An analysis will be performed using the Per Protocol Analysis Set. 
• An analysis will be performed using the alternative imputation methods described in 
Section 7.1. 
8.6.4 
Secondary Endpoints 
For secondary endpoints, between group comparisons from baseline to week 8 will be 
performed as described in Section 8.6.1 as follows: 
• Seizure response at Week 8 (a percent reduction from baseline in seizure frequency 
greater than or equal to 50%, see Section 5.7.4) will be analyzed, based on the Efficacy 
Analysis Set, using logistic regression. The baseline covariate will be the natural 
logarithm of the baseline seizure frequency (+ 1): observable seizures from the diary will 
be used for Observable Seizures Subjects and absence seizures from EEG will be used for 
Absence Seizures Only Subjects. An additional covariate will be included that indicates 
whether the subject is an Observable Seizures Subject or an Absence Seizures Only 
Subject. 
• Reduction from baseline in frequency of observable seizures will be analyzed, based on 
the Efficacy Analysis Set, using linear regression. The response variable in the model 
will be the change in the natural logarithm of the observable seizure frequency (+ 1) from 
baseline to Week 8 and the baseline covariate will be the natural logarithm of the baseline 
frequency (+ 1) of observable seizures (see Section 5.7.5). Estimates and 90% confidence 
intervals of percent reduction in observable seizure frequency will be derived from the 
model for each treatment group and for the difference between groups. 
• Observable seizure response at Week 8 will be analyzed, based on the Efficacy Analysis 
Set, using logistic regression. Observable seizure frequency will be calculated based on 
approximately 6 weeks between the end of titration and the week 8 visit. The baseline 
covariate will be the natural logarithm of the baseline frequency (+ 1) of observable 
seizures (see Section 5.7.5). 
• Reduction from baseline in frequency of absence seizures will be analyzed, based on the 
Efficacy Analysis Set, using linear regression. The response variable in the model will be 


 
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the change in the natural logarithm of the absence seizure frequency (+ 1) from baseline 
to Week 8 and the baseline covariate will be the natural logarithm of the baseline 
frequency (+ 1) of absence seizures. Estimates and 90% confidence intervals of percent 
reduction in absence seizure frequency will be derived from the model for each treatment 
group and for the difference between groups. 
• Absence seizure response at Week 8 will be analyzed, based on the Efficacy Analysis 
Set, using logistic regression. The baseline covariate will be the natural logarithm of the 
baseline frequency (+ 1) of absence seizures. 
• Change from baseline in each of the 8 CANTAB scores will be analyzed, based on the 
Efficacy Analysis Set – CANTAB, using GEE with identity link function. The baseline 
covariate will be the baseline value of the corresponding CANTAB score. 
• Change from baseline in 6MWT distance traveled (in meters and percent predicted) will 
be analyzed, based on the Efficacy Analysis Set – 6MWT, using GEE with identity link 
function. The baseline covariate will be the baseline value of the corresponding 6MWT 
measure. 
• Since a high proportion of subjects do not experience onset of PED during the 6MWT, 
onset of PED will be analyzed as a binary indicator for whether PED occurred (yes/no).  
Onset of paroxysmal exertional dyskinesia (PED) during the 6MWT (yes/no) will be 
analyzed, based on the Efficacy Analysis Set – 6MWT, using GEE with logistic link 
function. The baseline covariate will be the baseline value of the indicator for onset of 
PED. 
• Change from baseline in GMFM-88 Total score will be analyzed, based on the Efficacy 
Analysis Set – GMFM-88, using GEE with identity link function. The baseline covariate 
will be the baseline value of GMFM-88 Total score. 
Missing data will be imputed as specified in Section 7.1. 
Each endpoint will be summarized by visit, by treatment group, for subjects while taking 
UX007, and overall. 
The following additional analyses will be performed: 
• An analysis will be performed using the Per Protocol Analysis Set for endpoints 
involving all seizures, and the Per Protocol Analysis Set – Observable Seizures for 
endpoints involving seizures from the diary only, the Per Protocol Analysis Set – 
Absence Seizures for endpoints involving seizures from EEG only, and the Per Protocol 
Analysis Set – CANTAB for the CANTAB endpoints (see Section 6.4). 
• For seizure response, an analysis will be performed with seizure frequency at baseline 
and Week 8 derived for each subject based on subject seizure type at randomization: 
observable seizures from the diary will be used for Observable Seizures Only Subjects 
and absence seizures from EEG will be used for Absence Seizures Subjects (see Section 
5.6). 


 
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• For endpoints involving seizures, an analysis will be performed using the alternative 
imputation methods described in Section 7.1. 
• For endpoints involving observable seizures from the seizure diary, an analysis will be 
performed using observable seizure frequency at week 8, including titration period, 
calculated based on seizure diary data collected for approximately 8 weeks from baseline 
to week 8. 
8.6.5 
Exploratory Efficacy Endpoints 
Summary statistics, including p-values for differences between treatment groups during the 
double-blind placebo-controlled treatment period, will be provided by visit for the following 
exploratory endpoints over the entire study period by treatment group and overall: specific 
seizure types derived from seizure diary, specific seizure types derived from EEG, CNS, 
CGI-I, SF-10 and SF-12 v2. 
A data listing will be provided for the following exploratory endpoints available at select 
sites over the entire study period: PPVT, PEDI-CAT, Gait analysis during 6-minute walk test 
(6MWT), GMFM-88 domains (lying/rolling, sitting, crawling/kneeling, standing, and 
walking/running/jumping), Beery-VMI and RCPM. 
8.6.6 
Subset Analyses of Primary and Select Secondary Endpoints 
Analyses of primary and secondary endpoints involving seizures will be repeated for the 
following subgroups: Efficacy Analysis Set – Observable Seizures and Efficacy Analysis Set 
– Absence Seizures, for the subjects with ≥80% dosing compliance from baseline to week 8 
(see Section 8.5.4). 
8.7 
Safety Analyses 
All safety analyses will be based on the Safety Analysis Set. In general safety analyses will 
be completed using summary statistics, graphs or subject listings. No planned inferential 
testing of safety endpoints is planned. If after the planned analysis it is determined by the 
medical writer and study medical monitor that inferential tests of significance may help to 
provide context for safety information these tests may be performed and identified in the 
CSR.  Summaries will be done by study period and overall. 
Analyses and summaries will be performed by study period, by treatment group, for subjects 
while taking UX007, and overall. 
8.7.1 
Adverse Events 
Adverse Events will be assessed at all visits and throughout the course of the study. An AE 
will be considered a treatment emergent adverse event (TEAE) if it occurs or worsens in 
severity on or after the date of the first dose of study drug. An AE will be considered a 
UX007 emergent adverse event if it occurs or worsens in severity on or after the first date of 


 
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first dose of UX007 during the study. It is expected that the date of first dose of UX007 
during the study will be the date of Randomization visit for the UX007 group and the date of 
Week 8 visit for the placebo group; however, the date of first UX007 dose actually received 
will be used. 
UX007 emergent AEs will be summarized by SOC and preferred term during the period 
exposed to UX007 by treatment group and overall for all subjects who receive UX007.  
TEAEs will be summarized by SOC and preferred term during the course of the study by 
treatment group and overall for all subjects who receive study drug. 
Exposure adjusted event incidence, defined as total number of occurrences of an event 
summed across all subjects in the group divided by the total observed time for events for 
subjects in the group, will be summarized for TEAEs and UX007 emergent AEs by SOC and 
preferred term by treatment group and overall. 
During the double-blind placebo-controlled period; TEAEs will be summarized by 
treatment group and overall, and UX007 emergent AEs will be summarized by treatment 
group and overall. If no placebo subjects also receive UX007 during the double-blind 
placebo-controlled period, then there will only be one group for UX007 emergent AEs during 
the double-blind placebo-controlled period.  During the open-label extension period, TEAEs 
and UX007 emergent AEs will both be summarized by treatment group and overall. 
A high-level safety summary will display the numbers of subjects who experience one or 
more AEs in each of the following categories: 
• All TEAEs and UX007 emergent AEs 
• All treatment related TEAEs and UX007 emergent AEs 
• Serious TEAEs and UX007 emergent AEs 
• All treatment related SAEs and UX007 emergent SAEs 
• Grade 3/4 TEAEs and UX007 emergent AEs 
• TEAEs and UX007 emergent AEs leading to study discontinuation  
• Fatal TEAEs and UX007 emergent AEs 
• TEAEs and UX007 emergent AEs in the GI SMQ (see Appendix C) 
• Related TEAEs and UX007 emergent AEs in the GI SMQ 
Reported AE terms were coded to MedDRA (version 17.1) lowest level terms (LLT) linked 
to preferred terms (PT) and system organ classes (SOC). The number and percent of subjects 
with any treatment-emergent adverse events (TEAEs) will be displayed by SOC and PT. 
Within each level of summarization (SOC or PT), subjects will be counted only once if they 
had more than one event at that level. The same summary will be performed for TEAEs in 


 
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the MedDRA GI SMQ, all related TEAEs, serious TEAEs, those causing discontinuation of 
investigational product and fatal TEAEs. 
The number and percent of subject TEAEs will also be summarized by greatest reported 
severity grade (AE grading defined in study protocol) for each event preferred term. 
The number and percent of subjects experiencing one or more TEAEs for each PT in the 
GI SMQ will be summarized. 
The number and percent of subjects experiencing one or more TEAE, TESAEs, and 
treatment related TEAEs by descending PT will be summarized. 
The number and percent of subjects experiencing one or more TEAE by SOC and PT in 
order of descending frequency will be summarized by age group (18 and older vs. under 18), 
gender and seizure type (Observable Seizures Subjects, Absence Seizures Only Subjects). 
The number and percent of subjects who withdraw from the study or discontinue study 
medication due to a TEAE or SAE will be summarized. 
The number and percent of subject TEAEs will be summarized by greatest reported 
relationship (relationship defined in protocol) to study medication. 
All TEAEs will be listed individually by subject. In addition, a separate listing will be 
produced for AEs that are not treatment-emergent. Separate individual subject listings for 
SAEs and TEAEs leading to Study Withdrawal or discontinuation of Study Medication will 
also be produced. 
8.7.2 
Vital Signs and Weight 
The following vital signs and weight will be summarized by time point for the observed 
value and the change from baseline value.   
• Temperature (°C) 
• Respiration Rate (breaths/min) 
• Heart Rate (beats/min) 
• Systolic Blood Pressure (mmHg) 
• Diastolic Blood Pressure (mmHg) 
• Weight (kg) 
8.7.3 
Physical Examination 
Physical examinations will include assessments of general appearance; head, eyes, ears, nose, 
and throat; the cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, 


 
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genitourinary, musculoskeletal, and neurologic systems. Physical examination abnormality 
findings will be listed over time by subject.  
8.7.4 
Electrocardiogram 
The following ECG results and change from baseline results will be summarized and 
provided in subject listing: 
• RR Duration (msec) 
• Heart Rate (beats/min) 
• PR Duration (msec) 
• QRS Duration (msec) 
• QT Duration (msec) 
• QTCB - Bazett’s Correction Formula (msec) 
• QTCF - Fridericia’s Correction Formula (msec) 
• Overall Statement (Categorical indicator of evaluability, abnormality and clinical 
significance of abnormality) 
8.7.5 
Select Clinical Laboratory Parameters 
Clinical laboratory data will be summarized by the type of laboratory test. Reference ranges 
and markedly abnormal results will be used in the summary of laboratory data.  
Summary statistics will be calculated for each laboratory analyte at baseline and at each 
scheduled time point. Changes from baseline results will be presented in pre- versus 
post-treatment cross tabulations (with classes for below, within, and above normal ranges).  
A listing of subjects with any markedly abnormal laboratory results will be provided.  
The frequency and percentage of subjects who experience abnormal clinical laboratory 
results (i.e., outside of reference ranges) and/or clinically significant abnormalities will be 
presented for each clinical laboratory measurement. 
The following laboratory results will be summarized by time point for the observed value as 
well as for the change from baseline value: 
• 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 
• Hematology: Hematocrit, Hemoglobin, Platelet count, Red blood cell (RBC) count, 
White blood cell (WBC) count, Beta-hydroxybutyrate (BHB)  (at Screening) 
• Urinalysis: Appearance, Color, pH, Specific gravity, Ketones, Protein, Glucose, 
Pregnancy test (if applicable) 


 
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For fasting serum glucose, triglycerides, ALT, AST and GGT, CTCAE severity grades will 
be summarized in shift tables pairing each subject’s baseline severity grade with the subject’s 
highest post-baseline severity grade. 
Specifically, CTCAE severity grades for increased triglycerides are:  
• Grade 1: 150 – 300 mg/dL; 1.71 – 3.42 mmol/L 
• Grade 2: > 300 – 500 mg/dL; > 3.42 – 5.7 mmol/L 
• Grade 3: >500 – 1000 mg/dL; > 5.7 – 11.4 mmol/L 
• Grade 4: >1000 mg/dL; > 11.4 mmol/L 
CTCAE severity grades for hypoglycemia are: 
• Grade 1: <LLN – 55 mg/dL; <LLN – 3.0 mmol/L 
• Grade 2:  <55 – 40 mg/dL; <3.0 – 2.2 mmol/L 
• Grade 3: <40 – 30 mg/dL; <2.2 – 1.7 mmol/L 
• Grade 4: < 30 mg/dL; <1.7 mmol/L 
CTCAE severity grades for increased ALT and increased AST are: 
• Grade 1: >ULN to 3.0 x ULN 
• Grade 2: >3.0 x ULN to 5.0 x ULN 
• Grade 3: >5.0 x ULN to 20.0 x ULN 
• Grade 4: >20.0 x ULN 
And CTCAE severity grades for increased GGT are: 
• Grade 1: >ULN to 2.5 x ULN 
• Grade 2: >2.5 x ULN to 5.0 x ULN 
• Grade 3: >5.0 x ULN to 20.0 x ULN 
• Grade 4: >20.0 x ULN 
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  


 
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• 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. 
8.7.6 
Suicidal Ideation and Behavior 
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 
pediatric population (Posner et al. 2011).  
The following outcomes are C-SSRS categories and have binary responses (yes/no).  
The categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the results. 
• Category 1 – Wish to be Dead 
• Category 2 – Non-specific Active Suicidal Thoughts 
• Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
• Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
• Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
• Category 6 – Preparatory Acts or Behavior 
• Category 7 – Aborted Attempt 
• Category 8 – Interrupted Attempt 
• Category 9 – Actual Attempt (non-fatal) 
• Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no). 
Composite endpoints based on the above categories are defined below. 
• Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS 
• Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS 
• Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS 


 
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C-SSRS endpoints will be summarized by treatment group and presented in a listing. 
8.7.7 
Prior and Concomitant Medications 
A prior medication is defined as any medication started before the date of the first dose of 
study drug. A concomitant medication is defined as any medication taken on or after the date 
of the first dose of study drug. A medication started before the date of the first dose of study 
drug and also taken after the date of first dose of study drug 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 WHO Drug Dictionary Enhanced Version 2014 December or newer and summarized 
by treatment group for the Safety Analysis Set and listed by subject. If a subject took a 
specific medication multiple times or took multiple medications within a specific therapeutic 
class, that subject would be counted only once for the coded drug name or therapeutic class.  
8.7.8 
Pharmacokinetics of UX007 
Summary statistics, including mean, standard deviation, coefficient of variation, 
geometric mean, median, minimum, and maximum will be presented over time for plasma 
peak levels of UX007, plasma levels of UX007 metabolites [C4 ketone (BHB), C5 ketones 
(beta-hydroxypentanoate [BHP]), and heptanoate], non-fasting BHB and trough (pre-dose 
[within 15 minutes]) UX007 at each available time point. Data will be listed for all subjects 
with available data. All subjects and samples excluded from the analysis will be clearly 
documented in the study report. 
 


 
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9 PLANNED DATA PRESENTATIONS 
Data presentations planned to support writing the UX007G-CL201 CSR are listed in Table 6. 
Table 6: Planned Data Presentations 
Output 
Type 
Title 
 
Demographic Data 
Table 
Subject Disposition – Randomized Population 
Table 
Protocol Deviations – Efficacy Analysis Set 
Table 
Demographics – Efficacy Analysis Set 
Table 
Demographics by Age Group – Efficacy Analysis Set 
Table 
Glut1 DS Disease History – Efficacy Analysis Set 
Table 
Seizure History – Efficacy Analysis Set 
Table 
Study Drug Exposure – Efficacy Analysis Set 
Table 
Summary of Diet Diary Review – Efficacy Analysis Set 
Table 
Dosing Compliance – Days Dose Missed by Study Period – Efficacy Analysis Set 
 
Primary and Secondary Efficacy Analyses – Seizures 
Table 
Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set 
Table 
Observable Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set 
Table 
Absence Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis Set 
Table 
Observable Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy 
Analysis Set 
Table 
Absence Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis 
Set 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set 
Table 
Observable Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set 
Table 
Absence Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set 
 
Additional Efficacy Analyses – Seizures 
Table 
Seizures – Week 8 Analysis – Summary – Per Protocol Analysis Set 
Table 
Observable Seizures – Week 8 Analysis – Summary – Per Protocol Analysis Set 
Table 
Absence Seizures – Week 8 Analysis – Summary – Per Protocol Analysis Set 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Per Protocol Analysis Set 
Table 
Observable Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Per Protocol 
Analysis Set 
Table 
Absence Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Per Protocol 
Analysis Set 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Per Protocol Analysis Set 
Table 
Observable Seizure Response – Week 8 Analysis – Logistic Regression – Per Protocol Analysis Set 
Table 
Absence Seizure Response – Week 8 Analysis – Logistic Regression – Per Protocol Analysis Set 


 
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Output 
Type 
Title 
Table 
Absence Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set – Absence at Baseline 
Table 
Absence Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis 
Set – Absence at Baseline 
Table 
Absence Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Absence at Baseline 
Table 
Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set – Dosing Compliance ≥80% 
Table 
Observable Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set – Dosing Compliance 
≥80% 
Table 
Absence Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set – Dosing Compliance 
≥80% 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis Set – 
Dosing Compliance ≥80% 
Table 
Observable Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy 
Analysis Set – Dosing Compliance ≥80% 
Table 
Absence Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis 
Set – Dosing Compliance ≥80% 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – Dosing 
Compliance ≥80% 
Table 
Observable Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Dosing Compliance ≥80% 
Table 
Absence Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Dosing Compliance ≥80% 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis Set – 
Alternate Imputation Method 
Table 
Observable Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy 
Analysis Set – Alternate Imputation Method 
Table 
Absence Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis 
Set – Alternate Imputation Method 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – Alternate 
Imputation Method 
Table 
Observable Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Alternate Imputation Method 
Table 
Absence Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Alternate Imputation Method 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis Set – 
Complete Case Method 
Table 
Observable Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy 
Analysis Set – Complete Case Method 
Table 
Absence Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis 
Set – Complete Case Method 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – Complete 
Case Method 
Table 
Observable Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Complete Case Method 


 
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Output 
Type 
Title 
Table 
Absence Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set – 
Complete Case Method 
Table 
Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set –Alternate Seizure Frequency 
Derivation 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis Set –
Alternate Seizure Frequency Derivation 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set –Alternate 
Seizure Frequency Derivation 
Table 
Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set –Analysis Including Dose Titration 
Period 
Table 
Observable Seizures – Week 8 Analysis – Summary – Efficacy Analysis Set –Analysis Including 
Dose Titration Period 
Table 
Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy Analysis Set –
Analysis Including Dose Titration Period 
Table 
Observable Seizures – Reduction from Baseline – Week 8 Analysis – ANCOVA – Efficacy 
Analysis Set –Analysis Including Dose Titration Period 
Table 
Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set –Analysis 
Including Dose Titration Period 
Table 
Observable Seizure Response – Week 8 Analysis – Logistic Regression – Efficacy Analysis Set –
Analysis Including Dose Titration Period 
 
Secondary Efficacy Analyses 
Table 
CANTAB Simple Choice Median Reaction Time – Week 8 Analysis – Summary – Efficacy 
Analysis Set – CANTAB 
Table 
CANTAB Five Choice Median Reaction Time – Week 8 Analysis – Summary – Efficacy Analysis 
Set – CANTAB 
Table 
CANTAB Simple Choice Standard Deviation – Week 8 Analysis – Summary – Efficacy Analysis 
Set – CANTAB 
Table 
CANTAB Spatial Span Length – Week 8 Analysis – Summary – Efficacy Analysis Set – CANTAB 
Table 
CANTAB Paired Associates Learning Test Total Errors (Adjusted) – Week 8 Analysis – Summary 
– Efficacy Analysis Set – CANTAB 
Table 
CANTAB Paired Associates Learning Test First Trial Memory Score – Week 8 Analysis – 
Summary – Efficacy Analysis Set – CANTAB 
Table 
CANTAB Spatial Working Memory Between Errors – Week 8 Analysis – Summary – Efficacy 
Analysis Set – CANTAB 
Table 
CANTAB Spatial Working Memory Strategy – Week 8 Analysis – Summary – Efficacy Analysis 
Set – CANTAB 
Table 
CANTAB – Change from Baseline – Week 8 Analysis – GEE – Efficacy Analysis Set – CANTAB 
Table 
CANTAB – Change from Baseline – Week 8 Analysis – GEE – Per Protocol Analysis Set – 
CANTAB 
Table 
6MWT Distance (meters) – Week 8 Analysis – Summary – Efficacy Analysis Set – 6MWT 
Table 
6MWT Distance (percent predicted) – Week 8 Analysis – Summary – Efficacy Analysis Set – 
6MWT 
Table 
Onset of PED – Week 8 Analysis – Summary – Efficacy Analysis Set – 6MWT 


 
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Output 
Type 
Title 
Table 
6MWT – Change from Baseline – Week 8 Analysis – GEE – Efficacy Analysis Set – 6MWT 
Table 
Onset ofPED – Week 8 Analysis – GEE – Efficacy Analysis Set – 6MWT 
Table 
GMFM-88 Total Score – Week 8 Analysis – Summary – Efficacy Analysis Set – GMFM-88 
Table 
GMFM-88 Total Score – Change from Baseline – Week 8 Analysis – GEE – Efficacy Analysis Set 
– GMFM-88 
 
Exploratory Efficacy Analyses 
Table 
Frequency of Seizure Types via Diary – Week 8 Analysis – Summary – Efficacy Analysis Set 
Table 
Frequency of Seizure Types via EEG – Week 8 Analysis – Summary – Efficacy Analysis Set 
Table 
CGI-S and CGI-I – Week 8 Analysis – Summary – Efficacy Analysis Set – CGI-I 
Table 
CGI-I – Week 8 Analysis – t-tests – Efficacy Analysis Set 
Table 
SF-10 – Week 8 Analysis – Summary – Efficacy Analysis Set – SF-10 
Table 
SF-12 v2 – Week 8 Analysis – Summary – Efficacy Analysis Set – SF-12 
Table 
SF-10 – Change from Baseline– Week 8 Analysis – t-tests – Efficacy Analysis Set 
Table 
SF-12 – Change from Baseline– Week 8 Analysis – t-tests – Efficacy Analysis Set 
Table 
CNS – Week 8 Analysis – Summary – Efficacy Analysis Set – CNS 
Table 
CNS – Change from Baseline – Week 8 Analysis – t-tests – Efficacy Analysis Set 
 
Safety Analyses of Adverse Events 
Table 
Overall Summary of Adverse Events – Safety Analysis Set 
Table 
Overall Summary of Adverse Events by Study Period  – Safety Analysis Set 
Table 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term – Safety Analysis 
Set 
Table 
Serious Treatment Emergent Adverse Events by System Organ Class and Preferred Term – Safety 
Analysis Set 
Table 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term and Greatest Severity 
– Safety Analysis Set 
Table 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term and Greatest Reported 
Relationship – Safety Analysis Set 
Table 
Grade 3 or 4 Treatment Emergent Adverse Events by System Organ Class and Preferred Term – 
Safety Analysis Set 
Table 
Related Treatment Emergent Adverse Events by System Organ Class and Preferred Term – Safety 
Analysis Set 
Table 
Gastrointestinal Treatment Emergent Adverse Events by Preferred Term – Safety Analysis Set 
Table 
UX007 Emergent Adverse Events by System Organ Class and Preferred Term – Safety Analysis Set 
Table 
Serious UX007 Emergent Adverse Events by System Organ Class and Preferred Term – Safety 
Analysis Set 
Table 
Related Serious Treatment Emergent Adverse Events by System Organ Class and Preferred Term – 
Safety Analysis Set 
Table 
Related Gastrointestinal Treatment Emergent Adverse Events by Preferred Term – Safety Analysis 
Set 
Table 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term (by age group) – 
Safety Analysis Set 


 
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Output 
Type 
Title 
Table 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term (by gender) – 
Safety Analysis Set 
Table 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term (by seizure type) – 
Safety Analysis Set 
Table 
Treatment Emergent Adverse Events by Preferred Term – Safety Analysis Set 
Table 
Serious Treatment Emergent Adverse Events by Preferred Term – Safety Analysis Set 
Table 
Related Treatment Emergent Adverse Events by Preferred Term – Safety Analysis Set 
Table 
Exposure Adjusted Treatment Emergent Adverse Event Incidence by System Organ Class and 
Preferred Term – Safety Analysis Set 
Table 
Exposure Adjusted UX007 Emergent Adverse Event Incidence by System Organ Class and 
Preferred Term – Safety Analysis Set 
 
Safety Analyses of Laboratory and Other Parameters 
Table 
Chemistry Laboratory Data Summary – Safety Analysis Set 
Table 
Chemistry Laboratory Shift Table – Safety Analysis Set 
Table 
Hematology Laboratory Data Summary – Safety Analysis Set 
Table 
Hematology Laboratory Shift Table – Safety Analysis Set 
Table 
Urinalysis Laboratory Data Summary – Safety Analysis Set 
Table 
Urinalysis Laboratory Shift Table – Safety Analysis Set 
Table 
Chemistry Abnormal and/or Clinically Significant Findings – Safety Analysis Set 
Table 
Hematology Abnormal and/or Clinically Significant Findings – Safety Analysis Set 
Table 
Urinalysis Abnormal and/or Clinically Significant Findings – Safety Analysis Set 
Table 
Vital Signs and Weight Summary – Safety Analysis Set 
Table 
ECG Results Summary – Safety Analysis Set 
Table 
ECG Results Shift Table – Safety Analysis Set 
Table 
Hy’s Law Status Shift Table – Safety Analysis Set 
Table 
PK Parameters Summary – Safety Analysis Set 
Table 
Suicidal Ideation Summary – Safety Analysis Set 
 
Efficacy Analyses Figures 
Figure 
Seizures – Week 8 Analysis – Individual and Geometric Mean with 90% CI – Efficacy Analysis Set 
Figure 
Observable Seizures – Week 8 Analysis – Individual and Geometric Mean with 90% CI – Efficacy 
Analysis Set – Observable Seizures 
Figure 
Observable Seizures – Week 8 Analysis – Individual and Geometric Mean with 90% CI – Efficacy 
Analysis Set – Observable Seizures Only 
Figure 
Absence Seizures – Week 8 Analysis – Individual and Geometric Mean with 90% CI – Efficacy 
Analysis Set – Absence Seizures 
Figure 
Absence Seizures – Week 8 Analysis – Individual and Geometric Mean with 90% CI – Efficacy 
Analysis Set – Absence Seizures Only 
Figure 
Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 – Cumulative 
Distribution Function – Efficacy Analysis Set 
Figure 
Observable Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 – 
Cumulative Distribution Function – Efficacy Analysis Set – Observable Seizures 


 
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Output 
Type 
Title 
Figure 
Observable Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 – 
Cumulative Distribution Function – Efficacy Analysis Set – Observable Seizures Only 
Figure 
Absence Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 – Cumulative 
Distribution Function – Efficacy Analysis Set – Absence Seizures 
Figure 
Absence Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 – Cumulative 
Distribution Function – Efficacy Analysis Set – Absence Seizures Only 
Figure 
Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 with 90% CI – Efficacy 
Analysis Set 
Figure 
Seizure Response – Week 8 Analysis – Efficacy Analysis Set 
Figure 
Observable Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 with 90% CI 
– Efficacy Analysis Set 
Figure 
Observable Seizure Response – Week 8 Analysis – Efficacy Analysis Set 
Figure 
Absence Seizures – Week 8 Analysis – Percent Reduction from Baseline to Week 8 with 90% CI – 
Efficacy Analysis Set 
Figure 
Absence Seizure Response – Week 8 Analysis – Efficacy Analysis Set 
Figure 
CANTAB Simple Choice Median Reaction Time – Week 8 Analysis – Individual and Mean with 
90% CI – Efficacy Analysis Set 
Figure 
CANTAB Five Choice Median Reaction Time – Week 8 Analysis – Individual and Mean with 90% 
CI – Efficacy Analysis Set 
Figure 
CANTAB Simple Choice Standard Deviation – Week 8 Analysis – Individual and Mean with 90% 
CI – Efficacy Analysis Set 
Figure 
CANTAB Spatial Span Length – Week 8 Analysis – Individual and Mean with 90% CI – Efficacy 
Analysis Set 
Figure 
CANTAB Paired Associates Learning Test Total Errors (Adjusted) – Week 8 Analysis – Individual 
and Mean with 90% CI – Efficacy Analysis Set 
Figure 
CANTAB Paired Associates Learning Test First Trial Memory Score – Week 8 Analysis – 
Individual and Mean with 90% CI – Efficacy Analysis Set 
Figure 
CANTAB Spatial Working Memory Between Errors – Week 8 Analysis – Individual and Mean 
with 90% CI – Efficacy Analysis Set 
Figure 
CANTAB Spatial Working Memory Strategy – Week 8 Analysis – Individual and Mean with 90% 
CI – Efficacy Analysis Set 
Figure 
6MWT Distance (meters) – Week 8 Analysis – Individual and Mean with 90% CI – Efficacy 
Analysis Set 
Figure 
6MWT Distance (percent predicted) – Week 8 Analysis – Individual and Mean with 90% CI – 
Efficacy Analysis Set 
Figure 
GMFM-88 Total Score – Week 8 Analysis – Individual and Mean with 90% CI – Efficacy Analysis 
Set 
Figure 
SF-10 – Week 8 Analysis – Efficacy Analysis Set 
Figure 
SF-12 – Week 8 Analysis – Efficacy Analysis Set 
Figure 
CGI-I – Week 8 Analysis – Efficacy Analysis Set 
 
Demographics Listings 
Listing 
Subject Disposition – Randomized Population 
Listing 
Analysis Sets – Randomized Population 


 
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Output 
Type 
Title 
Listing 
Subjects Who Failed to Meet One or More Inclusion/Exclusion Criteria – Screened Population 
Listing 
Protocol Deviations – Screened Population 
Listing 
Demographics and Baseline Characteristics – Randomized Population 
Listing 
Glut1 DS Disease Diagnosis and History – Screened Population 
Listing 
Ketogenic Diet History – Screened Population 
Listing 
Seizure History – Screened Population 
Listing 
Medical History – Screened Population 
Listing 
Prior and Concomitant Medications – Screened Population 
Listing 
Study Drug Dosing – Randomized Population 
Listing 
Dosing Compliance and Missed Doses – Randomized Population 
 
Efficacy Listings 
Listing 
Seizures – Randomized Population 
Listing 
Seizure Classification by Diary – Seizure Frequency by Type – Randomized Population 
Listing 
Seizure Classification by EEG – Seizure Frequency by Type – Randomized Population 
Listing 
CANTAB – Randomized Population 
Listing 
6MWT – Randomized Population 
Listing 
GMFM-88 Scores – Randomized Population 
Listing 
CGI-I – Randomized Population 
Listing 
SF-10 – Randomized Population 
Listing 
SF-12 v2 Questions – Randomized Population 
Listing 
SF-12 v2 Domain and Component Scores – Randomized Population 
Listing 
CNS – Randomized Population 
Listing 
PPVT – Randomized Population 
Listing 
PEDI-CAT – Randomized Population 
Listing 
Beery-VMI and Raven’s Coloured Progressive Matrices – Randomized Population 
Listing 
Gait Analysis – Randomized Population 
 
Safety Listings 
Listing 
Treatment Emergent Adverse Events – Safety Analysis Set 
Listing 
Serious Treatment Emergent Adverse Events – Safety Analysis Set 
Listing 
UX007 Emergent Adverse Events – Safety Analysis Set 
Listing 
Serious UX007 Emergent Adverse Events – Safety Analysis Set 
Listing 
Adverse Events During the Run-In Period – Safety Analysis Set 
Listing 
Adverse Events Leading to Withdrawal from Study or Discontinuation from Study Drug – Safety 
Analysis Set 
Listing 
Treatment Emergent Adverse Events Leading to Death – Safety Analysis Set 
Listing 
Chemistry Laboratory Data – Safety Analysis Set 
Listing 
Hematology Laboratory Data – Safety Analysis Set 
Listing 
Urinalysis Laboratory Data – Safety Analysis Set 


 
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Output 
Type 
Title 
Listing 
PK Data – Safety Analysis Set 
Listing 
Suicidal Ideation – Safety Analysis Set 
Listing 
Vital Signs and Weight – Safety Analysis Set 
Listing 
ECG – Safety Analysis Set 
Listing 
Laboratory Results and Hy’s Law – Safety Analysis Set 
 
 


 
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10 REFERENCES 
Beery, K, and Beery, N. 2004. The Beery-Buktenica Developmental Test of Visual-Motor 
Integration (Manual). Bloomington, MN: Pearson Assessments. 
Dunn, L, and Dunn, D. 2007. PPVT-4 Manual. Bloomington, MN: NCS Pearson, Inc. 
FDA. Draft Guidance 2012. Guidance for Industry: Suicidal Ideation and Behavior:  
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Geiger, R, Strasak, A, Treml, B, Gasser, K, Kleinsasser, A, Fischer, V, Geiger, H, 
Loeckinger, A, and Stein, JI. 2007. "Six-minute walk test in children and adolescents." J 
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Gibbons, WJ, Fruchter, N, Sloan, S, and Levy, RD. 2001. "Reference values for a multiple 
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Glauser, TA, Ayala, R, Elterman, RD, Mitchell, WG, Van Orman, CB, Gauer, LJ, and Lu, Z. 
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Glauser, TA, Nigro, M, Sachdeo, R, Pasteris, LA, Weinstein, S, Abou-Khalil, B, Frank, LM, 
Grinspan, A, Guarino, T, Bettis, D, Kerrigan, J, Geoffroy, G, Mandelbaum, D, Jacobs, T, 
Mesenbrink, P, Kramer, L, and D'Souza, J. 2000. "Adjunctive therapy with oxcarbazepine in 
children with partial seizures. The Oxcarbazepine Pediatric Study Group." Neurology 54 
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Guy, W. 1976. "The Clinical Global Impression Scale." In Handbook of Psychiatric 
Measures, 2008, edited by A. John Rush Jr, M.B First and D Blacker, 90-92. Washington, 
DC: American Psychiatric Publishing, Inc. 
Haley, SM, Coster, WJ, Dumas, HM, Fragala-Pinkham, MA, Kramer, J, Ni, P, Tian, F, Kao, 
YC, Moed, R, and Ludlow, LH. 2011. "Accuracy and precision of the Pediatric Evaluation of 
Disability Inventory computer-adaptive tests (PEDI-CAT)." Dev.Med.Child Neurol. 53 
(12):1100-1106. 
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. 
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. 


 
Study Number: UX007G-CL201 
Statistical Analysis Plan 
11 January 2017, Version 2.0 
 
 
Proprietary and Confidential 
Page 62 
Raven, J, Raven, J, and Court, J. 1998. Manual for Raven's Progressive Matrices and 
Vocabulary Scales.  Section 2: The Coloured Progressive Matrices. San Antonio, TX: 
Harcourt Assessment. 
Trevathan, E, Kerls, SP, Hammer, AE, Vuong, A, and Messenheimer, JA. 2006. 
"Lamotrigine adjunctive therapy among children and adolescents with primary generalized 
tonic-clonic seizures." Pediatrics 118 (2):e371-e378. 
Wiens, BL, and Dmitrienko, A. 2005. "The fallback procedure for evaluating a single family 
of hypotheses." J Biopharm Stat 15 (6):929-42. 
 
 
 


 
Study Number: UX007G-CL201 
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11 APPENDICES 
Appendix A: Efficacy Endpoint Summary Table 
 
Appendix B: Schedule of Events 
 
Appendix C: Gastrointestinal Standardized MedDRA Query 
 
Appendix D: SAS Code for Primary Statistical Analysis


 
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APPENDIX A 
EFFICACY ENDPOINT SUMMARY TABLE 
Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
Seizure Diary + EEG 
Efficacy 
Analysis Set 
Reduction from 
baseline in frequency of 
seizures 
All 
Primary 
Diary: daily from Screening to 
52/ET; EEG: Screening, 
Randomization, Week 8, 26, 31 
ANCOVA 
Estimation 
Seizure Diary + EEG 
Efficacy 
Analysis Set 
Seizure response 
All 
Secondary 
Diary: daily from Screening to 
52/ET; EEG: Screening, 
Randomization, Week 8, 26, 31 
Logistic 
Regression 
Estimation 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
observable seizures 
All 
Secondary 
Daily from Screening to 52/ET 
ANCOVA 
Estimation 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Observable seizure 
response 
All 
Secondary 
Daily from Screening to 52/ET 
Logistic 
Regression 
Estimation 
EEG 
Efficacy 
Analysis Set – 
Absence 
Seizures 
Reduction from 
baseline in frequency of 
absence seizures 
All 
Secondary 
Screening, Randomization,  
Week 8, 26, 31 
ANCOVA 
Estimation 
EEG 
Efficacy 
Analysis Set – 
Absence 
Seizures 
Absence seizure 
response 
All 
Secondary 
Screening, Randomization,  
Week 8, 26, 31 
Logistic 
Regression 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB RTI 
Simple Choice Median 
Reaction Time 
(RTIMDSRT) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 


 
Study Number: UX007G-CL201 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB RTI Five 
Choice Median 
Reaction Time 
(RTIMDFRT) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB RTI 
Simple Choice Standard 
Deviation (RTISRTSD) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB SSP Span 
Length (SSPSLF) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB PAL Total 
Errors (Adjusted) 
(PALTEA) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB PAL First 
Trial Memory Score 
(PALFTMS) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB SWM 
Between Errors 
(SWMBE48) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
CANTAB 
Efficacy 
Analysis Set 
Change from baseline 
in CANTAB SWM 
Strategy (SWMS68) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in 6MWT distance 
traveled (in meters) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 


 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in 6MWT distance 
traveled (in percent 
predicted) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Linear 
Estimation 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Time (in minutes) to 
onset of paroxysmal 
exertional dyskinesia 
(PED) 
All 
Secondary 
Screening, Randomization,  
Week 4, 8, 26, 31, 36, 52, ET 
GEE Logistic 
Estimation 
GMFM-88 
Efficacy 
Analysis Set 
Change from baseline 
in GMFM-88 Total 
score 
Select Sites 
Secondary 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
GEE Linear 
Estimation 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
generalized tonic-clonic 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
generalized tonic 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
generalized clonic 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
generalized atonic 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 


 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
partial/focal with 
secondary 
generalization seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
myoclonic seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
myoclonic atonic 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
myoclonic tonic 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
complex partial/focal 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
simple partial/focal 
motor seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
simple partial/focal 
sensory seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 


 
Study Number: UX007G-CL201 
Statistical Analysis Plan 
11 January 2017, Version 2.0 
 
 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
simple partial/focal 
psychological seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
typical absence seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
atypical absence 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
myoclonic absence 
seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
absence eyelid 
myoclonia seizures 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
Seizure Diary 
Efficacy 
Analysis Set – 
Observable 
Seizures 
Reduction from 
baseline in frequency of 
unclassified seizures 
including epileptic 
spasms 
All 
Exploratory 
Daily from Screening to 52/ET 
Summary 
Statistics 
Summary 
Statistics 
CNS 
Efficacy 
Analysis Set 
Change from baseline 
in CNS Total Score 
All 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 


 
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Statistical Analysis Plan 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
CGI-I 
Efficacy 
Analysis Set 
CGI Improvement scale 
All 
Exploratory 
Randomization, Week 8, 26, 31, 
36, 52, ET 
Summary 
Statistics 
Summary 
Statistics 
SF-10 
Efficacy 
Analysis Set 
Change from baseline 
in SF-10 Physical 
Summary Score (PHS-
10) 
Ages 5-17 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-10 
Efficacy 
Analysis Set 
Change from baseline 
in SF-10 Psychosocial 
Summary Score (PSS-
10) 
Ages 5-17 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Physical Functioning 
(PF) score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Role Limitations due 
to Physical Health (RP) 
score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Bodily Pain (BP) 
score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in General Health 
Perceptions (GH) score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 


 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Vitality (VT) score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Social Functioning 
(SF) score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Role Limitations due 
to Emotions Problems 
(RE) score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Mental Health (MH) 
score 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Physical Component 
Summary Scale (PCS-
12) 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
SF-12 v2 
Efficacy 
Analysis Set 
Change from baseline 
in Mental Component 
Summary Scale (MCS-
12) 
Ages 18+ 
Exploratory 
Randomization, Week 8, 26, 52, 
ET 
Summary 
Statistics 
Summary 
Statistics 
PPVT 
Efficacy 
Analysis Set 
Change from baseline 
in PPVT standardized 
score 
Select Sites 
Exploratory 
Screening, Week 8, 26, 31, 36, 
52, ET 
Summary 
Statistics 
Summary 
Statistics 


 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
PEDI-CAT 
Efficacy 
Analysis Set 
Change from baseline 
in Daily Activities 
score 
Select Sites 
Exploratory 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
PEDI-CAT 
Efficacy 
Analysis Set 
Change from baseline 
in Mobility score 
Select Sites 
Exploratory 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
PEDI-CAT 
Efficacy 
Analysis Set 
Change from baseline 
in Social/Cognitive 
score 
Select Sites 
Exploratory 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
PEDI-CAT 
Efficacy 
Analysis Set 
Change from baseline 
in Responsibility score 
Select Sites 
Exploratory 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
Gait analysis during 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in stride length 
Select Sites 
Exploratory 
Screening, Randomization, Week 
4, 8, 26, 31, 36, 52, ET 
Data Listing 
Data Listing 
Gait analysis during 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in velocity 
Select Sites 
Exploratory 
Screening, Randomization, Week 
4, 8, 26, 31, 36, 52, ET 
Data Listing 
Data Listing 
Gait analysis during 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in cadence 
Select Sites 
Exploratory 
Screening, Randomization, Week 
4, 8, 26, 31, 36, 52, ET 
Data Listing 
Data Listing 


 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
Gait analysis during 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in base of support 
Select Sites 
Exploratory 
Screening, Randomization, Week 
4, 8, 26, 31, 36, 52, ET 
Data Listing 
Data Listing 
Gait analysis during 
6-minute walk test 
(6MWT) 
Efficacy 
Analysis Set 
Change from baseline 
in percentage of cycle 
time spent in double 
support 
Select Sites 
Exploratory 
Screening, Randomization, Week 
4, 8, 26, 31, 36, 52, ET 
Data Listing 
Data Listing 
GMFM-88 
Efficacy 
Analysis Set 
Change from baseline 
in GMFM-88 Lying 
and Rolling score 
Select Sites 
Secondary 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
GMFM-88 
Efficacy 
Analysis Set 
Change from baseline 
in GMFM-88 Sitting 
score 
Select Sites 
Secondary 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
GMFM-88 
Efficacy 
Analysis Set 
Change from baseline 
in GMFM-88 Crawling 
and Kneeling score 
Select Sites 
Secondary 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
GMFM-88 
Efficacy 
Analysis Set 
Change from baseline 
in GMFM-88 Standing 
score 
Select Sites 
Secondary 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 
GMFM-88 
Efficacy 
Analysis Set 
Change from baseline 
in GMFM-88 Walking, 
Running and Jumping 
score 
Select Sites 
Secondary 
Randomization, Week 4, 8, 26, 
31, 36, 52, ET 
Data Listing 
Data Listing 


 
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Test / Instrument 
Eligible Study 
Population 
Endpoint 
Subjects 
Applicable 
Endpoint 
Level 
Timepoints for  
Assessments 
Statistical 
Approach:  
Week 8  
Analyses 
Statistical 
Approach: 
Week 52 
Analyses 
Beery-VMI 
Efficacy 
Analysis Set 
Change from baseline 
in standard score 
Select Sites 
Exploratory 
Screening, Week 8, 26, 52, ET 
Data Listing 
Data Listing 
RCPM 
Efficacy 
Analysis Set 
Change from baseline 
in total score 
Select Sites 
Exploratory 
Screening, Week 8, 26, 52, ET 
Data Listing 
Data Listing 
 
 


 
Study Number: UX007G-CL201 
Statistical Analysis Plan 
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Page 74 
APPENDIX B 
SCHEDULE OF EVENTS 
VISIT NUMBER* 
1 
2 
3 (Phone) 
4 
5 
6 
7 
DE
1# 
DE
2# 
8 
9 
VISIT NAME 
Screening 
Randomization 
End of 
Titration 
Treatment Period 
Extension Period 
WEEK 1 
-6 
0 
2 
4 
8 
14 
26 
31 
36 
44 
52/
ET 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 2 
X 
 
 
 
 
 
 
 
 
 
 
EFFICACY MEASURES 
Seizure incidence (diary review) 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Computerized Neuropsychological Test - 
Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 4 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Peabody Picture Vocabulary Test (PPVT) 4 
X 
 
 
 
X 
 
X 
X 
X 
 
X 
Short Form-10 (SF-10) or SF-12 Health 
Survey (age-appropriate instrument) 
 
X 
 
 
X 
 
X 
 
 
 
X 
Pediatric Evaluation of Disability Inventory 
Computer Adaptive Test (PEDI-CAT)4 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
6-minute Walk Test (6MWT)5 
PED Observation  
Gait Analysis [select sites] 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Gross Motor Function Measure-88 
(GMFM-88)4, 5 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Columbia Neurological Score (CNS) 
 
X 
 
 
X 
 
X 
 
 
 
X 
Clinical Global Impression: 
Improvement (CGI-I) & Severity (CGI-S)6 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
Overnight Electroencephalogram (EEG)7 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Beery-Buktenica Developmental Test of 
Visual Motor Integration (Beery-VMI) 4 
X 
 
 
 
X 
 
X 
 
 
 
X 


 
Study Number: UX007G-CL201 
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Page 75 
VISIT NUMBER* 
1 
2 
3 (Phone) 
4 
5 
6 
7 
DE
1# 
DE
2# 
8 
9 
VISIT NAME 
Screening 
Randomization 
End of 
Titration 
Treatment Period 
Extension Period 
WEEK 1 
-6 
0 
2 
4 
8 
14 
26 
31 
36 
44 
52/
ET 
Raven’s Coloured Progressive Matrices 
(RCPM)4 
X 
 
 
 
X 
 
X 
 
 
 
X 
PHARMACOKINETICS/BIOASSAYS 
Peak Plasma UX007 and Metabolites8 
X7 
X 
 
 
X 
 
 
X 
X 
 
X 
Population PK assessment8 
 
 
 
 
 
 
X 
 
 
 
 
SAFETY ASSESSMENTS 
Vital Signs & Weight9 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG)10 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination11 
X 
 
 
 
X 
 
X 
 
 
 
X 
Clinical Laboratory Tests12  
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
Urine Pregnancy Test (if applicable) 
X 
X 
 
 
X 
 
X 
 
 
 
X 
Suicidal Ideation & Behavior Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Interim Monitoring Calls13 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
TREATMENT & DIETARY ASSESSMENTS 
Dispense Study Drug14 
 
X 
 
X 
X 
X 
X14 
 
 
X 
 
Treatment Compliance & Accountability15 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietitian Consultation & Diet Diary16 
X 
X 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*The Study Reference Manual will outline and describe a recommended schedule of the assessments during the 1-day and 2-day visits. 
# DE = Dose Exploration Period.  Visits DE-1 (Week 31) and DE-2 (Week 36) (± 3 days) apply only to subjects who participate in the Dose Exploration Period. 
1 Assessments at Week 2 will be completed via telephone call; no visit to the study site will be required.  Subjects will return to the clinic at Week 4 and at the 
end of the double-blind Treatment Period for Week 8 (± 3 days).  Visits during the Extension period will occur at 6-13 week intervals (± 2 weeks). 
2 Medical history includes subject demographics and Glut1 DS diagnosis confirmed by SLC2A1 mutation analysis. 


 
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3 The seizure diary should be completed each study day, even on study days without seizures. Site personnel should help ensure that participants 
(parents/caregivers) are not leaving any blank pages in the seizure diaries.  
4 All neuropsychological tests and assessments should be performed after the consumption of food and, as indicated, study drug.  PPVT, Beery-VMI, RCPM, 
PEDI-CAT, and GMFM-88 will be administered at select sites only. 
 5 The 6MWT will include assessments of PED; a subset of sites may also perform gait analysis using a computerized portable walkway.  Portions of the 6MWT, 
gait analysis and the GMFM-88 tests may be videotaped to monitor administration technique and assess qualitative changes in function.  Subject identity will be 
protected by blurring out the facial area in the video.  
6 CGI-S will be assessed at Baseline (Week 0); CGI-I will be assessed at Weeks 8, 26, 31, 36 and 52 (or Early Termination). 
7 Confirmatory EEG at Screening for patients with absence seizures only is required for ~3 hours.  For Week 0 EEG, begin EEG PRIOR TO Randomization date 
(requires 2-day visit); Week 8, 26, and 31 visits require a 2-day overnight visit to complete EEG. Monitoring periods of less than 12 hours in duration for Week 
8, 26, and 31 visits will be considered a protocol violation. 
8 At the Screening and Randomization Visits, a non-fasting blood sample will be drawn to assess non-fasting BHB. At subsequent post-randomization visits, 
blood samples for UX007 and metabolites will be drawn approximately 90 min following consumption of food and study drug.  At Week 26, 3 blood samples 
will be drawn: pre-dose (within 15 min), and 2 additional timepoints at 60 and 180 min following consumption of food and study drug.   
9 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.  
10 Perform ECG prior to, or at least 15 min after administration of any motor function tests (if indicated at visit) so that the ECG is performed at resting heart rate. 
11 Physical examinations to include assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, 
respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. 
12 Clinical laboratory tests include standard serum chemistry, hematology, and urinalysis.  Fasting is not required. 
13 The study coordinator will telephone the subject/caregiver between each Extension Period visit to assess AE, discuss any problems or difficulties with 
treatment, assess protocol compliance, and inquire about study drug consumption and remaining supply.  Additional telephone contacts may be made as needed.  
A follow-up call is recommended within 4 weeks following early termination or study completion. 
14 Following Randomization, study drug will be titrated over a 2-week period to achieve up to 35% of total daily calories from study drug. Subjects in the Dose 
Exploration Period will titrate study drug as outlined in the Administration Guideline in the Study Reference Manual. The manual randomization process will be 
followed at Randomization and Week 4 visits only. 
15 Instruct subjects to return all empty and opened study drug bottles to the next visit. 
 
16 Subjects and/or caregivers are required to maintain record of daily diet in the study diary for at least 3 days prior to each visit (except Screening).  The diet 
diary will be reviewed with the dietitian or study staff upon each visit. The dietitian may telephone subjects and/or caregivers, as needed, to provide dietary 
advice and support. The 3-day diet history is recorded during the Screening (Baseline) Period and will be used to qualify subjects for the study. A 3-day diet 
diary is not required at the time of the Screening Visit, only a dietitian consultation. The 3-day diet history recorded prior to randomization will be reviewed by 
the site dietitian to establish daily caloric intake 
 
 


 
Study Number: UX007G-CL201 
Statistical Analysis Plan 
11 January 2017, Version 2.0 
 
 
Proprietary and Confidential 
Page 77 
APPENDIX C 
GASTROINTESTINAL STANDARDIZED MEDDRA QUERY 
Table 7 shows the MedDRA PTs that 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. 
Table 7: Gastrointestinal SMQs 
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 
 
 
 
 


 
Study Number: UX007G-CL201 
Statistical Analysis Plan 
11 January 2017, Version 2.0 
 
 
Proprietary and Confidential 
Page 78 
APPENDIX D 
SAS CODE FOR PRIMARY STATISTICAL ANALYSIS